Volume 166, Number 1 • January/February 2014 Established 1844 D

Editor Volume 166, Number 1 • January/February 2014 Established 1844 D. LUKE GLANCY, MD

Associate Editor L.W. JOHNSON, MD

EDITORIAL BOARD Zhuang Feng, MD, PhD 2 Blastic Plasmacytoid Dendritic Cell Neoplasm: Report of a Case MURTUZA J. ALI, MD Jun Zhou, MD Presenting With Lung and Central Nervous System Involvement and RONALD AMEDEE, MD Gail Bentley, MD Review of the Literature SAMUEL ANDREWS, II, MD BOB BATSON, MD Genevieve F. Maronge, MD 10 The Supply of Hematolgoy/Oncology Specialists EDWIN BECKMAN, MD Paragi Gururaja Ramnaryan, MD, MPH GERALD S. BERENSON, MD Perry G. Rigby, MD C. LYNN BESCH, MD JOHN BOLTON, MD Michael H. Moses, MD 15 Treatment of Submucous Cleft Palate With Selective Use of the MICHELLE BOURQUE, JD Mark W. Stalder, MD Furlow Z-Palatoplasty JAMES N. BRAWNER, III, MD David T. Pointer Jr., BS BRETT CASCIO, MD Ryan Wong, MD QUYEN CHU, MD Charles L. Dupin, MD GUSTAVO A. COLON, MD Hugo St. Hilaire, MD, DDS RICHARD COULON, MD LOUIS CUCINOTTA, MD Marc Manix, MD 21 Distal Ventriculoperitoneal Shunt Catheter Migration to the VINCENT A. CULOTTA, JR., MD Anthony Sin, MD Right Ventricle of the Heart - A Case Report JOSEPH DALOVISIO, MD Anil Nanda, MD, MPH, FACS NINA DHURANDHAR, MD JAMES DIAZ, MD, MPH & TM, Dr. PH Brian Revis, MD 26 Malposition of a Hemodialysis Catheter in the Accessory Hemiazygos JOHN ENGLAND, MD Mohammad Kazem Fallahzadeh, MD Vein JULIO FIGUEROA, MD Neeraj Singh, MD ELIZABETH FONTHAM, MPH, Dr. PH EDWARD FOULKS, MD Lauren E. Richey, MD, MPH 28 Rapid HIV Testing in a New Orleans Emergency Department is HENRY G. HANLEY, MD Elizabeth J. Carpenter, MD Effective in Identifying New HIV Diagnoses and in Linking Patients to ELIAS B. HANNA, MD James M. Barbeau, MD, JD Care LYNN H. HARRISON, JR., MD Christiane M. Hadi, MD, MPH ROBERT HEWITT, MD MICHAEL HILL, MD D. Luke Glancy, MD 34 In Memoriam: Edward S. Connolly, MD LARRY HOLLIER, MD JOHN HUNT, MD Sabrina L. Noah 35 Protecting the Private Practice of Medicine BERNARD JAFFE, MD NEERAJ JAIN, MD TRENTON L. JAMES, II, MD KEVIN KRANE, MD Departments MAUREEN LICHTVELD, MD, MPH FRED A. LOPEZ, MD D. Luke Glancy, MD 36 ECG OF THE MONTH F. BROBSON LUTZ, JR., MD William P. Abide Jr., MD Amaurosis Fugax in a 45-Year-Old Woman DAVID MARTIN, MD JORGE A. MARTINEZ, MD, JD Chris Stark, BS 38 RADIOLOGY OF THE MONTH ELIZABETH MCBURNEY, MD Jagan D. Gupta, MD Progressive Slurring of Speech and Difficulty Reading in a ELLEN MCLEAN, MD Tracy Austin, MD 62-Year-Old Male NORMAN E. MCSWAIN, JR., MD Enrique Palacios, MD REINHOLD MUNKER, MD Harold Neitzschman, MD DAVID MUSHATT, MD JOSEPH NADELL, MD Faisal Musa, MD 41 CLINICAL CASE OF THE MONTH HAROLD R. NEITZSCHMAN, MD Jorge A. Martinez, MD, JD Altered Mental Status and Headache in a Young Man STEVE NELSON, MD Catherine Hebert, MD NORA OATES, MD Matthew Safley, DO DONALD PALMISANO, MD, JD, FACS David Smith, MD PATRICK W. PEAVY, MD Fred Lopez, MD ROBERTO QUINTAL, MD RAOULT RATARD, MD, MS, MPH & TM Theresa Nuttli, MD 46 PATHOLOGY IMAGE OF THE MONTH ROBERT RICHARDS, MD Robin R. McGoey, MD Altered Mental Status, Alcohol Abuse, and Hyperammonemia DONALD RICHARDSON, MD FRANK A. RIDDICK, JR., MD WILLIAM C. ROBERTS, MD DONNA RYAN, MD JERRY ST. PIERRE, MD CHARLES SANDERS, MD OLIVER SARTOR, MD CHARLES SCHER, MD RICHARD SPECTOR, MD JACK P. STRONG, MD PRAMILLA N. SUBRAMANIAM, MD KEITH VAN METER, MD DIANA VEILLON, MD HECTOR VENTURA, MD CHRIS WINTERS, MD GAZI B. ZIBARI, MD Journal of the Louisiana State Medical Society

Blastic Plasmacytoid Dendritic Cell Neoplasm: Report of a Case Presenting With Lung and Central Nervous System Involvement and Review of the Literature

Zhuang Feng, MD, PhD; Jun Zhou, MD; Gail Bentley, MD

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic malignancy with almost invariably cutaneous involvement and poor prognosis. We report a case of BPDCN in a 58-year-old man who presented with skin, lymph node, bone marrow, peripheral blood, lung, and central nervous system involvement. To the best of our knowledge, central nervous system (CNS) involvement as initial presentation has not been reported since the latest World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues in 2008. Review of the literature was performed on BPDCN cases published in 2008-2013 in PubMed. The major clinical, histopathologic, immunophenotypic, and cytogenetic aspects of the disease were discussed. Dermatologists and dermatopathologists should be aware of this rare disease for which nearly half of the patients present with only cutaneous lesions at diagnosis, as it may allow for early diagnosis and appropriate treatment.

INTRODUCTION WHO classification renamed it as BPDCN as a distinct entity under the category of myeloid neoplasm.4 The etiology of Blastic plasmacytoid dendritic cell neoplasm (BPDCN) BPDCN is not, but it has been suggested to be associated is a rare hematopoietic malignancy. The recognition and with acute myeloid/myelomonocytic leukemia (Petrella et nomenclature of BPDCN has been dramatically evolving. al., 2005; Herling et al., 2007). BPDCN was first described by Adachi et al. in 1994 as a The literature of formerly called blastic NK-cell lym- CD4+CD56+ cutaneous lymphoma. The World Health Or- phoma published prior to 2008 may be heterogeneous ganization (WHO) classification of tumors of hematopoietic because CD56 can be expressed in other hematopoietic and lymphoid tissue in 2001 named it as blastic natural killer lineages, including true NK lymphoma and acute myeloid (NK)-cell lymphoma due to its CD56 expression.1 Later, leukemia with monocytic differentiation. In addition, the European Organisation for Research and Treatment markers recently developed for PDCs, including CD123 of Cancer (EORTC) classification of cutaneous lymphoma (the interleukin-3 receptor), blood dendritic cell antigen 2 renamed it as CD4+CD56+ hematodermic neoplasm in (BDCA2/CD303),5 and T-cell leukemia/lymphoma 1 (TCL1) 2005.2 BPDCN was first suggested of dendritic cell origin and CD2-associated protein (CD2AP),6 were rarely tested by Lucio et al. in 1999. More recently, it was confirmed as in the literature published prior to 2008. In this article, we a tumor of precursor plasmacytoid dendritic cells (PDCs) report a case of BDPCN presenting with skin, lymph node, (Chaperot et al., 2001; Chaperot et al., 2004). PDCs produce bone marrow, peripheral blood, lung, and central nervous type 1 interferon (IFN1) and play an important role in the system involvement and have reviewed the literature since modulation of innate and adaptive immunity. PDCs are the latest WHO classification of tumors of hematopoietic produced in the bone marrow and account for less than and lymphoid tissue in 2008 to delineate the characteristics 0.1% peripheral blood mononuclear cells. When immune of the disease. response is activated, PDCs can be recruited into lymph nodes, tonsils, spleen, and mucosa-associated lymphoid METHODS tissue.3 PDCs generally are not identified in skin and subcutaneous tissue, and how cutaneous involvement almost Light microscopy slides were prepared from paraffin- invariably occurs in BPDCN is unclear. In 2008, the latest embedded tissue sections and stained with routine hema-

2 J La State Med Soc VOL 166 January/February 2014 Figure 1: (A) Bone marrow core biopsy showing a hypercellular marrow with diffuse infiltrate of tumor cells (H&E 400x). (B) Bone marrow aspirate smear showing infiltrate of tumor cells with high nuclear cytoplasmic ratio, irregular nuclei, finely dispersed chromatin, prominent nucleoli, grey-blue agranular cytoplasm with a clear intracytoplasmic vacuole and pseudopodia-shaped cytoplasmic extension (Wright-Giemsa stain 1000x under oil immersion). toxylin and eosin after fixation in 10% neutral buffered CASE REPORT formalin. Immunohistochemical analyses were performed on formalin-fixed paraffin-embedded tissue sections using A 58-year-old man presented with a two-week history the avidin-biotin-peroxidase method and antibodies to CD3, of generalized weakness, fatigue, and dyspnea on exertion CD4, CD5, CD8, CD10, CD20, CD43, CD45, CD56, CD57, in December 2009. On examination, the patient had a 5 cm CD68, and terminal deoxynucleotidyl transferase (TDT). soft, non-tender, purplish-red nodular skin lesion on the CD123 was performed by Mayo Clinic. Three-color flow right forearm that grew larger over the past couple of weeks. cytometric analysis (FACScan, Becton Dickinson, Mountain There were also multiple small purplish papular lesions on View, CA) was performed on fresh cell suspension and the face, back, and left shoulder. Bilateral cervical multiple cerebrospinal fluid (CSF) using antibodies to CD2, CD3, enlarged lymph nodes were present. Upon admission, he CD4, CD5, CD7, CD13, CD16, CD19, CD56, CD57, and TDT. had anemia and thrombocytopenia with white blood cell In situ hybridization for Epstein-Barr virus (EBV), encoded 5,400/ul, hemoglobin 10.1 g/dl, and platelets 84,000/ul. small mRNAs (EBER) were performed. Cytogenetic studies Bone marrow core biopsy showed a markedly hypercellular were performed with standard protocols. Q banding was marrow that was diffusely replaced by medium-sized blasts used for chromosome identification and karyotypes were with high nuclear cytoplasmic (N:C) ratio, scant pale cyto- defined according to the International System for Human plasm, irregular nuclear contour, and prominent nucleoli Cytogenetic Nomenclature. Fluorescence in situ hybridiza- occupying more than 90% of marrow space (Figure 1A). tion (FISH) analysis was performed using LSI TCR alpha/ Few mitotic figures were also noted. Bone marrow aspirate delta dual color break-apart DNA probe (Vysis, Downers smears showed a predominance of blasts with high N:C Grove, IL). The LSI TCR alpha/delta probe was a mixture ratio, grey-blue agranular cytoplasm with a clear intracy- of two probes that hybridize to the opposite sites of 14q11.2 toplasmic vacuole, pseudopodia-shaped cytoplasmic exten- with spectrum green on the telomeric side and spectrum sion, finely dispersed chromatin, and prominent nucleoli, orange on the centromeric side of the breakpoints. Gene comprising more than 90% of the cells (Figure 1B). By im- rearrangement studies of the joining (J) region of the B-cell munohistochemistry (IHC), the blasts were positive for CD2 immunoglobulin heavy chain (IgH) and/or the T-cell recep- (weak), CD4 (strong), CD56, CD43, CD68 (weakly positive), tor (TCR) gamma chain were analyzed utilizing polymerase and CD45 (weak non-specific staining) but were negative chain reaction (PCR) amplification to detect the presence of for CD1a, CD3, CD8, CD20, CD117, TDT, myeloperoxidase, monoclonal populations which were visualized as a discrete lysozyme, and TIA-1. Immunophenotypic analysis of bone band in the range of 160 base pairs (bp) to 190bp for the marrow by flow cytometry identified 89% CD45-positive TCR gamma region and 75bp to 150bp for the JH region cells with expression of CD4, CD56, TDT and cytoplasmic of the IgH, respectively. Literature review was conducted CD3, partial expression of CD2, CD5, and CD7, but nega- by searching PubMed (U.S. National Library of Medicine) tive for surface CD3, CD13, CD16, CD19, and CD57. CT with the following keyword “blastic plasmacytoid dendritic thorax showed a 4.8 x 8.5 cm consolidation within the right cell neoplasm”. lower lung and multiple enlarged mediastinal lymph nodes. Transbronchial lung biopsy showed lung parenchyma in-

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Figure 2: (A) Skin punch biopsy showing a superficial and deep dermal predominantly perivascular infiltrate of tumor cells (H&E 20x). (B) Skin biopsy showing dense infiltrate of tumor cells with irregular nuclei, fine chromatin, and prominent nucleoli (H&E 500x under oil immersion). (C-D) Tumor cells showing positivity for CD4 (C) and CD56 (D) (IHC 500x under oil immersion). volved by the same tumor cells. Fine needle aspiration of (BMT), the patient had a relapse of the disease with newly subcarinal lymph node showed infiltrate of the tumor cells. developed multiple 1-1.5 cm slightly raised red lesions on CSF showed detection of CD4+CD56+ tumor cells compris- the extremities in August 2010. Skin punch biopsy showed ing 32% of CD45-positive cells by flow cytometry. Peripheral a superficial and deep dermal predominantly perivascular blood smears showed circulating blasts. Cytogenetic analy- infiltrate of tumor cells with irregular nuclei, fine chromatin, sis showed normal male karyotype 46, XY.20 FISH analysis and prominent nucleoli. By IHC, the tumor cells were posi- showed no translocation affecting TCR A/D constant re- tive for CD4 and CD56 but negative for CD3. The patient gion. Gene rearrangement studies of TCR gamma and JH was treated with BEAM (carmustine, etoposide, cytarabine, of IgH were negative. Serological studies showed that the and melphalan) chemotherapy, along with targeted radia- patient was positive for EBV VCA IgG (3.30; reference range tion for the skin lesions, but showed only partial response. 0.00-1.09) and negative for EBV VCA IgM (0.13; reference The patient then received matched related donor allogeneic range 0.00-1.09). The patient was diagnosed with BPDCN peripheral blood stem cell transplantation (SCT) in August and treated with CHOP (cyclophosphamide, doxorubicin, 2010. In January 2011, the patient had another relapse of vincristine, and prednisone) chemotherapy for six cycles, the disease with new skin lesions. By IHC, skin punch bi- as well as intrathecal therapy. The patient achieved only opsy showed the tumor cells were positive for CD4, CD43, partial remission and subsequently was treated with ICE CD56, and CD123 and negative for CD3, CD5, CD8, CD20, (ifosfamide, carboplatin, and etoposide) chemotherapy for CD57, CD68, and TDT (Figure 2A-2D). EBER by in situ two cycles. While waiting for bone marrow transplantation hybridization was negative. Complete blood count showed

4 J La State Med Soc VOL 166 January/February 2014 pancytopenia. The patient was given high-dose cytosine cutaneous disease only and patients with both cutaneous arabinoside (ara-C) chemotherapy and attained clinical re- and extracutaneous diseases.15 Initial staging results did not mission. Unfortunately the disease relapsed again in April affect survival.7,15 Therefore, even though BPDCN presents 2011 with multiple new skin lesions and 80% blasts in the with only cutaneous diseases in almost half of the cases, it peripheral blood. Due to resistant/refractory to treatment, has been suggested these patients should also be treated comfort and supportive measures were given to the patient. with initial aggressive therapy. The patient died of the disease 17 months after diagnosis. Treatments DISCUSSION Due to its rarity and dramatically evolving recognition, no standard treatment is available, and patients usually Clinical Features receive multiple regimens. First-line treatments are vari- Since BPDCN was classified as a distinct entity by WHO able, including palliative care, monochemotherapy, non- in 2008, more than 200 cases that meet the new diagnostic Hodgkin’s lymphoma (NHL)-type, acute myeloid leukemia criteria have been reported in the literature.4 BPDCN is a (AML)-type and acute lymphoblastic lymphoma (ALL)- rare hematopoietic malignancy without known predispos- type, radiation therapy, and BMT/SCT. Previous studies ing factors. It has a male-to-female ratio of 2.6-2.7:1.3,7,8 Most on formerly called blastic NK-cell lymphoma/agranular patients are elderly with a median age of 62-67 years at the CD4+CD56+ hematodermic neoplasm demonstrated that time of diagnosis.3,7-9 Pediatric cases as young as 4 years CHOP/CHOP-like regimen was inadequate; AML-type of age10 and a unique congenital case of a 3-day-old baby regimen was associated with a poor prognosis; and hyper- (Yang et al., 2012), although much less common, have been CVAD regimen was associated with a favorable prognosis.16 reported. The diagnosis is generally based on skin biopsy. Dalle et al. showed that, when used as first-line therapy, BPDCN usually presents with solitary, multiple, or general- CHOP/CHOP-like regimens and radiation therapy had a ized skin or subcutaneous lesions in the presence or absence mean relapse free survival of five and five and a half months of systemic involvement such as peripheral blood, bone respectively compared to 25.3 months with BMT.7 In a re- marrow, and lymph nodes.4 The skin lesions can be macules, cent retrospective study of 39 BPDCN patients (Roos-Weil papules, plaques, or nodules and range in size from 0.5 to 12 et al., 2013), allogeneic SCT in first remission was associ- cm with a median size of 3 cm at diagnosis.8,10 Ulceration is ated with favorable survival, while age, donor type, stem not a feature, although Jegalian et al. reported a 12-year-old cell source, and chronic graft versus host disease (GVHD) female patient presenting with a 12 cm ulcerated cutaneous had no significant impact on outcomes. In a case series of lesion died from infectious complication six months after six BPDCN patients (Dietrich et al., 2010), two patients diagnosis.10 In the largest case series since 2008 by Dalle without allogeneic SCT died rapidly of the disease at six et al., all 47 patients had cutaneous involvement (100%) at and 13 months after first-line treatment; two patients with diagnosis, with 40% as solitary lesion, 38% as multiple le- allogeneic SCT in active disease achieved CR but relapsed sions affecting one or two areas, and 21% as disseminated at six and 18 months after transplantation; and two patients skin disease.7 Systemic involvement at diagnosis usually with allogeneic SCT in remission remained disease free at occurs in bone marrow (48%-68%), peripheral blood (33%- 57 and 16 months after SCT. The authors suggested that 73%), and lymph nodes (24%-41%).7-9 Initial presentation allogeneic SCT in first CR should be considered in patients at uncommon sites including maxilla, breast, kidney, liver, up to 70 years of age. Dalle et al. showed that survival of spleen, and lung has been reported in very rare cases.10,11 patients with BMT was significantly higher (31.3 months To the best of our knowledge, our patient is the first case vs. 12.8 months) than those without BMT.7 Ham et al. (2012) presenting with CNS involvement since the latest WHO clas- reported a 26-year-old patient who was treated with AML- sification in 2008. By literature studies, no cases with CNS type chemotherapy followed by allogeneic SCT in first involvement at diagnosis were reported, although relapse CR-achieved long-term disease free survival at 30 months in the CNS was documented in few cases.12,13 Nearly half of after diagnosis. Jegalian et al. indicated that BPDCN was BPDCN patients (35%-48%) presented with only cutaneous less aggressive in pediatric patients than in adult patients. disease at diagnosis.7-9 Nonetheless, systemic involvement Of the total 25 pediatric patients, all three patients who eventually develops with progression of the disease. Leuke- received AML-type therapy were dead at the time of clini- mic disease without cutaneous involvement at presentation, cal follow-up. In contrast, among 14 patients who received albeit rare, has been reported.8,12,14 Although response occurs ALL-type therapy, only one patient who presented with a after treatment, relapse invariably occurs, and fatal outcome 12 cm ulcerated cutaneous lesion died of therapy related occurs rapidly. Complete remission (CR) after initial treat- infectious complications. The authors suggested that, for ment was seen in 47%-68% patients with a mean relapse-free pediatric patients, high-risk ALL-type chemotherapy should period of 12.6 months (range 2-42 months).7-9 BPDCN has be used as first-line treatment, and SCT may be reserved for an aggressive course and a poor prognosis with a mean those with relapse of disease or on their second remission.10 survival of 16.7 months.7 In an Austrian study of 33 patients, Interestingly, Dohm et al. (2011) reported a patient after there was no difference in survival between patients with allogeneic SCT developed fulminant leukemic progression

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Table 1: Summary of the immunophenotypic profiles of BPDCN Antibody Expression Reference CD2 variable, + in 33%-51% 8,9,15 CD3 -; rare cases cytoplasmic CD3+ 11,18,20 CD4 + (80%-100%) 4,6,14,15,17,21-23 CD5 -; one case + 19 CD7 -; a few cases + (subset or focal) 10,11 CD33 -; rare cases + 8,13 CD43 + (96%) 4,6,14,15,17,21-23 CD45RA + (dim) 4,6,14,15,17,21-23 CD56 + (75%-100%) 6,14,15,17,21-23 CD68 variable, + in 52%-85%, cytoplasmic 8-10,15 dots in some cases CD34 -; rare cases + 4 CD117 -; rare cases + 4 TdT variable, + in 14%-63% 9-12, 15 CD123 + (75%-100%) 6,14,15,17,21-23 TCL1 + (82%-100%) 6,14,15,17,21-23 BDCA2/CD303 + (50%-100%) 6,14,15,17,21-23 CD2AP + (45%-95%) 6,14,15,17,21-23 BCL11A + (83%-100%) 6,14,15,17,21-23 CLA + (90%-100%) 6,14,15,17,21-23 CD19, CD20, CD22, CD79a, PAX5 - 4,7-10 EBER - 4,7-10 MPO, Lysozyme - 4,6,14,15,17,21-23 S100 variable, + in 75% children, + in 16%- 3,8,10 25% adults

Table 1: Summary of the immunophenotypic profiles of BPDCN, or blastic plasmacytoid dendritic cell neoplasm. BPDCN; BDCA2/ CD303, blood dendritic cell antigen 2; TCL1, T-cell leukemia/lymphoma 1; CD2AP, CD2-associated protein; CLA, cutaneous lymphocyte antigen; BCL11A, B-cell lymphoma/leukemia 11A; MPO, myeloperoxidase; TdT, terminal deoxynucleotidyl transferase; EBER, EBV-encoded nuclear RNA. during extracorporeal photopheresis for GVHD. Whether a rather pleomorphic infiltrate with admixed blastoid cells extracorporeal photopheresis stimulates malignant trans- in the background.15 On bone marrow aspirate smears, the formation of PDCs remains to be determined, but careful blasts have scant agranular cytoplasm with eccentrically clinical selection of GVHD treatment might be warranted. located nucleus and perinuclear hof.4 On cytology preparation, the blasts have round to oval nuclei, finely dispersed Morphology chromatin, prominent nucleoli, scant pale-blue agranular Histopathologically, BPDCN in the skin is character- cytoplasm, occasional cytoplasmic microvacuoles, and ized by a diffuse infiltrate of medium-sized blasts with high pseudopodia-shape cytoplasmic extension.8,13 N:C ratio, scant cytoplasm, finely dispersed chromatin, and prominent nucleoli in the dermis underlying a Grenz zone Immunophenotype without epidermotropism present. Cota et al. showed that The immunophenotypic profiles of BPDCN are sum- the typical blasts were seen in 44% of skin biopsy specimens marized in Table 1. BPDCN characteristically expresses of BPDCN, with the majority (56%) of cases presenting as CD4, CD56, CD43, CD45, and PDC-associated antigens

6 J La State Med Soc VOL 166 January/February 2014 Table 2: Summary of the specificity of immunohistochemical profiles of BPDCN vs. myeloid leukemia cutis BPDCN % Myeloid leukemia cutis % CD123 75-100 9-17 TCL1 82-100 9-17 BDCA2/CD303 50-100 3 CD2AP 45-95 4 BCL11A 83-100 25 CLA 90-100 78 CD4 80-100 9-61 CD56 75-100 52 MPO 0 30-67

Table 2: Summary of the specificity of immunohistochemical profiles of BPDCN versus myeloid leukemia cutis.6,14,15,17,21-23 such as CD123, TCL-1, BDCA2 (CD303) without expression CXCL12, which was associated with high leukemic change of T-cell, B-cell, and NK-cell or myelomonocytic lineage and poor prognosis.8 EBV antigens/EBV-encoded nuclear specific markers, although expression of CD2 and CD7 is RNA (EBER) and T-cell/B-cell gene rearrangement were not an uncommon finding.4 CD4-negative cases9,14,15 and consistently negative.8-10 CD56-negative8-10,15 cases have rarely been reported in case reports. Despite CD123 and TCL1 being generally positive The Specificity of PDC-Associated Antigens in BPDCN, CD123-negative and TCL1-negative cases were The diagnosis of BPDCN is largely based on the PDC- reported.8,14,15,17 BPDCN also expressed BDCA2, CD2AP, associated antigens such as CD123, TCL1, BDCA2, and CLA, BCL11A (B-cell lymphoma/leukemia 11A), and CLA but most of these markers have been shown to be expressed (cutaneous lymphocyte antigen).9,10,14,15 TDT-positive and by other lesions as well. The specificity of PDC-associated HLA-DR-positive cases were not uncommon.9-12,15 TDT was antigens is summarized in Table 2.6,14,15,17,21-23 Benet et al. expressed in 14%-64% of cases.9,10,15 Interestingly, our case showed that CD123 and CD303 (BDCA2) were expressed in showed that TdT was expressed in bone marrow by flow 11 out of 123 (9%) and 4 out of 124 (3%) myeloid leukemia cytometry but not expressed in skin by IHC. Khoury et al. cutis (LC) cases, respectively.21 Vitte et al. reported that, in demonstrated that the level of TdT expression by IHC was 42 chronic myelomonocytic leukemia (CMML) patients with higher in lymph node than in skin.18 These findings may skin involvement, 45%-50% of the skin lesions expressed suggest different patterns of TdT expression in various in- CD123, CD303 (BDCA2), and TCL1, indicating the associa- volved tissues and potential association with various stages tion of BPDCN with myelodysplastic/myeloproliferative of the disease. CD2 was aberrantly expressed in 33%-52% of neoplasms such as CMML.23 Cronin et al. revealed that cases.8,9,15 CD5 expression was extremely rare and reported CD123 was expressed in 4 out of 23 (17%) of myeloid leuke- in a single case on bone marrow specimen.19 We speculate mia cutis (LC) and 10 out of 12 (83%) of BPDCN cases, while that the partial expression of CD5 in our case is either an TCL1 was expressed in 2 out of 23 (9%) of LC and 9 out of aberrant expression or may represent neoplastic PDCs un- 11 (82%) of BPDCN cases.17 In a study by Petrella et al. of 29 dergoing cell fate conversion to lymphoid phenotype. CD7 formerly called agranular CD4+CD56+ hematodermic neo- was expressed in a few cases, occasionally in the form of plasms (HN) cases and 18 myelomonocytic leukemia cutis subset or focal positivity.10,11 BPDCN was generally nega- (LC) cases, TCL1 was expressed in 26 out of 29 (90%) of HN tive for CD3, CD20, CD34, CD117, myeloperoxidase, and and 3 out of 18 (17%) LC cases, while CLA was expressed in EBV.8-10,14,15 Rare cases were reported to express cytoplasmic 26 out of 29 (90%) of HN and 14 out of 18 (78%) of LC cases.22 CD3.11,18,20 CD34 and CD117 were expressed in rare cases CLA as a skin lymphocyte homing molecule is rather non- (Adams et al., 2009; Chen et al., 2011). CD33 is generally specific for BPDCN, and has been reported to be universally negative,9 but rare CD33-positive cases were reported.8,13 expressed in myeloid LC and cutaneous T-cell lymphoma CD68 was expressed in quite a few cases, and in some cases, (Campbell et al., 2010; Sachdev et al., 2012). Marafioti et al. in the form of cytoplasmic dots.8-10 In three case series, CD68 showed that CD2AP was expressed in 35 out of 37 (95%) of positivity was 53%-86%.8,9,15 Focal positivity of S100 was formerly called CD4+CD56+ HN and 1/24 (4%) of LC cases, reported in three-fourths of pediatric cases (75%) and may but not expressed in 24 CML, CMML, B-ALL, and T-ALL represent a favorable prognostic factor,10 whereas S100 was cases. In contrast, BCL11A was expressed in 39 out of 39 expressed in 17%-25% of adult patients.3,8 Hashikawa et al. (100%) HN, 6 out of 24 (25%) LC, 1 out of 7 (14%) CML, 3 showed 8 out of 15 (53%) skin biopsy specimen-expressed out of 5 (60%) CMML, 7 out of 7 (100%) B-ALL, and 4 out

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Table 3: Summary of the most frequent genomic alterations in BPDCN Change Chromosome Cytoband % of patients Candidate genes Loss 13 q12.11-q34 50-78 RB1 Loss 12 p13.2 50-67 CDKN1B, ETV6 Loss 9 p21.3 50-66 CDKN2A, CDKN2B, MTAP Loss 9 q34 50-55 NOTCH, TRAF2, CARD9 Loss 5 q23.1-a35.2 21-44 SMAD5, MSH3, MCC, APC Loss 15 q11.2-a26.3 33-36 CYP1A1 Loss 3 p22.2-p21.1 29 PTPN23 Loss 19 p13.4-p13.2 22-29 CDKN2D, PRKCSH Loss 17 p13.3-p11.2 22 TP53 Loss 7 p22.3-p22.1 21 MAD1L1 Loss 6 q23.3-q27 11-21 PARK2

Table 3: Summary of the most frequent genomic alterations in BPDCN. Adapted from ref. 25. BPDCN, blastic plasmacytoid dendritic cell neoplasm; CDKN, cyclin-dependent kinase inhibitor; MTAP, methylthioadenosine phosphorylase; TRAF2, tumor necrosis factor receptor-associated factor 2; CARD9, caspase recruitment domain; RB1, retinoblastoma tumor suppressor gene; CYP1A1, cytochrome P450 family 1 subfamily a polypeptide 1; PRKCSH, protein kinase C substrate 80K-H; PTPN23, protein- tyrosine-phosphatase-n23; MCC, mutated in colorectal cancer; APC, adenomatous polyposis coli tumor suppressor gene; PARK2, Parkinson protein 2; MAD1L1, mitotic arrest deficient-like 1; TP53, tumor protein 53.9,12,24,25 of 5 (80%) T-ALL cases.6 Therefore, it has been suggested sociating with progression of the disease. Other sporadic that immunophenotypic analysis using a panel of antibodies genomic aberrations include loss of 1p31.3-33 (containing including CD4, CD56, and at least 2 PDC-associated antigens CDKN2C/p18) and gain of 16p/q, loss of 6q and 7p, t(1;6), (such as CD123, TCL1, BDCA2, CD2AP, and BCL11A), as t(9;22), t(11;19)(q23;p13.3), trisomy 7, gain of 9p24 and loss well as specific markers to rule out other lineages, should of 11q22, and loss of Y. Jardin et al. showed that TET2 (ten be performed to confirm the diagnosis. eleven translocation 2) and TP53 mutation were seen in 54% and 38% of BPDCN patients by using PCR.12 Additionally, Genetics Wiesner et al. demonstrated that expression of cell cycle Genetic studies are limited for BPDCN, and no defin- inhibitor p27 KIP1 (encoded by CDKN1B) and p16 INK4a ing recurrent genetic abnormalities have been identified. (encoded by CDKN2A) was downregulated in tumor cells.25 BPDCN was shown to be associated with normal karyo- These findings suggest that loss of tumor suppressor genes type8,10,11,17 and variable genomic changes by conventional such as CDKN1B, CDKN2A, ARF, CDKN2B, RB1, and TP53, cytogenetic analysis, comparative genomic hybridization and resultant functional loss of cell cycle checkpoint control- (CGH) and PCR.9,12,24,25 The most frequent genomic altera- ling proteins, may lead to dysregulation of G1/S transition tions in BPDCN are summarized in Table 3.9,12,24,25 Lucioni of the cell cycle and tumorigenesis. et al. showed deletion of 9p21.3 containing CDKN2A (en- To the best of our knowledge, this is the first case of coding p16-INK4a) and CDKN2B was found in 14 out of 21 BPDCN with central nervous system involvement as initial (66.6%) patients and represented a worse prognosis factor presentation since the latest WHO classification in 2008. (median overall survival of 11 months for homozygous Dermatologists and dermatopathologists should be aware of loss versus 26 months for hemizygous loss).9 Interestingly, this rare disease for which nearly half of the patients present Petrella et al. (2012) reported an 82-year-old male patient with only cutaneous lesions at diagnosis. The diagnosis of had normal karyotype on bone marrow specimen by con- BPDCN is generally based on the skin biopsy and immu- ventional cytogenetic analysis; losses of chromosome 6, 12 nophenotypic analysis. High-dose chemotherapy followed (CDKN1B and ETV6), and 13 on skin biopsy specimen and by allogeneic SCT in first remission has been suggested to additional losses of chromosome 2 and 5 on bone marrow provide durable remission and favorable survival. specimen by CGH; loss of 2p, 5q, 12p (ETV6), and 13q but not 17 (TP53) on bone marrow specimen; and loss of ETV6 REFERENCES on snap-frozen skin sections by FISH analysis, suggesting that the difference in CGH results between skin and bone 1. Chan JKC, Jaffe ES, Ralfkiaer E. Blastic NK-cell lymphoma. World marrow specimens may reflect genomic alterations as- Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon.

8 J La State Med Soc VOL 166 January/February 2014 2001:214-215. cells. Am J Clin Pathol. 2007;127:687-700. 2. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification 21. Benet C, Gomez A, Aguilar C, et al. Histologic and immunohistologic for cutaneous lymphomas. Blood. 2005;105:3768-3785. characterization of skin localization of myeloid disorders: a study 3. Jegalian AG, Facchetti F, Jaffe ES. Plasmacytoid dendritic of 173 cases. Am J Clin Pathol. 2011;135:278-290. cells: physiologic roles and pathologic states. Adv Anat Pathol. 22. Petrella T, Meijer CJ, Dalac S, et al. TCL1 and CLA expression in 2009;16:392-404. agranular CD4/CD56 hematodermic neoplasms (blastic NK-cell 4. Facchetti F, Jones DM, Petrella T. Blastic plasmacytoid dendritic lymphomas) and leukemia cutis. Am J Clin Pathol. 2004;122:307- cell neoplasm. WHO Classification of tumors of Hematopoietic and 313. Lymphoid Tissues. IARC, Lyon. 2008:145-147. 23. Vitte F, Fabiani B, Benet C, et al. Specific skin lesions in chronic 5. Jaye DL, Geigerman CM, Herling M, Eastburn K, Waller EK, myelomonocytic leukemia: a spectrum of myelomonocytic and Jones D. Expression of the plasmacytoid dendritic cell marker dendritic cell proliferations: a study of 42 cases. Am J Surg Pathol. BDCA-2 supports a spectrum of maturation among CD4+ CD56+ 2012;36:1302-1316. hematodermic neoplasms. Modern pathology : an official journal of the 24. Jardin F, Callanan M, Penther D, et al. Recurrent genomic United States and Canadian Academy of Pathology, Inc. 2006;19:1555- aberrations combined with deletions of various tumour suppressor 1562. genes may deregulate the G1/S transition in CD4+CD56+ 6. Marafioti T, Paterson JC, Ballabio E, et al. Novel markers of haematodermic neoplasms and contribute to the aggressiveness normal and neoplastic human plasmacytoid dendritic cells. Blood. of the disease. Leukemia. 2009;23:698-707. 2008;111:3778-3792. 25. Wiesner T, Obenauf AC, Cota C, Fried I, Speicher MR, Cerroni L. 7. Dalle S, Beylot-Barry M, Bagot M, et al. Blastic plasmacytoid Alterations of the cell-cycle inhibitors p27(KIP1) and p16(INK4a) dendritic cell neoplasm: is transplantation the treatment of choice? are frequent in blastic plasmacytoid dendritic cell neoplasms. J Br J Dermatol. 2010;162:74-79. Invest Dermatol. 2010;130:1152-1157. 8. Hashikawa K, Niino D, Yasumoto S, et al. Clinicopathological features and prognostic significance of CXCL12 in blastic plasmacytoid dendritic cell neoplasm. J Am Acad Dermatol. Dr. Feng is with the Department of Pathology and Laboratory Medicine 2012;66:278-291. at Tulane University School of Medicine in New Orleans. Drs. Zhou 9. Lucioni M, Novara F, Fiandrino G, et al. Twenty-one cases of and Bentley are with the Department of Pathology at the Detroit blastic plasmacytoid dendritic cell neoplasm: focus on biallelic Medical Center and Wayne State University School of Medicine. locus 9p21.3 deletion. Blood. 2011;118:4591-4594. 10. Jegalian AG, Buxbaum NP, Facchetti F, et al. Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications. Haematologica. 2010;95:1873-1879. 11. Borchiellini D, Ghibaudo N, Mounier N, et al. Blastic plasmacytoid dendritic cell neoplasm: a report of four cases and review of the literature. J Eur Acad Dermatol Venereol. 2012. 12. Jardin F, Ruminy P, Parmentier F, et al. TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm. Br J Haematol. 2011;153:413-416. 13. Zheng G, Schmieg J, Guan H, Ali SZ. Blastic plasmacytoid dendritic cell neoplasm: cytopathologic findings. Acta cytologica. 2012;56:204-208. 14. Facchetti F, Pileri SA, Agostinelli C, et al. Cytoplasmic nucleophosmin is not detected in blastic plasmacytoid dendritic cell neoplasm. Haematologica. 2009;94:285-288. 15. Cota C, Vale E, Viana I, et al. Cutaneous manifestations of blastic plasmacytoid dendritic cell neoplasm-morphologic and phenotypic variability in a series of 33 patients. Am J Surg Pathol. 2010;34:75-87. 16. Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol. 2005;123:662-675. 17. Cronin DM, George TI, Reichard KK, Sundram UN. Immunophenotypic analysis of myeloperoxidase-negative leukemia cutis and blastic plasmacytoid dendritic cell neoplasm. Am J Clin Pathol. 2012;137:367-376. 18. Khoury JD, Medeiros LJ, Manning JT, Sulak LE, Bueso-Ramos C, Jones D. CD56(+) TdT(+) blastic natural killer cell tumor of the skin: a primitive systemic malignancy related to myelomonocytic leukemia. Cancer. 2002;94:2401-2408. 19. Chang HJ, Lee MD, Yi HG, et al. A case of blastic plasmacytoid dendritic cell neoplasm initially mimicking cutaneous lupus erythematosus. Cancer Res Treat. 2010;42:239-243. 20. Herling M, Jones D. CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic

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The Supply of Hematology/Oncology Specialists

Genevieve F. Maronge, MD; Paragi Gururaja Ramnaryan, MD, MPH; Perry G. Rigby, MD

National hematology and oncology organizations and experts in the field, predict a shortage of hematology/ oncology specialists in the United States. Four types of hematology/oncology graduate medical education programs picked to represent direct patient care specialists are presented as physician supply in quantitative data proportional to the averages of the United States in this paper. The hematology/oncology physician production in Louisiana is similar to the average of all programs in the United States. The complexities of having several hematology/oncology graduate medical education programs, along with other specialists, make physician supply more difficult to predict. The patient care demand will rise gradually as the population increases and aging of the population ensues. Technology proliferates, and reform adds patient numbers. As the US shortage of hematology/oncology specialists occurs, the state of Louisiana is tracking the United States in supply and will show the shortage in the same way, same timing, and for the same reasons.

INTRODUCTION gists is not a straightforward task and includes a number of factors, like number-per-population, number-per-cancer There is a perpetual discussion and debate on the patients and cancer survivors, the geographic distribution subject of physician shortage and particular attention paid among the states and rural and urban area, and the number to that of primary care.1,2 The shortage in specialists’ fields of hematologists/oncologists in academics versus non- is beginning to gain recognition, however.3 This is quite academic settings (in a field dependent on active research), relevant to the subspecialty of hematology/oncology in cancer center locations and utilization, waiting time for that cancer is a disease growing as the population increases appointments and visits, and quality of care in a setting and ages, and it requires a delicate and skillful approach to where demand may outweigh supply.6,7 Certainly there is diagnosis and therapy, with lethal potential to the patient a fraction of the cancer-patient population that suffer if they experiencing it. If we consider that the numbers of cancer are delayed in receiving attention due to long wait times and deaths are decreasing over time,4 along with increases in delayed appointments, as well as other potential barriers, technology, we can infer that cancer care is improving. This i.e., finance, transportation, and resources. does not indicate a decrease in patients or visits, however, as there are more patients surviving and living with can- METHODS cer, requiring more physicians. It is therefore vital that we assess our physician supply and how demand will be met A straightforward approach to begin an examination now and in the future. is to identify supply and demand. We used data from the Is there a shortage of physicians in the United States 2010 AMA masterfile and the 2012 edition of Physician as a whole, what kind, and how is this assessed? Graduate Characteristics and Distribution from the Division of Survey Medical Education (GME) programs are ultimately the sup- and Data Resources to examine the supply.8 Figure 1 dem- ply line of physicians to renew the provision of healthcare, onstrates the supply of hematology/oncology specialists as and these vary in size, type, and location. It is probable that it relates to the population in the United States as compared they are not increasing the production of specialists fast to Louisiana. We evaluated four specialty programs that 5 enough as it relates to population change. The demand provide medical care to cancer patients: medical oncolo- is impacted by a population that is dynamic by growth gists, hematology alone, hematology/oncology, and oncol- and aging and complicated by technology and constant ogy alone, as well as pediatric hematology/oncology. This advancements in standards of care. Healthcare reform is demonstrates that Louisiana is comparable to the United an additional variable that is particularly relevant in this States overall in supply. political climate. We then examined the demand. The demand is repre- Quantitating a shortage of hematologists and oncolo- sented by the current utilization patterns and delivery sys-

10 J La State Med Soc VOL 166 January/February 2014 supply be addressed by increasing physicians. GME is the direct source of practicing physicians in the US caring for cancer patients. To become a hematologist/oncologist requires completion of medical school, followed by a residency training program and then a fellowship in that specialty. We analyzed the residency feeder programs and trends over the last 15 years as shown in Figure 2, lacking sustained growth. Table 1 shows data from the AMA master file and the US Census Bureau from 2010 illustrating there are about 10,000 physicians in the adult care of hematology/oncology patients and approximately two physicians for every 100,000 people. In Louisiana, there were 146 adult hema- Figure 1: The supply of hematology/oncology specialists comparing the United States to tology/oncology specialists, in equal Louisiana, related to a proportion of a population. proportion to that of the United States. Table 2 shows the total hematology/ oncology fellows in the US in 2011 per the Accreditation Council for Gradu- ate Medical Education (ACGME) data resource book. There are 1,570 fellows currently training in adult hematology/oncology. There are 637 fellows who complete their training and are added to the oncology workforce annually after completion of five to six years of post-graduate training. The number of practicing hematology/oncology physicians in the United States who are trained in a GME program in Louisiana and the number who remain in Louisiana after training is also relevant, shown in Table 3 with a net retention of 41%. Figure 2: The residency feeder programs and trends over the last 15 years. The number of specialists practicing in Louisiana currently who did not tems. This is overall complex and difficult to define and has train in Louisiana is 77, so this adds another dimension to been done by a number of methods, but regardless of vari- examining needs and sources. This begs the question: how ous methods, we found there is a consensus as illustrated many hematology/ oncology doctors will be training in by the Association of American Medical Colleges (AAMC) 9 Louisiana in the next 10 years, and how many will practice 2008 workforce report. The findings were “under any set in Louisiana? Likely, trends will continue, but increase is of plausible assumptions, the United States is likely to face uncertain. a growing shortage of physicians…” They also published Incidence rates of cancer in the United States and Loui- a report in 2011 summarizing recent publications and sum- siana are integral to this analysis. Figure 3 shows a map of maries around the country from 33 states and six national the incidence rates in the United States in 2008 per state as organizations, as well as 22 different specialties that have 10 observed from Surveillance, Epidemiology, and End Results all reached this same conclusion. Program (SEER) data. Specifically noted is that Louisiana is higher compared with most of the country, with an inci- RESULTS dence of 468-487 cases per 100,000 people. So compared to the country as a whole, Louisiana has comparable numbers Replacement of Physicians and Increasing Supply of hematologists/oncologists; however, there is a higher One answer to this growing demand is that short incidence of cancer overall.

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Table 1: Data from the AMA master file and the US Census Bureau for 2010 US Louisiana Type of practicing specialty N 100k population N 100k population Hematologist 1,512 0.49 21 0.46 Hematologist/Oncologist 4,275 1.38 58 1.28 Oncologist 4,268 1.38 67 1.48 Pediatric-Hematologist/ 1,255 0.41 18 0.40 Oncologist TOTAL 11,310 3.66 164 3.62

Table 2: The total hematology/oncology fellows in the United States in 2011 per the ACGME Data Source Book Total Hematology & Oncology Residents/Fellows in the United States Specialty N Hematology 32 Hematology & Oncology 1,450 Oncology 97 Pediatric - Hematology & Oncology 400 Total 1,979

Table 3: The practicing hematology/oncology physicians in the United States who are trained in Louisiana, 2004-2012 Retention of hematology/oncology fellows in Louisiana N Total hematology/oncology physicians trained in a Louisiana GME program 135 Total hematology/oncology physicians trained in a Louisiana GME program & practicing in state as 55 hematologist/oncologist (direct patient care) % retention 41

The analysis of SEER data for Louisiana (Figure 4) in a ana, comparing recruitments. GME programs in the state breakdown by parish shows that many areas have a higher had not reconstituted until after Katrina, which closed one incidence than that illustrated for Louisiana as a whole. program for several years (Louisiana State University School There are also a number of rural areas in Louisiana where of Medicine in New Orleans). Recruitment of types of hema- it is illustrated there is a high incidence of cancer without tology/oncology specialists, distribution and geography is hematology/oncology practices in those vicinities, bring- also similar to corresponding US characteristics. ing up the issue of access to care. Other complexities and The comparison of individual states data to the US challenges of this situation include a high percentage of averages is perhaps the best marker of the present quan- impoverished and underserved, lower socioeconomic status, titative requirement. If the prediction of hematology/ and lower health literacy, making the task of delivering care oncology specialist’s shortage in the United States is actual, even greater. then Louisiana is also likely to experience a shortage. The characteristic of programs and physician mobility means DISCUSSION recruitment across boundaries increases competition. Many changes occurring presently and simultaneously in specialty The surprise is that Louisiana hematology/oncology GME programs, not just hematology/oncology, increase physicians are quantitatively proportional to the average complexity and hide unintended consequences. Expan- of the United States, despite the displacements and distrac- sion of hematology/oncology specialty programs should tions of Hurricane Katrina.11 Loss of physicians was early, be considered in future planning to alleviate impending and replacement was gradual. Production from supply is shortages, especially since the production time is many somewhat less than half of practicing physicians in Louisi- years in duration.

12 J La State Med Soc VOL 166 January/February 2014 Figure 3: Map of the incidence rates of cancer for Louisiana.

Figure 4

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CONCLUSION

GME programs in hematology/oncology should consider future expansion to offset a national shortage of practicing specialists, variable in individual states. Other measures improving practice efficiencies, educational programs, and distribution characteristics should also be explored. Matching individual state GME and practice and targeting US average proportions are measures to begin to focus on. Planning directions for cancer care and blood diseases should include GME increases, as well as recruitment, distribution, and physician quality.

REFERENCE

1. Blumenthal D, et al. New Steam from an Old Cauldron. The Physician – supply debate. NEJM 2004; 350:17. 2. Cooper RA. States With More Physicians Have Better-Quality Health Care. Health Affairs (Web Exclusive) 2008:w91-w101. 3. Council on Graduate Medical Education Resource Paper - State and Managed Care Support for GME: innovation and implication. 4. Carla P, Kent E, Mariotto, et al. Cancer Survivors: A Booming Population. Cancer Epidemiology, Biomarkers, and Prevention 2011; 20:1996-2005. 5. Darves B: Physician Shortages in the Specialties Taking a Toll. www.nejmjobs.org 6. Erikson C, Salsberg E, Forte Gaetano, et.al: Future Supply and Demand for Oncologists: Challenges to Assuring Access to Oncology Services. J Oncology Practice March 2007; 3(2):79-86. 7. Hortobagyi GN: A Shortage of Oncologists? The American Society of Clinical Oncology Workforce Study. Am. Soc. Clin. Onc. April 20, 2007; 25(12):1468-1469. 8. 2010 Louisiana Specific AMA Physician Masterfile. 9. AAMC 2008 workforce: Complex of Physician Supply and Demand 10. AAMC 2011 report. Recent Studies and Reports on Physician Shortage in the U.S. 11. Rigby PG, Braun K, Hilton C, Pinsky W, et al. The Medical Education Commission Report 2007:GME is Recovering From Katrina. J LA State Med. Soc. 2009; 161:32-40. 12. Cooper RA: Expanding Physician Supply-An Imperative for Health Care Reform. The Pharos Spring 2010; 35-37.

Dr. Maronge is a Fellow in the Section of Hematology/Oncology at Louisiana State University School of Medicine in New Orleans. Dr. Ramnaryan is an Assistant Professor in the Department of Internal Medicine at the LSU School of Medicine in New Orleans. Dr. Rigby is a Professor of Medicine in the Section of Hematology/Oncology at LSU School of Medicine in New Orleans.

14 J La State Med Soc VOL 166 January/February 2014 Treatment of Submucous Cleft Palate With Selective Use of the Furlow Z-Palatoplasty

Michael H. Moses, MD; Mark W. Stalder, MD; David T. Pointer Jr., BS; Ryan Wong, MD; Charles L. Dupin, MD; Hugo St. Hilaire, MD, DDS

Purpose: Submucous cleft is an uncommon entity that can be complicated by functional abnormalities, specifically velopharyngeal incompetence (VPI), secondary to abnormal palatal muscular insertion. This study aims to characterize our experience using the Furlow Z-palatoplasty for the treatment of VPI in patients with submucous clefts.

Methods: A retrospective chart review was conducted looking at 24 patients diagnosed with symptomatic submucous clefts between 2000 and 2007 at Children’s Hospital of New Orleans. Demographics such as age, gender, diagnosis, need for surgical correction, type of operation, complications, presence of genetic syndromes, need for secondary surgery, and need for myringotomy tubes were examined.

Results: The average age at initial surgery for the entire study population was 6.2 years. The success rate of our Furlow procedure was 66.7%, with 33.3% requiring secondary pharyngeal flaps. The genetic syndromic patient population had an average age at initial surgery of four years and experienced a lower primary success rate of 50%. The non-syndromic patient population had an average age at initial surgery of 7.3 years, with an 85.7% primary success rate.

Conclusions: Our data supports the notion that Furlow Z-palatoplasty is an effective procedure in the treatment of submucous cleft palate with VPI, frequently without the need for secondary surgical procedures in the majority of patients, particularly those patients without syndromes.

INTRODUCTION for these patients. In the setting of submucous cleft with associated VPI, First described by Roux more than 100 years ago, numerous procedures have been employed for surgical submucous cleft is an uncommon condition that is defined correction, including pharyngeal flaps, V-Y pushback by the presence of three anatomical features: bifid uvula, palatoplasty, minimal incision palatopharyngoplasty, and palatal muscular diastasis, and notching of the hard pal- Furlow Z-palatoplasty.3,9,11-13 A consensus approach to ate.1-3 Kaplan further described the “occult submucous cleft” treatment remains elusive, however. At our institution, for when he found that the same functional problem can occur patients who are unresponsive to speech therapy, the Fur- in the presence of abnormal muscular insertion without low Z-palatoplasty is used for initial surgical management. the presence of the classic triad.4 These similar conditions Pharyngeal flaps are reserved as secondary procedures for both can result in velopharyngeal incompetence (VPI) due patients in whom the initial Z-palatoplasty is unsuccessful. to the abnormal insertion of the palatal musculature onto The purpose of this study is to report our experience the hard palate instead of forming a continuous muscular using the Furlow Z-palatoplasty for primary correction of sling across the midline. VPI in the submucous cleft population. The efficacy of this True submucous cleft occurs uncommonly, with inci- procedure was characterized based on subjective improve- dence reports ranging from 1:1,200 to 1:20,000.3-9 Also, the ments in speech and the need for secondary procedures. incidence of submucous cleft in patients demonstrating VPI has been reported to be between 27% and 62%.4,10 Due to METHODS the relative scarcity of these patients, there is a paucity of literature addressing this condition, and its diagnosis and A retrospective chart review was conducted for those treatment remain a challenge for the physicians that care patients diagnosed with submucous cleft that were seen

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Patients were evaluated before and after surgery by the speech pathologists on our multi-disciplinary team. Assessments were made on each follow-up visit to evaluate correction of VPI and to determine whether the patient would require further surgical correction. Nasal escape, compensatory substitutions, volume/pitch changes, nasal resonance, tongue placement, oral-nasal balance, and articulation were all assessed.

RESULTS

A total of 24 patients with the diagnosis of submucous cleft palate were treated by our team during the period of time included in this study (Figure 1). Seventeen of the 24 patients required surgical intervention to correct their submucous cleft due to the presence of velopharyngeal incompetence. Fifteen of those 17 patients underwent Furlow Z-palatoplasty. Five of those 15 patients later required a secondary pharyngeal flap for persistent VPI, yielding a 67% success rate for correction of VPI by Furlow Z-palatoplasty in this group. The other two surgical patients underwent a primary pharyngeal flap, as it was felt that a Furlow Z- palatoplasty would have been unsuccessful due to their individual palatal anatomic idiosyncrasies. The average age at surgery for all 17 surgical patients was 6.2 years, and this group was followed on average for 3.75 years after their initial procedure. Seven of the 24 patients with submucous cleft did not require surgical correction of any kind, as their condition improved with speech Figure 1: This schematic illustrates the basic concept of a therapy alone. z-plasty, whereby local tissue flaps are juxtaposed in such a Eleven of the 24 patients had previously been diagnosed manner as to lengthen the original AB tissue segment. with a genetic syndrome (Figure 2). Eight of these 11 patients had VPI that required surgical correction with the Furlow by the Children’s Hospital of New Orleans Craniofacial procedure, which provided adequate oral-nasal balance in and Cleft Team between 2000 and 2007. This study was four of the eight patients, for a 50% success rate in this sub- approved by the Institutional Review Board. Operative group. The other four patients demonstrated persistent VPI notes and charts were reviewed for data regarding the pa- and required a secondary pharyngeal flap to successfully tients’ age, gender, diagnosis, type of operation, need for improve their speech. The average age at surgery for the 11 myringotomy tubes, subsequent complications, length of syndrome-associated patients was four years. follow-up, need for secondary procedures, and presence of Among the 13 non-syndromic, submucous cleft pal- genetic syndromes. In addition, speech therapy notes were ate patients, seven had sufficient VPI to require a primary carefully reviewed to track changes in patients’ speech pat- Furlow Z-palatoplasty (Figure 3). Six of these 7 cases (86%) terns before and after surgery. resulted in functional oral-nasal balance, with only one (14%) requiring secondary pharyngeal flap for persistent SURGICAL PROCEDURE VPI (Figure 4). The average age at surgery for this group was 7.3 years. The classic Furlow Z-palatoplasty, as described for Eustachian tube dysfunction and treatment were also overt cleft palates, was used for primary surgical manage- analyzed in our submucous cleft population. Thirteen of the ment in this series.14-15 Double opposing z-plasties were 24 (54%) patients required placement of pressure equalizing designed on the oral and nasal surfaces of the soft palate. (PE) tubes by an otolaryngologist. Nine of the 11 syndromic The levator and tensor musculature were elevated with a patients (82%) ulitmately required PE tube placement, com- posteriorly based flap that included the nasal mucosa on the pared with only 4 of the 13 non-syndromic patients (31%). right side and oral mucosal on the left side. The interdigi- tating z-plasties were then closed, restoring the integrity of DISCUSSION the palatal muscular sling and effectively lengthening the soft palate. Dysfunction of the velopharyngeal sphincter from

16 J La State Med Soc VOL 166 January/February 2014 Figure 2: This schematic illustrates the steps involved in the Furlow Z-palatoplasty repair of submucous cleft palate, the purpose of which is to recreate anatomically appropriate attachments of palatal musculature, and to lengthen the palate.

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obvious abnormalities of the pharyngeal wall are readily seen and diagnosed early. However, submucous cleft palate is a relatively rare variant of palatal cleft. Due to the subtle anatomic variations associated with this condition, it may not be recognized on routine well child exams, and diagnosis is often delayed until the child is older, at which time VPI, compensatory corrections, and articulation errors may already be present.11 There have been many attempts to account for this inconsistency, and a number of approaches for evaluation of VPI have been outlined in the literature. Bunke et al. utilized multiple techniques, including detailed intraoral exams, subjective speech evaluations, flow studies involving simultaneous intranasal and intraoral pressure measurements, and lateral cephalometric X-rays.26 Videonasendoscopy and videofluoroscopy have also been described as effective diagnostic modalities.9,11 At our institution, the degree of VPI is established by subjective speech evaluation performed by a speech pathologist and the plastic surgeon. We also use nasopharyngeal endoscopy to further characterize patients with equivocal evaluations. In these patients, it is important that language be sufficiently developed to permit proper assessment of oral-nasal balance so that effective characterization of VPI can be achieved. In conjunction with the inconsistencies that exist regarding diagnosis of submucous clefts, debate remains regarding the optimal timing of surgical treatment, and a number of approaches have been reported. In his experience, Calnan advocated treatment similar to that of an overt cleft palate (assuming the diagnosis is made in time), with correction at about one year of age.2 Porterfield advocated repair of all patients at 16 to 18 months of age.16 There have also been several studies that reported no correlation at all between age at surgery and successful postoperative outcomes, raising further questions about the need for and timing of surgical intervention.13,17 Ultimately, most authors recommend waiting until speech has adequately developed so that appropriate evaluation of VPI may be performed before considering surgical correction.5,9,11,13,17 A variety of operative procedures have been described for the surgical treatment of submucous clefts. Calnan reported improvements in speech using a procedure that employed VY retroposition and lengthening of the velum.2 Kaplan used the combination of a VY pushback with a superiorly based pharyngeal flap and also reported improvements in speech in that patient series.4 In his review of 22 submucous clefts, Cleveland suggested the necessity of a pharyngeal flap to achieve successful correction of speech.19 Porterfield also suggested the combination of a primary pharyngeal flap in conjunction with a palatal procedure in the primary correction of submucous clefts.19 However, this procedure is not without risk for significant complications, including airway obstruction, bleeding, flap dehiscence, per- Figure 3: This schematic illustrates the steps involved in sistent oral-nasal imbalance, and obstructive sleep apnea.20-25 pharyngeal flap repair of submucous cleft palate. This repair is not an anatomic repair but rather, reduces the size of the In contrast, there is significant evidence that palatoplasty 11 opening between the oral and nasal cavities to reduce the alone is adequate treatment for VPI. symptoms of velopharyngeal insufficiency. Similar to other reported protocols, at our institution patients with marginal insufficiency are treated with an

18 J La State Med Soc VOL 166 January/February 2014 Figure 4: (Left) Patient with submucous cleft palate and VPI requiring Furlow Z-palatoplasty. (Right) The same patient after Furlow Z-palatoplasty. interventional trial of speech therapy for 6 to 12 months.26 use of the Furlow Z-palatoplasty in the correction of velo- In those patients for whom surgery is indicated, the Furlow pharyngeal incompetence. Z-palatoplasty is used as our primary repair procedure.13 The Z-palatoplasty offers the advantage of directly correct- REFERENCES ing the dysfunctional anatomy, creating a functional velar musculature while simultaneously lengthening the palate, 1. Roux, JP. Memoires sur Staphylorrhaphie, p. 84. J.S. Chaude, Paris, and avoids undermining the mucosa of the hard palate. Our 1825. patients are followed closely after the procedure and only 2. Calnan, JS. Submucous Cleft Palate. Brit. J. Plast. Surg., 6: 264-282, undergo secondary pharyngeal flap if it is clear that there 1954. 3. Seagle MB, Patti CS, Williams WN, Wood VD. Submucous Cleft is persistent or recurrent VPI. Palate: A 10-year Series. Ann. Plast. Surg. 42: 142-148, 1999. The patients in our series experienced a 67% success 4. Kaplan, E. The Occult Submucous Cleft Palate. Cleft Palate J. 12: rate for correction of VPI with primary Z-palatoplasty, 33% 356-265, 1975. of the patients ultimately required a secondary pharyngeal 5. Weatherly-White RC, Sakura C, Brenner L, Stewart J, Ott J. flap. Interestingly, when we stratified our patient popula- Submucous Cleft Palate: Its Incidence, Natural History, and tion to account for association of genetic syndromes, we Inidications for Treatment. Plast and Reconstr Surg. 49: 297-304, noticed a higher rate of failure in the syndromic (50%) when 1972. compared to non-syndromic patients (14%). The average 6. Lindeman G, Sewerin P. Prevalence of Cleft Uvulae among 2732 age at surgery (4 years in syndromic patients vs. 7.3 years Danish Cleft Palates. Cleft Palate J. 14: 226-231, 1967. 7. Mesking L, Gorlin R, Issalsom RJ. Abnormal Morphology of the in non-syndromic patients) was almost doubled in the non- Soft Palate. Cleft Palate J. 1: 342-346, 1964. syndromic patient population. The need for PE tubes was 8. Shapiro BL, Meskin LH, Cervenka J, Pruzansky S. Cleft Uvulae: a also more frequent in the syndromic patients. This may microform of facial clefts and its genetic basis. The Third Conference indicate that the functional deficit was less severe in the non- on the Clinical Delineation of Birth Defects. Baltimore, June, 1970. syndromic population or that population may potentially Baltimore: Williams & Wilkins, 80-82. have been able to better compensate for their VPI, and thus, 9. Velasco MG, Ysunza A, Hernandez X, Marquez C. Diagnosis and further delayed diagnosis. Treatment of Submucous Cleft Palate: A Review of 108 Cases. Cleft Palate Journal. 25: 171-173, 1988. 10. Shprintzen R, Schwartz R, Daniller A, Hoch L. Morphologic CONCLUSION Significance of Bifid Uvula. Pediatrics. 75: 553-561, 1985. 11. Ysunza A, Pamplona MC, Mendoza M, Molina F, Martinez P, We found the Furlow Z-palatoplasty to be an effective Velasco M, Prada N. Surgical Treatment of Submucous Cleft procedure in the treatment of patients with submucous Palate: A Comparative Trial of Two Modalities for Palatal Closure. cleft palate and VPI. With this procedure, one can achieve Plast and Reconstr Surg. 107: 9-14, 2001. adequate correction of VPI and avoid secondary corrections 12. Peat B, Albery E, Jones K, Pigott R. Tailoring Velopharyngeal in the majority of patients, particularly in those patients Surgery: The Influence of Etiology and Type of Operation. Plast without evident genetic syndromes. We were able to achieve and Reconstr Surg. 93: 948-953, 1994. 13. Chen, PK, Wu J, Hung KF, Chen YR, Noordhoff SM. Surgical functional oral-nasal balance in two-thirds of our patients. Correction of the Submucous Cleft Palate with Furlow Through its success at our institution, we recommend the Palatoplasty. Plast and Reconstr Surg. 97: 1136-1146, 1996.

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14. Furlow LT. Cleft palate repair: preliminary report on lengthening 23. Valnicek SM, Zucker Rm, Halpern LM, et al. Perioperative and muscle transposition z-plasty. Presentation -- Annual meeting complications of superior pharyngeal flap surgery in children. of Southeastern Society of Plastic Surgeons. May 16, 1978. Plast Reconstr Surg. 93: 954-8, 1994. 15. Furlow, L. T., Jr. Flaps for cleft lip and palate surgery. Clin. Plast. 24. Wells MD, Vu TA, Luce EA. Incidence and sequelae of nocturnal Surg. 17: 633, 1990. respiratory obstruction following posterior pharyngeal flap 16. Porterfield HW, Trabue, JC. Submucous Cleft Palate. Plast and operation. Ann Plast Surg. 43: 252-7, 1999. Reconstr Surg. 35: 45-50, 1965. 25. Liao YF, Chuang ML, Chen P, Chen NH, Yun C, Huang CS. 17. McWilliams BJ. Submucous clefts of the palate: how likely are Incidence and severity of obstructive sleep apnea following they to be symptomatic? Cleft Palate Craniofac J. 28: 247-51. 1991. pharyngeal flap surgery in patients with cleft palate. The Cleft 18. Cleveland KM, Falk ML. Several factors which may precipitate Plate Cranofac Jour. 39: 312-16, 2002. the use of pharyngeal flap. Cleft Palate J. 7: 105-111, 1970. 26. Buncke HJ, Page P, Price B, et al. The evaluation and management 19. Porterfield, H. W., Mohler, L. R., and Sandel, A. Submucous cleft of velopharyngeal insufficiency. Presentation – Convention of the palate. Plast and Reconstr Surg. 58: 60-65, 1976. American Cleft Palate Association. 1964. 20. Canady JW, Cable BB, Karnell MP, Karnell LH. Pharyngeal flap surgery: Protocols, complications, and outcomes at the University of Iowa. Otolaryngo Head Neck Surg. 129: 321-6, 2003. 21. Fraulin FO, Valnicek SM, Zuker RM. Decreasing the perioperative Dr. Moses is with the Children’s Hospital of New Orleans, Division complications associated with the superior pharyngeal flap of Plastic and Reconstruction Surgery. Drs. Stalder, Dupin, and operation. Plast Reconstr Surg. 102: 10-8, 2000. Hilaire are with the Louisiana State University Division of Plastic & Reconstruction Surgery. Mr. Pointer Jr. and Dr. Wong are with the 22. Pena M, Choi S, Boyagian M, et al. Perioperative airway Tulane University School of Medicine. complications following pharyngeal flap palatoplasty. Ann Otol Rhinol Laryngol. 109: 808-11, 2000.

20 J La State Med Soc VOL 166 January/February 2014 Distal Ventriculoperitoneal Shunt Catheter Migration to the Right Ventricle of the Heart - A Case Report

Marc Manix, MD; Anthony Sin, MD; Anil Nanda, MD, MPH, FACS

Ventriculoperitoneal shunts (VPS) have few complications other than mechanical obstruction and infection. A VPS catheter located in the chest is a rare complication, while intracardiac catheter migration is rarer still. We present a case of intracardiac migration of a distal VPS catheter after initial documented peritoneal placement. Puncture or erosion of a cervical vein may predispose a patient to such a migration. Negative inspiratory pressure and orthograde blood flow may then draw the catheter proximally through a vein and eventually to the heart or pulmonary artery. We discuss the mechanisms and management of this rare, yet dangerous, complication of a routine neurosurgical procedure.

INTRODUCTION but the headaches returned, leading to presentation in our clinic. A shunt malfunction was suspected at presentation, The ventriculoperitoneal shunt (VPS) is the most com- so a shunt series of plain film X-rays was ordered as part mon surgical treatment for hydrocephalus, and the opera- of the initial workup. The X-rays showed a catheter coiled tion has been practiced for the past 60 years. While it has a around itself in the thorax without any extension to the ab- low complication rate, complications do sometimes occur. domen (Figure 1d). A CT scan of the neck and chest showed Most often, these tend to be mechanical obstructions or that the catheter extended through the neck into the right infection. Numerous case reports in the literature illustrate subclavian vein and continued through the right heart to the many possible complications seen with the VPS, but it the pulmonary vasculature (Figure 2). is rare for a portion of a VPS catheter to travel into the chest as this is not a part of the normal course for tubing since DISCUSSION it is tunneled to the peritoneal cavity. We present a case where the distal end of a catheter placed in the peritoneum Neurosurgeons frequently see VPS complications. migrated to the heart. However, thoracic complications are rare, as shunt catheters normally do not enter this area. Intracardiac migration is CASE REPORT seen even less often, with only 12 cases reported in the literature. A 34-year-old male presented with reports of gradually Taub described supra- and transdiaphragmatic routes worsening headaches. The patient had a prior VPS place- for the migration of the peritoneal catheter to the chest.1 ment at an outside institution (Figure 1) two years prior. The routes can be distinguished radiographically, as any The past medical history was significant for spina bifida tubing seen in the abdomen must pass through the dia- and tethered cord, for which he had a lipoma removal and phragm to enter the thorax. Taub and Lavyne hypothesize release of tethered cord six months prior presentation. The that transdiaphragmatic migration occurs either when a operation was complicated by a postoperative cerebrospinal catheter erodes the diaphragm or when it passes through fluid leak and development of a pseudomeningocele in the the Foramen of Bochadalek or Morgagni.21,26 Because no lumbar spine. This led to severe headaches, as well as low portion of the catheter was visible in imaging studies of the back pain and swelling. The VP shunt was then placed for abdomen, we decided that the site of entry in the case was diversion of CSF by an outside neurosurgeon in order to supradiaphragmatic. resolve the pseudomeningocele and relieve the pressure in Morell, the first to describe the migration of a VPS the lumbar cistern, allowing the dural defect to heal. The catheter into the heart, proposed two possible ways it might patient reported good relief of symptoms for eight months, occur.2 He first postulated that there is iatrogenic damage

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Figure 1: Immediate postoperative plain film X-ray shunt series of neck (top left) and abdomen (bottom left) showing medial course of the shunt catheter and placement in the peritoneal cavity. Staples used to close the abdominal incision are seen as well. Abdominal X-ray (bottom right) shows shunt catheter no longer located in the abdomen and lies completely supradiaphragmatic.

to a vein when using the shunt passer, with some portion of with negative inspiratory pressure, draws the catheter the distal catheter within the vessel. This may occur when proximally through the vein and eventually to the heart or tunneling too deep or too medial in the supraclavicular area. pulmonary artery. This seems the most plausible mechanism After removal of the shunt passer, a portion of the catheter is as 10 of the 12 reported cases describe damage to a jugular left intravenous, and the orthrograde blood flow, combined vein. Of the 10, seven described passage through the internal

22 J La State Med Soc VOL 166 January/February 2014 Figure 2: CT thorax without contrast shows catheter (arrow) deep to the clavicle (top) and coiled in the right heart heart (bottom).

jugular vein, which may occur when the catheter is tunneled chest will reveal the vessel in which the catheter travels, too deep. The other proposed mechanism was erosion into as well as the specific course within the chest cavity. An an adjacent vein by the distal catheter. Once the portion of echocardiogram will show the exact location in the heart, the catheter is in lumen of the vessel, the same described and it will also help rule out thrombus, cardiac perforation, mechanism of inspiratory pressure coupled with blood flow valvular damage, or tamponade. Cardiac rhythm monitor- draws the catheter proximally to the heart. ing or an electrocardiogram will show any ectopy if there The diagnosis is easily made with plain films, as in our is a focus due to the catheter. case, but the surgeon should obtain further imaging for A review of the literature shows an evolution in the complete operative planning. CT scanning of the neck and treatment for this specific problem. The patient in the first

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Figure 3: Illustration of a proposed mechanism for migration of the shunt catheter with iatrogenic perforation of a vein during the tunneling of the catheter (top left) and subsequent migration of a portion of the catheter in the lumen of the vessel secondary to negative inspiratory pressure and blood flow (top right). A second proposed mechanism for intraluminal migration of the shunt catheter is via a portion of the catheter lying next to the vessel. After a period of time (bottom left), there is erosion through the vessel wall and movement of the catheter through the vein as a result of negative pressure and venous return (bottom right).

24 J La State Med Soc VOL 166 January/February 2014 reported case underwent a thoracotomy and open heart distal catheter of a ventriculoperitoneal shunt into the heart: case surgery for treatment. Frazier describes a sub-xyphoid report. Neurosurgery 2002;51:819-822. pericardial window for direct observation of the heart as the 4. Imamura H, Nomura M. Migration of ventriculoperitoneal shunt catheter was withdrawn [3]. Fluoroscopic guided removal into the heart – case report. Neurol Med-Chir (Tokyo) 2002;42:181- 183. of the distal catheter and placement in the peritoneal cavity 5. Ruggiero C, Spennato P, De Paulis D, et al. Intracardiac migration is the most common treatment, but some authors used the of the distal catheter of ventriculoperitoneal shunt: a case report. assistance of interventional radiology and percutaneous Childs Nerv Syst 2010;26:957-962. techniques to remove the tubing from the heart. Imamura and Ruggiero both elected to withdraw the catheter into the right atrium under fluoroscopy, but chose Drs. Manix, Sin, and Nanda are with the Louisiana State University not to reposition the catheter in the peritoneum [4,5]. They Health Sciences Center-Shreveport’s Department of Neurosurgery. used a cervical incision to shorten the distal catheter and left their patients with a ventriculo-atrial (VA) shunt. They point out the advantages of this procedure: a shorter operative time without the need for general anesthesia. However, VA shunts carry the risks ofcardiac insufficiency, cardiac arrhythmias, tamponade, mural thrombi, pulmonary emboli, as well as endocarditis and sepsis in the setting of infection.

CONCLUSION

This case shows a rare yet dangerous complication of a basic surgical procedure. Migration of a peritoneal catheter into the heart puts the patient at risk for pulmonary emboli, cardiac arrhythmias, sepsis, tamponade, and valvular damage. The diagnosis is easily made with plain films, but CT scanning and an echocardiogram should be part of the complete workup. Treatment options include removing the catheter under fluoroscopic guidance, with assistance of loop snare devices, grasping forceps, and helical baskets per interventional radiology should there be difficulty with the manual retrieval. Moreover, the majority of cases reported in the literature describe the catheter passing intravascular through the external or internal jugular vein. This likely happened because the shunts were passed too medial and too deep, placing the catheter either through or adjacent to these vessels. There does not appear to be a need for more invasive procedures, such as a thoracotomy or pericardial window, given the success and lack of complications with minimally invasive techniques. Perhaps the open surgical procedures should be reserved for more complicated cases not amenable to percutaneous methods. Most importantly, the case report presented demonstrates the need for careful and proper technique in the setting of a basic surgical procedure. Remaining cognizant of the path of the shunt passer and obtaining proper post-operative imaging are the best ways to avoid this complication.

REFERENCES

1. Taub E, Lavyne MH. Thoracic complications of ventriculoperitoneal shunts: case report and review of the literature. Neurosurgery 1994;34:181-183. 2. Morell RC, Bell WO, Hertz GE, et al. Migration of a ventriculoperitoneal shunt into the pulmonary artery. J Neurosurg Anesthesiol 1994;6:132-134. 3. Frazier JL, Wang PP, Patel SH, et al. Unusual migration of the

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Malposition of a Hemodialysis Catheter in the Accessory Hemiazygos Vein

Brian Revis, MD; Mohammad Kazem Fallahzadeh, MD; Neeraj Singh, MD

Figure 1 , Panel A Panel B

A 30-year-old Caucasian female underwent a kidney Hemodialysis catheters are associated with several transplant but experienced delayed graft function, neces- complications such as pneumothorax, bleeding, arrhyth- sitating dialysis. Her previous right internal jugular dialysis mias, thrombosis, infections, and malposition.1 Malposition catheter had been removed during surgery. On ultrasound, complicates 1% to 33% of hemodialysis catheter placements her right internal jugular vein was found to be stenosed and should be promptly identified due to the risk of vas- proximally, and a left internal jugular vein dialysis catheter cular laceration or perforation.2 Malposition usually occurs (20cm, 12 Fr) was placed under ultrasound guidance with within the major tributaries of the superior vena cava, no complications. A chest X-ray was obtained to confirm the including subclavian, internal thoracic, pericardiophrenic, correct position, and it was concerning for cannulation of and superior intercostal veins.1 Hemodialysis catheters can the aorta (arrow in Figure 1, Panel A). A blood gas analysis also be misplaced outside the venous system into adjacent done from the dialysis catheter suggested venous blood. structures like pleura.1 Physicians should also be aware of Fluoroscopy showed the catheter coursing from left internal accidental arterial cannulation.1 Cannulation of the acces- jugular vein into the accessory hemiazygos vein (arrow in sory hemiazygos vein is rare but can happen when the ac- Figure 1 Panel B). The catheter was repositioned, and the cessory hemiazygos vein drains into the left brachiocephalic tip was correctly advanced to the junction of superior vena vein instead of the azygos vein normally.1 Interestingly, cava and right atrium. For comparison, a chest X-ray image accessory hemiazygos vein has been reported to be used of a properly placed hemodialysis catheter in a different for placement of hemodialysis catheter in a patient with patient is demonstrated in Figure 2. unusual anatomy of central venous system, including bilat-

26 J La State Med Soc VOL 166 January/February 2014 Figure 2 eral occlusion of brachocephalic veins and drainage of left Dr. Revis is with the Division of Nephrology, Department of Internal Medicine at The Ohio State University. Dr. Fallahzadeh is with the internal jugular and subclavian veins directly into superior John C. McDonald Regional Transplant Center, Willis Knighton Health 3 vena cava through an enlarged accessory hemiazygos vein. System in Shreveport, Louisiana. Dr. Singh works with Dr. Revis at Ohio State and Dr. Fallahzadeh at the John C. McDonald Regional REFERENCES Transplant Center. He is also in the Division of Nephrology, Department of Internal Medicine at Louisiana State University Health Sciences 1. Muhm M, Sunder-Plassmann G, Druml W. Malposition of a Center in Shreveport. dialysis catheter in the accessory hemiazygos vein. Anesth Analg. 1996; 83: 883-5. 2. Stolic RV, Stolic DZ. A left jugular vein catheter for hemodialysis malpositioned in right brachiocephalic vein. Iran J Kidney Dis. 2012; 6:98. 3. Letachowicz K, Kolodziej M, Miedzybrodzki K, et al. Tunneled- cuffed catheter implanted into the accessory hemiazygos vein because of occlusion of the left innominate vein. Hemodial Int. 2012; 16: 310-4.

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Rapid HIV Testing in a New Orleans Emergency Department is Effective in Identifying New HIV Diagnoses and in Linking Patients to Care

Lauren E. Richey, MD, MPH; Elizabeth J. Carpenter, MD; James M. Barbeau, MD, JD; Christiane M. Hadi, MD, MPH

A retrospective chart review of patients who agreed to a rapid HIV test in the emergency department in the initial year of institution of the rapid test was conducted. Out of 8,204 patients, 99 were newly diagnosed with HIV in the first year of the institution of the rapid HIV test (1.2%). Eighty-five (86%) had a documented referral to the infectious disease clinic, and 59 (60%) were linked to care within one year of diagnosis. The majority (58%) of the patients with a new diagnosis of HIV had been seen in the Interim Louisiana State University Public Hospital (ILPH) healthcare system in the five years prior to their diagnosis. Forty-nine percent of the patients met diagnostic criteria of AIDS at diagnosis. Rapid HIV testing in the emergency department is an effective way to find previously undiagnosed patients and link them to subspecialty care.

BACKGROUND lence of unknown HIV infection in emergency departments is that these patients may not have access to primary care In the United States, there are more than 1 million or routine HIV testing in the outpatient setting. Uninsured people living with HIV/AIDS.1 It is estimated that a quar- patients in emergency departments have been shown to ter of them are unaware of their infection and are at risk of have a higher prevalence of HIV than insured patients.11 transmitting the virus to others.1 In September of 2006, the The Louisiana Department of Health and Hospitals’ CDC recommended that in order to identify these patients Office of Public Health reported 6,834 persons living with early in the course of their disease that HIV screening be HIV/AIDS in the New Orleans Metropolitan Area at the part of routine medical services, offered to every patient end of 2009.12 The number of new HIV diagnoses in Loui- aged 13 to 64, on a voluntary opt-out approach.2 Identifying siana increased from 979 in 2005, to 1,152 in 2007, to 1,262 patients early serves two purposes; 1) to improve an indi- in 2009, and 31% of these new diagnoses were in the New vidual patient’s prognosis by linking the patient to care at Orleans Metropolitan area.12,13 Twenty-four percent of the an earlier stage of the disease and 2) to prevent transmission newly diagnosed patients had AIDS, which demonstrates of the virus by patients who are unaware of their infection.3 advanced disease at the time of diagnosis.13 The Interim Routine HIV testing has been shown to be cost-effective in Louisiana State University Public Hospital (ILPH), part of both high- and low-prevalence settings,4 and a meta-analysis the Medical Center of Louisiana New Orleans (MCLNO), of 11 studies has shown that patients who are aware of their primarily serves uninsured and underinsured patients. The HIV infection decrease risk behaviors.5 system is also capable of linking patients to high-quality In 2002, a rapid test to detect HIV was approved by the subspecialty care, regardless of insurance status. This makes FDA. This test was comparable to available HIV tests and it an excellent location to identify previously undiagnosed was capable of providing results within 20 minutes.6 The HIV infections. ILPH’s Emergency Department began offer- rapid test allowed for more efficient HIV testing because it ing free rapid HIV tests to its patients in February of 2008. eliminated the need for a second visit to obtain results.7 It The purpose of this study is to determine how many new also allowed more patients to receive the result of their test.8 HIV infections were diagnosed with the test and whether This rapid test allowed for HIV screening to be performed in these patients were successfully linked to subspecialty care. high-paced settings such as emergency rooms. Emergency department patients are known to have a higher prevalence METHODS of HIV than the general population and are a potential place to identify patients who do not have traditional risk Rapid HIV testing was instituted on an opt-in basis factors.2,9,10 One possible explanation for the increased preva- beginning in February 2008 in the Emergency Department

28 J La State Med Soc VOL 166 January/February 2014 Table 1: Demographics of patients with newly diagnosed HIV infection. (N=99) Male 68 (69%) Race/Ethnicity African-American 77 (78%) White 16 (16%) Other 2 (2%) Unknown 4 (4%) Mean Age at Diagnosis (in years) [Range] 39 [19 to 61] Insurance (any) 23 (23%) Medicaid 17 (17%) Medicare 2 (2%) Private 1 (1%) Medicaid and Medicare 3 (3%) Free Care at ILPH1 34 (34%) Medical Care Through Prison 5 (5%) No Insurance 37 (37%) Risk Behavior (any) 37 (37%) Unprotected Heterosexual Contact 30 (30%) Intravenous Drug Use 8 (8%) Homosexual Contact 4 (4%) Commercial Sex Worker 1 (1%) Risk Factors (any) 60 (61%) Drug Use (non-IV) 53 (54%) Homelessness 9 (9%) Mental Illness 13 (13%) Unemployed 12 (12%) History of Imprisonment 11 (11%) History of an STD 26 (26%) History of Alcohol Use 58 (59%) Tobacco Use 62 (63%)

ILPH = Interim Louisiana Public Hospital New Orleans; IV = Intravenous; STD = Sexually Transmitted Disease

1”free care” is a program through the hospital that provides care to qualified indigent patients in Louisiana of ILPH. The Louisiana Office of Public Health provided the patient would like an HIV test. Those opting in for a the funding for the rapid HIV screening tests, and the tests test were given a handout about HIV screening. Prior to were performed in the blood bank of ILPH. The test was discharge from the emergency room rapid test results, were available 24 hours a day and was performed by a trained provided to the patient. Patients with a negative result were laboratory technician. Patients were offered the test at triage given their results, and the handout was reviewed. Patients and given a form to complete. The form was simple and in- with positive results were counseled and advised they were cluded the reason for the visit, asked about known medical preliminarily positive, and information regarding outpatient problems, and specifically asked HIV status and whether follow-up was provided. The results were discussed by the

J La State Med Soc VOL 166 January/February 2014 29 Journal of the Louisiana State Medical Society

Table 2: Reason for visit to emergency room on day of new HIV diagnosis Shortness of Breath/Cough/Cold 12 (12%) Abscess 7 (7%) Chest Pain 7 (7%) Limb Pain 6 (6%) Abdominal Pain 6 (6%) Neurologic Complaint (numbness/weakness/dizzy) 6 (6%) Headache 4 (4%) Fever 3 (3%) Psych Evaluation/Bizarre Behavior 3 (3%) Flank Pain 3 (3%) HIV test 1 (1%) emergency room staff, either the physician or nurse. All 53%): eight for Pneumocystis jirovecii pneumonia (PCP), and positive samples were sent for a confirmatory Western blot. nine for other types of pneumonia. Table 3 summarizes the A retrospective chart review of adult patients agreeing to a initial clinical and laboratory findings and details of the rapid HIV test at the Emergency Department from February hospital admissions. 2008 through February 2009 was conducted. IRB approval The initial CD4 cell count of patients with a new HIV was obtained prior to data collection. Statistical software diagnosis was available for 71 of the 99 patients. The mean (SPSS 18.0) was used for analysis. CD4 count was 214 cells/mm3 (95% CI 170-258). At diagnosis, 85 (86%) of the patients were referred to an infectious RESULTS disease specialist. The majority of the referrals were to the HIV clinic at the same institution (88%). Fifty-nine patients During the 57,891 patient encounters in the first year of had a documented HIV clinic visit within 12 months follow- institution of the rapid HIV test from February 2008 to Feb- ing their positive test (60%). Fifty-four patients presented ruary 2009, 8,204 patients were tested (14%).14 One hundred to the HIV clinic at ILPH, 25 (46%) within the first month, and thirty-eight patients (1.7%) out of 8,204 patients tested 17 (31%) within one to three months, and the remainder positive for HIV by rapid testing with the Oraquick. Three greater than three months, which represents delayed entry (2%) were false positives, which were not confirmed by into care. Forty-five patients were started on highly active Western Blot. The false positive rate was 0.03%. The majority antiretroviral therapy (45% of the total); the majority, 30 of the rapid tests were performed on oral fluid (89%), which (30%), were started on a fixed-dose combination prepara- became available in April of 2008. Thirty-six (26%) upon tion containing efavirenz, emtricitabine, and tenofovir. At chart review had a previous history of HIV. Ninety-nine of last clinical record, two (2%) of the patients were deceased. the positives were new HIV diagnoses, resulting in a 1.2% One of them went to hospice for cerebral toxoplasmosis prevalence of newly diagnosed HIV in the tested population. and the other one died in the ICU of acute respiratory fail- The demographics of the patients newly diagnosed ure and sepsis. Of the 40 patients not linked to care within with HIV are provided in Table 1. Most of the patients were one year, the majority (21 patients, 53%) were referred to male (69%) and African-American (79%). Very few had any our HIV clinic. Five (13%) were referred elsewhere; three insurance, including Medicaid (23%). The patients presented were referred out of state because the patient lived out of with a broad range of chief complaints, which are listed in state, and two were referred to a community HIV clinic. Table 2. Hypertension was the most common co-morbidity. Of the remaining patients, one patient refused referral, one Fifty-seven (58%) of the newly diagnosed patients had patient went to hospice, and the others (12 patients) were been seen within the past five years in the ILPH system prior not referred. to their diagnosis. The majority of those visits were in the emergency room (41 patients; 71%). Twenty-seven patients DISCUSSION had been seen three or more times in the ILPH system in the five years prior to diagnosis (27%). Only four of the 99 The point prevalence of HIV was 1.2% for this opt-in patients with a new diagnosis of HIV had a previously docu- emergency room-based patient population and was con- mented negative HIV test at ILPH. On initial presentation, sistent with prevalence rates seen in other studies.2 One thirty-three patients were admitted to the hospital (33%). hundred thirty-eight patients tested positive for HIV with The majority was admitted for pneumonia (17 patients, only three false positives; however, 36 had a previous diag-

30 J La State Med Soc VOL 166 January/February 2014 Table 3: Laboratory and clinical outcomes Mean CD4 Count (range) in Cells/mm3 214 [2 to 715] CD4 Count Less Than 200 35 (49%) CD4 Count Less Than 50 19 (27%) Positive RPR 14 (14%) Hepatitis C Antibody Positive 13 (13%) Hepatitis B Surface Antigen Positive 3 (3%) Admission to Hospital 33 (33%) Reason for Admission Opportunistic Infection 14 (44%) PCP 8 (25%) Cerebral Toxoplasmosis 2 (6%) Pneumonia (all types excluding PCP) 9 (28%) Trauma 3 (9%) Meningitis 2 (6%) Median Length of Hospital Stay (range) 5 (1 to 42) Referred to Infectious Disease Specialist 85 (86%) Referred to ILPH HIV Clinic 76 (88%) Referred to Other Clinic 9 (12%) Attended Any HIV Clinic Within 1 Year 59 (60%) Attended ILPH HIV Clinic Within 1 Year 54 (55%) Early Entry to Care (less than 3 months) 42 (78%) Delayed Entry to Care (greater than 3 months) 12 (22%) Started on HAART 45 (45%) Efavirenz/Tenofovir/Emtricitabine 30 (67%) Atazanavir/Ritonavir/Tenofovir/Emtricitabine 7 (16%)

RPR = Rapid Plasma Reagin; PCP = Pneumocystis Jirovecii Pneumonia; ILPH = Interim LSU Public Hosptial New Orleans; HAART = Highly Active Antiretroviral Therapy. nosis of HIV. The false-positive rate was very low (0.03%), The emergency department was an effective location to find compared with the post-marketing surveillance which patients with HIV in this study, but the late stage of disease reported false-positive rates of 0.05% for blood and 0.22% implies that improved access to HIV testing in other venues, for oral fluid,15 especially considering the majority of the while patients are asymptomatic, may detect patients at an tests were performed on oral fluid (89%). Almost half of the earlier stage of the disease. newly diagnosed patients met diagnostic criteria for AIDS The high numbers of new positives found in this (49%), which was a higher percentage than was typically population may be the result of this type of opt-in screening seen among those newly diagnosed in New Orleans, which program since the majority of the patients did not have tradi- was 24%;13 however, this was an emergency room popula- tional risk behaviors. This opt-in program offered tests to all tion, which is more likely to have advanced disease because patients at triage without regard to a clinician’s assessment the patient presented with an acute illness or trauma. This of their risk, which resulted in increased screening of pa- high percentage of patients meeting the criteria for AIDS tients without traditional risk factors. The American College implies late diagnosis and may reflect the lack of access to of Emergency Physicians Board of Directors has determined medical care in this primarily uninsured patient population. HIV testing in the emergency department to be feasible as

J La State Med Soc VOL 166 January/February 2014 31 Journal of the Louisiana State Medical Society

long as it does not interfere with the primary mission and is ies. The use of the Oraquick, which is a rapid antibody test, integrated into the healthcare system with linkage to care,16 precluded the inclusion of any patient with acute HIV in our which this testing program has accomplished. One of the key study. The diagnosis of acute HIV would require clinical components of the rapid testing program at our hospital was suspicion and an HIV viral load test. the 24-hour availability of the test and the rapid turnaround In summary, rapid HIV testing in the emergency depart- of results. In a busy emergency room, rapid turnaround of ment at the Interim LSU Public Hospital in New Orleans test results ensures that patient discharges are not delayed, successfully identified 99 patients with a new diagnosis of and is an important part of physician buy-in of rapid testing. HIV in the first year and linked the majority of these patients In our facility, which is a Level 1 trauma center, the blood to an HIV specialist. bank was most suited for this project because it is staffed by trained technicians 24/7. The patient’s receipt of test ACKNOWLEDGEMENTS results prior to discharge is an important aspect of linkage to care and linkage numbers would likely have been lower We would like to thank the ILPH administration, if results were provided post-discharge. emergency room physicians, and the personnel for their Eighty-six percent of the patients were referred for sub- time and efforts regarding administering the HIV tests, as specialty care, and the majority (60%) of the patients were well as the laboratory personnel for processing the tests seen at the HIV clinic affiliated with the hospital. Most had and the Infection Control personnel for their role in linking early entry to care, defined as entry less than three months patients to care. We would also like to thank the Louisiana from diagnosis (78%). Patients who were referred to other Office of Public Health for providing the funding for rapid HIV clinics or followed up at other HIV clinics were not HIV testing kits. counted in the number of patients linked to care - unless these records were available in the chart at ILPH - because REFERENCES there was no access to records at these outside clinics. This is unlikely to represent a large number of patients as only 1. CDC. HIV in the United States Fact Sheet. July 2010. . were referred out of state because they lived out of state, 2. CDC. Rapid HIV Testing in Emergency Departments--- Three U. and two to a community HIV clinic. This linkage to care S. Sites, January 2005- March 2006. MMWR 2007;56:597-601. is slightly lower than other studies in similar populations, 3. Dieffenbach CW, Fauci A. Universal Voluntary Testing 2,10 and Treatment for Prevention of HIV Transmission. JAMA which ranged from 77% to 88%, but this may reflect the 2009;301:2380-2. population in this study and the passive nature of the link- 4. Paltiel AD, Weinstein MC, Kimmel AD, et al. Expanded Screening age as compared with these other studies. for HIV in the United States—An Analysis of Cost-Effectiveness. More than half of the patients had presented for care N Engl J Med 2005;352:586-95. at ILPH in the past five years, and more than a quarter of 5. Marks G, Crepaz N, Senterfitt JW, Janssen RS. Meta-Analysis of the patients had been seen three or more times in the past High-Risk Sexual Behavior in Persons Aware and Unaware They five years without being tested and diagnosed. This demon- are Infected With HIV in the United States. J Acquir Immune Defic strates significant missed opportunities for early diagnosis. Syndr 2005;39:446-453. 6. CDC. Notice to Readers: Approval of a New Rapid Test for HIV Since there was no general screening in place prior to the Antibody. MMWR 2002;51:1051-1052. initiation of the rapid HIV test in February of 2008, these 7. CDC. Rapid HIV Test Distribution --- United States, 2003—2005. patients were likely not offered testing because they did MMWR 2006;55:673-676. not meet physician-directed testing for either their clinical 8. Kassler WJ, Dillon BA, Haley C, et al. On-site, Rapid HIV Testing picture or their reported risk behaviors. These missed op- with Same-Day Results and Counseling. AIDS 1997; 11:1045-1051. portunities reinforce the importance of opt-out screening 9. Kelen GD, Hexter DA, Hansen KN, et al. Trends in Human as compared with physician directed screening in finding Immunodeficiency Virus (HIV) Infection Among a Patient patients with undiagnosed HIV. Population of an Inner-City Emergency Department:Implications The strengths of this study lie in the large number of for Emergency Department-Based Screening Programs for HIV. Clin Infect Dis 1995;21:867-75 patients diagnosed and the breadth of data on the emer- 10. Lyss SB, Branson BM, Kroc KA, et al. Detecting Unsuspected gency room visit, hospital admission, and laboratory values HIV Infection with Rapid Whole-Blood HIV Test in an Urban on these patients. It is one of the largest studies of its kind Emergency Department. J Acquir Immune Defic Syndr 2007;44:435- and the first in this urban population in New Orleans. The 442. study also provides insight into the population of patients 11. Kelen GD, Shahan JB, Quinn TC. Emergency Department Based missed by physician-directed screening, which were young, HIV Screening and Counseling: Experience with Rapid and African-American men without traditional risk factors. Its Standard Serologic Testing. Ann Emerg Med 1999;33:147-55. limitations are primarily the use of retrospective data, which 12. Louisiana Department of Health and Hospitals, Office of Public Health, HIV/AIDS Program. Louisiana HIV/AIDS Surveillance rely on the physician-documented referral, risk factors, and Quarterly Report, March 31, 2010. Pages 1-39. risk behaviors, which may underestimate the real values. 13. Louisiana Department of Health and Hospitals, Office of Public Another limitation is the lack of an active linkage, which Health, 2007/2008 HIV/AIDS Program Report. Pages 1-90. resulted in lower clinic attendance than seen in other stud-

32 J La State Med Soc VOL 166 January/February 2014 14. LSU Health Care Services Division 2008 Annual Report. . 15. Wesolowski LG, MacKellar DA, Facente SN, et al. Post-marketing Surveillance of OraQuick Whole Blood and Oral Fluid Rapid HIV Testing. AIDS 2006;20:1661-1666. 16. ACEP Board of Directors. HIV Testing and Screening in the Emergency Department. Ann Emerg Med 2007;50:209.

Dr. Richey is with the Infectious Disease Division, Medical University of South Carolina in Charleston. Dr. Carpenter is with the Department of Pulmonary, Critical Care, and Sleep Medicine at the University of South Florida in Tampa. Dr. Barbeau is with the Department of Pathology, Louisiana State University Health Sciences Center in New Orleans. Dr. Hadi is with the Department of Infectious Disease, Immunizations and Refugee Health, Marion County Public Health Department and Indiana University in Indianapolis.

J La State Med Soc VOL 166 January/February 2014 33 Journal of the Louisiana State Medical Society

In Memoriam: Edward S. Connolly, MD 1934-2014

D. Luke Glancy, MD

The Journal of the Louisiana State Medical Society, neurosurgery, and the state of Louisiana lost a friend and leader with the death of Edward S. Connolly on 1 February 2014.

A native of Omaha, Nebraska, Dr. Connolly graduated from Stanford University and then received his medical degree from Creighton University School of Medicine. After completing his neurosurgical training at the University of California, San Francisco, he remained on the faculty there until 1972, when he came to New Orleans as chairman of the Department of Neurosurgery at the Ochsner Clinic, a position he held until 1996. He remained at Ochsner as a senior consultant until his retirement in 2003. A superb and innovative surgeon, he was a kind and caring physician in every way. An excellent mentor, Dr. Connolly was a professor of neurosurgery at both the LSU and Tulane Medical Schools. He was a past president of the American Academy of Neurological Surgeons and of the Louisiana Neurosurgical Society.

Dr. Connolly joined the Editorial Board of the Journal of the Louisiana State Medical Society in 2003. He was the ideal board member, always providing prompt and insightful reviews.

Ed Connolly was a prince. He will be missed by many. The Journal sends its condolences to his wife Elise and their six children and nine grandchildren.

34 J La State Med Soc VOL 166 January/February 2014 Protecting the Private Practice of Medicine

Louisiana’s First Physician-Owned Accountable Care Organization: The Inaugural 90 Days

Sabrina L. Noah

New Orleans nephrologist Dr. to the primary care doctor, which improves quality of care.” Joshua Lowentritt, like many physi- Equally as important physicians benefit from this model, cians, has watched the practice of because ACOs “create a mechanism to capture payment for Medicine be overtaken by laborious the services and the coordination (we) are already provid- reporting requirements, eroding re- ing,” said Dr. Lowentritt. imbursement rates, and a decreasing The ACO model works by ensuring the entire care team ability to spend time providing quality is jointly accountable for the health of their patients by giv- care. In the actual day-to-day care of ing them financial incentives to collaborate and rewarding patients, “physicians are being asked efficiencies. Simply put when an ACO succeeds in both to do more while reimbursements con- delivering high-quality care and spending healthcare dollars tinue to decline,” said Dr. Lowentritt. Dr. Joshua wisely, physicians will share in the savings it achieves for Like most physicians, Dr. Lowen- Lowentritt the Medicare program. Since ACOs are operated through tritt and his partners took steps to seek collaboration, there is a natural check and balance, ensuring out new models of practice that would that a physician’s medical decisions are not based on com- provide physicians with the opportunity to provide the mercial interests, but rather professional medical judgment best care possible for the patient, while simultaneously that puts patients’ interests first. decreasing the growing non-clinical burdens of operating Unlike traditional closed networks, ACOs encourage a practice. “I wanted to find an opportunity to preserve the collaboration and allow both patients and physicians to type of medicine that we have been providing in Louisiana,” access clinicians in a wide scope and seek out the best and said Dr. Lowentritt. most efficient use of their medical dollar. Dr. Lowentritt The Medicare Shared Savings Plan (MSSP), created emphasized that “we didn’t want to lose our independence under the Affordable Care Act, allows physicians to self- as private practitioners.” ACOs allow for independent manage their Medicare patients under a new program practices to work collaboratively without sacrificing their model called an Accountable Care Organization (ACO). autonomy. This rewards physicians who provide high- The MSSP also allows for waivers of anti-trust laws and quality, cost-effective care and benefits patients who can Stark regulations allowing physician ownership of the ACO now access a wide population of practitioners. networks. According to the Kaiser Health Foundation “more Dr. Lowentritt and his 35 physician partners have now than half of all ACO’s are physician-owned and operated.” formed The Louisiana Physicians ACO and will begin car- This new model offers physicians the unique opportunity to ing for approximately 6,000 patients by spring of this year. regain managerial and financial control of a medical system This network of multidisciplinary independent physicians increasingly dominated by managed care systems. will serve patient populations in Hammond, New Orleans, ACOs are built with the primary care provider as the Metairie, and Alexandria and is planning to expand to north linchpin of a patient-centered medical home (PCMH). These Louisiana by the end of next year. entities are comprised of physicians, nurses, and care coor- We will continue to follow Dr. Lowentritt and the Loui- dinators who share the responsibility of providing quality, siana Physicians ACO throughout the next year and check financially responsible, coordinated care. Specially trained in on their progress, hopefully gaining valuable insight on care coordinators, under the direction of a physician, assist this new practice model along the way. the patient with their treatment plan by providing follow- up care, prescription compliance, and tracking health **This is the first installment in a new four-part series outcomes. Dr. Lowentritt and his partners believe the ACO that will report on emerging trends and new practice models in model allows for a “refocusing the healthcare system back medicine.

J La State Med Soc VOL 166 January/February 2014 35 Journal of the Louisiana State Medical Society ECG of the Month

Amaurosis Fugax in a 45-Year-Old Woman

D. Luke Glancy, MD; William P. Abide Jr., MD

Figure: ECG in a 45-year-old woman with amaurosis fugax.

What is your diagnosis?

Explication follows on next page.

36 J La State Med Soc VOL 166 January/February 2014 DIAGNOSIS: Normal sinus rhythm; left atrial enlargement.

The negative component of the P wave in lead V1 is 1 mm (0.1 mV) deep and 0.08 seconds in duration, more than sufficient to meet the criteria of Morris et al. for left atrial 1 enlargement. In addition, P waves in lead II, aVF, and V2-V6 are 0.12 seconds in duration2 and bifid with >0.04 seconds between the two peaks3 – the two defining features of P mitrale. Left atrial enlargement often is the initial, and may be the only, electrocardiographic manifestation of mitral stenosis. In addition, evidence of a systemic embolus, such as amaurosis fugax, in a young or middle-aged woman suggests mitral stenosis, even though its prevalence in the developed world has decreased strikingly over the last half century. This patient had moderately severe mitral stenosis with a valve area of 1.1 cm.2

REFERENCES

1. Morris JJ Jr, Estes EH Jr, Whalen RE, et al. P-wave analysis in valvular heart disease. Circulation 1964;29:242-252. 2. Reynolds G. The atrial electrogram in mitral stenosis. Br Heart J 1953;15:250-258. 3. Thomas P, DeJong D. The P wave in the electrocardiogram in the diagnosis of heart disease. Br Heart J 1954;16:241-254.

Dr. Glancy is a Professor and Dr. Abide is a Fellow in the Sections of Cardiology, Departments of Medicine, Louisiana State University Health Sciences Center and the Interim LSU Hospital, New Orleans.

J La State Med Soc VOL 166 January/February 2014 37 Journal of the Louisiana State Medical Society Radiology Case of the Month

Progressive Slurring of Speech and Difficulty Reading in a 62-Year-Old Male

Chris Stark, BS; Jagan D. Gupta, MD; Tracy Austin, MD; Enrique Palacios, MD; Harold Neitzschman, MD

A 62-year-old male with controlled hypertension, coronary artery disease, and borderline diabetes presented to the emergency room after experiencing a gradual one-month progression of slurring of speech and difficulty reading. The patient maintained his vital signs throughout his ambulance ride to the hospital and was clinically stable at time of arrival to the emergency department.

Figure 1: Axial Figure 2: Axial T1 T1 post-contrast

Figure 3: Figure 4: Axial Coronal T1 gradient echo post-contrast

38 J La State Med Soc VOL 166 January/February 2014 INTERPRETATION OF FINDINGS the prostate is believed to originate from epithelial cells of prostatic ducts and acini, as well as the endothelium of the Figures 2 and 3 demonstrate an intra-axial enhancing prostatic urethra. Neuroendocrine tumors of the prostate lesion within the left temporal lobe with mild effacement of have a much greater tendency to become metastatic than the surrounding sulci, mild mass effect, and no midline shift. adenocarcinomas.5 It is imperative to accurately diagnose Figures 1 and 4 demonstrate an intra-axial complex lesion small cell carcinoma and avoid its common misdiagnosis as containing components of subacute blood and hemosiderin. poorly differentiated adenocarcinoma, as both the prognosis and therapeutic modalities vary greatly.6 FINAL DIAGNOSIS Patients rarely present with neurologic symptoms as the initial manifestation of metastatic prostate cancer. Metastatic small cell cancer of the prostate gland. When spinal and/or brain metastasis does occur, it is most likely the result of late, disseminated disease and/or failure DISCUSSION of diagnosed cancer to respond to hormone-deprivation therapy. Overall, cancer metastasis to the central nervous Prostate cancer is second only to lung cancer as the lead- system (CNS) is rare, and presentation with a solitary brain ing cause of cancer-related deaths in men. Approximately metastasis as the only site of prostate cancer spread is even 1 in 10 men will have a clinical diagnosis of prostate cancer rarer. But, because neurologic complications of metastatic in their lifetime.1 The specific etiology of prostate cancer is prostate cancer require prompt treatment, physicians should unknown. However, a man’s risk of developing prostate consider prostate cancer metastasis in the differential diag- cancer is related to many factors; the primary risk factor nosis of new-onset low back pain or headache in men more being advanced age. Prostate cancer is uncommon in men than 50 years of age.7 Patients can also present with nonfocal younger than 45 but becomes more prevalent after age 50. neurologic symptoms related to intracranial hypertension.9 Thirty percent of men more than 50 years of age, and 70% of The most common intracranial sites of prostate cancer men more than 80 years old will develop prostate cancer.2,3 metastasis are the leptomeninges (67%), cerebrum (25%), Early prostate cancer can be asymptomatic or present and cerebellum (8%).10 Prostate cancer has been shown with symptoms of urinary and/or sexual dysfunction. These to metastasize by following the venous drainage system symptoms include polyuria, dysuria, nocturia, urinary hesi- through the lower paravertebral plexus, or Batson’s plexus; tancy, and hematuria. In addition, because of the prostate’s brain metastases are the result of contiguous spread. Nev- intimate relation to other anatomic structures, such as the ertheless, because of the protective layer of the dura mater, vas deferens, men with prostate cancer may also develop subdural and intraparenchymal metastases from prostate sexual dysfunction, i.e. erectile dysfunction or painful ejacu- cancer are rare. This is in contrast to other primary cancers, lation. Over time, prostate cancer may enlarge and invade such as lung and breast tumors, which are more likely to adjacent organs, or the tumor cells may metastasize via the have intraparenchymal metastases than leptomeningeal bloodstream or lymphatic system. Prostate cancer spreads involvement.7 to the lungs in about 50% of patients with metastatic dis- With brain metastasis, gadolinium-enhanced MRI is ease and to the liver in about 25% of those with metastases. required to exclude or confirm. Compared with CT scanning, Furthermore, 90% of prostatic metastases involve the spine, MRI is more sensitive in detecting multiple metastases, espe- with a predilection for the lumbar spine.4,5 cially at the gray-white junction.11 Treatment options include Initial screening for prostate cancer typically begins at surgical intervention, radiotherapy, hormonal therapy, or age 50. Screening examinations include the digital rectal combinations of the aforementioned. Radiotherapy is the exam (DRE) and the prostate specific antigen (PSA) test. most common treatment for patients with multiple brain Other tests that can be used to directly or indirectly evaluate metastases or leptomeningeal involvement. Though treat- for disease include: transrectal ultrasound, cystoscopy, and ment options are available, brain metastasis from prostate urodynamic tests. Definitive diagnosis of prostate cancer is carcinoma is likely indicative of terminal event due to obtained via tissue sampling through transrectal biopsy or advanced, systemic disease. In addition, leptomeningeal transperineal biopsy. Moreover, to evaluate for metastatic carcinomatosis, the most frequent form of brain metastasis disease, imaging tests, such as CT and bone scans, may be from prostate cancer, has a very poor prognosis. Surgical performed. Ultimately, patients with suspected CNS metas- removal of a solitary lesion can extend survival, but overall, tasis should be promptly evaluated and treated. brain metastasis is associated with a poor prognosis. Unfor- The vast majority of prostate malignancies are adeno- tunately, once prostate cancer has spread to the brain, the carcinomas. However, approximately 4% of prostate cancers one-year survival rate is 18%, with an average survival of exhibit transitional cell morphology and <2% have neuro- 7.6 months.8,12 endocrine characteristics. Neuroendocrine classification in prostatic malignancy includes conventional adenocarci- REFERENCES noma with focal neuroendocrine differentiation, carcinoid and carcinoid-like tumors, and small cell undifferentiated 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. neuroendocrine prostate carcinoma. Small cell carcinoma of CA Cancer J Clin 1999;49:8-31

J La State Med Soc VOL 166 January/February 2014 39 Journal of the Louisiana State Medical Society

2. Seidman H, Mushinski MH, Gelb SK, Silverberg E. Probabilities prostate cancer. Report of 13 cases and critical analysis of the of eventually developing or dying of cancer--United States, 1985. literature. J Exp Clin Cancer Res. 2005 Jun;24(2):203-7. CA Cancer J Clin 1985;35:36-56. 9. Tremont-Lukats IW, Bobustuc G, Lagos GK, Lolas K, Kyritsis 3. Scardino PT, Shinohara K, Wheeler TM, Carter SS. Staging of AP, Puduvalli VK. Brain metastasis from prostate carcinoma: prostate cancer. Value of ultrasonography. Urol Clin North Am The M. D. Anderson Cancer Center experience. Cancer. 2003 Jul 1989;16:713-34 15;98(2):363-8. 4. Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, 10. Lynes WL, Bostwick DG, Freiha FS, Stamey TA. Parenchymal brain et al. Metastatic patterns of prostate cancer: an autopsy study of metastases from adenocarcinoma of prostate. Urology 1986;28:280- 1,589 patients. Hum Pathol 2000;31:578-83. 7. 5. Moshe S, Bernstein Z, Abacioglu U, et al. Small Cell 11. DeAngelis LM. Metastatic disease of the nervous system. Curr (Neuroendocrine) Carcinoma of the Prostate: Etiology, Diagnosis, Treat Options Neurol 1999;1:409-16. Prognosis, and Therapeutic Implications - A Retrospective Study 12. Gupta A, Baidas S, Cumberlin RK. Brain stem metastasis as the of 30 Patients From the Rare Cancer Network. Am J Med Sci only site of spread in prostate carcinoma. A case report. Cancer 2008;336(6):478-488. 1994;74:2516-9 6. Wang W, Epstein JI. Small Cell Carcinoma of the Prostate – A morphologic and Immunohistochemical Study of 95 Cases. Am J Surg Pathol 7. Ramsis, B. Neurologic Complications of Prostate Cancer. American All of the authors on this article are with the Tulane School of Medicine Family Physician 2002;65(9):1834-40. in New Orleans. Mr. Stark is a third-year Medical Student, Dr. Gupta is 8. Salvati M, Frati A, Russo N, Brogna C, Piccirilli M, D’Andrea a second-year Radiology Resident, Dr. Austin is an Intern, Dr. Palacios is a Clinical Professor of Neuroradiology, and Dr. Neitzschman is a G, Occhiogrosso G, Pichierri A, Caroli E. Brain metastasis from Professor of Radiology and Chairman of the Department of Radiology.

40 J La State Med Soc VOL 166 January/February 2014 Clinical Case of the Month

Altered Mental Status and Headache in a Young Man

Faisal Musa, MD; Jorge A. Martinez, MD, JD; Catherine Hebert, MD; Matthew Safley, DO; David Smith, MD; Fred Lopez, MD

INTRODUCTION He had not seen a provider for more than a year and had not taken antiretroviral therapy during this time. His CD4 Central nervous system (CNS) toxoplasmosis can be cell count 18 months earlier was 299 cells/mm3 (Normal a life-threatening disease in patients with human immu- Reference Range is 228-2,290), and CD4% was 18.1%(Normal nodeficiency virus (HIV) infection.1 We describe a case of Reference Range is 37%-63%). a young adult man with acquired immune deficiency syn- Upon admission to the emergency department, his tem- drome (AIDS) who presented with altered mental status perature was 97.3˚F, heart rate 64 beats/minute, blood pres- and headache secondary to toxoplasmosis. sure 120/83 mmHg, respiratory rate 16/minute, and oxygen saturation of 100% on room air. He weighed 52 kilograms. CASE PRESENTATION His height was 167 centimeters. His body mass index was 18.6. On physical examination, he was alert and oriented to A 31-year-old man with advanced human immunode- place and person and was dysarthric. The rest of his physical ficiency virus (HIV) infection presented to the emergency examination revealed no reported abnormalities. department with a chief complaint of worsening confusion His laboratory workup revealed a normal complete for several weeks. He had been having headaches intermit- blood count and comprehensive metabolic panel. His CD4 tently for about a year, which had progressively worsened cell count was 30 cells/mm,3 and CD4% was 5%. His urine over the last month. He denied cough, fever, chills, weak- toxicology test was positive for marijuana and cocaine. A CT ness, weight loss, tremors, or visual disturbances. He had a scan of the brain showed large left frontal and left temporal history of smoking tobacco and marijuana. He lived alone. lesions with edema and a 3.8 cm heterogeneously enhancing Figure 1: An Figure 2: axial T1- T2 FLAIR weighted imaging at a post-contrast slightly higher image with level reveals fat saturation smaller lesions demonstrates in the right an irregularly hemisphere enhancing left (arrowheads). frontal lobe mass (arrow).

J La State Med Soc VOL 166 January/February 2014 41 Journal of the Louisiana State Medical Society

Figure 3: Fused component in the left frontal lobe. There was a midline shift PET-CT images at of 6 mm from the midline to the right. the same level as The patient was initially admitted to the medical inten- Figure 1 show no sive care unit. He was started on dexamethasone to decrease hypermetabolism the cerebral edema, levetiracetam for seizure prophylaxis, in the region of and empiric treatment with leucovorin, sulfadiazine, and the dominant pyrimethamine for possible toxoplasmosis. Of note, he had mass (m). The smaller lesions a positive toxoplasma serology five years prior. MRI of the in Figure 2 brain demonstrated multiple heterogeneously contrast- also were not enhancing lesions throughout both cerebral hemispheres. hypermetabolic. The largest of these lesions measured 4.1 cm x 4.0 cm x 3.5 cm in the left frontal lobe. The lesion and its associated edema resulted in a mass effect with sulcal effacement and intimal shift of the midline to the right side (Figures 1, 2). Rapid plasma regain and serum cryptococcal antigen were negative. A lumbar puncture was not performed due to the increased risk of herniation. After 10 days of treatment with antitoxoplasmosis therapy, he had no change in his neurologic exam. A subsequent positron emission tomography of the brain did not show any significant changes and no areas of increased metabolic Figure 4: Anti- activity (Figure 3). A brain biopsy was performed. The tissue toxoplasma specimens were consistent with toxoplasmosis (Figures 4, 5). immunohisto- With the biopsy demonstrating toxoplasmosis, the pa- chemistry highlighting tient was discharged to complete a course of pyrimethamine, the toxoplasma sulfadiazine, and leucovorin. Antiretroviral therapy was to oocyst (60x). be initiated as an outpatient. DISCUSSION

Epidemiology and Etiology Toxoplasmosis, an infection with a worldwide distribution, is caused by the intracellular protozoan parasite, Toxoplasma gondii. Feline cats are the only animals in which T. gondii can complete its reproductive cycle.2 Following feline ingestion of any form of T. gondii, the parasite infects the gut epithelial cells and reproduces. The feline then ex- cretes infectious oocysts in feces. When non-felines, including humans, ingest T. gondii oocysts, the organisms invade intestinal epithelium and disseminate throughout the body. Figure 5: They then encyst in any type of nucleated cell and can lie Toxoplasma dormant within tissues for the life of the host. There are four oocyst with means of acquiring toxoplasmosis in humans: ingestion of encysted infectious oocysts from the environment (usually from soil toxoplasma contaminated with feline feces); ingestion of tissue cysts in bradyzoites (40x). meat from an infected animal; through vertical transmission from an infected mother to her fetus; or via blood transfusion or organ transplantation from an infected donor.2 Immunocompetent persons with primary infection are usually asymptomatic, but latent infection can persist for the lifetime of the host.3 Seroprevalence rates of toxoplasmosis vary substantially among different countries (eg, approximately 15% in the United States to more than 50% in certain European countries).4 Among HIV-infected patients, seroprevalence of antibodies to T. gondii mirror rates of seropositivity in the general population.5 In patients with

42 J La State Med Soc VOL 166 January/February 2014 AIDS, there is no higher incidence of toxoplasmosis in cat DIAGNOSTIC EVALUATION owners compared to non-cat owners.6 Patients who are HIV-infected with <100 CD4 cells/ A definitive diagnosis of central nervous system toxo- mm3, and are toxoplasma seropositive have an approxi- plasmosis requires a compatible clinical syndrome, identi- mately 30% probability of developing reactivated toxoplas- fication of one or more mass lesions by brain imaging, and mosis in absence of prophylaxis.7, 8 The mechanism by which detection of the organism in a biopsy specimen.4 However, HIV induces susceptibility to toxoplasmosis appears to be the majority of clinicians initially treat a seropositive pa- multifactorial, including depletion of CD4 T cells; impaired tient with compatible symptoms, signs, and imaging for production of IL-2, IL-12, IFN-gamma; and impaired cyto- presumptive TE, reserving a biopsy in those who do not toxic T-lymphocytic activity.9 improve (clinically or radiographically) after two weeks of The introduction of anti-toxoplasma prophylaxis and directed therapy. The vast majority of patients with toxo- potent antiretroviral therapy (ART) has altered the occur- plasma encephalitis are seropositive for anti-toxoplasma IgG rence of toxoplasmic encephalitis.10 In the Multicenter AIDS antibodies.21 Anti-toxoplasma IgM antibodies are usually Cohort Study (MACS), the incidence of CNS toxoplasmosis absent; quantitative IgG antibody titers are not helpful. The decreased from 5.4 per 1,000 people in years 1990 to 1992 to absence of antibodies to toxoplasma makes the diagnosis less 3.8 per 1,000 people in years 1993 to 1995, and 2.2 per 1,000 likely but does not exclude it.4 Magnetic resonance imaging people in years 1996 to 1998.11 (MRI) is more sensitive than computed tomography (CT) for It is much harder to determine the incidence of extra- identifying cerebral toxoplasmosis, which usually presents cerebral toxoplasmosis. Most of the available data is from as multiple, ring-enhancing brain lesions often associated before the introduction of ART and from France, where the with edema.22,23 Thallium single photon emission computed seroprevalence to T. gondii is high. The most prominent risk tomography (SPECT) and positron emission tomography factor for the development of extracerebral toxoplasmosis is (PET) can be useful in distinguishing toxoplasmosis or other advanced immunosuppression (mean CD4 cell counts of 57 infections from CNS lymphoma.24,25 Lymphoma has greater and 58 cells/mm3).12,13 Concurrent CNS disease was present thallium uptake on SPECT and greater glucose and methio- in 41% of patients in the report of 199 extracerebral cases.13 nine metabolism on PET than neurotoxoplasmosis or other infections.26,27 Cerebrospinal fluid (CSF) may demonstrate CLINICAL PRESENTATION a mild mononuclear pleocytosis and elevated protein level. Tachyzoites can occasionally be seen on cytocentrifuged Eighty to ninety percent of acute T. gondii infections cerebrospinal fluid samples stained with Giemsa. Detection in immunocompetent hosts are asymptomatic. When of T. gondii by PCR has demonstrated high specificity (96% symptomatic infection does occur, the most common to 100%) but variable sensitivity (50% to 98%).28,29 Thus, a manifestation is bilateral, symmetrical, non-tender cervical positive PCR result establishes the diagnosis, but a negative lymphadenopathy.14,15 Twenty to thirty percent of symp- test does not rule it out. tomatic patients will have generalized lymphadenopathy. Constitutional symptoms, such as fever, chills, and sweats PROPHYLAXIS AND TREATMENT may be present but are typically mild. Headaches, myalgias, pharyngitis, diffuse non-pruritic maculopapular rash, or Treatment usually consists of a combination of medica- hepatosplenomegaly may also occur. Most immunocompe- tions for six weeks. The regimen of choice is pyrimethamine tent patients have a benign, self-limited course lasting from and sulfadiazine.4,30-32 Patients who are intolerant to sulfa- weeks to months, but rarely longer than a year.16 diazine can take clindamycin.4,33 Alternative regimens for T. gondii usually reactivates in patients with AIDS, most those who do not tolerate more standard regimens include commonly doing so in the CNS leading to cerebral abscesses. trimethoprim-sulfamethoxazole, or pyrimethamine plus Patients with cerebral toxoplasmosis typically present with azithromycin, or pyrimethamine plus atovaquone, or sulfa- headache, confusion, and fever.6 This disease is an impor- diazine plus atovaquone, or atovaquone.4,34,35 All pyrimeth- tant cause of focal brain lesions in HIV-infected patients.8,17 amine-containing regimens should also include leucovorin Characteristically, toxoplasma-associated encephalitis has (folinic acid) to prevent drug-induced hematologic toxicity. a subacute onset with focal neurologic abnormalities fre- Adjunctive corticosteroids should be used for patients with quently accompanied by headache, altered mental status, radiographic evidence of midline shift, signs of critically el- and fever.18,19 The most common focal neurologic signs are evated intracranial pressure, or clinical deterioration within motor weakness and speech disturbances. Patients can also the first 48 hours of therapy.36 Anticonvulsants should be ad- present with seizures, cranial nerve abnormalities, visual ministered to patients with a history of seizures but should field defects, sensory disturbances, cerebellar dysfunction, not be given routinely for prophylaxis to all patients with meningismus, movement disorders, and neuropsychiatric the presumed diagnosis of CNS toxoplasmosis.4 Immune manifestations.18,19 Toxoplasmosis rarely presents as a rap- reconstitution inflammatory syndrome (IRIS) can lead to idly fatal form of diffuse encephalitis.20 a paradoxical worsening of symptoms with development of worsening edema surrounding brain lesions as CD4 cell counts rapidly improve.37-39 Management of IRIS includes

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continuing treatment of toxoplasmosis and HIV and increas- 13. Rabaud C, May T, Amiel C, et al. Extracerebral toxoplasmosis in ing the dose of steroids as needed to control symptoms. patients infected with HIV. A French National Survey. Medicine After six weeks of treatment, secondary prophylaxis (Baltimore) 1994; 73:306-314. is instituted and can be safely stopped once the patient re- 14. Remington JS. Toxoplasmosis in the adult. Bull N Y Acad Med 1974; 50:211-227. covers and CD4 has been consistently >200/ul for at least 15. McCabe RE, Brooks RG, Dorfman RF, Remington JS. Clinical 4 six months on antiretroviral therapy. It usually consists of spectrum in 107 cases of toxoplasmic lymphadenopathy. Rev Infect the same regimen but with lower doses of pyrimethamine, Dis 1987; 9:754-774. sulfadiazine, and leucovorin. Alternative regimens include 16. O’Connell S, Guy EC, Dawson SJ, et al. Chronic active clindamycin, pyrimethamine, and leucovorin, or atova- toxoplasmosis in an immunocompetent patient. J Infect 1993; quone with or without pyrimethamine, or atovaquone with 27:305-310. sulfadiazine.4,33,40,41 17. Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Primary prophylaxis is indicated for patients with Infect Dis. 1992 Aug;15(2):211-222. 18. Navia BA, Petito CK, Gold JW, Cho ES, Jordan BD, Price RW. HIV and CD4 counts <100 cells/mm3 who are T. gondii Cerebral toxoplasmosis complicating the acquired immune 4,42 4 IgG-positive. The preferred agent is TMP-SMX. Other deficiency syndrome: clinical and neuropathological findings in 35 options are dapsone plus pyrimethamine or atvaquone. 27 patients. Ann Neurol. 1986 Mar;19(3):224-238. Primary prophylaxis may be discontinued if CD4 count is 19. Renold C, Sugar A, Chave JP, Perrin L, Delavelle J, Pizzolato G, greater than 200 cells/mm3 for more than three months.4 Burkhard P, Gabriel V, Hirschel B. Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome. Medicine REFERENCES (Baltimore). 1992 Jul;71(4):224-239. 20. Gray F, Gherardi R, Wingate E, Wingate J, Fenelon G, Gaston A, Sobel A, Poirier J. Diffuse “encephalitic” cerebral toxoplasmosis 1. Cohen BA. Neurologic manifestations of toxoplasmosis in AIDS. in AIDS. Report of four cases. J Neurol. 1989 Jul;236(5):273-277. Semin Neurol. 1999;19(2):201–211. 21. Luft BJ, Brooks RG, Conley FK, et al. Toxoplasmic encephalitis in 2. Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma gondii: from patients with acquired immune deficiency syndrome. JAMA 1984; animals to humans. Int J Parasitol 2000; 30:1217-1258. 252:913-317. 3. Jones JL, Kruszon-Moran D, Sanders-Lewis K, Wilson M. 22. Levy RM, Mills CM, Posin JP, et al. The efficacy and clinical impact Toxoplasma gondii infection in the United States, 1999 2004, of brain imaging in neurologically symptomatic AIDS patients: decline from the prior decade. Am J Trop Med Hyg 2007; 77:405-410. a prospective CT/MRI study. J Acquir Immune Defic Syndr 1990; 4. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention 3:461-471. and treatment of opportunistic infections in HIV-infected adults 23. Ciricillo SF, Rosenblum ML. Use of CT and MR imaging to and adolescents: recommendations from CDC, the National distinguish intracranial lesions and to define the need for biopsy Institutes of Health, and the HIV Medicine Association of the in AIDS patients. J Neurosurg 1990; 73:720-724. Infectious Diseases Society of America. MMWR Recomm Rep 2009; 24. O’Doherty MJ, Barrington SF, Campbell M, et al. PET scanning 58:1-207. and the human immunodeficiency virus-positive patient. J Nucl 5. Falusi O, French AL, Seaberg EC, et al. Prevalence and predictors Med 1997; 38:1575-1583. of Toxoplasma seropositivity in women with and at risk for human 25. Lorberboym M, Wallach F, Estok L, et al. Thallium-201 retention immunodeficiency virus infection. Clin Infect Dis 2002; 35:1414- in focal intracranial lesions for differential diagnosis of primary 1417. lymphoma and nonmalignant lesions in AIDS patients. J Nucl Med 6. Wallace MR, Rossetti RJ, Olson PE. Cats and toxoplasmosis risk 1998; 39:1366-1369. in HIV-infected adults. JAMA 1993; 269:76-77. 26. Miller RF, Hall-Craggs MA, Costa DC, et al. Magnetic resonance 7. San-Andrés FJ, Rubio R, Castilla J, et al. Incidence of acquired imaging, thallium-201 SPET scanning, and laboratory analyses immunodeficiency syndrome-associated opportunistic diseases for discrimination of cerebral lymphoma and toxoplasmosis in and the effect of treatment on a cohort of 1115 patients infected AIDS. Sex Transm Infect 1998; 74:258-264. with human immunodeficiency virus, 1989-1997. Clin Infect Dis 27. Skiest DJ, Erdman W, Chang WE, et al. SPECT thallium-201 2003; 36:1177-1185. combined with Toxoplasma serology for the presumptive 8. Porter SB, Sande MA. Toxoplasmosis of the central nervous system diagnosis of focal central nervous system mass lesions in patients in the acquired immunodeficiency syndrome. N Engl J Med 1992; with AIDS. J Infect 2000; 40:274-281. 327:1643-1648. 28. Cinque P, Scarpellini P, Vago L, et al. Diagnosis of central nervous 9. Cohen O, Wiessman D, Fauci AS. The Immunopathogenesis system complications in HIV-infected patients: cerebrospinal fluid of HIV Infection. In: Paul WE ed. Fundamental Immunology. analysis by the polymerase chain reaction. AIDS 1997; 11:1-17. Philadelphia: Lippincott-Raven 1999:1455-509. 29. Mesquita RT, Ziegler AP, Hiramoto RM, et al. Real-time 10. Jones JL, Roberts JM. Toxoplasmosis hospitalizations in the United quantitative PCR in cerebral toxoplasmosis diagnosis of Brazilian States, 2008, and trends, 1993-2008. Clin Infect Dis 2012; 54:e58-61. human immunodeficiency virus-infected patients. J Med Microbiol 11. Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller 2010; 59:641-647. EN, Becker JT, Cohen B, McArthur JC; Multicenter AIDS Cohort 30. Dannemann B, McCutchan JA, Israelski D, et al. Treatment of Study. HIV-associated neurologic disease incidence changes:: toxoplasmic encephalitis in patients with AIDS. A randomized trial Multicenter AIDS Cohort Study, 1990-1998. Neurology. 2001 Jan comparing pyrimethamine plus clindamycin to pyrimethamine 23;56(2):257-260. plus sulfadiazine. The California Collaborative Treatment Group. 12. Belanger F, Derouin F, Grangeot-Keros L, Meyer L. Incidence Ann Intern Med 1992; 116:33-34. and risk factors of toxoplasmosis in a cohort of human 31. Nath A, Sinai AP. Cerebral Toxoplasmosis. Curr Treat Options immunodeficiency virus-infected patients: 1988-1995. HEMOCO Neurol 2003; 5:3-12. and SEROCO Study Groups. Clin Infect Dis 1999; 28:575-581.

44 J La State Med Soc VOL 166 January/February 2014 32. Luft BJ, Hafner R, Korzun AH, et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team. N Engl J Med 1993; 329:995-1000. 33. Katlama C, De Wit S, O’Doherty E, et al. Pyrimethamine- clindamycin vs. pyrimethamine-sulfadiazine as acute and long- term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996; 22:268-275. 34. Jacobson JM, Hafner R, Remington J, et al. Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 2001; 15:583-589. 35. Kovacs JA. Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. The NIAID-Clinical Center Intramural AIDS Program. Lancet 1992; 340:637. 36. Benson CA, Kaplan JE, Masur H, et al; CDC; National Institutes of Health; Infectious Diseases Society of America. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. [published erratum appears in MMWR Morb Mortal Wkly Rep 2005;54:311]. MMWR Recomm Rep 2004;53:1–112. 37. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 2000; 133:447-454. 38. Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 2006; 57:167-170. 39. Tremont-Lukats IW, Garciarena P, Juarbe R, El-Abassi RN. The immune inflammatory reconstitution syndrome and central nervous system toxoplasmosis. Ann Intern Med 2009; 150:656-657. 40. Torres RA, Weinberg W, Stansell J, et al. Atovaquone for salvage treatment and suppression of toxoplasmic encephalitis in patients with AIDS. Atovaquone/Toxoplasmic Encephalitis Study Group. Clin Infect Dis 1997; 24:422-429. 41. Katlama C, Mouthon B, Gourdon D, et al. Atovaquone as long- term suppressive therapy for toxoplasmic encephalitis in patients with AIDS and multiple drug intolerance. Atovaquone Expanded Access Group. AIDS 1996; 10:1107-1112. 42. Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000; 342:1416-1429.

Dr. Musa is a fourth-year Resident in Internal Medicine-Pediatrics at LSU School of Medicine in New Orleans. Dr. Martinez is a Professor and Program Director of the Internal Medicine and Emergency Medicine-Internal Medicine training programs at LSU Health Sciences Center in New Orleans. Dr. Hebert is an Associate Professor and Associate Program Director of the Internal Medicine training program at LSU Health Sciences Center in New Orleans. Dr. Safley is a fourth-year resident in Pathology and Chief Resident at LSU School of Medicine in New Orleans. Dr. Smith is an Assistant Professor at LSU School of Medicine in New Orleans, Department of Radiology. Dr. Lopez is the Richard Vial Professor of Medicine and Vice Chair in the Department of Medicine at LSU School of Medicine in New Orleans, Louisiana.

J La State Med Soc VOL 166 January/February 2014 45 Journal of the Louisiana State Medical Society Pathology Image of the Month

Altered Mental Status, Alcohol Abuse, and Hyperammonemia

Theresa Nuttli, MD; Robin R. McGoey, MD

A 74-year-old woman with a past medical history of diabetes, hypertension, and alcohol abuse was brought to the emergency department and subsequently admitted to the intensive care unit with an altered mental status and weakness. Laboratories revealed acute renal failure (BUN 15 mg/dL, creatinine 2.5 mg/dL), elevated serum transaminase (AST of 83 IU/L), hyperammonemia (187 ug/dL), and marked normocytic anemia requiring transfusion of three units of packed red cells (hemoglobin 4.3 g/dL; hematocrit 13.1%). Blood ethanol level at the time of admission was <5 mg/dL, and full urine toxicology was negative. Alcohol abuse was reported to consist of, on average, “one pint of gin per day.” Her hospital course was nine days and included complete inotropic blood pressure support and intubation. On the ninth day, she was declared dead, and authorization for an unrestricted autopsy was granted by the coroner. At autopsy, two liters of serous ascitic fluid was drained from the peritoneal cavity, and non-ruptured, distended varices were identified at the gastroesophageal junction. Additional findings included changes compatible with hypertensive cardiovascular disease, including hypertrophy of the interventricular cardiac septum and glomerulosclerosis along with renal atrophy. The liver weighed 1,300 grams (normal 1,475 gm ± 362) and was markedly discolored yellow-tan. Its parenchyma was more firm than usual. Representative microscopic sections from the decedent’s liver are shown in the image below.

What are the pink inclusions seen within the hepatocytes’ cytoplasm, and with what liver diseases are they associated?

Figure 1: (A - left) Liver cells showing eosinophilic twisted rope appearing Mallory-Denk bodies in the hepatocyte cytoplasm, hovering around the cell’s nucleus (hematoxylin-eosin, original magnification x40). (B - right) Immunohistochemistry with an anti- pan cytokeratin antibody showing strong staining of Mallory-Denk bodies (original magnification x40).

46 J La State Med Soc VOL 166 January/February 2014 DIAGNOSIS: Mallory-Denk bodies (a.k.a. Mallory’s hya- tributed to an alcohol-related metabolic insult to the liver, line) – seen most commonly in alcoholic liver disease. MDBs can also be seen within the hepatocyte cytoplasm in Wilson disease, primary biliary cirrhosis, non-alcoholic DISCUSSION steatohepatitis (NASH), alpha-1-antitrypsin (A1AT) deficiency, porphyria, and morbid obesity.8 By contrast, MBDs Mallory-Denk bodies (MDBs) are eosinophilic cyto- have not been seen in association with viral hepatitis, acute plasmic inclusions in liver cells that are characteristic of cholestasis, or with the majority of hepatotoxic injuries. As alcoholic liver disease. They are composed primarily of such, the prevailing thought is that MDBs signal chronic cytokeratin intermediate filaments (IF) complexed with injury and are identifiable rather late in the course of disease other proteins such as ubiquitin and p62.1,2 Other widely after oxidative and other stresses have been incurred over recognized IF inclusion body diseases include Alzheimer’s some time.6 (the neurofibrillary tangle) and Parkinson (Lewy bodies) The usefulness for the pathologist of finding MDBs on disease. MDBs, however, are the most prevalent IF-related liver biopsy related to discriminating between the diagnoses aggregates.3 IF cytokeratins function to maintain structural of steatosis (a.k.a. “fatty liver disease”) due to either alcohol polarity and provide an intracellular scaffold that helps or due to a cryptogenic cause, as would be the case in NASH, resist forces applied to the cell. In certain disease states, has attracted a good deal attention in the literature. The fre- liver cytokeratin production can be altered and leads to quency of MDBs in steatosis is believed to be approximately cytokeratin misfolding. Such misfolding causes aberrant 40% by routine H&E and up to 70% if immunohistochemi- aggregation and accumulation of the proteins within the cal stains are utilized.9 Though the literature fails to reach hepatocyte cytoplasm, such that they are rendered micro- a consensus on their frequency, specifically in NASH, with scopically visible as MDBs.4,5 reports that range from 10-70% of cases, there does seem to With routine hematoxylin and eosin (H&E) staining, be agreement that the MDBs in NASH are smaller in number, MDBs take on an eosinophilic, twisted-rope-appearance. less well-developed in their appearance, and virtually absent Though in the hepatocyte cytoplasm, they tend to hover in pediatric cases.10-12 As such, MDBs that are abundant and around the cell’s nucleus. In the case presented here, they well-developed implicitly favor an alcohol-related etiology were widely distributed and diffusely present throughout all when seen in association with steatosis on histopathologic hepatic zones; a representative image from autopsy demon- liver biopsy. strates several liver cells with prominent ropey inclusions in The clinical and prognostic significance of MDBs is yet a perinuclear location (Figure 1a). By immunohistochemical to be clearly understood. Several animal models, including staining with an anti-pan cytokeratin antibody, the MDBs transgenic mice, and continued research efforts effectively are further highlighted (Figure 1b). continue to provide essential information about their patho- Intracytoplasmic, intrahepatic inclusions visible on genesis and the cells that contain them. For example, such H&E must also prompt the pathologist to consider the fol- cells remain viable and capable of cellular division.13 Cells lowing: intracytoplasmic hyaline bodies (IHBs), ground with MDBs are relatively more leukotactic and induce neu- glass inclusions, glycogen bodies, A1AT droplets, and me- trophilic attraction to their surrounding tissue.14 And, finally, gamitochondria. The size and morphology of the inclusion, MDB accumulation appears reversible such that, in the the clinical context of the patient, and, on occasion, use of mouse model, MDBs virtually disappear from injured he- additional special staining modalities, usually makes the patocytes during the recovery phases of experimentation.15 distinction between the various bodies a straightforward Alcohol-related diseases are the third most common process.6 MDBs-like inclusions with similar morphology preventable cause of death in the United States, accounting but different composite proteins have also rarely been seen for approximately one death every seven minutes.16 The in cells other than hepatocytes, such as type 2 pneumocytes most important risk factor for the development of alcoholic and trophoblast cells. At the present time, it is currently un- liver disease is the total amount of alcohol consumed.5 Ac- clear why hepatocytes, as contrasted with other cell types, cording to the Dietary Guidelines for Americans, drinking in are endowed with such a relative ability to accumulate moderation is defined as no more than one drink per day inclusion bodies.6 for women and no more than two drinks per day for men The association of MDBs with alcoholic hepatitis was where a standard drink contains 12 grams of alcohol.17 Com- initially reported in 1911.7 Though most commonly at- parisons of what constitutes a standard drink are shown in

Table 1: What constitutes a standard drink?18 Type of drink Amount in ounces Alcohol content in grams Wine 5 12 Beer 12 12 Liquor (80 proof) 1.5 12

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Table 1.18 And, for the risk of alcohol-related liver disease, 1994; 20:1061-1077. recent studies have shown that the risk begins at 30 grams 9. Ray MB. Distribution patterns of cytokeratin antigen determinants of ethanol per day.19 By report, the decedent in the current in alcoholic and nonalcoholic liver diseases. Hum Pathol 1987;18:61- case ingested “a pint of gin” each day. With conversion, this 66. 10. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:3- translates into roughly 16 ounces of liquor of daily use or 10 20. times the amount that defines moderate drinking. 11. Brunt EM. Non alcoholic fatty liver disease in: AD Burt, BC Diagnosing alcoholic liver disease can be a challenge Portmann, LD Farrell (Eds.), McSween’s Pathology of the Liver, for clinicians. Physical and laboratory findings are often Churchill Livingstone Elsevier, 2007 nondiagnostic, especially in patients with early alcoholic 12. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and liver disease. Patients commonly deny alcohol abuse and obesity: an autopsy study with analysis of risk factors. Hepatology frequently underreport alcohol consumption. Therefore, 1990;12:1106-1110. clinicians must have a low threshold of suspicion for alcohol 13. Denk H, Frank WW, Kerkaschki D et al. Mallory bodies in experimental animals and man. Int Rev Exper Pathol 1979; 20:77- abuse and rely on indirect evidence such as information 121. from family, questionnaires, or observation of physical, 14. Peters M, Liebman HA, Tong MJ et al. Alcoholic hepatitis: 5 social, and psychological consequences of abuse. As clini- granulocyte chemotactic factor form Mallory body stimulated cians may utilize liver biopsy information to help make human peripheral blood mononuclear cells. Clin Immunol clinicopathologic correlates about patients, it is important for Immunopathol 1983; 28:418-430. them to consider whether or not MDBs were demonstrated 15. Denk H, Franke WW. Rearrangement of the hepatocyte along with steatosis, whether histologic staining was via the cytoskeleton after toxic damage: involution, dispersal and customary H&E or required use of immunohistochemical peripheral accumulation of Mallory body material after drug modalities, and whether there were an abundance of or a withdrawl. Dur J Cell Biol 1981;23:241-249 16. http://www.cdc.gov/injuryresponse/alcohol-screening paucity of either vague or well-established forms of intra- (Accessed on October 26, 2013). cytoplasmic MBDs. By not only adding these descriptive 17. U.S. Department of Agriculture and U.S. Department of Health features to the pathologist’s report, but also by increasing and Human Services. Dietary Guidelines for Americans, 7th the clinician’s awareness of their meaning, the level of index Edition, Washington, DC: US Government Printing Office; 2010, of suspicion for whether chronic alcohol usage has served p. 30–32. to play a role in the liver derangement being demonstrated 18. http://pubs.niaaa.nih.gov/publications/ RethinkingDrinking may effectively be enhanced. (Accessed on October 26, 2013). 19. Bellentani S, Saccoccio G, Costa G, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos ACKNOWLEDGEMENTS Study Group. Gut. 1997;41:845–850.

The authors would like to gratefully acknowledge the support of the Orleans Parish Coroner’s Office: Dr. Frank Minyard and Chief Investigator John Gagliano for providing In the Department of Pathology at Louisiana State University School of the case material for this report. Medicine in New Orleans, Dr. Nuttli is a third-year Pathology Resident and Dr. McGoey is an Associate Professor of Pathology and Residency Program Director. REFERENCES

1. Franke WW, Denk H, Schmid M et al. Ultrastructural, biochemical and immunologic characterization of Mallory bodies in livers of griseofulvin treated mice. Lab Invest 1979;40:207-220. 2. Denk H, Krepler E, Lackinger U, et al. Immunological and biochemical characterization of the keratin related component of Mallory bodies: a pathological pattern of hepatocytic cytokeratins. Liver 1982;2:165-175. 3. Strnad P, Zatloukal K, Stumptner C et al. Mallory Denk bodies: lessons learned from keratin containing hepatic inclusion bodies. Bio Biophsy Acta 2008;1782:764-774. 4. Crawford JM. Histologic findings in alcoholic liver disease. Clin Liver Dis 2012;16: 699. 5. O’Shea RS, Dasarathy S, McCullough AJ, et al. Alcoholic liver disease. Hepatology 2010; 51:307. 6. Zatloukal K, French SW, Stumptner C et al. From Mallory to Mallory-Denk bodies: what, how and why? Exper Cell Res 2007:2033-2049. 7. Mallory F. Cirrhosis of the liver. Five different types of lesions from which it may arise. Bul Johns Hopkins Hosp 1911;22:69-75. 8. Jenson K, Gluud C. The Mallory body: morphological, clinical and experimental studies (Part 1 of a literature survey). Hepatology

48 J La State Med Soc VOL 166 January/February 2014 Editor Volume 166, Number 2 • March/April 2014 Established 1844 D. LUKE GLANCY, MD

Associate Editor L.W. JOHNSON, MD

EDITORIAL BOARD MURTUZA J. ALI, MD David H. Ballard, MS 50 Elbow Synovium as the Initial Site of Colon Adenocarcinoma RONALD AMEDEE, MD Brett M. Cascio, MD Metastasis: Diagnosis by Arthroscopic Biopsy SAMUEL ANDREWS, II, MD BOB BATSON, MD Guillermo Sangster, MD 53 Celiacomesenteric Trunk: A Rare Anatomical Variation With Potential EDWIN BECKMAN, MD Sandra Ramirez, MD Clinical and Surgical Implications GERALD S. BERENSON, MD Carlos Previgliano, MD C. LYNN BESCH, MD Aya Al Asfari, MD JOHN BOLTON, MD Alireza Hamidian Jahromi, MD MICHELLE BOURQUE, JD Alberto Simoncini, MD JAMES N. BRAWNER, III, MD BRETT CASCIO, MD Oluwayemisi Ojemakinde, MD 56 Radiological Evolution of Relapsing Polychondritis QUYEN CHU, MD Threta Reddy, MD GUSTAVO A. COLON, MD Carlos Previgliano, MD RICHARD COULON, MD Guillermo Sangster, MD LOUIS CUCINOTTA, MD Adam Welliko, MD VINCENT A. CULOTTA, JR., MD Eduardo Gonzalez-Toledo, MD JOSEPH DALOVISIO, MD NINA DHURANDHAR, MD Brian Gelpi, MD 60 Bilateral Ultrasound-Guided Supraclavicular Block in a Patient With JAMES DIAZ, MD, MPH & TM, Dr. PH Pavan R. Telang, MD Severe Electrocution Injuries of the Upper Extremities JOHN ENGLAND, MD Christian G. Samuelson, MD JULIO FIGUEROA, MD Craig S. Hamilton, MD ELIZABETH FONTHAM, MPH, Dr. PH Seth Billiodeaux, MD EDWARD FOULKS, MD HENRY G. HANLEY, MD Terrell Caffery, MD 63 Plasmacytoma Presenting as Missing Rib on Chest Film: A Case ELIAS B. HANNA, MD Matthew Foy, MD Report and Review of the Literature LYNN H. HARRISON, JR., MD ROBERT HEWITT, MD Mohammad Kazem Fallahzadeh, MD 67 Mucinous Cystic Neoplasm of Pancreas in a Male Patient: A MICHAEL HILL, MD Gazi B. Zibari, MD, FACS, FICS Case Report and Review of the Literature LARRY HOLLIER, MD Greg Wellman, MD JOHN HUNT, MD Sophia T. Abdehou, MD BERNARD JAFFE, MD Hosein Shokouh-Amiri, MD, FACS, FICS NEERAJ JAIN, MD TRENTON L. JAMES, II, MD Crystal P. Le, BS 70 Sphenoid Sinus Dehiscence as a Risk For Visual Consequences in an KEVIN KRANE, MD Alejandra A. Valenzuela, MD Immunocompromised Patient MAUREEN LICHTVELD, MD, MPH Michael Rosenberg, MS FRED A. LOPEZ, MD Laveil Allen, MD F. BROBSON LUTZ, JR., MD Enrique Palacios, MD, FACR DAVID MARTIN, MD JORGE A. MARTINEZ, MD, JD Sabrina L. Noah 73 Protecting the Private Practice of Medicine ELIZABETH MCBURNEY, MD ELLEN MCLEAN, MD NORMAN E. MCSWAIN, JR., MD REINHOLD MUNKER, MD Departments DAVID MUSHATT, MD JOSEPH NADELL, MD Manpreet Singh, MD 75 ECG OF THE MONTH HAROLD R. NEITZSCHMAN, MD Paul A. LeLorier, MD Unexpected Atrioventricular Conduction in High-Grade STEVE NELSON, MD Murat M. Celebi, MD Atrioventricular Block NORA OATES, MD D. Luke Glancy, MD DONALD PALMISANO, MD, JD, FACS PATRICK W. PEAVY, MD Bruce Bordlee Jr., BS 78 RADIOLOGY OF THE MONTH ROBERTO QUINTAL, MD Andrew Oncale, BS 49-Year-Old Female With an Anterior Mediastinal Mass RAOULT RATARD, MD, MS, MPH & TM Jonathan Stone, MD ROBERT RICHARDS, MD Enrique Palacios, MD DONALD RICHARDSON, MD Harold Neitzschman, MD FRANK A. RIDDICK, JR., MD WILLIAM C. ROBERTS, MD Lee S. Engel, MD, PhD, FACP 81 CLINICAL CASE OF THE MONTH DONNA RYAN, MD William Davis, MD, FACP Abstracts From the Louisiana American College of Physicians JERRY ST. PIERRE, MD Associates Meeting CHARLES SANDERS, MD OLIVER SARTOR, MD Robin R. McGoey, MD 92 PATHOLOGY IMAGE OF THE MONTH CHARLES SCHER, MD William P. Newman, MD Sudden Unexplained Death in a Young Adult With Known Alcohol RICHARD SPECTOR, MD Abuse JACK P. STRONG, MD PRAMILLA N. SUBRAMANIAM, MD Erratum KEITH VAN METER, MD DIANA VEILLON, MD J La State Med Soc. 2012 Nov-Dec;164(6):315-9. HECTOR VENTURA, MD CHRIS WINTERS, MD The French connection: Drs. Jean-Charles Faget and Edmond Souchon, the first Americans to achieve the rank of “Internes des Hopitaux des Paris” GAZI B. ZIBARI, MD (IHP).

Phillips, J; Seguy, B.

Erratum in: J La State Med Soc. 2014 March-April;166(2):49. Phillips, J [corrected to include Seguy, B].

PMID: 23431673 [PubMed - indexed for MEDLINE] Journal of the Louisiana State Medical Society

Elbow Synovium as the Initial Site of Colon Adenocarcinoma Metastasis: Diagnosis by Arthroscopic Biopsy

David H. Ballard, MS; Brett M. Cascio, MD

An acutely painful and swollen isolated joint has a broad differential. We present the case of an elderly male with four-month progressive, painful swelling of the right elbow. After an initial workup for inflammatory arthropathies was nondiagnostic and a trial of conservative management failed to relieve his pain, a diagnostic arthroscopy was performed. Biopsy revealed metastatic colon adenocarcinoma isolated to the synovial tissue of the elbow. This case provides an example of the presentation and progression of synovial metastasis from a visceral cancer and can potentially guide physicians in the diagnosis and management of similar cases.

INTRODUCTION Radiographs showed early arthritic change with a small olecranon spur. Magnetic resonance imaging (MRI) showed Unilateral joint pain has many potential etiologies, rare- hypertrophic synovitis (approximately 2 cm thickness), ly including metastatic cancer. Metastasis to the joint may humeral and ulnar erosions, inflammation of the common involve bone, cartilage, or synovial tissue. Synovial metasta- extensor tendon, and edema in both the olecranon bursa sis is often unilateral to a single joint and may mimic the pre- and synovial capsule. This imaging was suggestive of an sentation of inflammatory or autoimmune arthropathies.1-3 inflammatory arthropathy. Hematologic workup showed Imaging usually reveals nonspecific signs such as synovitis. no evidence of systemic inflammation – complete blood Definitive diagnosis requires histopathologic examination count, C-reactive protein, and erythrocyte sedimentation of synovial fluid or tissue, and this can be accomplished by rate were all within normal limits. Serum was negative for joint aspiration or arthroscopic biopsy.4,5 Even with prompt rheumatoid factor. Elbow aspiration yielded sanguineous, diagnosis and aggressive surgical or anti-neoplastic therapy, nonpurulent fluid with no evidence of crystals, organisms, the prognosis of synovial metastasis is poor with an average or atypical cytology. Initial management included compres- survival of less than six months.1-3 We present a rare case of sion wrapping, posterior splint immobilization, physical colon adenocarcinoma metastasis to the synovium of the therapy, and analgesic medication. right elbow that may serve as an example for diagnosis and The patient responded well to the immobilization and management of suspected synovial metastasis. frequent physical therapy sessions (five days/week) – his pain decreased, and range of motion increased. However, CASE REPORT four weeks post-presentation, he experienced spontaneous recurrence of severe elbow pain. MRI revealed ulnar nerve A 79-year-old white male presented with a four-month compression with worsening hypertrophic synovitis and history of progressive right elbow pain and swelling. The bursitis (Figure 1). Arthroscopy was recommended and patient denied trauma, and the pain was not relieved by scheduled. nonsteroidal anti-inflammatories (NSAIDs). Pertinent Arthroscopy revealed diffuse synovitis and intra- history included surgical resection of the sigmoid colon articular nodular tissue. The synovium and olecranon bursa for Stage IIA (T3N0M0) adenocarcinoma 19 months prior. were biopsied. Intra-articular synovial adenocarcinoma was The patient refused postsurgical chemotherapy. Physical found and confirmed to be of colorectal origin being posi- examination revealed a swollen and erythematous right tive for both CDX-2 and CK20. Surgery was halted upon elbow with pitting edema. Range of motion (ROM) was discovery of metastasis. Following uncomplicated postop- limited by pain. Flexion-extension was 60 to 90 degrees, and erative recovery, imaging for metastasis revealed localized pronation-supination was very limited. Sensory and motor synovial involvement with no other local tissue or systemic nerves were intact. involvement. Mutation analysis of the metastatic tumor

50 J La State Med Soc VOL 166 March/April 2014 Figure 1: Sagittal (left) and axial (right) MRI of right elbow revealing widespread hypertrophic synovitis, reducing intra-articular volume and compressing adjacent structures such as the ulnar nerve. was negative both EGFR and KRAS. The chemotherapy is typically aggressive and often presents with concurrent regimen of folinic acid, fluorouracil, oxaliplatin (FOLFOX), bone and soft tissue involvement. The average post-diag- and cetuximab was initiated. Localized radiation therapy to nosis survival time is less than six months.1,2 the right elbow was also incorporated in the treatment plan. Synovial metastasis usually presents as an acute-to- Four months post-arthroscopy, a new lung mass subacute joint pain not relieved by NSAIDs or narcotics. developed. Seven months post-arthroscopy, the patient The knee is by far the most common site of synovial metas- presented with recalcitrant elbow pain. Physical exam re- tasis (>50%). The lung is the most common site of primary vealed cachexia, wrist drop, and severely diminished ROM. disease, followed by the colon. From both sources, the his- Radiographs revealed pathologic fracture of the humerus, topathology is most commonly adenocarcinoma. Synovial and trans-humeral amputation was performed three weeks metastasis from the breast is extremely rare, and prostatic later. Pathologic examination of the limb showed a 9.7 cm metastasis has not been reported.1,2 Investigation of whether mass of the synovium, which spread to the distal humerus, lung and colon cancers have a predilection for synovial tis- proximal ulna, proximal radius, and surrounding muscles sue or if synovial metastasis results because of the frequency but with no nerve or blood vessel involvement. The patient of these common etiologies is an area for future research. reported improved quality-of-life, controlled pain, and de- Radiographs, MRIs, and CTs have a limited role in nied phantom pain post-surgery. The patient continued on diagnosing synovial metastasis, often with nonspecific chemotherapy for his lung mass and died from its sequalae findings such as synovitis and bursitis. As with the case five months post-amputation, one year following the diag- at hand, the synovium is often intermediate intensity on nosis of synovial metastasis. T1-weighted imaging and hyperintense on T2-weighted imaging.3,4,6 MRIs and CTs are useful once malignancy is DISCUSSION diagnosed to assess surrounding tissue pathology and periarticular infiltration.3,7 Nuclear imaging techniques, such as Unilateral joint pain can present in a variety of ways, 99mTechnetium pyrophosphate bone scans, have been useful including gout, chondrocalcinosis, avascular osteonecrosis, in some cases, demonstrating increased uptake in the intra- septic arthritis, autoimmune arthropathies, and cancer. Pri- articular synovium.7,8 mary malignancies, metastasis, paraneoplastic syndromes, or antineoplastic therapies are possible etiologies for joint Biopsy of synovial tissue with subsequent pathologic pain associated with cancer.2 Synovial metastasis is rare, workup is required for definitive diagnosis of synovial me- with only 49 cases reported in the literature.6 Synovial metastasis.4,5 Once common joint pathologies are ruled out, the tastasis is postulated to occur through either hematologic first step to investigate suspected synovial metastasis should spread or adjacent bone invasion. This metastatic invasion be clinical joint aspiration. Although it was negative in the

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case at hand, atypical cytology of joint aspirate has been biopsy and palliative synovectomy of hypertrophic syno- diagnostic in some cases.2,3 The aspirate will often appear vitis,9,12-14 it is important for the surgeon to exercise caution sanguineous, as it did with this case.7 If the aspirate cytology in the event of encountering either primary or metastatic is unremarkable and there is reasonable suspicion of syno- malignancy during the procedure. Inadvertent spread of vial metastasis, arthroscopic biopsy should be considered. the disease may result from even minimally invasive diag- At time of writing, we report the third case of metastasis nostic procedures, including arthroscopy.7 If malignancy is to the elbow synovium. The previous cases had broncho- confirmed, it is reasonable, and in the patient’s best interest, genic squamous cell carcinoma and colon adenocarcinoma to discontinue the surgery and develop an alternative plan. as the primary cancers. Similar to this case, both previously reported cases featured normal cytology of the joint aspirate REFERENCES and required synovial biopsy for diagnosis.8,9 Colon adenocarcinoma recurrence after polypectomy 1. Abu-Hilal M, Matteson E. Rheumatic manifestations in or partial colectomy usually occurs within five years post- malignancy. Current Rheumatology Reviews. 2008;4:50-58. resection. The liver is the most common metastatic site, and 2. Capovilla M, Durlach A, Fourati E, et al. Chronic monoarthritis a spread to other organs is rare without prior liver metasta- and previous history of cancer: think about synovial metastasis. Clin. Rheumatol. 2007;26(1):60–63. sis.10 There are few reported cases of colon adenocarcinoma 3,7,11 3. Ryu K, Masui F, Saito S, Marumo K. Chronic arthritis of the knee metastasizing to the intra-articular synovium. due to synovial metastasis. Jikeikai Med J. 2010;57:141-7. This patient’s metastasis to the synovium featured 4. Pieters RS, Galvin J. The rare presentation of sinus tarsi syndrome the most common histopathology (adenocarcinoma) and secondary to metastasis in a patient with endometrial carcinoma. the second most common primary tumor location (colon). Radiology Case Reports. (Online) 2011;6:414. Similar to the other reported cases, unilateral joint pain was 5. Sheldon PJ, Forrester DM, Learch TJ. Imaging of intraarticular the first manifestation of a disseminated cancer.3,7 Unusual masses. Radiographics. 2005;25(1):105–119. and perhaps unique to our patient was the fact that the 6. Levine HR, Tingle E, Carter B, Dockery D. Synovial metastasis synovium was the sole initial metastatic site. The lung, bone, from lung cancer. Proc (Bayl Univ Med Cent). 2013;26(1):25–27. 7. Currall VA, Dixon JH. Synovial metastasis: an unusual cause of and muscles were later involved, but extensive oncologic pain after total knee arthroplasty. J Arthroplasty. 2008;23(4):631– workup only showed synovial involvement initially. 636. Most reported cases have either a concurrent metastatic 8. Philipson JD, Birkhead R, Phillips PE. Arthritis of the elbow or primary visceral site. Bone often precedes the synovium caused by metastatic bronchogenic carcinoma. Clin Exp Rheumatol. as a metastasis site, and some postulate that synovial me- 1983;1(2):165–9. tastasis occurs by infiltration from adjacent bone.1 This 9. Ter Borg E, Slee P, Seldenrijk C. Monoarthritis of the elbow due does not appear likely in this case, however, as the reverse to metastatic colon carcinoma: diagnosis based on the presence of occurred with synovial metastasis preceding and leading adenocarcinoma cells in synovial fluid. Rheumatology International. 2008;28:1177-1178. to subsequent bone involvement. Our case is atypical with 10. Scheer A, Auer RA. Surveillance after curative resection of a long latency period after resection of the primary tumor. colorectal cancer. Clin Colon Rectal Surg. 2009;22:242-50. The patient’s symptoms began 15 months following the 11. Uysal M, Goksu SS, Coskun HS, Savas B, Ozdogan M, Bozcuk primary tumor resection, and the diagnosis of synovial H. Intraarticular hemorrhage due to bevacizumab in a patient metastasis was made at 19 months post-procedure. Due with metastatic colorectal cancer: a case report. J Med Case Rep. to the aggressive nature of synovial metastases, localized 2012;6(1):188. radiation and systemic chemotherapy can be palliative in 12. Morbidi M, Magnani M, Della Rocca C. Synovial metastasis of the some patients,8 but this approach did not prevent further shoulder detected by arthroscopy as the presenting manifestation growth and spread in this patient. of lung adenocarcinoma. Arthroscopy. 1998;14(5):508–511. 13. Tandogan RN, Aydogan U, Demirhan B, Arican A, Yücetürk A. Intra-articular metastatic melanoma of the right knee. Arthroscopy. CONCLUSION 1999;15(1):98–102. 14. Tokis AV, Andrikoula SI, Chouliaras VT, Vasiliadis HS, Georgoulis This case of intra-articular synovial metastasis provides AD. Diagnosis and arthroscopic treatment of primary synovial an example of disease progression and can serve as a tem- chondromatosis of the shoulder. Arthroscopy. 2007;23(9):1023.e1–5. plate for diagnosis and management of similar cases. The differential for subacute unilateral joint pain is extensive, and synovial metastasis should not be a primary consideration. Mr. Ballard is a third-year Medical Student at Louisiana State University However, with the right clinical picture, and after ruling Health Sciences Center in Shreveport. Dr. Cascio is the Director of out more common etiologies, the physician should consider Sports Medicine at Lake Charles Memorial Hospital in Lake Charles. including synovial metastasis in their differential. When sy- He is also a Clinical Assistant Professor at LSUHSC in New Orleans. novial metastasis is suspected, the first step in management should be to obtain joint aspirate for cytologic workup. This can yield a diagnosis if atypical cytology is present. If the aspirate cytology is negative, arthroscopic biopsy of synovial tissue should be considered. While arthroscopy allows for

52 J La State Med Soc VOL 166 March/April 2014 Celiacomesenteric Trunk: A Rare Anatomical Variation With Potential Clinical and Surgical Implications

Guillermo Sangster, MD; Sandra Ramirez, MD; Carlos Previgliano, MD; Aya Al Asfari, MD; Alireza Hamidian Jahromi, MD; Alberto Simoncini, MD

The arterial supply of the abdominal viscera is derived via three single arteries: the celiac axis, the superior mesenteric artery, and the inferior mesenteric artery. These arteries usually originate separately from the ventral aspect of the abdominal aorta. In some cases, two or more of these arteries may originate from a common trunk. The celiacomesenteric trunk is a rare condition that can generate clinical and surgical complications. Preoperative knowledge of vascular anomalies is critical when planning a surgical approach. We report a patient who underwent Multi-detector Computed Tomography (MDCT) before a vascular procedure, and a common trunk for celiac axis and superior mesenteric artery (celiac mesenteric trunk) was incidentally found.

CASE PRESENTATION spleen, pancreas, and gut from the distal esophagus to the ampullary region.1,2 A 70-year-old white male presented to the emergency The SMA arises anteriorly from the abdominal aorta department complaining of two days history of severe pain at L1 level, 1 to 2 cm below the celiac artery, immediately in the left lower extremity. Physical examination revealed a superior to the origin of the renal arteries. The SMA courses blood pressure of 154/102, a pulse rate of 81 per min, and behind the pancreatic body where it enters the mesentery a cool left foot with 2+ femoral and radial pulses. There and supplies the distal duodenum, jejunum, ileum, and were no palpable/dopplerable posterior tibial and dorsa- colon from the cecum to the mid transverse portion.1 lis pedis pulses present in the left leg. A diagnosis of left Variant arterial anatomy is common, occurring in nearly lower extremity ischemia was made, and the patient was half of the population.3 However, a common origin for the started on a Heparin drip. The patient was also found to celiac and superior mesenteric arteries (celiacomesenteric have a pulsatile mass in his abdomen. He was considered trunk) is seen in less than 1% of patients.1,3 The presence of a a candidate for surgery, and a computed tomographic common trunk has important clinical implications. A patient angiogram (CTA) of the abdomen and pelvis with lower with this anomaly lacks the collateral protection of a dual extremity runoff was performed. The examination revealed vascular supply to the abdominal viscera. Atherosclerosis a 5.5 cm fusiform infra-renal abdominal aortic aneurism and or complications of a vascular interventional procedure peripheral vascular disease with occlusion of left popliteal can place the abdominal viscera at risk.4 In cases where a artery above the knee. Reconstitution of the contrast flow liver transplant is planned, or when a surgical management below the popliteal artery and runoffs was found. The CTA of patients with pancreatic and hepato-biliary neoplasms incidentally depicts a common origin for the celiac axis and is arranged, recognition of these vascular anomalies may SMA from the abdominal aorta (celiacomesenteric trunk) significantly affect the surgical approach.4-6 It has also (Figures 1, 2). The origin of the inferior mesenteric artery been shown that there is an increased risk of hepatic artery was unremarkable. complications after liver transplantation, as well as during chemo-embolization in patients with mesenteric arterial DISCUSSION variants.7.8 During embryonic development, the 10th to 13th vi- In classic anatomy, the celiac trunk originates anteriorly telline arteries (primitive intestinal arteries) communicate from the abdominal aorta at T12 level, just as the aorta enters between the aorta and a primitive ventral anastomotic the abdomen. It divides into three branches: the left gastric artery. Typically the ventral anastomosis and the 11th and artery, the splenic artery, and the common hepatic artery. 12th vitelline arteries regress, while the 10th and 13th roots The celiac axis gives arterial supply to the liver, gallbladder, give origin to the celiac trunk and the SMA, respectively.

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A celiacomesenteric trunk occurs when the 10th to 12th vitelline arteries regress and a large portion of the ventral anastomosis persists to connect the celiac artery or its major branches to the SMA (Figure 3).1,2,9 The CTA is considered the modality of choice for the evaluation of arterial anatomy, with a diagnostic accuracy of 97%-98% for detection of arterial variations.10 The volu- metric acquisition of data allows creating isotropic volume rendering and multi-planar reconstruction, providing a 3D model of the patient´s arterial anatomy. Another advantage is that it can show the relationship between the arteries and the adjacent organs.10-12

CONCLUSION

Adequate radiologic knowledge and detection of vascular anatomic variations is essential to avoid unexpected complications and potential iatrogenic injuries during surgical and minimally invasive procedures. CT angiography is a reliable tool for identifying celiac and mesenteric arterial Figure 1: Axial maximum intensity projection MDCT shows a anatomy variants. common celiacomesenteric trunk (white arrow) arising from the anterior surface of the abdominal aorta.

Figure 2: (left) Sagittal maximum intensity projection MDCT image shows celiac axis (CA) and superior mesenteric artery (SMA) originating from a common trunk (C).

(right) Oblique 3D volume-rendered image demonstrates common celiac-SMA trunk (white solid arrow) and an infra-renal fusiform aortic aneurism (arrowhead).

54 J La State Med Soc VOL 166 March/April 2014 8. Liu DM, Salem R, Bui JT, et al. Angiographic considerations in patients undergoing liver-directed therapy. J Vasc Interv Radiol 2005;16:911–35. 9. Song SY, Chung JW, Yin YH, et al. Celiac axis and common hepatic artery variations in 5002 patients: systematic analysis with spiral CT and DSA. Radiology 2010;255:278-88. 10. Winston CB, Lee NA, Jarnagin WR, et al. CT angiography for delineation of celiac and superior mesenteric artery variants in patients undergoing hepatobiliary and pancreatic surgery. AJR Am J Roentgenol 2007;189:W13-9. 11. Iezzi R, Cotroneo AR, Giancristofaro D, et al. Multidetector-row CT angiographic imaging of the celiac trunk: anatomy and normal variants. Surg Radiol Anat 2008;30:303-10. 12. Horton KM, Fishman EK. Volume-rendered3DCT of the mesenteric vasculature: normal anatomy, anatomic variants, and pathologic conditions. Radiographics 2002;22:161-72.

Drs. Sangster, Previgliano, Al Asfari, and Simoncini are with the Department of Radiology at Louisiana State University Health Sciences Center in Shreveport. Dr. Ramirez is with the Department of Radiology at Pontificia Universidad Javeriana in Bogota, Colombia. Dr. Hamidian Jahromi is with the Department of Surgery at LSUHSC-Shreveport.

Figure 3: Embryology of normal vascular anatomy and variant celiac-SMA trunk. In the primitive vasculature, (a) the 10th to 13th vitelline arteries connect the aorta with a ventral longitudinal anastomosis. In a normal anatomy, (b) the 10th and 13th persist to invidually form the celiac axis and superior mesenteric artery; the remaining segments regress before birth. If the 10th to 12th vitelline arteries regress but there is abnormal persistence of ventral anastomosis, a celiacomesenteric trunk occurs (c).

REFERENCES

1. Walker TG. Mesenteric Vasculature and Collateral Pathways. Semin Intervent Radiol 2009;26: 167–174. 2. Nonent M, Larroche P, Forlodou P. Celiac-Bimesenteric Trunk: Anatomic and Radiologic Description—Case Report. Radiology 2001;220:489–491. 3. Wayne MG, Narang R, Verzosa S, et al. Superior Mesenteric Artery Originating from the Celiac Axis: A Rare Vascular anomaly. World Journal of Surgical Oncology 2011;9:71. 4. Petscavage J, Maldjian P. Celiomesenteric trunk: Two variants of a rare anomaly. Australasian Radiology 2007;51:B306–B309. 5. Winston CB, Lee NA, Jarnagin WR, et al. CT angiography for delineation of celiac and superior mesenteric artery variants in patients undergoing hepatobiliary and pancreatic surgery. Am J Roentgenol 2007;189:W13-9. 6. Egorov VI, Yashina NI, Fedorov AV, et al. Celiaco-mesenterial arterial aberrations in patients undergoing extended pancreatic resections: correlation of CT angiography with findings at surgery. Journal of the Pancreas 2010;11:348-57. 7. Ishigami K, Zhang Y, Rayhill S, et al. Does variant hepatic artery anatomy in a liver transplant recipient increase the risk of hepatic artery complications after transplantation? Am J Roentgenol 2004;183(6):1577–84.

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Radiological Evolution of Relapsing Polychondritis

Oluwayemisi Ojemakinde, MD; Threta Reddy, MD; Carlos Previgliano, MD; Guillermo Sangster, MD; Adam Wellikoff, MD; Eduardo Gonzalez-Toledo, MD

Relapsing Polychondritis (RP) is a systemic condition characterized by chronic, episodic inflammation, especially of cartilaginous and proteoglycan-rich structures. The etiology of this rare autoimmune disease is unknown, and so far, there is very little data available for non-Caucasians. RP presents with a constellation of non-specific inflammation, which sometimes appear in characteristic locations. Radiology is important in supporting the diagnosis, and this paper presents a case of a non-Caucasian patient monitored radiologically from early onset to the terminal stages.

CASE REPORT tracheal stenosis. Chest CT at this time showed smooth anterior and lateral wall thickening with sparing of the A 29-year-old African-American female initially pre- posterior wall of the trachea, a typical finding which is sented during a pregnancy with scleritis, nasal and aural almost pathognomonic1 for RP (Figure 1). Her symptoms chondritis, inflammatory arthritis, and axonal neuropathy. became progressive over a period of 18 months, despite use A clinical diagnosis of Relapsing Polychondritis (RP) was of BIPAP and steroid treatment. Attempts at bronchoscopy made, and management commenced with steroids with resulted in cardiac arrest from which she was resuscitated. good response. Her initial chest radiograph and baseline However, volume-rendered CT bronchography and virtual chest computed tomography (CT) showed very minimal bronchoscopy immaculately demonstrated the progressive abnormalities. airway narrowing (Figure 2A & B). She had a long stent A year later, she developed symptoms concerning placed via tracheostomy to bypass the tracheal stenosis, for obstructive sleep apnea, tracheobronchomalacia, and and a left main stem stent was placed to alleviate continuing respiratory distress (Figure 3). Over the course of 32 months and despite the use of Methotrexate, this patient developed progressive sensorineural hearing loss and cataracts. By the 40th month of her disease, she developed recalcitrant pneumonia (Figure 4) and pleural effusions on the left. The onset of progressive dysphagia in this patient prompted an esophagogram, which revealed a left tracheosophageal fistula that was repaired endoscopically (Figure 5). The patient terminally had whole lung collapse on the left (Figure 6), and she opted for home hospice. She had other complications of therapy, including acute kidney injury, Mallory Weis tear, osteoporosis, and obesity. The patient succumbed to respiratory compromise soon after.

DISCUSSION

RP is a rare disease with only 3.5 cases per million population reported in the United States. It has been recognized as Figure 1: Non-contrast chest CT showing smooth anterior and a disease entity as far back as 1923 with 600 cases reported by lateral wall thickening with sparing of posterior wall. 1997.1 Although this disease has been found in all races, it is

56 J La State Med Soc VOL 166 March/April 2014 Figure 2: CT virtual bronchoscopy (A-left) and bronchography (B-right) demonstrating narrowed left main stem bronchus with progression of wall thickening.

Figure 3: Non-contrast CT showing anteroposterior collapse of Figure 4: Non-contrast CT showing airspace disease with the tracheal cartilage. Note relative sparing of posterior wall. consolidation in the left lower lobe. An endobronchial stent is seen in the left main stem bronchus. more common in Caucasians, and there is consequently in the literature for any paper describing the clinical and very little data on non-Caucasian patients. Several attempts radiological evolution of this entity. The disease typically have been made to identify the etiology, and some progress responds to steroids, but other immunosuppressants such as made includes identification of its autoimmune nature and Methotrexate have also been used to provide relief. Current the discovery of antibodies to cartilage-specific collagen.1 therapy also involves bronchoscopic/surgical palliation, Pathology demonstrates inflammation and subsequent and radiological imaging is indispensable for monitoring fibrosis in affected cartilage. The constellation of clinical therapy to achieve the best quality of life for patients with features, which characterizes the condition, is currently the this currently incurable disease. mainstay of diagnosis.2,3 Radiology, especially CT, is essen- Several radiological features have been associated with tial to management, as it provides confirmatory evidence the disease, but only one is pathognomonic; namely, inflam- of clinical features and can be used safely for follow-up.4 mation of the anterior and lateral tracheal wall, sparing the To the best of our knowledge, there is no current evidence posterior wall.5.6 Since this disease shares common features

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Figure 6: AP chest radiograph showing a complete collapse Figure 5: An esophagram showing an esophagobronchial of the left lung with ipsilateral pleural effusion. There is a fistula with contrast draining into the stented left main pneumonic consolidation in right lung. Note barium in left bronchus. Note a calcified lymph node in the left hilum. lower lobe due to an esophagobronchial fistula. with other autoimmune disorders, there are few readily dif- ologists in particular, to better correlate diagnostic features ferentiating features. Its relapsing nature can clinically point at any stage of the patient’s presentation and thus reduce to the diagnosis, and this paper demonstrates the temporal the time-to-diagnosis of an entity that can mimick several profile of the radiological features in order to pinpoint any other autoimmune conditions. Early diagnosis results in characteristic pattern. However, clinical experience has implementation of the best available current therapy and shown variability in the course and extent of organ involve- saves the patient’s and physician’s time. ment in different patients.3 Prognosis is linked to laryngeal, tracheal, and cardio- REFERENCES vascular involvements.7 Chondritis of the respiratory tract is one of the most serious complications of RP, occurring 1. Compton N., Buckner J.H, Harp K.I, Raugi G.J. Polychondritis especially in women, and accounts for up to 50% of deaths due to RP.3,7,8 Pneumonia, which is the most common cause (accessed 14 April, 2013). of death, is directly related to airway chondritis.9 The respi- 2. Damiani, J M. Relapsing polychondritis-report of ten cases. The ratory tract is involved in up to 50% of documented cases,1,3,10 Laryngoscope 1979;89(6):929. 3. Mcadam L.P, BluestoneR, Pearson C.M et al. Relapsing and so it is crucial to look for respiratory signs in order to Polychondritis: Prospective Study of 23 Patients and a Review of offer timely and appropriate treatment. the Literature. Medicine 1976;55(3):193-215. The case in point was followed up radiologically from 4. Tillie-Leblond I, Wallaert B, Leblond D, et al. Respiratory diagnosis to the patient’s terminal stage, using various mo- Involvement in Relapsing Polychondritis. Clinical, Functional, dalities, and thus, the evolution of RP as seen in the patient is Endoscopic, and Radiographic Evaluations. Medicine 1998; informative. This paper also contributes to currently sparse 77(3):168-176. data in a non-Caucasian patient of a disease known to occur 5. Prince JS, Duhamel DR, Levin DL, et al. Nonneoplastic lesions of predominantly in Caucasians.1 the tracheobronchial wall: Radiologic findings with bronchoscopic correlation. Radiographics 2002;22:S215-S230. 6. Lee KS, Ernst A, Trentham DE, Lunn W et al. Relapsing CONCLUSION polychondritis: prevalence of expiratory CT airway abnormalities. Radiology. Aug 2006;240(2):565-73. This case presents with radiological features that ac- 7. Michet CJ Jr, McKenna CH, Luthra HS, O’Fallon WM. Relapsing curately correlate with clinically demonstrable features of polychondritis. Survival and predictive role of early disease RP. The temporal evolution of the disease is emminently manifestations. Ann Intern Med 1986 Jan;104(1):74-8. demonstrated by radiological imaging and gives us an “in- 8. Ernst A, Rafeq S, Boiselle P, et al. Relapsing polychondritis and side view” of a well-described, albeit uncommon, clinical airway involvement. Chest 2009 Apr;135(4):1024-30. condition. This profile would enable physicians, and radi- 9. Trentham D.E, Le C.H. Relapsing polychondritis. Ann Intern Med

58 J La State Med Soc VOL 166 March/April 2014 1998 Jul 15;129(2):114-22. 10. Luthra HS. Relapsing polychondritis. Rheumatology, Vol 27. St Louis: Mosby; 1998:1-4.

Drs. Ojemakinde, Reddy, Previgliano, and Sangster are with the Department of Radiology at Louisiana State University Health Sciences Center in Shreveport. Dr. Wellikoff is Assistant Professor of Medicine and Director of Interventional Pulmonology at LSUHSC-Shreveport. Dr. Gonzalez-Toledo is Professor of Radiology, Neurology, and Anesthesiology at LSUHSC-Shreveport.

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Bilateral Ultrasound-Guided Supraclavicular Block in a Patient With Severe Electrocution Injuries of the Upper Extremities

Brian Gelpi, MD; Pavan R. Telang, MD; Christian G. Samuelson, MD; Craig S. Hamilton, MD; Seth Billiodeaux, MD

The performance of bilateral supraclavicular brachial plexus nerve blocks is controversial. We present the challenging case of a 29-year-old male who suffered bilateral high-voltage electrocution injuries to the upper extremities, resulting in severe tissue damage, sensory and motor deficits, and wounds in both axillae. This injury necessitated bilateral below-elbow amputations. His postoperative course was complicated by pain refractory to intravenous narcotics. The decision was made to attempt bilateral supraclavicular brachial plexus blocks. Our concerns with this approach included the risks of pneumothorax and respiratory failure due to phrenic nerve block. Initial attempts at brachial plexus blockade using nerve stimulation were unsuccessful; therefore, ultrasound guidance was employed. With vigilant monitoring in an intensive care unit setting, we were able to safely perform bilateral continuous supraclavicular brachial plexus nerve blocks with an excellent analgesic response and no noted complications.

CASE REPORT the decision was made to attempt bilateral supraclavicular brachial plexus block placement using ultrasound guid- A 29-year-old, otherwise healthy male suffered severe ance. Our chief concerns with this approach were the risks bilateral electrocution injuries to his upper extremities of pneumothorax and phrenic nerve blockade resulting in when he grasped a high voltage power line with a rating diaphragmatic paralysis. of 75,000 volts with both hands. The patient presented The risks and benefits of the procedure were discussed with severe burns with blistering and weeping wounds. in detail with the patient, and informed consent was ob- Exit wounds were found in both axillae. Marked sensory tained. Initially, the patient’s left supraclavicular region was and motor deficits of the upper extremities were noted bi- marked and prepped. The point of entry was indentified, laterally, along with dislocation of left hip and left second and 1 ml of 1% lidocaine was injected superficially. The proximal interphalangeal joint. The patient was taken to brachial plexus, surrounding vasculature, and anatomic the operating room, and bilateral below-elbow amputations landmarks were identified under ultrasound guidance. An and proximal forearm fasciotomies were performed under 18-gauge Tuohy needle was used. Using inline technique, general anesthesia. the tip of the needle was visualized and directed beneath The patient was transferred to the intensive care unit the brachial plexus (Figure 1). A catheter was then inserted postoperatively. Pain control with IV narcotics was inad- through the Tuohy needle, and its final position was con- equate. The anesthesiologist in charge of the patient’s case firmed under ultrasound. The Tuohy needle was withdrawn had attempted to perform supraclavicular brachial plexus over the catheter, which measured 3.5 cm at the skin. We blockade using the nerve stimulation technique without then injected 10 ml of normal saline for improved visualiza- success. Neither paresthesia, nor an appropriate twitch tion and to rule out intraneuronal injection and pneumo- response, could be elicited due to the extent of the patient’s thorax. Ropivacaine at 0.2% was injected in 2 ml increments nerve injury and the loss of typical anatomic correlation every two minutes after negative aspiration, totaling 10 ml. following below-elbow amputation. The patient reported no pain during the injection of local The acute pain service was consulted to evaluate and anesthetic. The patient was monitored closely for signs manage the patient’s ongoing pain, which was maximal at and symptoms of intravascular absorption, pneumothorax, the bilateral stump sites. The presence of axillary wounds phrenic nerve paralysis, Horner’s Syndrome, and other pos- precluded axillary brachial plexus blockade. Due to the high sible complications. rate of phrenic nerve paralysis with interscalene blockade, Within 10 minutes of the procedure, a significant

60 J La State Med Soc VOL 166 March/April 2014 are responsible for approximately 1,000 deaths in the United States every year and are unique with respect to relatively low mortality rates but very high rates of short- and long-term morbidity.1 The mortality of electrocution is estimated to be anywhere from 3% to 59%, depending on the voltage, with fatal heart arrhythmias the leading cause of death.2 While any electrical trauma has the potential to precipitate cardiac arrhythmia, high-voltage injuries (>1,000 volts) are associated with a greater degree of tissue damage. Up to 35% of all victims require partial or total limb amputation following electrical trauma. Neurological complications are common irrespective of the type of electrical injury.3 Neuronal death is followed by fibrosis and scarring. Retrospective studies have reported significant long-term neurological deficits in up to 73% of patients five years following electrical injury and chronic pain in up to 25%.3 Poor perioperative pain control has been linked to the development of chronic postoperative pain syndromes,4 which are caused by damage to inhibitory neurons and proliferation of excitatory afferent neurons. This case also highlights the utility of regional anesthesia for acute pain control. When considering regional techniques, a number of factors need to be taken into account, including the location of block placement, expected effects, and potential complications. In the case of our patient, a bilateral approach to the brachial plexus Figure 1: Ultrasound-guided supraclavicular block showing anatomic was clearly needed, and an axillary approach was clearly landmarks and needle placement, brachial plexus (BP), needle tip precluded due to the presence of wounds in the axillae. (NT), pleura (PL), first rib (RIB), and subclavian artery (SA). Such an approach would have significantly increased the risk of local infection. Furthermore, an axillary bra- reduction in the patient’s visual-analogue pain score was chial plexus block does not reliably alleviate pain in the achieved (from 10/10 to 5/10). The patient was monitored entire upper extremity,5 and is more appropriate for distal for a further 30 minutes for signs of delayed complications, upper extremity indications. An interscalene approach to with none noted. brachial plexus blockade is associated with a near-certain ip- The procedure was then repeated on the right side, silateral phrenic nerve blockade and subsequent ipsilateral with a bolus of 10 ml 0.5% ropivacaine following success- diaphragmatic paralysis,6 making the placement of bilateral ful catheter placement. Once again, no complications were interscalene blocks an unacceptable solution.6,7 Compared noted, and the patient reported a significant reduction in to the interscalene approach, the supraclavicular brachial pain (10/10 to 2/10). plexus block has a lower (though still considerable) risk of Both supraclavicular brachial plexus nerve block cath- phrenic nerve paralysis.5,6,8,9 We determined that a supracla- eters were connected to individual pumps and a continuous vicular approach for continuous brachial plexus blockade infusion of 0.2% ropivacaine was initiated at 8 ml per hour. was the most viable option for this patient, despite concerns The patient continued to report reduced pain and was able regarding the possibility bilateral phrenic nerve paralysis. to tolerate physical therapy. A significant reduction in nar- A supraclavicular brachial plexus nerve block can be cotic analgesic consumption was noted over the following performed by eliciting paresthesia, by using nerve stimula- three days. Both catheters were removed at the time of ICU tion, by using ultrasound guidance, or any combination of discharge, and the remainder of the patient’s hospitalization these techniques.10,11 Eliciting paresthesia becomes extremely was uneventful. unreliable in the event of trauma to the brachial plexus, and in the presence of extensive nerve damage due to electrocu- DISCUSSION tion, it may be difficult to elicit a twitch response using the nerve stimulation technique, with apparent conduction of This case highlights the need for acute pain control in the electrical impulse potentially blocked or attenuated at patients with electrical injuries. Adequate pain control is multiple levels. Furthermore, given that the twitch response of paramount importance, not only for the management is typically observed at the hand or wrist, the anatomical of acute distress symptoms, but for reducing the risk of correlation in this case was complicated by the fact that the subsequent chronic pain syndrome. Electrocution injuries patient had undergone bilateral below-elbow amputations.

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The use of ultrasound allows the clinician to determine effect on pulmonary function. Anaesthesia 2001;56(4):352-356. the size, depth, and precise location of the brachial plexus 6. Yang CW, Kwon HU, Cho CK, et al. A comparison of and its neighboring structures under direct visualization.11 infraclavicular and supraclavicular approaches to the brachial Pre-block anatomical examination can define the optimal site plexus using neurostimulation. Korean J Anesthesiol 2010;58(3):260- 266. and depth of needle insertion, help avoid vascular and pleu- 7. Plunkett AR, Brown DS, Rogers JM, et al. Supraclavicular ral puncture, and impart confidence to the anesthesiologist continuous peripheral nerve block in a wounded soldier: when 9,12 performing the block. In a recent study, Cornish et al. dem- ultrasound is the only option. Br J Anaesth 2006;97(5):715-717. onstrated that it is possible to avoid phrenic nerve paralysis 8. Urmey WF, Talts KH, Sharrock NE. One hundred percent incidence using a bent needle technique, further demonstrating how a of hemidiaphragmatic paresis associated with interscalene combination of clinician technique and ultrasound guidance brachial plexus anesthesia as diagnosed by ultrasonography. may reduce the risk of complications.13 However, though Anesth Analg 1991;72(4):498-503. ultrasound-guided supraclavicular block placement has 9. Perlas A, Lobo G, Lo N, et al. Ultrasound-guided supraclavicular block: outcome of 510 consecutive cases. Reg Anesth Pain Med been demonstrated to be a safe alternative to the electrical 2009;34(2):171-176. nerve stimulator-guided supraclavicular block, there is little 10. De Tran QH, Clemente A, Doan J, et al. Brachial plexus blocks: a evidence as yet to support the superiority of one technique review of approaches and techniques. Can J Anaesth 2007;54(8):662- over the other.14 As such, the choice of technique should 674. be determined by a combination of physician preference 11. Mirza F, Brown AR. Ultrasound-guided regional anesthesia (typically determined by familiarity and comfort level) and for procedures of the upper extremity. Anesthesiol Res Pract specific indications for a particular approach, as in our case. 2011;2011:579824. The performance of bilateral supraclavicular blocks is 12. Chan VW, Perlas A, Rawson R, et al. Ultrasound-guided certainly controversial, given the potential consequences supraclavicular brachial plexus block. Anesth Analg 2003;97(5):1514- 1517. of bilateral phrenic nerve paralysis and/or pneumothorax. 13. Cornish PB, Leaper CJ, Nelson G, et al. Avoidance of phrenic nerve The unusual circumstances specific to our case necessitated paresis during continuous supraclavicular regional anaesthesia. a bilateral approach, despite the high risk of complications, Anaesthesia 2007;62(4):354-358. with every possible precaution taken to mitigate these risks. 14. Abrahams MS, Aziz MF, Fu RF, et al. Ultrasound guidance The blocks were performed sequentially rather than simul- compared with electrical neurostimulation for peripheral nerve taneously, with a window of observation between blocks block: a systematic review and meta-analysis of randomized to assess for immediate complications. The procedure was controlled trials. Br J Anaesth 2009;102(3):408-417. conducted in the intensive care unit under constant monitoring, with emergency resuscitation equipment, including Dr. Gelpi is a final-year Resident with the Department of Anesthesiology endotracheal tubes and thoracostomy tubes, available at at Louisiana State University Health Sciences Center in Shreveport. the bedside. Dr. Telang is a Pain Management Specialist with Alabama Spine and Pain and a former Pain Medicine Fellow with the Department of Anesthesiology at LSUHSC-Shreveport. Dr. Samuelson is a Resident CONCLUSION with the Department of Anesthesiology at LSUHSC-Shreveport. Dr. Hamilton is a Clinical Research Associate at LSUHSC-Shreveport. This unique case highlights the need for acute pain Dr. Billiodeaux is a Pain Management Specialist with Lake Charles control in patients with electrocution injuries and some Memorial Health System and a former member of Faculty in the of the clinical challenges that may be encountered. In ad- Department of Anesthesiology at LSUHSC-Shreveport. dition, it highlights the utility of brachial plexus blockade for painful upper extremity injuries and defines a group of patients for whom nerve-stimulator guidance may not be possible. Finally, it stresses the potential complications of bilateral brachial plexus blockade and the need for intensive patient monitoring.

REFERENCES

1. Hussmann J, Kucan JO, Russell RC, et al. Electrical injuries-- morbidity, outcome and treatment rationale. Burns 1995;21(7):530- 535. 2. Lee J, Sinno H, Perkins A, et al. 14,000 volt electrical injury to bilateral upper extremities: a case report. Mcgill J Med 2011;13(1):18. 3. Singerman J, Gomez M, Fish JS. Long-term sequelae of low-voltage electrical injury. J Burn Care Res 2008;29(5):773-777. 4. Searle RD, Simpson KH. Chronic Post Surgical Pain. Contin Educ Anaesth Crit Care Pain 2010;10(1):12-14. 5. Mak PH, Irwin MG, Ooi CG, et al. Incidence of diaphragmatic paralysis following supraclavicular brachial plexus block and its

62 J La State Med Soc VOL 166 March/April 2014 Plasmacytoma Presenting as Missing Rib on Chest Film: A Case Report and Review of the Literature

Terrell Caffery, MD; Matthew Foy, MD

A 33-year-old man presented to the emergency department (ED) with chief complaint of chest pain, persist- ing for approximately one year. Chest X-ray revealed he was missing the right posterior fifth rib. Physical examination showed no surgical scars, and he reported no history of chest trauma. A CT of his chest demonstrated a mass involving the posterior aspect of the right fifth rib, and subsequent biopsy revealed plasma cells. Laboratory results indicated the tumor was a solitary plasmacytoma of the rib. He was referred to oncology and treated with radiation therapy. This case report illustrates an unusual presentation of a solitary plasmacytoma of the rib.

INTRODUCTION posterior lateral chest wall pain. The pain was constant, sharp in nature, and worsened with movement. His vital Plasma cell tumors are clonal proliferations of cells. signs were within normal limits, and the remainder of the There are several types of plasma cell tumors defined by physical exam was unremarkable except for minimal tender- location and manifestation. Multiple myeloma is the most ness to palpation over the right posterior lateral chest wall. common type of plasma cell tumor and is marked by mul- Chest X-ray showed absence of a right posterior fifth tiple bony lesions. Solitary plasmacytomas are remarkable rib (Figure 1). No surgical scars were noted, and the patient for only a localized mass.1 There are two types of solitary denied any history of removal of a rib. CT of the chest was plasmacytomas: extramedullary plasmacytomas, which performed and showed an 8.6 cm mass involving the poste- occur in the soft tissue and solitary plasmacytoma of bone rior aspect of the right fifth rib (Figure 2). CT-guided biopsy (SPB). showed sheets of well-differentiated plasma cells infiltrating Data from population-based cancer registries in the the bone (Figure 3). Serum protein electrophoresis and bone United States indicate multiple myeloma occurs 16 times marrow biopsy were normal. Urine protein electrophoresis more frequently than solitary plasmacytomas.2 In general, demonstrated a random urine protein level of 28 mg/dL plasma cell tumors occurred more frequently in men than and monoclonal band of beta-globulin of 89.4%. Urine im- women (Incidence Rate Ratio [IRR] of 2.14), and in blacks munofixation revealed free lambda light chains. Analysis compared to whites (IRR of 1.30, 95% CI 1.10-1.53).2 Inci- with serum immunofixation and serum free light chains dence rates of plasma cell tumors were nine times higher were not performed. The patient’s hemoglobin, hematocrit, in individuals more than 60 years old.2 Of the solitary plas- serum calcium level, serum creatinine level, serum IgA, macytomas, SPB was more common than extramedullary IgG, and IgM levels were all within normal limits. A plain plasmacytoma (IRR of 1.41, 95% CI 1.25-1.59).2 radiograph skeletal survey showed no other lytic lesions. Solitary plasmacytomas of bone comprise a significant The patient was diagnosed with a solitary plasma- minority (< 5%) of plasma cell tumors.3 SPBs typically oc- cytoma of the rib and referred to oncology clinic. At last cur in the vertebrate, with presentation in the rib being less follow-up, the patient had undergone radiation therapy and common.4 In most cases, SPBs present as osteolytic lesions of was doing well. His serum protein electrophoresis remains the bone on chest X-ray.5 This article describes an unusual ra- negative at two years, and a skeletal survey shows no further diologic presentation of SPB of the rib in a 33-year-old man. skeletal lytic lesions.

CASE REPORT DISCUSSION

A 33-year-old Hispanic man with no past medical his- We conducted a literature review using the search tory presented to the ED with a one-year history of right terms “solitary plasmacytoma” and “rib.” Exclusion crite-

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Figure 1: PA chest film demonstrating the absence of the right Figure 2: CT scan of the chest showing destruction of the fifth rib (see arrows). posterior aspect of the right fifth rib by a mass (see arrows). ria included: no English abstract available, no information urinary monoclonal immunoglobulin and recommend few- regarding radiologic presentation of the tumor, and lack of er than 5% plasma cells in the bone marrow for diagnosing clarity regarding the diagnosis of solitary plasmacytoma of SPB. Diagnostic studies for SPB include CT-guided biopsy rib. Overall, 69 articles were identified. From these articles, or fine needle aspiration. In addition, Soutar and colleagues a total of 15 case reports met inclusion criteria. Of these, suggested the following investigations be performed: full nine articles were written in English (Table 1),6-14 and six blood count, biochemical screen, serum immunoglobin articles were written in another language but had abstracts levels, serum and urine protein electrophoresis and im- written in English (Table 2).15-20 Though reports originating munofixation, full skeletal survey, MRI of the thoracic and in the United States were identified,4,21,22 none of them met lumbar spine, and bone marrow aspirate and trephine. They inclusion criteria. Namely, these reports lacked radiographic also recommend that, for some patients, additional testing details of solitary plasmacytoma of the rib. may be helpful, including: MRI of the pelvis, femora and Solitary plasmacytoma of bone is relatively rare as a humeri, immunophenotyping and molecular assessment of cause for an isolated bone lesion. The most common site of bone marrow plasma cells, and PET scanning. SPBs is the vertebrate.5,23 No studies to date have compared Radiologic examination of SPB of the rib generally re- SPBs of the rib to SPBs located on other bones. SPBs have veals lesions of the bone.6,8-10,20 Two cases in our literature been reported to occur more commonly in males than fe- review reported a mass with destruction of the rib,15,19 con- males, at an estimated ratio of 2:1.3 The median age reported sistent with the current case, where the tumor presented as a is 55 years.5 In our review of the literature, SPB of the rib was missing rib on chest X-ray. In our case, the CT scan revealed reported in 12 males and three females, with age ranges of a large mass, indicative of a tumor. 26 to 73 years, and a median age of 45 years.6-20 Clinical pre- Regarding treatment of SPB, Soutar and colleagues3 sentation of SPB of the rib varies. Patients most commonly suggest that radiotherapy is the treatment of choice for SPB, complain of pain in their chest.3,10,13,17 Other chief complaints with consideration of standard chemotherapy for multiple include limb weakness9,20 and coughing.13,18 However, in myeoloma in patients not responding to radiotherapy. some cases, SPB is an incidental finding on radiographs.8,12 Surgical therapy is contraindicated in the absence of struc- In contrast to multiple myeloma, the most common tural instability or neurological compromise; though early type of plasma cell neoplasia, SPBs differ by the absence referral to either an orthopedic or neurosurgical specialist of elevated calcium levels, renal insufficiency, anemia, and is suggested for SBP involving the spine. Despite these multiple bone lesions (CRAB).24 Corwin and colleagues21 guidelines, our review of the literature revealed that surgi- also note that there should be histological confirmation of cal resection or removal of the tumor was performed in 12 plasmacytoma, and a bone marrow biopsy should reveal cases,6-9,11-14,16,17,19,20 whether or not surgery was performed fewer than 10% plasma cells. In their guidelines, Soutar and was not reported in two cases, and only one case reported colleagues3 add that there should be absent or low serum or conservative treatment with radiotherapy. None of the

64 J La State Med Soc VOL 166 March/April 2014 demonstrated a relationship between the presence of myeloma proteins after radiation and progression of solitary plasmacytoma to multiple myeloma.26-28 In the emergency department, complaints of chest pain and coughing are typically representative of more minor diagnoses, with suspicion of SPB being very low in the differential. A chest X-ray was ordered in this case due to the daily occurrence, constant nature, the duration of pain, and lack of findings on physical exam. The absence of the rib on plain chest X-ray prompted further radiological examination with CT, which ultimately revealed a tumor. Destructive processes of the bone should be given consideration in findings of bony lucency on plain radiographs.

REFERENCES

1. Jaffe ES, Harris NL, Stein H, et al. World Health Organization classification of tumours: Pathology and genetics Figure 3: CT-guided biopsy, magnified at 100x, with hematoxylin and of tumours of haematopoietic and lymphoid tissues. IARC eosin (H&E) stain demonstrating sheets of well-differentiated plasma cells Press; Lyons: 2001. infiltrating the bone. 2. Dores GM, Landgren O, McGlynn KA, et al. Plasmacytoma of bone, extramedullary plasmacytoma, articles or abstracts indicated spinal involvement; in which and multiple myeloma: Incidence and survival in the United case, surgical resection would have been appropriate. In states, 1992-2004. Br J Haematol 2009;144(1):86-94. the current case, the patient was successfully treated with 3. Soutar R, Lucraft H, Jackson G, et al. Guidelines on the diagnosis radiotherapy and remained in remission at 27 months from and management of solitary plasmacytoma of bone and solitary initial diagnosis. extramedullary plasmacytoma. Br J Haematol. 2004: 124(6):717-726. The degree of progression of SPB to multiple myeloma 4. Frassica DA, Frassica FJ, Schray MF, et al. Solitary plasmacytoma is debated in the literature, ranging from an estimated 36%5 of bone: Mayo Clinic experience. In J Radiat Oncol Biol Phys. to 75%3 of cases. Of the 15 cases identified in the literature 1989;16(1): 43-48. review, one patient was reported to have recurrence of a 5. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al. Solitary 19 plasmacytoma of bone and asymptomatic multiple myeloma. tumor at five months and 14 months. The other patients Blood. 2000;96(6):2037-2944. reportedly remained asymptomatic for durations ranging 6. George SM, Ratnakar KS, Shome, DK, et al. Plasmacytoma of the 18 11 from eight months to three years. rib in young male. Asian Cardiovasc Thorac Ann. 2002;10(3):282-284. Patients with SBP, on average, have a median overall 7. Kadokura M, Tanio N, Nonaka, M, et al. A surgical case of solitary survival time of 10 years.5 In their epidemiological study of plasmacytoma of rib origin with biclonal gammopathy. Jpn J Clin patients in the United States, Dores and colleagues2 reported Oncol. 2003;30(4):191-195. the five-year survival of patients with SPB, who were under 8. Lee HY, Kin JI, Kin KN. Solitary plasmacytoma of the rib. Korean the age of 60, was 77%. For patients with SPB, who were J Thorac Cardiovasc Surg. 2012;45:269-271. 9. Mankodi AK, Rao CV, Katrak SM. Soliatry plasmacytoma more than 60 years old, the survival rate was 53%. These presenting a peripheral neuropathy: A case report. Neurol India. rates are higher than those found for multiple myeloma, 1999;47(3):234-237. where survival was 43% and 26% for patients who were 10. Pattanayak L, Samantaray S, Rout, N. Solitary plasmacytoma of the less than and more than 60 years old, respectively. Warsame rib: A rare cytological detection. Indian J of Cancer. 2010;47(4):485- et al.25 examined rates of progression and survival in 127 486. patients treated at the Mayo Clinic for SPB. Patients were 11. Rocco G, Robustellini M, Rossi G, et al. Solitary bone plasmacytoma followed for 7 to 28 months (median = 56 months). Of the of rib presenting as a superior sulcus tumor. J Thorac Cariovasc 127 patients, 85 patients progressed to multiple myeloma, Surg. 1993;105(5);944-945. and 27 patients died due to progression. 12. Sato Y, Hara M, Ogino, H, et al. CT-pathologic correlation in a case of solitary plasmacytoma of the rib. Radiat Med. 2001;19(6):303-305. Patients who receive treatment for SBP should be fol- 13. Singal R, Dalal AK, Attri AK, et al. Solitary plasmacytoma of the lowed closely for recurrence or progression to multiple rib: A rare case. Lung India. 2011;28(4):309-311. 3 myeloma. Soutar et al. recommends patients be followed 14. Wilkinson, S, Forrester-Wood, CP. Surgical resection of a solitary every six weeks for six months and then followed regu- plasmacytoma originating in a rib of a patient with Castlesman’s larly after six months. Follow-up should include physical Disease. Ann Thorac Surg. 2003;75:1018-1019. examination and laboratory tests. In particular, physicians 15. Bousnina S, Zendah I, Marniche K, et al. Solitary plasmacytoma should measure myeloma protein, as multiple studies have of the rib: A rare tumor not to miss. Rev Pneumol Clin. 2006;

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62(4):243-246. 24. Kilciksiz S, Karakoyun-Delik O, Agaoglu FY, et al. A review 16. Cavajal Balaguera JJ, Mallagray Casas S, Dancausa Monge A, et al. for solitary plasmacytoma of bone and extrameduallary Horner’s syndrome associated with a solitary bone plasmacytoma plasmacytoma. Sci World J. 2012;2012. of the first rib. Arch Bronconeumol. 1994;30(8):410-413. 25. Warsame R, Gertz MA, Lacy MQ, et al. Trends and outcomes of 17. Hihara J, Takeo S, Furuyama M, et al. A case of solitary modern staging of solitary plasmacytoma of bone. Am J Hematol plasmacytoma that originated in a rib. Nihon Kyobu Gakkai Zasshi. 2012;87:647-651. 1993;41(3):456-460. 26. Liebross RH, Ha CS, Cox JD, et al. Solitary bone plasmacytoma: 18. Ketata W, Triki F, Msaad S, et al. A rare localization of solitary outcome and prognostic factors following radiotherapy. Int J plasmacytoma. Rev Pneumol Clin. 2009;65(3):165-168. Radiat Oncol Biol Phys. 1998;41:1063-1067. 19. Kodate M, Takagishi T, Osaki T. Plasmacytoma of chest a wall. 27. Reed V, Shah J, Medeiros LJ, et al. Solitary Plasmacytomas: Kyobu Geka. 2010;63(10):879-882. Outcomes and prognostic factors after definitive radiation 20. Palao S, Masjuan J, Lopez J, et al. Solitary costal plasmacytoma: therapy. Cancer. 2011;117(19):4468-4474. A rare cause of subacute demyelinating ployradiculoneuropathy. 28. Wilder RB, Ha CS, Cox JD, et al. Persistence of myeloma protein Neurologia. 2006;21(5):265-268. for more than one year after radiotherapy is an adverse prognostic 21. Corwin J, Lindberg RD. Solitary plasmacytoma of bone vs. factor in solitary plasmacytoma of bone. Cancer. 2002;94:1532-1537. extramedullary plasmacytoma and their relationship to multiple myeloma. Cancer. 1979;43:1007-1013. 22. Meis JM, Butler JJ, Osborne BM, et al. Solitary plasmacytomas of bone and extramedullary plasmacytomas: A clinicopatholgic and Dr. Caffery is an Assistant Professor of Louisiana State University Health Immunohistochemical study. Cancer. 1987;59:1475-1485. Sciences Center’s School of Medicine and the Program Director of 23. Chang MY, Shih LY, Dunn P, et al. Solitary Plasmacytoma of bone: the Louisiana State University Health Science Center’s Emergency Medicine Residency Program in Baton Rouge. Dr. Foy is an Assistant treatment, progression, and survival. J Clin Oncol 1994;93:397-402. Professor of LSUHSC’s School of Medicine and is affiliated with the Internal Medicine Residency Program in Baton Rouge.

66 J La State Med Soc VOL 166 March/April 2014 Mucinous Cystic Neoplasm of Pancreas in a Male Patient: A Case Report and Review of the Literature

Mohammad Kazem Fallahzadeh, MD; Gazi B. Zibari, MD, FACS, FICS; Greg Wellman, MD; Sophia T. Abdehou, MD; Hosein Shokouh-Amiri, MD, FACS, FICS

Mucinous cystic neoplasms (MCNs) are among the most common primary cystic neoplasms of pancreas. These lesions usually occur in body and tail of the pancreas and are characterized by the presence of ovarian type stroma in the pathological evaluation. Mucinous cystic neoplasms have significant malignant potential; therefore, their diagnosis and resection is of utmost importance. Mucinous cystic neoplasms typically occur in women. Only a few cases have been previously reported in male patients. In this case report, we present a 48-year-old man who was referred to our center due to an incidentally found cystic lesion in the tail of the pancreas that was increasing in size in serial evaluation. The patient underwent open distal pancreatectomy. The pathology showed mucinous cystic neoplasm with characteristic ovarian type stroma and positive staining for estrogen and progesterone receptors. This case report shows that mucinous cystic neoplasms can occur in men and should be considered in differential diagnosis of cystic pancreatic lesions in this population.

INTRODUCTION cion of the malignant nature of the lesion, he was referred to us and underwent open distal pancreatectomy. Grossly, Mucinous cystic neoplasms (MCNs) are one of the three the lesion consisted of a 5 x 3 x 2 cm multilocular cyst in the most common cystic neoplasms of pancreas and comprise tail of the pancreas. Microscopically, the cyst demonstrated nearly half of these cases.1 MCNs are usually located in a flat epithelium, which varied from a mucin-producing the body and tail of the pancreas and are characterized by columnar epithelium to a cuboidal epithelium (Figure 2, the presence of the ovarian type stroma in the pathological Panel A). No significant atypia was identified. Subjacent evaluation.1,2 Due to the significant malignant potential of to the epithelium, a distinctive ovarian-type stroma was mucinous cystic neoplasms, their diagnosis and resection present, composed of densely packed spindled cells with is of utmost importance.1,2 MCNs almost always occur in regular elongated and wavy nuclei (Figure 2, Panel A). women.1 Occurrence of MCN in males is very rare and only These nuclei showed strong immunoreactivity with estrogen a few cases have been previously reported.2-8 In this article, and progesterone receptor stains (Figure 2, Panels B and C). we present a case of MCN in a male patient who was treated After finding this type of pathology, male karyotyping was at our center. ordered for the patient. Cytogenetic analysis of bone marrow aspirate revealed a normal male karyotype. CASE PRESENTATION The patient recovered well postoperatively and is symptom-free three months after the surgery. A 48-year-old Caucasian male was referred to our clinic because of a cystic mass in the tail of the pancreas. This DISCUSSION mass was incidentally found one year prior to the referral to us on a CT scan performed due to an abdominal gunshot Based on World Heath Organization (WHO) criteria, wound that resulted in splenectomy. The trauma surgeon MCNs are defined as cystic epitheilal neoplasms composed did not resect the pancreatic lesion and decided to monitor of mucin producing columnar epithelium and an ovarian- its progression. On serial abdominal CT scans, the mass in- type stroma which forms a band of densely packed stromal creased in size from 4.3 x 3.7 cm at the initial CT scan to 4.7 cells beneath the epithelium.1,3 Immunohistochemial stain- x 4.6 cm one year later (Figure 1). Although the patient was ing of the ovarian-type stroma in MCN is usually positive asymptomatic due to the increase in the size and the suspi- for estrogen and progesterone receptors.1,2 Presence of this

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over, ERCP could show distortion of pancreatic or biliary ducts by MCNs, which is in favor of malignant nature of MCNs. ERCP could also relieve the biliary obstruction in patients with jaundice. However, ERCP is not necessary for diagnosis and is not used in most patients with MCNs. Like ERCP, MRCP could also be helpful in differentiation of pseudocysts or branch duct IPMNs from MCNs.1 By providing a clear imaging of the tail of pancreas and its ductal system, EUS could also be helpful in differentiating MCNs from other cystic lesions.1 Moreover, EUS could be used for FNA. FNA could also be achieved percutaneously under CT-guidance. FNA analysis of MCNs shows hon- eycomb sheets and clusters of mucin-producing columnar cells. Abundant mucin in the background of the MCNs could be helpful in differentiation of these lesions from serous cystic neoplasms or pseudocysts.11 The degree of cellular atypia in FNA could also be predictive of malignancy.12 Figure 1: Abdominal CT scan showing a cystic mass in the tail of the Because of the possibility of malignant trans- pancreas (arrow). formation of MCNs, they should be resected irrespective of their size or location.1,5 MCNs are ovarian-type stroma is essential for pathological diagnosis of usually located in the body and tail of the pancreas;5 open, 1,3 1,2 MCNs. MCNs typically occur in premenopausal women. laparoscopic, or robotic distal pancreatectomy with or with- To our knowledge, only 10 cases of MCN in men diagnosed out splenectomy is the operation of choice for these lesions.1 based on WHO criteria have been previously reported in MCNs could also rarely happen in the head of the pancreas; 2-8 the literature. Our case is the 11th case of MCN reported formal pancreatoduodenectomy is the operation of choice in a man. for these lesions.1 Extra caution should be implemented Because MCNs rarely happen in men, to rule out any during the surgery not to rupture the cyst, as it could lead chromosomal abnormality in our patient, we performed to intra-abdominal seeding of tumor cells.1 Moreover, in karyotyping, which showed normal male XY karyotype. order to provide an optimal sample for pathologist, the cyst This shows that MCNs can happen in men without any should be removed intact and not marsupialized.1 chromosomal abnormality. Complete resection of MCNs with benign nature is As in our patient, MCNs are usually asymptomatic considered a complete cure.1,10 These lesions do not recur; and are incidentally found during abdominal imaging for therefore, no follow-up imaging is needed.1,13 However, 1 evaluation of another often unrelated clinical indication. patients with malignant lesions have poor prognosis; their However, MCNs can occasionally present with abdominal five-year survival is 15%-35%.13 The most important predic- pain and fullness, nausea, vomiting, recurrent pancreatitis, tor of prognosis in malignant MCNs is the extent of tumor 1,5,9 or gastric outlet obstruction. Presence of symptoms such invasion.14 After resection, patients with malignant MCNs as weight loss or jaundice should raise the suspicion of the are recommended to have follow-up imaging with CT or 1,9 malignant nature of the MCNs. MRI for evaluation of possible recurrences or metastases.1 In cross-sectional imaging by ultrasonography, CT, In summary, we present a case MCN of pancreas with or MRI, MCNs are usually found as spherical macrocystic characteristic pathological finding of ovarian-type stroma 1 masses. MCNs usually do not communicate with pancreatic in a man. Our study shows that MCN could occur in men ducts but could result in the dilatation of the pancreatic ducts and should be considered in the differential diagnosis of 1,10 through pressure effect and obstruction. The following pancreatic lesions in men, as well as women. findings in the imaging of MCNs are in favor of malignant nature of these lesions: large size (>5cm), the presence of REFERENCES calcification, multiple papillary invaginations, a mural node or asymmetrically thickened wall, an eccentrically 1. Sakorafas GH, Smyrniotis V, Reid-Lombardo KM, et al. Primary located mass within a cystic area, local vascular invasion, pancreatic cystic neoplasms revisited: part II. Mucinous cystic pericystic reaction, extrahepatic biliary obstruction, splenic neoplasms. Surg Oncol. 2011;20:e93-101. vein obstruction or ascites.1,5 ERCP could be very helpful in 2. Yamao K, Yanagisawa A, Takahashi K, et al. Clinicopathological differentiation of MCNs which usually do not communicate features and prognosis of mucinous cystic neoplasm with ovarian- with pancreatic ducts versus psuedocysts or branch duct type stroma: a multi-institutional study of the Japan pancreas IPMNs which communicate with pancreatic ducts.1 More- society. Pancreas. 2011;40:67-71.

68 J La State Med Soc VOL 166 March/April 2014 Figure 2: Panel A: Photomicrograph illustrating the epithelial lining with prominent underlying ovarian-type stroma (Hematoxylin and Eosin stain, 100x original magnification). Panel B: Photomicrograph illustrating strong nuclear immunoreactivity of the ovarian- type stroma with estrogen receptor stain (100x original magnification). Panel C: Photomicrograph illustrating strong nuclear immunoreactivity of the ovarian-type stroma with progesterone receptor stain (100x original magnification).

3. Casadei R, Pezzilli R, Calculli L, et al. Pancreatic mucinous cystic 11. Recine M, Kaw M, Evans DB, et al. Fine-needle aspiration cytology neoplasm in a male patient. JOP. 2012;13:687-689. of mucinous tumors of the pancreas. Cancer. 2004;102:92-99. 4. Tokuyama Y, Osada S, Sanada Y, et al. Mucinous cystic neoplasm 12. Fasanella KE, McGrath K. Cystic lesions and intraductal neoplasms of the pancreas in a male patient. Rare Tumors. 2011;3:e14. of the pancreas. Best Pract Res Clin Gastroenterol. 2009;23:35-48. 5. Reddy RP, Smyrk TC, Zapiach M, et al. Pancreatic mucinous 13. Sarr MG, Carpenter HA, Prabhakar LP, et al. Clinical and cystic neoplasm defined by ovarian stroma: demographics, clinical pathologic correlation of 84 mucinous cystic neoplasms of the features, and prevalence of cancer. Clin Gastroenterol Hepatol. pancreas: can one reliably differentiate benign from malignant 2004;2:1026-1031. (or premalignant) neoplasms? Ann Surg. 2000;231:205-212. 6. Suzuki M, Fujita N, Onodera H, et al. Mucinous cystic neoplasm 14. Zamboni G, Scarpa A, Bogina G, et al. Mucinous cystic tumors in a young male patient. J Gastroenterol. 2005;40:1070-1074. of the pancreas: clinicopathological features, prognosis, and 7. Goh BK, Tan YM, Kumarasinghe MP, et al. Mucinous cystic tumor relationship to other mucinous cystic tumors. Am J Surg Pathol. of the pancreas with ovarian-like mesenchymal stroma in a male 1999;23:410-422. patient. Dig Dis Sci. 2005;50:2170-2177. 8. Wouters K, Ectors N, Van Steenbergen W, et al. A pancreatic mucinous cystadenoma in a man with mesenchymal stroma, Drs. Fallahzadeh, Zibari, Wellman, Abdehou, and Shokouh-Amiri expressing oestrogen and progesterone receptors. Virchows Arch. are with the John C. McDonald Transplant Center, Willis-Knighton 1998;432:187-189. Health System in Shreveport. 9. Crippa S, Salvia R, Warshaw AL, et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg. 2008;247:571-579. 10. Sarr MG, Murr M, Smyrk TC, et al. Primary cystic neoplasms of the pancreas. Neoplastic disorders of emerging importance-current state-of-the-art and unanswered questions. J Gastrointest Surg. 2003;7:417-428.

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Sphenoid Sinus Dehiscence as a Risk For Visual Consequences in an Immunocompromised Patient

Crystal P. Le, BS; Alejandra A. Valenzuela, MD; Michael Rosenberg, MS; Laveil Allen, MD; Enrique Palacios, MD, FACR

Isolated sphenoid sinus disease is a rare entity with severe and potentially life threatening sequela. Because of the proximity of the sinus to the orbit, anatomical defects within the surrounding bony structures can facilitate communication with orbital content, predisposing the patient to substantial visual consequences. We report a case of a 51-year-old immunocompromised male who presented with headache and gradual unilateral decreases in vision. Computed tomography revealed opacification of the left sphenoid sinus accompanied by unusual bony dehiscence of the proximal optic canal. Early recognition and treatment of sphenoid sinusitis requires urgent surgical intervention with delay of treatment potentially leading to irreversible blindness or other devastating consequences. Bony dehiscence of the sphenoid sinus overlying the optic nerve has only been found in 4% of cadavers. It is associated with increased risk of orbital complications and predicts a poor prognosis. Immediate intervention is particularly important in immunocompromised individuals who are at greater risk of these severe complications.

INTRODUCTION noid sinus and unusual bony dehiscence at the proximal optic canal. Magnetic Resonance Imaging (MR) (Figure 1, Isolated sphenoid sinusitis is an uncommon condi- B) revealed mild left proptosis with diffuse inflammatory tion that comprises less than 3% of all cases of sinusitis.2 enhancement of the intraconal fat and optic nerve sheath The sphenoid sinus is intimately juxtaposed near cranial spanning mid orbit to apex. The coronal sections confirmed nerves II-VI. An anomalous ostium increases the risk for perineural inflammatory process of the optic nerve. disease complications due to the sinus’s inability to contain Urgent functional endoscopic sinus surgery with left any swelling. Additionally, bony dehiscence of the sinus sphenoidectomy and sinus drainage was performed, and overlying the optic nerve has been found in 4% of cadavers. the patient improved within 24 hours. Subsequently, the These variations increase the risk of orbital complications patient’s condition declined over the next few days, and he secondary to the lack of a barrier to prevent spread of infec- expired after developing an acute ischemic infarction in the tion.2 The incidence of permanent vision loss in these cases left basal ganglia with ophthalmoplegia and left cavernous is as high as 10.5%, thereby requiring a prompt diagnosis. sinus thrombosis. Immunocompromised individuals require immediate intervention due to the greater risk of severe infection causing DISCUSSION bony dehiscence and other complications.3 Acute sphenoid sinusitis is an uncommon condition CASE REPORT that is often misdiagnosed in the evaluation of refractory headache with visual changes.1,2 Anatomical variances of A 51-year-old immunosuppressed male presented with the sphenoid sinus increase the risk of orbital complications. a three-month history of frontal headache with gradual vi- Accessory septa may modify the sinus drainage in 30% of sion loss in the left eye. Examination revealed significant cases. Bony dehiscence of the sphenoid sinus over the optic left periocular swelling, relative afferent pupillary defect, canal occurs in 4%-13% of cases.1,2,5 The bony covering of the chemosis, extraocular movement limitation, and no light optic canal within the sphenoid sinus may be congenitally perception in the left globe. dehiscent or secondary to an erosive inflammatory process. Orbital Computed Tomography (CT) (Figure 1, A) Dehiscence of this bony structure permits exposure of the demonstrated inflammatory opacification of the left sphe- optic nerve, allowing irreversible nerve ischemia second-

70 J La State Med Soc VOL 166 March/April 2014 Figure 1: CT axial (A) demonstrated a focal inflammatory process in the posterior sphenoid sinus on the left with developmental dehiscence of the lateral wall of the optic nerve canal (arrow), allowing the inflammatory process to extend into the apex of the orbit. MR contrast-enhanced images: Axial image (B) reveals enhancement of the inflammatory process extending from the posterior sphenoid sinus into the orbital apex and around the optic nerve (arrow). Inflammation of the medical rectus muscle and periorbital area is also noted at this level. Coronal image (C) at the level of the orbital apex (arrow) and a coronal image (D) at the level of the proximal optic nerve (arrow) showing perineural inflammatory enchancement. ary to direct compression by the expansive inflammatory tion must be taken with immunocompromised patients lesion or to ischemic infarction from thrombophlebitis or because of the increased likelihood of severe progressive vasculitis.2,6 infection causing erosive dehiscence alongside other com- Early diagnosis and surgical intervention are essential plications and even death.2,6 If acute sphenoid sinusitis is to prevent permanent blindness, which may ensue within suspected, broad spectrum IV antibiotics should be initi- one to two hours.2 Our case emphasizes the significance of ated, a detailed cranial nerve exam should be performed, anatomical variations, particularly bony dehiscence over and CT imaging of the orbit, paranasal sinuses, and skull the optic canal. These defects are rare but predict a poor base obtained. Irreversible damage to the optic nerve can prognosis. Lower thresholds for diagnosis and interven- occur before development of gross intraorbital pathology.

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Immediate surgery is necessary if the patient does not re- 4. Oruckaptan H, Akdemir P and Ozgen T. Isolated sphenoid spond promptly to medical therapy or at the first sign of a sinus abscess: clinical and radiological failure in preoperative complication. Surgery should aim to remove any purulent diagnosis. Case report and review of the literature. Surg Neurol. material or necrotic tissue, maintain adequate drainage of 2000;53(2):174–7. 2 5. Sapçı T, Derin E, Almaç S, Cumalı R, Saydam B,Karavus M. The the sinus, and obtain cultures. Early surgical intervention relationship between the sphenoid and the posterior ethmoid provides the best chances at preventing permanent vision sinuses and the optic nerves in Turkish patients. Rhinolog. loss. However, even with prompt treatment, full restoration 2004;42(1):30-34. of vision may not always be obtainable.6 6. Farboud A, Trinidade A, Shakeel M, Rajapksa S, Hanif J. Unilateral blindness secondary to acute sphenoid sinusitis. Royal Belgian REFERENCES Society for Ear, Nose, Throat. 2011;7(1):47-49.

1. Wankhar B, Bapuraj JR, Gupta AK, et al. Chronic sphenoid sinusitis revisited. Comparison of multidetector axial sections, multiplanar Drs. Le and Rosenberg are with the Tulane University School of reconstructions, and virtual sinoscopy with endoscopic sinus Medicine. Dr. Valenzuela is with the Department of Ophthalmology at surgery. Arch Otolaryngol Head Neck Surg. 2007;133(7):710-716. Tulane University School of Medicine. Drs. Allen and Palacios are with 2. Postma G, Chole R, Nemzek W. Reversible blindness secondary the Department of Radiology at Tulane University School of Medicine. to acute sphenoid sinusitis. Otolaryngol Head and Neck Surgery. 1995;112(6):742-6. 3. Patt B, Manning C. Blindness resulting from orbital complications of sinusitis. Otolaryngol Head Neck Surg. 1991;104: 789–795.

72 J La State Med Soc VOL 166 March/April 2014 Protecting the Private Practice of Medicine

Direct Primary Care: Kicking Insurance Out of the Exam Room

Sabrina L. Noah

The evolution of our healthcare system has forced a patient’s health. This is where patients go for check-ups, primary care physicians, like many other specialties, to vaccinations, or sprained ankles. If a patient has a chronic operate an insurance-centric business rather than practic- illness, their primary care physician is a partner in their ing medicine. In order to sustain a practice, physicians management every step of the way. Direct primary care must see 20-30 patients per day, making the average office practices are operated under the principle that the physician- visit only 15 minutes. Physician and patient satisfaction are patient relationship is the main focus. Bliss emphasized decreasing while reimbursements rates continue to decline. that “we want (the patients) to have trust in us; we want In response to these conditions a new practice model called them to believe that we work for them and not for a bunch direct primary care is gaining national attention. Direct of other interests.” primary care practices are designed to provide physicians He believes direct primary care’s success is ultimately with the freedom to practice medicine, instead of managing based on “a real doctor-patient relationship, reinforced by insurance claims. the economics, so that our customer is the patient. Our job Recently our Vice President of Legal Affairs Greg Wad- is to get the care right, not the coding.” Direct primary care dell traveled to Seattle, Washington, to interview the Co- practices do not take insurance; therefore, there is no need Founder and Vice President of Medical Affairs of Qliance, for billing approval, deductibles, or co-payments. With Dr. Garrison Bliss. A primary care physician with more lower overhead and dramatically less paperwork, direct than 30 years of experience, Dr. Bliss founded his first direct primary care providers are no longer forced to squeeze in primary care practice in 2007 after growing disillusioned an unmanageable number of patients and can instead take with the current direction of healthcare. In addition to ad- the time necessary with each patient to deliver high-quality, vocating for the national expansion of the direct primary personalized care. By eliminating insurance burdens from care practice model, he has also served as the President of the Society for Innovative Medical Practice Design and the Direct Primary Care Coalition. Direct primary care practices offer a membership-based approach to routine and preventive care. Patients pay a low monthly fee, typically $49 to $100, to their physician for all of their everyday health needs. Like a health club membership, this fee gives patients unrestricted access to visits and care, allowing them use of the services as much or as little as they want. “What distinguishes us from other practices is that we have eliminated the fee-for-service model of care,” said Bliss. However, don’t confuse direct primary care with other pre-paid models. “This is not a concierge model; this model has been applied from the wealthiest patients to the indigent and uninsured,” he added. A direct primary care practice pro- Dr. Garrison Bliss (left), co-founder and vice president of Medical Affairs of Qliance, vides routine healthcare, essential for the a direct primary care practice in Seattle, talks with LSMS Vice President of Legal well-being and ongoing maintenance of Affairs Greg Waddell (right).

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direct primary care practices, physicians have more time to a renewed commitment to providing the kind of care that do what they were trained to do, practice medicine. initially inspired them to dedicate their lives to medicine. By cutting out the instability of an insurance depen- In short, direct primary care facilities enable physicians to dent income stream, direct primary care practices allow do what they were trained to do, treat patients. physicians the financial security to focus on patient care. In Louisiana, the Louisiana State Medical Society has “Monthly fee based practices allow you to know what your introduced legislation, Senate Bill 516 authored by Sena- income is this year. Now you can plan,” said Bliss. The tor Sherri Buffington and Representative Stuart Bishop, to direct primary care model relies instead on the economic make it possible to operate a direct primary care practice. power of its patients to fund a practice dedicated to quality Current law requires that any entity receiving any type of and affordable healthcare. Simply stated, it allows patients prepayment for medical services be licensed as an HMO to directly contract with their primary care physician by or insurance company, which makes the practice model removing health insurance from the primary care equation. cost prohibitive. SB 516 amends the law to recognize that Patients in a direct primary care practice can purchase a direct primary care practice is a medical practice and not an insurance plan to cover emergencies and serious illnesses. an insurance company. We believe this legislation will be Because this insurance policy doesn’t need to cover routine signed into law, and we will be seeing direct Primary Care care, many patients choose a less comprehensive plan with practice open statewide soon. a higher deductible and lower premiums. For example in Bliss emphasized that, “The only people who will be Washington, Bliss’s practice has partnered with an insur- unhappy with a future built on Direct Primary Care will be ance company to offer a complementary catastrophic plan those who think that the present system works for the doc- to their patients. According to Bliss, the insurance company tor and the patient. I’m still waiting to meet that person”. can make the plan affordable because, “when primary care As we have seen here in Louisiana, and Bliss has seen in is working well, the insurance company doesn’t have to Washington, we can’t afford the alternative. regulate the rest of the healthcare as much. There are no incentives to over-refer.” **This is the second installment in a new four-part series In the 18 states direct primary care has already been that will report on emerging trends and new practice models in implemented, physicians report increased satisfaction and medicine.

74 J La State Med Soc VOL 166 March/April 2014 ECG of the Month

Unexpected Atrioventricular Conduction in High-Grade Atrioventricular Block

Manpreet Singh, MD; Paul A. LeLorier, MD; Murat M. Celebi, MD; D. Luke Glancy, MD

A 90-year-old man with a history of high blood pressure, a cerebrovascular accident without focal residua, dementia, and stage 3 chronic kidney disease went to the emergency department because of dizziness and near syncope. His medications were aspirin 81 mg qd, clopidogrel 75 mg qod, escitalopram oxalate 10 mg qd, quetiapine fumarate 25 mg qd, and memantine hydrochloride 10 mg qd. He had orthrostatic hypotension with supine blood pressure of 173/77 mmHg falling to 116/68 on standing, while pulse increased from 66 to 84 beats/min. He received IV fluid and returned home. Two days later, he saw his primary care physician because of episodes of dizziness and confusion. The Figure shows an electrocardiogram recorded during that visit.

Figure 1: Outpatient electrocardiogram recorded in a 90-year-old man with episodes of dizziness and confusion. See text for explication.

What is your diagnosis? Explication is on pg. 28

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DIAGNOSIS: Sinus rhythm; high-grade second-degree three main classes: “…(1) occult 2:1 A-V block in which an atrioventricular block with a junctional escape rhythm and three idioventricular beat ‘retracts’ an otherwise refractory barrier capture complexes, each with right bundle branch block aberration; within the A-V node; (2) alternation between dissociated in- possible septal myocardial infarct of indeterminate age; ST-T and tranodal transmission pathways; and (3) ‘ventriculophasic’ U wave changes suggesting hypokalemia. (vagal) depression of nodal conductivity.”6 Although there is now general agreement that true In most cases of second degree atrioventricular block, supernormal conduction does not occur in the AV node, su- the longer the R-P interval, the more likely is the P wave to pernormal conduction has been demonstrated in the bundle be conducted to the ventricles. Thus, in this ECG, the 2nd, branch-Purkinje system of the dog.7-8 Furthermore, Spear 6th, 10th, and 12th P waves, with R-P intervals of 0.67 to 0.81 and Moore have demonstrated supernormal conduction seconds, would be the most likely ones to be conducted; and in the distal bundle of His and proximal bundle branches, the 4th and 8th P waves, with R-P intervals of 0.42 to 0.50 but they could not demonstrate it in the proximal portion of seconds would also have a good chance to be conducted. the bundle of His.9 They ascribed this difference to the rela- None of them is. Instead, the 3rd, 7th, and 13th P waves tively low transmembrane resting potential of the proximal with much shorter R-P intervals, 0.19 to 0.23 seconds, are bundle of His, similar to that in the AV node, whereas the conducted. The 1st, 5th, 9th, and 11th P waves either occur electrophysiological properties of the distal bundle of His simultaneously with a junction-initiated QRS or 0.08 seconds are similar to those in bundle branches.9 after one and are not conducted. Thus, there appears to be Supernormal AV conduction allowing transmission of only a short window of time soon after junction-initiated P waves with R-P intervals of 0.19 to 0.23 s, but not those QRSs when atrioventricular conduction can occur. This with shorter or longer R-P intervals, would explain the seeming paradox needs explanation. unexpected AV conduction in our patient. If, as described In times past, supernormality often has been invoked above, supernormality does not occur in the AV node, to explain unexpected excitability or conductivity in cardiac could supernormality in the distal His bundle following tissue. Pick et al. defined the supernormal phase as, “…a His-initiated complexes of the escape rhythm explain the short, early, and limited period of the cardiac cycle during unexpected conduction? In fact, Moe et al. theorize such a which a stimulus elicits either a totally unexpected response, possibility in section F of their paper.6 or one that is less abnormal than expected considering the Whatever the fine points of the patient’s atrioventricu- state of recovery from the preceding impulse.”1 They then lar block, it was successfully treated with an electronic AV stated that they had collected 18 cases demonstrating a sequential pacemaker that captured 100% of the time, usu- supernormal phase of atrioventricular conduction in the ally in the P-synchronous mode. None of the patient’s other preceding five years, in addition to 10 cases that they had ECGs before the pacemaker implantation suggested a septal described previously.2-5 All were cases of advanced atrioven- myocardial infarct as the one in the Figure did. Furthermore, tricular block, and the authors concluded, “…supernormal his echocardiogram showed normal left ventricular function, AV conduction is an abnormal phenomenon encountered but also showed moderate aortic stenosis. only in the presence of AV block – in other words, only when the absolute or relative refractory period of the conduction REFERENCES system is unduly prolonged may a phase of supernormality become manifest.”1 1. Pick A, Langendorf R, Katz LN. The supernormal phase of In reviewing the previous literature, including the 10 atrioventricular conduction: I. Fundamental mechanisms. cases they reported earlier,2-5 but none of those in their cur- Circulation 1962;26:388-404. rent publication,1 they decided, “…that a supernormal phase 2. Mack I, Langendorf R, Katz LN. The supernormal phase of recovery of conduction in the human heart. Am Heart J 1947;34:374- was definitely in action in 32 instances… In 14 additional 389. 1 ones, alternative interpretation appears possible…” Alter- 3. Pick A, Fishman AP. Observations in heart block. Supernormality native explanations included vagal effects, second-degree of A-V and intraventricular conduction and ventricular parasystole AV block with escape complexes, dual AV nodal pathways, under the influence of epinephrine. Acta Cardiol 1950;5:270-287. and “…a prolonged rest period in the upper AV junction 4. Katz LN, Pick A. Clinical Electrocardiography I. The Arrhythmias. following retrograde conduction…”1 Their final conclusion Philadelphia: Lea & Febiger;1956. stated, “The application of the concept of supernormal con- 5. Langendorf R. Alternation of A-V conduction time. Am Heart J duction in conjunction with that of concealed conduction 1958;55:181-191. and of unidirectional block permits a satisfactory interpre- 6. Moe GK, Childers RW, Merideth J. An appraisal of ‘supernormal’ A-V conduction. Circulation 1968;38:5-28. tation of some otherwise inexplicable features of AV block 7. Arbel E, Sasyniuk BI, Moe GK. Supernormal ventricular 1 encountered in clinical electrocardiography.” conduction in dog heart (Abstract). Federation Proc 1971;30:553. 1 Six years after the paper of Pick et al, Moe and col- 8. Spear JF, Moore EN. Supernormal excitability and conduction in leagues wrote a seminal paper demonstrating that in most, the His-Purkinje system of the dog. Circ Res 1974;35:782-792. if not all, published cases of supernormality of AV conduc- 9. Spear JF, Moore EN. Supernormal conduction in the canine tion alternative mechanisms could explain the observed bundle of His and proximal bundle branches. Am J Physiol phenomena.6 They divided the alternative mechanisms into 1980;238:H300-H306.

76 J La State Med Soc VOL 166 March/April 2014 Dr. Singh is a Fellow and Drs. LeLorier and Glancy are Faculty in the Cardiology Section, Department of Medicine at the Louisiana State University Health Sciences Center in New Orleans. Dr. Celebi is a Cardiologist at the Touro Infirmary in New Orleans.

J La State Med Soc VOL 166 March/April 2014 77 Journal of the Louisiana State Medical Society Radiology Case of the Month

49-Year-Old Female With an Anterior Mediastinal Mass

Bruce Bordlee Jr., BS; Andrew Oncale, BS; Jonathan Stone, MD; Enrique Palacios, MD; Harold Neitzschman, MD

Castleman’s disease is an uncommon benign lymphoproliferative disorder characterized by hypervascular lymphoid hyperplasia. Two distinct histologic variants of Castleman’s disease exist – hyaline vascular type and plasma cell type. The etiology is uncertain; however, it is thought to be inflammatory or hamartomatous in nature. Castleman’s disease can occur at any age with a peak incidence in the third to fourth decade. This article presents a case of Castleman’s disease in a female patient and aims to educate about the natural history, diagnosis, and management of the disease.

Figure 1A

Figure 1: CT post-contrast (A) axial, (B) coronal, and (C) sagittal planes demonstrating a well marginated non-enhancing solid mass in the anterior portion of the superior mediastinum. No evidence of lymphadenopathy or any other significant findings. Figure 1B

78 J La State Med Soc VOL 166 March/April 2014 Figure 1C Figure 2: Histopathologic examination reveals diffuse lymphoid tissue exhibiting prominent follicles. Follicles show proliferation of vessels with thick, hyalinized walls. Mantle zones are composed of small lymphocytes in a concentric “onion-skin” pattern. Interfollicular zones show lymphocytes and monocytes interspersed with hyalinized fibrous tissue and vessels. Thymic remnants and heterotopic parathyroid tissue is also identified in surrounding adipose tissue.

HISTORY of Castleman’s disease is found within the mediastinum, making it the most common location. Ten to fifteen percent The patient is a 49-year-old female who presented with of cases are seen within the abdomen, retroperitoneum, a three-year history of a neck mass. The patient complained and pelvis. Another 10%-15% is seen in the head and neck. of fatigue and denied any weight loss, fever, chills, night Castleman’s has also been described in the extralymphatic sweats, abdominal pain, bleeding, or other symptoms. Her tissues, including the lung, larynx, parotid gland, pancreas, past medical history is positive for hypothyroidism diag- and muscle.2,4,6 The etiology is uncertain. It is thought to be nosed 10 years prior, for which she is on thyroid replacement inflammatory or hamartomatous in nature.3,4 Castleman’s therapy. On physical exam, the area of her lower neck was disease occurs at any age with a peak incidence in the third enlarged; however, there was no tenderness to palpation. to fourth decade; however, the multicentric form usually A CT was obtained that demonstrated a 3.7 x 2.2 cm soft affects older individuals.2,4 tissue density within the superior mediastinum just below Two distinct histologic variants exist. The most common the thyroid of nonspecific etiology. A surgical biopsy was of which is the hyaline-vascular type, which accounts for also obtained. 90% of cases. Histologically, it is identified by small lymphoreticular follicles distributed within a hyalinized stroma DISCUSSION (Figure 2). The plasma cell type, which is the second variant and accounts for only about 10% of cases, is distinguishable Castleman’s disease is an uncommon, benign lym- by larger lymphoreticular nodules that are separated by phoproliferative disorder characterized by hypervascular sheets of plasma cells and a less vascular stroma.7 lymphoid hyperplasia.1,7 Originally described in the medi- Castleman’s disease can also be categorized as either astinum by Castleman et al. in 1956, the disease can develop unicentric or multicentric. Typically, the unicentric variety wherever lymph nodes are present. Approximately 70% is of the hyaline-vascular type and is amenable to surgical

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treatment. Contrastly, the multicentric variety is often the 3. Johnson JT, Oral A, Nalesnik M, Roscoe GJ, Whiteside TL. plasma cell type, which is associated with systemic mani- Giant lymph node hyperplasia: clinical and immunohistologic festations.2,6 correlation of an intermediate variant. Ear Nose Throat J 1985; Patients with the hyaline-vascular type of disease tend 64:249–254. 4. Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and to be asymptomatic, but may complain about symptoms plasma-cell types of giant lymph node hyperplasia of the caused by compression of adjacent structures or may present mediastinum and other locations. Cancer 1972; 29:670–683. with a palpable mass. However, 50% of cases involving the 5. Ko, Sheung-Fat, Hsieh, Ming-Jeng, Ng, Shu-Hang, Lin, JUI-Wei, plasma cell variant show systemic manifestations, including Wan, Yung-Liang, Lee, Tze-Yu, Chen, Wei-Jen, Chen, Min-Chi. fever, anemia, and hyperglobulinemia.7 Pictorial Essay: Imaging Spectrum of Castleman’s Disease. AJR Laboratory evaluation of a patient with Castleman’s 2004; 182: 769-775. disease, hyaline vascular type, is almost always within 6. McAdams HP, Rosado-de-Christenson M, Fishback NF, normal limits, and laboratory assessment is almost never Templeton PA. Castleman disease of the thorax: radiologic features with clinical and histopathologic correlation. Radiology useful for the clinical diagnosis. The differential diagnosis, 1998; 209:221–228. especially in the head and neck region, should include other 7. Shin JH, Lee HK, Kim SY, Khang SK, Park SH, Choi CG, et al. benign lesions such as pleomorphic adenomas, Warthin Castleman’s disease in the retropharyngeal space: CT and MR tumor, schwannoma, carotid body tumors, and inflam- imaging findings. AJNR Am J Neuroradiol 2000; 21:1337–9. matory lymphadenectasis; but malignant tumors such as 8. Tan, T Y, Pang, K P, Goh, H K C, Teo, E L H, Abilash, B, Walford, lymphoma, mucoepidermoid carcinoma, adenoid cystic N. Castleman’s disease of the neck: a description of four cases carcinoma, and metastatic lymph node should also be con- on contrast-enhanced CT. The British Journal of Radiology 2004; sidered. Imaging studies such as US, CT, MRI/MRA are 77:253-6. sometimes helpful for establishing a differential diagnosis. 9. Zhong L, Wang L, et al. Clinical analysis of Castleman Disease (hyaline vascular type) in parotid and neck region. Oral Surgery In Castleman’s disease, ultrasonography and CT always Oral Medicine Oral Pathology Oral Radiology & Endodontics show uniformly hypoechoic masses with good through 2010;109:432-40. transmission.9 Treatment for Castleman’s Disease, hyaline vascular type, in the parotid and neck region is surgical resection. Mr. Bordlee Jr. and Mr. Oncale are fourth-year Medical Students at These patients tend to have a good prognosis without re- Tulane University Health Sciences Center in New Orleans. Dr. Stone is a Pathology Resident at Tulane University Health Sciences Center. currence. However, for the plasma cell type, the prognosis Dr. Palacios is Section Chief of Neuroradiology and Clinical Professor is poor, and the patient usually undergoes radiation and of Otorhinolaryngology at Tulane University Health Sciences Center. chemotherapy with or without surgical resection.9 Dr. Neitzschman is a Professor of Radiology and the Chairman of the Department of Radiology at Tulane University Health Sciences Center. REFERENCES

1. Chaloupka JC, Castillo M, Hudgins P. Castleman disease in the neck: atypical appearance on CT. AJR Am J Roentgenol 1990;154:1051–2. 2. Johkoh T, Muller NL, Ichikado K, et al. Intrathoracic multicentric Castleman disease: CT findings in 12 patients. Radiology 1998;209:477–481.

80 J La State Med Soc VOL 166 March/April 2014 Clinical Case of the Month

Abstracts From the Louisiana American College of Physicians Associates Meeting

Each year medical students in Louisiana and residents from the eight Internal Medicine training programs in Louisiana are invited to submit abstracts for the annual Louisiana American College of Physicians (ACP) Associates Meeting. The content of these abstracts includes clinical case vignettes or research activities. The abstracts have all identifying features removed (i.e., names, institutional affiliations, etc.) before being sent to physician judges. Each judge scores each abstract independently, and the scores from the judges are averaged and ranked. This year we are excited to be able to publish the 26 most highly ranked abstracts presented at this year’s competition. These abstracts (15 oral, 11 poster) were presented at the Associates Meeting held at the Louisiana State University Health Sciences Center in Shreveport on January 21, 2014. We would like to thank the Journal of the Louisiana State Medical Society and appreciate its efforts to publicize the hard work of these trainees.

Lee S. Engel, MD, PhD, FACP Chair, Louisiana Associates Liaison Committee

William Davis, MD, FACP Governor, Louisiana Chapter ACP

A Case of Mixed Pulmonary Infection With Two ogy and culture of bronchial endoscopy washings revealed Non-Tuberculous Mycobacterium Species in a Previously Mycobacterium Avium Complex. The azithromycin and Health Adult Male moxifloxacin regimen was initiated. Y. Nikitina, A. Bapat, and B. Nseir Discussion: Most cases of atypical mycobacteriosis Department of Internal Medicine are secondary infections associated with underlying lung University Medical Center, LSU-Health Sciences Center, disease and immunosuppression secondary to HIV/AIDS Lafayette or malignancy. In this patient, however, we report an unusual case of pulmonary infection due to M. kansasii and Case: A 41-year-old previously healthy African-Ameri- M. Avium Complex in an otherwise healthy male without can man presented with shortness of breath and productive underlying lung disease. cough. Chest radiograph and chest CT identified a diffuse nodular infiltrate with a large cavitary lesion and a large Isolated Small Intestinal Metastatic Disease as a Herald pneumothorax in the right hemithorax with additional of Recurrent NSCLC cavitary lesions in the left upper lobe. A sputum culture E. Miller, C. Caruthers, and S. Sanne was positive for a Mycobacterium kansasii, and the patient LSU-Health Sciences Center, New Orleans was subsequently started on isoniazid 300 mg, rifampin 600 mg, and ethambutol 600 mg. The M. kansasii susceptibility Introduction: The small bowel is a very rare location of testing revealed resistance to ciprofloxacin, rifampin, and metastatic deposits of non-small cell lung cancer (NSCLC). trimethoprim-sulfamethoxazole. Unfortunately, no follow- Case: A 58-year-old patient with a history of Stage III up sputum cultures were collected, but the patient reported (T2N2M0) NSCLC treated with chemotherapy and radia- completing a 15-month course of treatment. Three months tion presented to the hospital with one week of shortness of later, he presented to the emergency room with chest pain breath and chest discomfort. The patient’s NSCLC had been and shortness of breath with a productive cough for two- considered to be in virtual remission based on a PET scan month duration. Chest radiograph identified bilateral, up- following his treatment. At presentation, the patient was per lobe bullous emphysematous changes with probable found to have a severe microcytic anemia. Initial workup superimposed atypical infection of the left upper lobe. for a source for the patient’s blood loss was negative. A re- Blood-tinged sputum was noted on presentation. The cytol- view of the patient’s medical record suggested a suspicious

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finding on a surveillance CT involving the small bowel. derwent left adrenalectomy with removal of a 1.8 x 1 x 1 cm The patient underwent CT enterography and was found to mass. Histopathology was consistent with pheochromocy- have a partially obstructing mass located on the mesenteric toma with focal invasion of the periadrenal fat. The patient side of the small bowel. Laparoscopic exploration of his remained normotensive intraoperatively and post-surgery. abdomen was performed with resection of the mass and re- All laboratory abnormalities subsequently normalized. anastamosis of the small bowel; no signs of other masses or Discussion: Pheochromocytomas usually cause sus- metastatic deposits were evident. Gross pathology revealed tained hypertension or adrenergic spells but occasionally an 8 cm lesion fixed on the mesenteric side of the bowel se- present with few symptoms, especially if small. rosa eroding into the bowel lumen, which was determined to be a poorly differentiated carcinoma invading through both the mucosal and serosal surfaces. Immunostaining of The Mike Tyson Challenge: An Extreme Case of the sample revealed CK-7 and TTF-1 staining characteristics Rhabdomyolysis in line with the biopsy from the patient’s primary lesion in A. Wright and J. Spiegel the lung, and a diagnosis of NSCLC metastatic to the early LSU-Health Sciences Center, New Orleans ileum was made. The patient was considered to have a solitary metastatic event to the small bowel and was discharged Introduction: There are many causes of rhabdoymy- with plans to undergo salvage therapy. Several weeks later, olysis, including excessive exercise. One of the most serious the patient returned to the emergency room with nausea, complications of rhabdoymyolysis remains acute kidney weight loss, melena, and decreased appetite. On CT scan- injury (AKI), which is caused by non-protein heme pigment ning, he was found to have widespread carcinomatosis with that is released from myoglobin. Furthermore, inflammation implants throughout his large and small bowel, along with of the muscle can compress structures in the same fascial nodules in his liver, adrenal glands, and kidneys. compartment, resulting in compartment syndrome. Discussion: While an extremely rare location for iso- Case: A 24-year-old inmate was brought to the emer- lated metastasis in patients with NSCLC, metastatic disease gency department with severe thigh pain and dark-colored to the small bowel may be associated with mild and non- urine after participating in “The Mike Tyson Challenge.” specific symptoms that may not be immediately recognized During this challenge, he performed 372 squats over a as metastatic disease. While these lesions generally portray 45-minute time interval. The thigh pain began the next morn- a very poor prognosis, early and aggressive therapy may ing followed by “Coca-Cola”-colored urine. On physical improve time to further relapse and quality of life. exam, his thighs were extremely tense, and he underwent emergent bilateral fasciotomy for compartment syndrome. A Case of “Normotensive” Pheochormocytoma He was found to have a creatinine kinase of 401,880 U/L, R. Nair and J.D. Maier BUN of 45 mg/dl, serum creatinine 7.21 mg/dl, and potas- LSU-Health Sciences Center, Shreveport sium of 6.3 mmol/l. Urinalysis revealed 250 blood/ul but only 3 to 5 red blood cells/HPF. He received insulin, sodium Introduction: Pheochromocytoma is a rare cause of polystyrene sulfonate, IV fluid hydration, and hemodialysis. hypertension but is potentially lethal and should be con- He slowly improved while receiving three weeks of hemo- sidered in patients with suspected secondary hypertension. dialysis and physical therapy in the hospital. Although presence of a pheochromocytoma is less likely Discussion: In his prime, “Iron” Mike Tyson was the in the absence of typical symptoms and findings, atypical self-proclaimed “baddest man on the planet.” A workout presentations do occur, and laboratory and imaging studies based on his physical training was developed and named become more important for diagnosis. the “Mike Tyson Beast Workout” or “Challenge.” Some Case: A 60-year-old male with history of asthma, recent- rules of the “Beast Workout” are as follows: 1) The workout onset mild hypertension treated with low-dose amlodipine, must be performed in no more than one hour; 2) The aim is and no significant family medical history was noted to have to perform dead lifts, bench press, squats, chest press, and an incidental 2 cm left adrenal nodule - hyperintense on T2 dumbbell curls throughout the hour. Our patient barely MRI images of the lumbar spine - which was obtained for survived the squats. Fortunately, aggressive surgical in- evaluation of back pain. The patient had no symptoms of tervention, fluid hydration, and hemodialysis were able adrenergic spells except for occasional mild night sweats. to reverse the damage caused by the release of myoglobin Physical exam was unremarkable with blood pressure from injured muscle. 136/80 mmHg. Laboratory evaluation disclosed persistently elevated plasma metanephrines, 24-hour urine epinephrine, and urine metanephrines two to four times the upper limit of normal. Serum and 24-hour urine cortisol were within normal limits. A dedicated CT of the adrenals showed a 2.1 cm adrenal nodule with precontrast attenuation of >10 HU and essentially no contrast washout on delayed post-contrast phase, suggestive of pheochromocytoma. The patient un-

82 J La State Med Soc VOL 166 March/April 2014 Journal of the Louisiana State Medical Society

Native Valve Legionella Endocarditis as a Cause of one month. On the first incident, she admitted recent heavy Arterial Embolization drinking and had an elevated ethanol level. Lipase was J. Domercant, S.R. Charpentier, K. Siddarth, and S.M. Gupta normal, and neither CT nor ultrasound showed evidence Leonard J. Chabert Medical Center, Houma of acute pancreatitis. She was managed conservatively with bowel rest, IV hydration, and pain medication, and Introduction: Legionella Endocarditis is an extremely discharged home after three days. Two weeks later, she rare condition even among patients with prosthetic valves. presented with epigastric pain, subjective fever, nausea, and Even more infrequent in patients who have native valves, vomiting. She denied alcohol use or abdominal trauma since only a handful of cases have been reported. the prior admission but reported heavy cannabis usage. Sur- Case: A 43-year-old Caucasian male with no past medi- gical history included cholecystectomy. She took metoprolol cal history presented to the emergency department with dif- for hypertension. Abdominal exam revealed hypoactive fuse abdominal pain. Associated symptoms included 20- to bowel sounds, tenderness to palpation in the epigastrium, 30-pound weight loss, nausea, constipation fevers, and night and guarding. Lipase, AST, and ALP were 3,784 U/L, 101 sweats. Physical exam was significant for cachexia, acute U/L, and 156 U/L, respectively. Lipid panel was normal. distress secondary to abdominal pain and tenderness, and She was again managed supportively and discharged home hepatosplenomegally. Labs revealed leukocytosis with a left after three days. Four days later, she presented again with shift, and abdominal and pelvic CT with IV contrast showed abdominal pain and noted continued marijuana use. She infarcts within the spleen and in the lower pole of the right responded well to conservative management. kidney. The differential diagnosis after admission to the Discussion: As the most popular illicit drug in the hospital included endocarditis and hypercoagulable states world, the effects of cannabis are well-known. The mecha- secondary to malignancy. The former was confirmed with nism behind cannabis-induced pancreatitis is not well a Transesophageal Echocardiogram (TEE), which revealed understood, but one study suggests agonism of the CB1 an aortic valve that appeared to be bicuspid and a 0.9 cm x receptor may play a role. Another possibility is that mari- 0.7 cm calcified mass with adherent vegetations measuring juana often has chemical additives, commonly known as less than 2 mm in length. Blood and urine cultures were “lacing”. If marijuana was “laced” with a chemical or other negative, therefore empiric treatment for endocarditis with additive known to cause pancreatitis, this too could result vancomycin, gentamycin, ciprofloxacin, and ampicillin/ in pancreatitis. Cannabis-induced pancreatitis is a rare but sulbactam was continued. Per Infectious Disease recom- reported entity in the literature. This diagnosis should be mendations, acute convalescent IgM for rare etiologies such arrived at after other causes have been ruled out in a patient as Q fever, mycoplasma, and Legionella were ordered for with history of cannabis usage. With the already-present culture negative endocarditis. The final diagnosis of Legio- popularity of cannabis, and the growing popularity of le- nella endocarditis with embolic phenomena was made when galization of marijuana, cannabis-induced pancreatitis is a IgM for Legionella was detected. The antibiotic regimen was condition that may become more common. de-escalated to ciprofloxacin, and his symptoms continued to significantly improve. He was subsequently discharged Neutropenia and Splenomegaly After the Discontinuation symptom-free with outpatient follow-up for further evalu- of Methotrexate: A Case of Felty Syndrome ation and treatment. W. Penn and Z. Bruce Discussion: This case underscores an atypical presenta- Earl K. Long Medical Center, Baton Rouge tion of endocarditis and the importance of TEE in evaluation of such cases. The patient had two minor criteria of fever Introduction: Felty syndrome (FS) is the rare triad of and vascular phenomena on presentation with no known rheumatoid arthritis (RA), neutropenia, and splenomegaly. predisposing factors. Moreover, this case illustrates the RA occurs in about 1% of the population, while FS mani- ability of rare etiologies such as Legionella to present on fests in just 1%-3% of those with RA. It is important to dif- native valves. ferentiate FS from other life-threatening diseases such as lymphoma, leukemia, and HIV as treatments are markedly Cannabis-Induced Pancreatitis: A Case Report different. M.C. Raley, M. Bouquet, and G. Kahlon Case: A 52-year-old white female with long-standing LSU-Health Sciences Center, Shreveport seropositive RA treated with methotrexate, plaquenil, and adalimumab presented to clinic with chronic bilateral lower Introduction: Acute pancreatitis is a common cause of extremity neuropathy and significant weight loss. Physical hospitalization in the United States. One study noted almost examination revealed tender, deformed joints in the hands 275,000 admissions in a single year. Common etiologies and feet bilaterally, with multiple rheumatoid nodules are cholelithiasis, alcoholism, and medications. Cannabis- over the extensor surfaces of both forearms. Abdominal induced pancreatitis has been seldom reported in literature exam was significant for mild splenomegaly confirmed prior to this case. by ultrasound. Routine lab work revealed pancytopenia Case: A 54-year-old white female presented to the with an absolute neutrophil count (ANC) of 200/mm3. emergency department for abdominal pain three times in Peripheral blood smear was negative for blasts and large

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granular lymphocytes. Review of records revealed that her begins with flu-like symptoms followed by an asymptomatic WBC count had decreased over the preceding 15 months period, then a more severe second phase characterized by from a peak of 11,700/μL to a nadir of 2,700/μL, with a meningitis, liver, and kidney damage (also called Weil’s concurrent decrease in granulocytes. Subsequent bone mar- disease). The incubation period is 7-29 days. The bacteria row evaluation was significant for a mildly hypercellular spreads through infected rodent urine, contaminating wa- marrow with a polyclonal T-cell proliferation but negative ter/soil, often surviving there for months. Humans become for malignancy. Thorough investigation into other causes, infected through direct urine contact or through contami- including HIV, were negative. On further questioning, the nated water/soil/food. Bacteria enters the body through patient disclosed she had been non-compliant with metho- skin or mucus membranes, especially if cut or scratched. trexate due to peripheral neuropathy, which she attributed Other names for Leptospirosis include: Weil’s syndrome, to the drug. The decline in her WBC count and profound canicola fever, canefield fever, swamp fever, nanukayami neutropenia coincided with cessation of her methotrexate fever, 7-day fever, Rat Catcher’s Yellows, Fort Bragg fever, therapy. Given the triad of rheumatoid arthritis, neutrope- black jaundice, and Pretibial fever. nia, and splenomegaly with a negative marrow and no other overt cause, a diagnosis of FS was made. Not Your Ordinary Sore Throat Discussion: FS is a diagnosis of exclusion, and it is M.J. Katz and M.N. Peters important to rule out other causes of neutropenia even in Tulane University Health Sciences Center, New Orleans the presence of splenomegaly and RA. Ultimately, the goal of treatment is to prevent serious infection by augmenting Case: A 19-year-old man presented with a one-week granulocytosis. Methotrexate is considered superior to other history of sore throat and cough. Seven days earlier he had agents as illustrated by our patient who saw a precipitous been prescribed oral penicillin; however, his symptoms decline in her WBC count and ANC with its cessation, de- continued to worsen. Initial vital signs revealed temperature spite the continuation of plaquenil and adalimumab. 99.7o F, heart rate 126 beats/min, blood pressure 107/62 mmHg, respiratory rate 26/min, and room air oxygen satu- Rat Catching Fellow Without the Yellows ration 97%. Examination showed tender right posterolateral D. Lovre, S. Ahmed, M. Varghese, and S.M. Gupta neck lymphadenopathy and crackles at the left lung base. Leonard J. Chabert Medical Center, Houma White blood cell count was 40.9 x103/μL with 73% neutrophils and 15% bands. Chest radiograph revealed left-lower Case: A 42-year-old man with a history of hypertension lobe airspace disease. Intravenous piperacillin-tazobactam and hyperlipidemia was admitted to surgery for right up- was initiated for suspected pneumonia. His throat pain per quadrant (RUQ) pain and found to have cholelithiasis persisted, and a neck CT revealed right palatine tonsil en- without cholecystitis; surgery was not necessary. The pa- largement with diffuse inflammatory lymphadenopathy. tient complained of body aches and flu like symptoms of A subsequent chest CT showed numerous pulmonary two weeks duration, as well as dark and decreased urine nodules with multiple areas of consolidation, some of which output for one week. He was taking eight Tylenols and demonstrated cavitation. Transesophageal echocardiogram ibuprofens for four days. On physical exam, he was febrile revealed no vegetations. Given the concern for embolic phe- and tachycardic. He had mild tenderness to palpation in nomenon on CT scan, a Doppler ultrasound of the internal the RUQ and bilateral lower extremity muscles. His serum jugular veins was ordered and revealed a partially occlusive chemistries revealed elevated liver enzymes, creatine kinase, thrombus in the right internal jugular vein consistent with and blood urea nitrogen/creatinine. He had negative blood Lemierre’s Syndrome (LS). All blood cultures returned cultures and urine culture. Urinalysis demonstrated blood negative; multiple sputum samples revealed heavy group and protein without red blood cells on micro. Vancomycin C streptococci growth. and pipercillin-tazobactam were initiated, and he became Discussion: Lemierre’s Syndrome, or jugular vein sup- afebrile with normalized WBCs and liver function test but purative thrombophlebitis, is a condition characterized by worsening acute kidney injury. All of his medications were infectious involvement of the carotid sheath vessels. Clinical stopped. Despite 8-10 liters of intravenous normal saline, manifestations are the triad of antecedent pharyngitis, septic his blood urea nitrogen (BUN)/creatinine continued to rise; emboli, and persistent fever. Subsequent thrombophlebitis glomerulonephritis workup was negative. After more his- typically develops within one week of pharyngitis. Clinical tory, the patient reported killing a rodent in his house a few warning signs include jugular vein/sternocleidomastoid weeks prior. Leptospirosis-induced acute interstitial nephri- muscle tenderness and swelling with presence of pulmonary tis (AIN) was considered. After renal biopsy, the patient was septic emboli on chest radiograph. Ultrasound represents started on doxycycline and prednisone. His renal function a rapid way to evaluate for jugular venous thrombosis, improved, and he was discharged home on doxycycline and CT scan should be utilized to assess for pulmonary and prednisone. Renal biopsy showed interstitial nephritis. abscesses and cavitations. Causative organisms include Serum antigen was diagnostic for leptospirosis. normal oropharyngeal flora, namely Fusobacterium necropho- Discussion: Often misdiagnosed secondary to an array rum, Eikenella corrodens and Streptococci pyogenes/bacteroides. of symptoms, Leptospirosis is a biphasic disease. The disease Empiric antibiotic therapy should include a beta-lactamase

84 J La State Med Soc VOL 166 March/April 2014 resistant beta-lactam antibiotic such as ampicillin-sulbactam WH-11-1-0577). or piperacillin-tazobactam. Tailored intravenous antibiotic therapy should be given for at least two weeks, followed by Extragonadal Germ Cell Tumor: A Rapid Grower oral therapy for two weeks or until resolution of pulmonary G. Anazia, N. Jones, M. Yu, C. Billeaud, and D. Englert abscesses on CT scan. Anticoagulation is controversial and LSU-Health Sciences Center, New Orleans typically reserved for cases with significant thrombus extension. Given the significant mortality risk and urgent need Introduction: Extragonadal germ cell tumors (EGCT), for intravenous, an increased awareness of LS is warranted. which are defined as germ cell tumors without a primary tumor in the testes, are very rare. Of the 8,000 annual cases Colitis Therapeutics (6-MP, Sulfasalazine, Budesonide) of germ cell tumors (GCT), only 2%-5% are of extragonadal Suppress Intestinal Lymphatic Smooth Muscle Tonic origin. Contractility Implications For IBD Therapy? Case: A 22-year-old man presented to the emergency H. Galous, M. Al-Kofahi, D.C. Zawaieja, M. Muthuchanny, room after acute onset of cough three days prior associated P. Von der Weid, P. Jordan, A. Sheth, F. Becker, Y. Wang, with severe weakness. On initial physical exam, he was and J.S. Alexander afebrile, normotensive, in mild respiratory distress, and LSU-Health Sciences Center, Shreveport mildly tachypneic at 32 respirations per minute. His oxygen saturation was 98% on room air. He had decreased breath Background: The lymphatic system plays a central role sounds and dullness to percussion on the right. Testicular in drainage of tissue inflammatory mediators. Lymphatic exam was unremarkable. Labs were remarkable for a slight contractility is an important mechanism that facilitates leukocytosis, mild normocytic anemia, and hypoalbumin- clearance of inflammatory mediators. In IBD, depression emia. Alpha fetoprotein (AFP) drawn on initial presentation of lymphatic contractility may intensify inflammatory was elevated at 860. B-hCG and CEA were within normal responses. It is unclear how drugs used to treat IBD may limits. Chest X-ray revealed complete opacification of the influence this phenomenon, which may influence therapy right hemithorax. CT of the chest with IV contrast demon- for this condition. strated a large right-sided pleural effusion with right-to-left Methods: The effects of different IBD therapeutics on mediastinal shift and numerous heterogeneously-enhancing intestinal lymphatic smooth muscle (ILSM) tonic contrac- pleural based lesions, highly concerning for neoplasm. An tion was studied using 1% collagen gel contraction system ultrasound of the scrotum and testicles was obtained and in vitro. 6-mercaptopurine (6MP), sulfasalazine (5-ASA), showed a small left-sided hydrocele, but no masses. Tho- and budesonide were added to ILSM gels at concentra- racentesis was performed and revealed 1,800 cc of bloody tions similar to those used in IBD therapy. Tonic intestinal fluid, and biopsy was suggestive of either a synovial sar- muscle contraction was monitored over four days. Percent coma or a poorly-differentiated germ cell tumor. One week contraction was compared between untreated cultures and following discharge, the patient developed increasing pain drug treated gels after four days. Budesonide was used at and shortness of breath. Repeat CT of the chest showed that final concentrations of 5 and 25 nM. 6-mercaptopurine was the tumor had grown to occupy the entire right hemithorax, used at concentrations of 0.5, 2, and 5 ng/ml; sulfasalazine with shift of the mediastinal structures to the left. Due to his was used at a concentration of 0.2, 1.0, and 5.0ng/ml. rapid clinical deterioration, he was intubated and started Results: High-dose 6-MP 5 ng/ml showed a significant on empiric chemotherapy with etoposide, ifosfamide, and (37±5.6%, **p<0.01, avg/SE) suppression in contractility cisplatin, even before a final diagnosis was made. His tu- (day four), compared to controls (49±5.6%); 2 ng/ml 6-MP mor responded well to chemotherapy. Repeat biopsy was also suppressed tissue contractility (43±2.5%) but this did obtained and was consistent with a germ cell tumor most not reach statistical significance; 0.5 ng/ml did not suppress compatible with yolk sac origin. contraction (48±4.1%). Budesonide at low and high doses Discussion: Mediastinal germ cell tumors are aggres- (5, 25 ng/ml) significantly suppressed contractility (43±4.2% sive, rapidly growing tumors, typically found in younger and 42±3.6, both *p<0.05, respectively) compared to control men. Standard treatment consists of platinum-based chemo- group (50±5.2%). 5-ASA was tested at 0.2, 1.0, and 5.0 ng/ therapy, usually followed by surgical resection of residual ml; we found that only 1 ng/ml significantly suppressed disease. Due to their rapidity of cell growth, these tumors contractility (45±3.1%, *p<0.05) compared to control group are typically very responsive to chemotherapy. (50±3.1%). Conclusions: While IBD therapeutics are currently Mojo-Induced Critical Illness (MICI): A Syndrome of used to reduce inflammation, at higher doses some may Pseudo-Seizures and Multi-Organ Failure also depress lymphatic smooth muscle contractile function, T. Eady and A. Afshinnik which could negatively influence the export of interstitial Ochsner Clinic Foundation, New Orleans fluid and its complement of inflammatory mediators from the IBD-inflamed intestine. Introduction: Synthetic cannabinoids have gained This work is supported by a Department of Defense popularity for producing intoxication while avoiding detec- Grant Lymphatic Vascular Based Therapy in IBD (W81X- tion on drug screens. They have undergone minimal scien-

J La State Med Soc VOL 166 March/April 2014 85 Journal of the Louisiana State Medical Society

tific testing, and potential harmful side effects are not well Asthma control test (ACT) and HRQOL, via SF-36 standard understood. Here we present two cases of a new syndrome, quality-of-life scores, were assessed and demographics col- MICI, encountered in patients immediately after intoxication lected. Compliance was determined by ascertaining proper with the synthetic cannabinoid “Mojo.” medication usage. Case: Two unacquainted patients, ages 19 (patient A) Results: 49 bronchial asthmatic patients were stud- and 23 (patient B), were brought to their local emergency ied – 14 in charity clinics and 35 in private clinics. Insured departments after family witnessed repeated episodes of patients had mean SF-36 of 42.40 compared to uninsured loss of consciousness followed by thrashing of the arms/ patients who had mean of 35.94 (p=0.04). Analysis of the legs. Both patients were disoriented, uncooperative to different income levels with ANOVA model showed statis- questioning/commands, and extremely agitated. Both were tical significance (p=0.01) for SF-36. Upon further analysis intubated, started on propofol infusions, and transferred to between income levels of less than $25,000 and more than Ochsner Medical Center for presumed status epilepticus. $50,000, the mean was 38.66 and 47.58 (p=0.01). Analysis of Past medical history was limited to a one-year history of clinic location, age, and education level were not statistically questionable seizures (patient A) and poorly controlled significant, although there was a trend in SF-36 and ACT status asthmaticus (patient B). The patients’ mothers each scores. In private clinics, the mean SF-36 and ACT scores reported their sons’ heavy use of “Mojo” to avoid positive were 42.27 and 16.69, while in charity clinics, 39.02 and drug tests. Each had negative toxicology panels. CT, MRI, 14.64. Older age groups had a lower SF-36 when comparing and EEG were negative for any acute process/seizures. Both younger age group. For patients aged 18-25, mean SF-36 was developed acute hypoxic respiratory distress, tachycardia, 45.33, 25-50 years old was 41.73, and older than 50 was 40.69. persistent leukocytosis despite broad antibiotic coverage, Higher education level demonstrated improved SF-36 and rhabdomyolysis, and acute renal failure requiring emergent ACT scores. Patients who did not complete high school had dialysis. After 21 days, patient A was discharged in stable mean SF-36 and ACT scores of 37.90 and 14.14, high school condition. He adamantly refused all substance abuse other graduates were 39.94 and 15.43, and college graduates were than smoking “Mojo” the night prior to presentation. Patient 44.31 and 17.63. B became progressively hypoxic, hypercapnic, acidotic, with Conclusion: Patients with health insurance and higher leukocytosis greater than 70,000, and creatine kinase greater income have an improved quality of life and better asthma than 40,000, despite prompt discontinuation of propofol. He control. Higher education was associated with better quality was treated with lung protective ventilation, nitric oxide, of life and asthma control, although the differences were not broad spectrum antibiotics, but developed hypotension statistically significant. despite three vasopressors. On ICU day 11, he died surrounded by family. Vagus Nerve Palsy Caused By Herpes Zoster: A Case Discussion: MICI is a clinical syndrome that mimics Report status epilepticus. In this case report, after being admitted, A. Harless, M.A. Khan, and W. Davis both individuals developed similar patterns of multi-organ Ochsner Medical Center, New Orleans failure that included acute respiratory failure, severe rhabdomyolysis, and acute kidney failure requiring dialysis. Introduction: Vagal Nerve Palsy due to herpes zoster Although much remains unknown, we believe MICI is an represents a unique presentation of a common clinical en- important clinical syndrome that should be recognized by tity. We report a case of vagus nerve palsy in a patient with healthcare providers. hoarseness and dysphagia. Diagnosis was made by findings of uvula deviation, classic herpetic lesions, and direct Demographic Impact on Asthma and Health-Related Qual- laryngoscopy visualizing unilateral vocal cord paralysis. ity of Life - A Pilot Study Case: A 67-year-old female with a past medical history C. Caruthers, H. Shah, A. Agrawal, C. Desai, T. Solanky, of gastroesophageal reflux disease (GERD), migraine head- S. Kamboj, and P. Kumar aches, hyperlipidemia, and breast cancer status post-bilateral LSU-Health Sciences Center, New Orleans mastectomy. The patient was currently receiving treatment with neoadjuvant chemotherapy, including adriamycin and Background: Asthma is a chronic inflammatory cyclophosphomide. She presented to the ED with a two-day disorder with significant morbidity and mortality. It is a history of hoarseness and dysphagia. Physical exam find- medically managed disease affected by proper medication ings included uvula deviation to the right. All other cranial reconciliation. Presumably, the higher the compliance, the nerves were intact. Review of systems elicited paresthesia better control of asthma and improved health-related quality over the left lateral cervical region without associated skin of life (HRQOL). We analyzed the impact of demographic findings. The remainder of the physical exam, as well as factors on a patient’s ability to access medications and dis- laboratory results, was unremarkable. In the emergency ease comprehension. room, the patient developed tachypnea with audible stridor. Methods: IRB approval was obtained. Adults with An Ear, Nose, and Throat specialist (ENT) was consulted, asthma were studied at allergy-immunology clinics. In- and the patient was given empiric steroids and nebulizer formed consent was obtained from all research subjects. treatments. The ENT performed direct video laryngoscopy,

86 J La State Med Soc VOL 166 March/April 2014 which revealed unilateral left vocal cord paralysis. The Discussion: Review of the MSDS revealed the presence patient was then admitted for further management. On of Dicamba and Diquat dibromide. The toxicology profile of hospital day two, she developed new vesicular lesion at Diquat dibromide seemed to fit our patient’s symptoms and the level of the left C3 dermatome. Infectious disease was labs. Diquat is corrosive substance, is renally excreted, and consulted for lesions consistent with herpes zoster. Empiric ingestion is usually fatal. Severe gastrointestinal irritation, steroids were stopped and ganciclovir was prescribed as tissue dehydration, nausea, vomiting, diarrhea, chest and acyclovir was unavailable. By hospital day five, the patient’s abdominal pain, and respiratory distress are seen. Labs hoarseness and dysphagia had significantly improved. She demonstrate toxic liver damage and kidney failure. Our was treated with ganciclovir for a total of two weeks with patient appeared to have absorbed a significant amount complete resolution of symptoms. of the toxin, despite early charcoal treatment. Confirmed Discussion: Varicella zoster can become latent in the herbicide ingestion and subsequent medical clearance does cranial nerve and dorsal root ganglia, reactivating later in not rule out further delayed toxicity. life to produce shingles. Herpes zoster involving the seventh cranial nerve is well documented in the literature; however, Shock to the Heart ... A Blow From a Surprising Liver Mass isolated cranial nerve 10 involvement is rare. The diagnosis M. Oncale and B. Lewis of vagus nerve palsy caused by herpes zoster is achieved Tulane University Medical School, New Orleans by findings of uvula deviation and direct laryngoscopy of unilateral vocal cord paralysis, along with coinciding her- Case: A 76-year-old man with hypertension, coronary petic lesions of the head and neck. Early recognition and disease, and diabetes presented for routine follow-up. Social treatment with an antiviral agent is important for improved history was negative for alcohol, tattoos, travel, or illicit drug clinical outcomes. use. He denied blood transfusions or chemical exposures. Exam was benign. Labs revealed alkaline phosphatase 198 The Herbicidal Patient: Delayed Onset of Multi-Organ IU/L (38-126) and aspartate transaminase 49 IU/L (15-41). Failure and the Importance of the Material Safety Data Sheet Bilirubin, creatinine, coagulation, and complete blood R. Dhaliwal, S.M. Gupta, and S. Ahmed counts were normal; low-density-lipoprotein 86 mg/dl and Leonard J. Chabert Medical Center, Houma hemoglobin A1c 6.8%. Alkaline phosphatase fractionated as hepatobiliary origin. HIV and hepatitis panels were nega- Introduction: Ingestion of toxic chemicals, particularly tive. Abdominal ultrasound revealed an 8 cm hepatic mass. organophosphates and the resultant physiologic effects Computed tomography (CT) revealed a 12 x 8 cm mass, are well known by physicians. However, not all herbicides inferior vena cava (IVC) compression, but no evidence of contain organophosphates. The Material Safety Data Sheet cirrhosis. He was referred to hematology-oncology, where (MSDS) provides the starting point to evaluate toxic pre- repeat imaging one month later revealed an 11 x 13cm mass sentations of various herbicide components. with IVC tumor infiltration and extension to the right atrium Case: A 48-year-old Hispanic male with a past medical (RA), where a 4 x 4 cm mass was noted. Alpha-fetoprotein history of type 2 diabetes, hypertension, and depression was (AFP) was normal. Biopsy revealed moderately differenti- transferred to our hospital for psychiatric services after being ated HCC; some hepatocytes had fatty changes, but no evaluated 24 hours earlier at an outside hospital for a suicide evidence of hemosiderosis or cirrhosis. attempt after consuming 32 oz of an extended control weed Discussion: HCC is the third-leading cause of cancer- and grass killer. The patient had been evaluated within an related mortality worldwide. Seventy-five percent of cases hour of toxin consumption and was given activated charcoal; are attributable to viral hepatitis. Non-viral cases are due vital signs were stable and serial labs drawn were unremark- to non-alcoholic fatty liver disease. Most HCC cases are as- able. Medicine was consulted to evaluate hyperglycemia. At sociated with cirrhosis caused by viral hepatitis or alcohol. the time of evaluation, the patient complained of diarrhea, Cases of HCC in non-cirrhotics are typically symptomatic odynophagia, dysphagia, abdominal pain, and chest pain and occur in older adults. HCC commonly metastasizes to with food ingestion. Vital signs at the time were BP 126/62, lymph nodes, bone, and lung. It also has a propensity for HR 120, RR 14, T 98.9F. On physical exam, he was oriented, vascular invasion. Tumor extension to the portal system is diaphoretic, had mild tachypnea, tachycardia, and Zargar common; invasion of the IVC and/or heart without inva- Grade 2a caustic injury of his lips and oropharynx. Labs sion of the portal system is rare. Most patients with cardiac revealed WBC 18.5, 20% bands, glucose 623, CO2 18, BUN involvement also had cirrhosis and symptoms that included 57, Cr 6.42, AST 472, ALT 324, TBili 1.3, INR 0.8, AØ 70, dyspnea, edema, shock, right heart failure, pulmonary em- with a AG = 18, Osm Gap = 15, and ABG 7.31/29/81/14.6. boli, or sudden death. Mean survival in HCC patients with N-Acetylecysteine was started per poison control recom- IVC or RA extension is four months regardless of treatment; mendations. The patient became anuric, with worsening therefore, aggressive therapy is often futile. To our knowl- metabolic acidosis, renal, and hepatic function. Following edge, this is the first patient without hepatitis or cirrhosis to transfer to the ICU, he experienced respiratory decompen- present asymptomatically with cardiac involvement of HCC. sation requiring intubation. The patient had cardiac arrest Our case is also unique in that the etiology of this patient’s and could not be resuscitated. HCC remains cryptogenic.

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Intravenous Sodium Thiosulfate For Treatment of inherited mitochondrial syndrome typically diagnosed in Calcinosis in Rheumatic Disease childhood or early teenage years. The stroke-like episodes B.P. Miller typically present in a relapsing-remitting manner with Earl K. Long Medical Center, Baton Rouge gradual neurological decline leading to dementia. Case: A 32-year-old African-American male with a Introduction: Calcinosis, or dystrophic calcification, diagnosis of MELAS, confirmed by muscle biopsy eight is a poorly understood and debilitating condition that is a years prior, presented with a two-month history of short- common manifestation in connective tissue diseases such as ness of breath, dyspnea on exertion, and lower extremity scleroderma and systemic lupus erythematosus. Currently, edema. The patient was afebrile with a blood pressure of many treatment modalities have been tried with minimal 108/90, heart rate of 103, respiratory rate of 20, and a room success. While intravenous sodium thiosulfate (STS) is used air oxygen saturation of 100%. Cardiac exam revealed a to treat calciphylaxis and cyanide toxicity, data is not read- III/VI holosystolic murmur heard best at the apex and an ily available regarding its use in calcinosis. Due to similar S3. Lung exam was unremarkable. He had bilateral lower proposed mechanisms of disease, the administration of in- extremity pitting edema extending to his hips. Labora- travenous STS may have a role in the treatment of calcinosis tory studies showed a WBC count of 5.7 K/uL with 71% in patients with rheumatic disease. neutrophils. His complete metabolic profile revealed a Case: A 63-year-old woman with a history of limited HCO3 18 mmol/L, BUN 38 mg/dL, creatinine 1.67 mg/ scleroderma with calcinosis and Raynaud’s syndrome, pre- dL, bilirubin 3 mg/dL, AST 92 U/L, ALP 213 U/L, and sented to clinic after being treated by an outside physician. ALT 100 U/L. BNP was greatly elevated at >5,000 pg/mL. For several years, she had recurrent calcinosis deposits on Initial troponin was elevated at 0.14 ng/mL and peaked at her hands, wrists, knees, and elbows, which caused chronic 0.17 ng/mL. Lactic acid was also elevated at 3.9 mmol/L. pain and limited range of motion. These symptoms per- Urinalysis did not contain any protein. Urine electrolytes sisted, despite being treated with appropriate scleroderma revealed a fractional excretion of sodium of 6.7%; no urine therapy. Her calcinosis was treated with corticosteroids, col- eosinophils were present. EKG demonstrated normal sinus chicine, calcium channel blockers, and surgery with minimal rhythm with evidence of left atrial enlargement, and chest change in pain level and functional status. After discussion X-ray revealed mildly increased pulmonary vasculature. regarding risks and benefits of intravenous thiosulfate, a The patient was found to have four-chamber enlargement, 25-gram infusion of thiosulfate over one hour, per week moderate to severe tricuspid regurgitation, and an ejection was initiated. Despite missing several infusion sessions fraction <20% by echocardiogram. Diuresis with IV furose- throughout the year, and receiving 12.5 gram infusions at mide provided improvement in his respiratory status and times, she reported significant improvement in pain and edema; however, he continued to be oxygen-dependent at range of motion in her extremities. Overall, the infusions the time of discharge. were tolerated well, despite one episode of blurry vision Discussion: MELAS is a rare mitochondrial disorder and elevated temperature. that not only affects the nervous system, but can also have Discussion: This case illustrates the potential use of cardiac, renal, and endocrine manifestations, as were seen intravenous STS in patients suffering from calcinosis. Cal- in this patient with a dilated cardiomyopathy, renal insuf- cinosis affects approximately 25% of patients with sclero- ficiency, and diabetes mellitus. A hypertrophic cardiomy- derma and may lead to severe disability, pain, and infection. opathy is more commonly associated with MELAS, but a While both mechanisms of disease are poorly understood, dilated cardiomyopathy has also been described. calcinosis is pathologically different than calciphylaxis. However, the mechanism of action of STS may also benefit Acquired Hemophilia A: The AHA Moment calcinosis. One proposed mechanism of action involves the S. Fulton, S. Boda, and S. Greenberg formation of water soluble calcium-thiosulfate complexes LSU-Health Sciences Center, Shreveport that dissolve existing insoluble calcium salts embedded in tissue. STS may also improve endothelial function through Introduction: Recognition of Acquired Hemophilia A its antioxidant and anti-inflammatory properties. Our case (AHA) without personal or family history of bleeding is highlights the need for further studies of intravenous STS difficult. The infrequency of this disease warrants aware- as a potential treatment option for calcinosis. ness of its relatively complicated diagnostic ladder and laboratory findings. Dilated Cardiomyopathy Secondary to Mitochondrial Case: A 47-year-old African-American male with past Encephalopathy With Lactic Acidosis and Stroke-Like medical history of AIDS and anaplastic large cell lymphoma Episodes stage II in remission after chemo and radiation therapy in A. Graebert and B. Lo 1998 presented to the emergency department for continu- LSU- Health Sciences Center, New Orleans ous hemorrhaging for four hours after tongue biopsy. The biopsy site was sutured, and he was discharged home. Two Introduction: Mitochondrial encephalopathy with lactic months later, the patient presented to the ED with large, acidosis and stroke-like episodes (MELAS) is a maternally painful, erythematous areas of swelling to the left antecubital

88 J La State Med Soc VOL 166 March/April 2014 fossa, popliteal area of left leg and lower right calf. Because greater than 200 mg/dL. Causes of chylous ascites include: of painful ambulation, he had been using crutches for days malignancy, trauma, chronic liver disease, inflammation, prior. He was admitted to the hospital. Workup revealed and infection. Disruption of the lymphatic system from elevated partial thromboplastin time (PTT) of 75.6 seconds obstruction or traumatic injury is the underlying mechanism (N= 24.7-35.5 seconds), normal prothombin time (PT), for the formation of chylous ascites. While the exact cell of and international normalized ratio (INR). Mixing studies origin for KS remains unclear, the current opinion is that yielded an uncorrected and prolonged activated PTT of KS tumor cells are derived from lymphatic endothelium. 63.6 seconds after two hours. Measurement of Factor VIII Hence, the development of chylous ascites may possibly inhibitor yielded an elevated 432 Bethesda units/ml (refer- be due to in-situ KS in that region rather than metastasis ence range: <1.0 U/ml). Factor VIII activity was decreased to the thoracic duct as once thought. Chemotherapy for KS to <0.6% (reference range of 50-100%). AHA was diagnosed. can often improve symptoms (response rate 60-90%) as was However, lupus anticoagulant was positive. Patient was im- seen in our patient. mediately started on treatment with prednisone and rituxan followed by cytoxan. PTT after treatment decreased to 28.5 Treatment of Cutaneous Neoplasm With Spray seconds. The patient had no further episodes of extremity Cryotherapy bleeding or swelling. J. Minadeo, R.E. Cuenca, and D.A. Jansen Discussion: AHA is a rare and life-threatening bleeding LSU-Health Sciences Center, Shreveport disorder caused by auto-antibodies against Factor VIII. It most commonly occurs in patients more than 65. Although Introduction: Cutaneous neoplasms are a therapeutic it may be associated with autoimmune disorders, malig- challenge and produce a significant burden on the healthcare nancies, and medications, half of reported cases remain system, particularly in the elderly population. Treatments idiopathic. This patient with a relatively mild presentation producing significant eradication rates with acceptable cos- of AHA had a positive coexisting lupus anticoagulant and mesis at a low cost are needed. High energy transfer (25-W) Factor VIII inhibitor. The presence of both simultaneously spray cryotherapy technology using a unique liquid nitrogen is exceedingly rare and may denote a protective mechanism (LN2)-based catheter delivery system successfully treats in a grave bleeding disease. and eradicates neoplastic tissue and is FDA approved. We report the initial safety and feasibility results of 23 patients, Chylous Ascites in Kaposi Sarcoma: A Case Report 53 lesions, treated at various sites including head, neck, P. Johnson, E. Chang, E. Smith, and B. Lo trunk, and extremities. LSU-Health Sciences Center, New Orleans Methods: Spray cryotherapy is a rapid energy transfer technology employing liquid nitrogen sprayed through a Introduction: Chylous ascites is a known complication long catheter at -196oC. Twenty-three patients with biopsy- associated with Kaposi sarcoma (KS). There are only three proven skin neoplasia were treated under local anesthesia reported cases of chylous ascites in patients with KS. in an outpatient setting. Treatment parameters included Case: A 26-year-old Caucasian male with a history of duration of spray and the number of freeze and thaw cycles. AIDS (CD4-123), KS, pleural effusion, and pulmonary em- Lesions were re-examined for clinical response, cosmesis, boli was admitted for diffuse abdominal pain and scrotal and the need for re-treatment at 1, 4, 8, and 12 weeks. edema. Physical exam was notable for tachycardia, pallor, Results: Spray cryotherapy was easily delivered and decreased basilar breath sounds, diffuse abdominal pain covered all visible lesions with minimal bystander side with distention, positive fluid wave and shifting dullness effect. Visual re-examination demonstrated complete without rebound or guarding, tender scrotal edema, ingui- clinical responses in 21/23 patients and 51/53 lesions. nal adenopathy, and purple lesions on his upper palate and Mean follow-up is nine months. Two patients had lesions torso consistent with KS. A prior EGD and colonoscopy with partial responses, which were excised. Minimal pain, showed Kaposi’s lesions throughout the GI tract. An ab- good wound healing, and no adverse effects occurred. The dominal CT revealed diffuse adenopathy. A paracentesis desired clinical was achieved within 30 days. Side-effects was performed and 1,510 mL of milky, turbid, blood-tinged included one patient with edema at the treatment site. A fluid was removed. Fluid analysis was negative for malig- superficial distant injury inadvertently occurred during nancy but demonstrated 36,300; RBCs and triglycerides readying of the catheter. concentration of 740 mg/dL. The patient was started on Discussion: Current therapeutic modalities include liposomal doxorubicin for his KS during his hospitalization surgery and radiation; both efficacious but costly, painful, and finally achieved adequate pain control and improve- and often complex with variable cosmetic outcomes. Spray ment of his ascites and scrotal edema after three rounds of cryotherapy offers a low complexity, relatively low-cost treatment as an outpatient. therapeutic option for these neoplasms. These results sug- Discussion: Chylous ascites is an uncommon find- gest that this technique is safe, effective, and successful for ing that is caused by the presence of intestinal or thoracic tumor eradication and reduction. Our initial findings war- lymph in the peritoneal cavity. Chylous ascites is diagnosed rant a multi-center prospective trial. by milky ascitic fluid with a triglyceride content typically

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Corynebacterium Bacteremia - Not Always a Contaminant with a Hgb of 6.2 g/dL and an MCV of 90 fL. His platelet A.S.J. Chandranesan, A. Khan, and M. Choudhary count was normal, 300K/µL. A CT scan of the pelvis showed LSU-Health Sciences Center, Shreveport a large right-sided retroperitoneal hematoma and subcutaneous hematoma. Coagulation studies revealed a PT of 11.2 Case: A 56-year-old African-American male with past s, INR of 1.0, and a PTT elevated at 113 s. The patient was medical history of HIV presented to an outside hospital unaware of any bleeding disorders in his or his families’ with hemoptysis and fatigue for two weeks. He denied past medical history. D-dimer and fibrinogen were elevated fever, shortness of breath, recent travel, and sick contacts. so DIC seemed less likely. He received fresh frozen plasma He was non-compliant with HAART for three years. He quit and prothrombin complex concentrate, each improved his smoking two years ago. He was afebrile and cachectic in PTT temporarily. A mixing study did not correct. Further appearance. Chest exam revealed decreased breath sounds, coagulation studies showed a low Factor VIII activity level and dullness to percussion in the right-posterior field. WBC of 8 IU/dL and an elevated Factor VIII inhibitor level of count was 8.9 x 109/L with 85% neutrophils and 6% bands. 28 BU/mL. The patient was diagnosed with an acquired Blood culture grew gram-positive coccobacilli. Chest X-ray factor VIII inhibitor. He was started on rituximab and showed a right upper lobe cavitary lesion. The patient was received recombinant factor VIIa after a bleeding episode. started on empiric vancomycin and ceftriaxone. CD4 count His PTT improved and dropped as low as 71 s; however, he was 3. CT chest showed a thick-walled cavitary mass with became unstable after developing abdominal compartment air-fluid level in the right mid-upper lobe. Sputum AFB syndrome from the large pelvic hematoma and went into smears were negative. Sputum culture isolated normal cardiopulmonary arrest and died. respiratory flora. Fungal and mycobacterial blood cultures Discussion: Differential diagnosis of a prolonged PTT were negative. Repeat blood cultures grew the same gram- with normal PT includes deficiencies of factors VIII and IX, positive rod that was identified as Corynebacterium species. as well as inhibitors of these factors. A mixing study is used The isolate was sent to a reference lab where it was identi- to confirm the presence of an inhibitor. Confirmation of a fied as Rhodococcus equi (formerly Corynebacterium equi). The factor VIII inhibitor is made with low factor VIII activity patient was treated with vancomycin, imipenem/cilastin, levels and elevated factor VIII inhibitor levels. Treatment rifampin, and levofloxacin. Resolution of symptoms was involves attempts at raising factor VIII levels with DDAVP noted in 10 days. Bacteremia resolved in a month. HAART and factor VIII concentrates and to bypass factor VIII with was restarted. Outpatient follow-up in two months showed activated prothrombin complex concentrates or recombinant resolution of lung abscess, improvement in CD4 count, and factor VIIa in cases of bleeding. Agents used to eliminate undetectable HIV viral load. Levofloxacin and rifampin was the inhibitor include rituximab, cyclophosphamide with planned for additional six months. prednisone, IVIG, and cyclosporine. Discussion: Rhodococcus equi is a gram-positive, aerobic, non-motile intracellular weakly acid fast coccobacilli. It is Stressed, Stiff, and Spastic - More Than Just Graves’ often overlooked or discarded as non-pathogenic coryne- Hyperthyroidism form. It causes lung infection in horses and cattle. Most V. Narendra and G. Sun human infections are noted post-animal exposure or in LSU-Health Sciences Center, Shreveport immunocompromised. It causes subacute to chronic bron- chopneumonia complicated by abscess and suppurative Introduction: Stiff-Person syndrome (SPS) is a rare involvement of distant sites - brain and skin. Blood cultures neuroimmunologic disorder characterized by elevated are positive in 25%-50% cases. It is treated with more than glutamic acid decarboxylase antibody (GADA) titers and two antimicrobials until clinical improvement. This is fol- progressive rigidity, stiffness, and painful spasms of the lowed by two oral antibiotics for at least six months. HAART axial muscles. It is associated with other autoimmune therapy should be initiated in HIV positive patients. conditions, including type 1 diabetes mellitus and rarely, autoimmune thyroid disease. We describe SPS in a patient Hemophilia A is Not a Disease Just For Kids presenting with thyrotoxicosis. V. Patel, R. Ramirez, and R. McCarron Case: A 23-year-old woman presented with two weeks LSU-Health Sciences Center, New Orleans of bilateral lower extremity pain. She was tachycardic (130 bpm), tremulous, and hyperreflexic with left leg spasms. Introduction: Acquired factor VIII inhibitors (also re- Increased muscle tone, decreased range of motion, pedal ferred as Acquired Hemophilia A) is a rare bleeding diathe- edema, left foot tenderness, and lumbar lordosis were also sis caused by autoantibodies directed against clotting factor noted. Autoimmune-mediated hyperthyroidism was con- VIII and is associated with bleeding involving soft tissues. firmed with thyrotropin <0.01 [0.4-4.0 IU/mL], total thyrox- Case: A 79-year-old Caucasian male presented to the ine 18.1 [4.5-11.5 ug/dL], total triiodothyronine 141.88 ng/ emergency room with complaints of right hip pain and left dL [60-180 ng/dL, thyroperoxidase antibodies 131.5 [<6 IU/ elbow pain for two weeks after falling. On physical exam, mL], and thyroid stimulating immunoglobulin 423 [<140%]. he had a large edematous area with significant ecchymosis Creatinine kinase and aldolase were 2682 [20-180 U/L] and over his right gluteal area and left elbow. He was anemic 19.7 [<7.5 U/L], respectively. Impending thyroid storm pre-

90 J La State Med Soc VOL 166 March/April 2014 cipitated transfer to a tertiary referral center. Thyrotoxicosis disease; however, it does have the ability to invade local was treated with propylthiouracil, propranolol, iodine, and structures. Most patients present with vague abdominal steroids with clinical improvement. Lower extremity spas- pain, nausea, and vomiting, mostly due to the mass effect ticity and muscle stiffness persisted; however, brain MRI of the neoplasm on surrounding structures. Diagnosis can was unrevealing. GADA elevations (1,612 [<0.02 nmol/L]) usually be confirmed by biopsy and cytology, leading to confirmed clinical suspicions of SPS. She responded to a visualization of solid and pseudo-papillary in sheets of combination of baclofen and intravenous immunoglobulin uniform, epitheloid cells situated around a microvascular (IVIG). Her Graves’ hyperthyroidism was eventually treated stalk. Treatment includes distal pancreatectomy and ag- with I131 ablation; subsequent hypothyroidism required gressive surgical approach for possible metastatic disease. levothyroxine therapy. GADA has been as high as 44,147 Following resection of the neoplasm, survival is 95% at a [<0.5 U/mL] during worsening SPS symptoms, requiring five-year interval. further IVIG infusions. She achieved clinical stability of her SPS symptoms with a combination of baclofen, intermittent Scratch Me If You Can: A Case of Peliosis Hepatitis and IVIG infusions, and clonazepam. Recent GADA was 528 Splentis [<0.02 nmol/L]. N. Gupta and P.C. Porada Discussion: This case of SPS highlights the importance Ochsner Clinic Foundation, New Orleans of clinical suspicion for other autoimmune conditions. Muscle spasticity and stiffness are atypical of thyrotoxico- Introduction: Peliosis Hepatitis is a rare vascular condi- sis. Early recognition of an uncharacteristic presentation of tion characterized by multiple blood-filled cysts within the Graves’ hyperthyroidism resulted in expedient diagnosis liver parenchyma. Due to multiple etiologies and a vague and therapy in this patient, and combination therapy has presentation, this diagnosis requires a thorough history and resulted in favorable SPS symptom control. complete diagnostic workup. Case: A 23-year-old African-American male with a past Solid Pseudo-Papillary Tumor of the Pancreas medical history of HIV (CD4 = 650 cells/mm3) presented S. Mani, G. Grewal, K. Dalmau, J. Crowe, and S.M. Gupta to the emergency department with a chief complaint of left Leonard J. Chabert Medical Center, Houma upper quadrant abdominal pain for seven days. The pain was described as acute, intermittent, sharp, worse with Case: A 21-year-old African-American woman with a inspiration, and radiating to his left shoulder. His other past medical history of pancreatitis and morbid obesity was symptoms included fever; four to five episodes per day of initially admitted with pancreatitis with intractable nausea non-bloody, non-bilious emesis; and four to five episodes and vomiting for pain control and IV hydration. Shortly after per day of non-bloody loose stools. On physical exam, the discharge, she again presented with pancreatitis symptoms, patient was febrile, tachycardic, tender to palpation at the with an elevated lipase level of 575, and was transferred to LUQ, and had palpable hepatosplenomegaly. Abdominal our medical center. The patients’ epigastric pain continued CT scan revealed multiple small hypodensities in the liver to persist, rated as a 9/10 constant sharp/stabbing with and spleen that were concerning for micro-abscesses and a radiation to her back, and worsened with oral intake. There large area of hypoattenuation in the spleen extending to the were no alleviating factors noted. On admit to our facility, periphery. Upon further investigation of patient’s exposure the patient was afebrile and hypertensive (157/107) and history, he revealed that several months prior to admission had a BMI of 49. Labs on admit showed slightly elevated he began to care for a stray kitten. He denied any sick con- lipase level of 67 and anemia (hemoglobin 9.7 hematocrit tacts, recent travel, or any other exposure history. Serology 31.7). Treatment was started with intravenous fluids and for Bartonella henselae and ultrasound-guided biopsy of his pain medication, a CT scan of her abdomen showed a 4.5 liver lesions were obtained. Serology titers for Bartonella cm circumferential mass in the body of the pancreas without henselae IgM were positive (1:80), and liver biopsy revealed pancreatic ductal dilatation. Endoscopic ultrasound and fine a mixed inflammatory infiltrate including neutrophils and needle aspiration of this mass showed scattered clusters of eosinophils with adjacent fibrosis. In addition, there were cells with variation in size and shape and papillary struc- nonspecific findings in the setting of positive serology sug- tures seen in some clusters. These findings were consistent gestive of Bacillary Peliosis. Subsequently, therapy was with solid pseudopapillary tumor of the pancreas. The transitioned to Doxycycline twice daily for eight weeks. patient was subsequently scheduled for a distal pancreatec- Repeat imaging seven months later demonstrated resolu- tomy and splenectomy. On follow-up, the patient remained tion of his lesions. pain symptoms free. Discussion: The fastidious nature of these organisms of- Discussion: Solid pseudo-papillary tumor of the pan- ten precludes them from being found on cultures and tissue creas, also known as Frantz’s tumor, is a rare previously samples. Peliosis hepatitis is often an incidental finding on misdiagnosed neoplasm affecting young females with a abdominal imaging. Thus, this case illustrates an occurrence 10:1 predilection toward females and a mean age of 24. of peliosis hepatitis caused by Bartonella henselae, elucidating This tumor typically carries a better prognosis compared the imperativeness of obtaining a detailed history in HIV to adenocarcinoma and has a low likelihood of metastatic positive patients.

J La State Med Soc VOL 166 March/April 2014 91 Journal of the Louisiana State Medical Society Pathology Image of the Month

Sudden Unexplained Death in a Young Adult With Known Alcohol Abuse

Robin R. McGoey, MD; William P. Newman, MD

A 35-year-old, recently deceased woman with a medical history known only to include Hepatitis C and alcohol abuse was transferred to the autopsy service for an unrestricted autopsy under coroner authorization following a sudden unexplained death. External examination revealed marked scleral icterus and cutaneous jaundice. Internal examination was remarkable for 3 liters of ascitic fluid and established cirrhosis with a micronodular pattern (nodules all <0.3cm in diameter). Numerous, small, firm vegetations were identified along the edges of the tricuspid, mitral, and aortic valves. There was no obvious necrosis or tissue destruction seen grossly. Zones of prominent myocardial discoloration and hemorrhage were seen in all regions (anterior, lateral, and posterior) of the left ventricular myocardium, as well as within the interventricular septal myocardium. Multiple punctate lesions, up to 2 cm in diameter with a greenish hue and associated with tissue necrosis were seen overlying the cerebral cortex, as well as within the intracerebral parenchyma. Tissues were fixed in formalin for subsequent microscopic examination, and representative images from the aortic valve, and from the cerebral cortex, are seen below.

What is the cause of death in this case?

Figure 1A: Aortic valve vegetation showing hyaline, septate branching hyphae of uniform diameter and with angular branching approximately 45 degrees. Background tissue shows a prominent neutrophilic exudate and necrosis (hematoxylin-eosin, original magnification 40x).

92 J La State Med Soc VOL 166 March/April 2014 Figure 1B: Cerebral cortex hyphae, positive by GMS silver stain (40x).

Figure 1C: Cerebral cortex with hyphae, also staining positive by periodic acid Schiff (PAS) staining (40x).

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DIAGNOSIS: Disseminated, invasive aspergillosis Aspergillus is a rare entity, accounting for only one-quarter of all fungal causes of infective endocarditis.8 In 2010, DISCUSSION Kalokhe et al. reviewed approximately 50 cases of Aspergillus endocarditis and described the following notable features: Aspergillosis is a constellation of clinical diseases all vegetations that were large in size, most often situated on caused by the fungal pathogen of Aspergillus. Aspergillus is the mitral valve (49%), but multi-valvular in 21% of cases. a highly aerobic fungus with the capacity to infect almost Valvular destruction was common, and systemic vascular every major organ system. With more than 60 pathogenic emboli were frequently demonstrated. Patients were more species, the two known to most frequently cause human often male and possessed an underlying preexisting cardiac infection are A. fumigatus and A. flavus.1 Localized, single abnormality such as coronary artery disease or prosthetic organ Aspergillus is most frequently seen in the lung. When valves.8 Based on these features we conclude that, in the case the pattern is that of a stable, singular, nonprogressive presented here, a primary respiratory aspergillosis with pul- fungal ball within the lung parenchyma, it is known as an monary venous spread initially to the left heart was a more aspergilloma, and the patient complains of few symptoms. likely nidus for the invasion and subsequent dissemination More complex cystic nodules can be seen, however, with than a primary multi-valve endocardial infection. progressive cavitation and more advanced symptoms, typi- The diagnosis of invasive aspergillosis is based mainly cally called chronic cavitary, complex or chronic necrotizing upon isolating the organism either by microbiologic culture aspergillosis.2 or by histopathologic demonstration of the organism in tis- Tissue invasion by Aspergillus, a.k.a. invasive aspergil- sue, as seen in the current case. Initial clinical suspicion for losis, has long been known to pose a significant threat to the invasive aspergillosis, however, remains a challenge in so immunocompromised individual, with the first reported much that symptoms may be entirely nonspecific such as case dating back to 1953.3 Since its initial report, the litera- fever, chest pain, cough, malaise, and dyspnea, or without ture has cited up to a 150% relative increase in cases4 due any respiratory symptomatology at all, as is reported to be largely to the expanding profile of patients considered at the case in up to 40%.9 Though tissue diagnosis does require risk for tissue invasion by Aspergillus, which includes those invasive biopsy, major advantages of histology include undergoing chemotherapy, transplant patients - both bone diagnostic speed, low-cost, and its ability to demonstrate marrow and solid organ - those on immunosuppressive adjacent tissue reaction, such as necrosis, to the fungal ele- regimens including high-dose, prolonged corticosteroids; ments. Routine histology favors the use of the hematoxylin patients with chronic granulomatous disease; and those and eosin (H&E) stain. Though H&E does have the capacity affected by advanced human immunodeficiency virus to stain Aspergillus, it is limited in its identification of other (HIV) and AIDS.2,5 Widespread or systemic dissemination fungi and is frequently supplemented by additional stains of Aspergillus, also ascribed to the immunocompromised in- such as Gomori’s methenamine siliver (GMS) and periodic dividual, is diagnosed when Aspergillus infection is detected acid-Schiff (PAS) so that fungal morphology can be better in >1 noncontiguous site, thus reflecting blood-borne spread. highlighted. The images submitted for the current case This is in contrast to multi-site Aspergillus that occurs within (Figure 1 A, B, and C) illustrate the characteristic features one contiguous organ system, such as might be the case in of invasive Aspergillus as seen on H&E, GMS, and PAS, infection involving both the lung and the sinonasal tract.6 as well as the typical tissue response associated with the More recently, there has been a growing body of fungal infection. literature reporting invasive aspergillosis in immuno- Despite perceived advances in antifungal therapies, competent individuals without the classical risk factors. invasive and, moreover, disseminated aspergillosis remain These non-traditional patients appear, however, to have devastating opportunistic infections. On the basis of autopsy several comorbidities in common and can be categorized literature, the number of Aspergillus-related deaths increased into those who have conditions such as chronic obstructive by a factor of four in the United States during the 1980s and pulmonary disease, diabetes, liver failure, alcoholism, and 1990s, presumably a reflection not only of the increasing malnutrition.2 In one study of approximately 40 patients number of immunocompromised patients but also of the with documented invasive Aspergillus in the intensive care high associated mortality.10 In a 1996 review of more than unit (ICU), more than one-half of the patients (54%) had 1,000 cases, Denning found a case-fatality rate (CFR) of 99%, none of the widely accepted determinants of increased risk 86%, and 66% for cerebral, pulmonary, and sinus invasive for invasive aspergillosis.7 aspergillosis, respectively.11 More recently, in a case series In cases of disseminated aspergillosis, the primary site and systematic literature review, the CFR for central nervous of origin is most often reported to be that of the respiratory system (CNS) Aspergillus, as seen in the current case, was tract. As a ubiquitous soil borne fungus that survives and confirmed to be uniformly fatal and the highest of all forms grows on organic debris, the Aspergillus conidia have a of invasive aspergillosis.12 Despite the growing number of diameter small enough to reach the alveoli of the lung (2-3 cases of invasive aspergillosis in presumably immunocom- um). As such, aspergillosis has become the most prevalent petent individuals, the prognosis appears to be consistently airborne fungal pathogen. By contrast, endocarditis due to grim with comparable fatality rates.6 The unfortunate case presented here of disseminated,

94 J La State Med Soc VOL 166 March/April 2014 invasive aspergillosis undiagnosed until the time of au- 6. Lin SJ, Schranz J, Teutsch SM. Aspergillosis Case Fatality Rate: topsy underscores the importance of being mindful of the Systematic Review of the Literature. Clin Infect Dis. 2001;32:358- diagnosis of Aspergillus infections not only in the classically 66. immunodeficient patients but also in the presumably im- 7. Vandewoude KH, Blot SI, Benoit D et al. Invasive Aspergillosis in Critically Ill Patients: Attributable Mortality and Excess in munocompetent individuals. It is likely that in the current Length of ICU Stay and Ventilator Dependence. J Hosp Infect. case, the patient’s determinants of increased risk included 2004;56:269-276. alcoholism and liver failure due to established cirrhosis. 8. Kalokhe AS, Rouphael N, El Chami MF et al. Aspergillus Endocarditis: a Review of the Literature. Int J Infect Dis. 2010;1040- ACKNOWLEDGEMENTS 1047. 9. Aleksenko A, Gyasi RK. Disseminated Invasive Aspergillosis. The authors would like to gratefully acknowledge the Ghana Med J. 2006;40(2)69-72. support of the Orleans Parish Coroner’s Office: Dr. Frank 10. McNeil MN, Nash SL, Hajjeh RA, et al. Trends In Mortality Due to Invasive Mycotic Diseases in the United States, 1980-1997. Clin Minyard and Chief Investigator John Gagliano for providing Infect Dis. 2001;33:641-647. the case material for this report. 11. Denning DW. Therapeutic Outcome in Invasive Aspergillosis. Clin Infect Dis 1996;23:608-15. REFERENCES 12. Kourkoumpetis TK, Desalermos A, Muhammed M et al. Central Nervous System Aspergillosis. Medicine 2012;91:328-336. 1. Latge JP. Aspergillus fumigatus and Aspergillosis. Clin Microbiol Rev. 1999;12(2):310-350. 2. Kousha M, Tadi R, Soubani AO. Pulmonary Aspergillosis: a Clinical Review. Eur Respir Rev. 2011;20:156-174. In the Department of Pathology at Louisiana State University School of Medicine in New Orleans, Dr. McGoey is an Associate Professor 3. Rankin N. Disseminated Aspergillosis and Moniliasis Associated of Pathology and Residency Program Director, and Dr. Newman is a with Agranulocytosis and Antibiotic Therapy. Br Med J. Professor of Pathology and Director of the Autopsy Service. 1953;183:918-9. 4. Fraser DW, Ward JL, Ajello L, et al. Aspergillosis and Other Systemic Mycoses. The Growing Problem. JAMA. 1979;242:1631- 5. 5. Denning DW. Invasive Aspergillosis. Clin Infect Dis. 1998;26:781- 803.

J La State Med Soc VOL 166 March/April 2014 95 Editor Volume 166, Number 3 • May/June 2014 Established 1844 D. LUKE GLANCY, MD

Associate Editor L.W. JOHNSON, MD

EDITORIAL BOARD MURTUZA J. ALI, MD Zhuang Feng, MD, PhD 97 Subcutaneous Fat Necrosis of the Newborn Associated With RONALD AMEDEE, MD Baofeng Guo, MD Hypercalcemia After Therapeutic Hypothermia SAMUEL ANDREWS, II, MD Zhenzhen Zhang, MD, MPH BOB BATSON, MD EDWIN BECKMAN, MD John Carter, MD 100 Juvenile Ossifying Fibroma of the Middle Turbinate GERALD S. BERENSON, MD Ryan Winters, MD C. LYNN BESCH, MD Christina Yang, MD JOHN BOLTON, MD Hugo St. Hilaire, DDS, MD MICHELLE BOURQUE, JD Kimsey Rodriguez, MD JAMES N. BRAWNER, III, MD BRETT CASCIO, MD James H. Diaz, MD, MPH & TM, DrPH, 103 Emerging Causes of Superficial and Invasive Infections Following QUYEN CHU, MD FCCM, FACMT Marine Injuries and Exposures GUSTAVO A. COLON, MD RICHARD COULON, MD Nicole Richmond, MPH 109 The Association Between the Medical Home and Pediatric LOUIS CUCINOTTA, MD Tri Tran, MD, MPH Developmental Screening Among US Children Five Years and VINCENT A. CULOTTA, JR., MD Susan Berry, MD, MPH Younger: Results From the 2007 National Survey of Children’s Health JOSEPH DALOVISIO, MD NINA DHURANDHAR, MD Kevin Moore II 119 Hounsfield Unit Changes Over Time in Contusions of the Brain JAMES DIAZ, MD, MPH & TM, Dr. PH Addison Willett JOHN ENGLAND, MD Eduardo Gonzalez-Toledo, MD, PhD JULIO FIGUEROA, MD Asser Youssef, MD, FACS, FICS ELIZABETH FONTHAM, MPH, Dr. PH EDWARD FOULKS, MD D. Luke Glancy, MD 121 LSUHSC Department of Medicine White Coat Ceremony Address, HENRY G. HANLEY, MD 2014 ELIAS B. HANNA, MD LYNN H. HARRISON, JR., MD ROBERT HEWITT, MD MICHAEL HILL, MD LARRY HOLLIER, MD JOHN HUNT, MD BERNARD JAFFE, MD NEERAJ JAIN, MD TRENTON L. JAMES, II, MD KEVIN KRANE, MD MAUREEN LICHTVELD, MD, MPH FRED A. LOPEZ, MD F. BROBSON LUTZ, JR., MD DAVID MARTIN, MD JORGE A. MARTINEZ, MD, JD ELIZABETH MCBURNEY, MD ELLEN MCLEAN, MD NORMAN E. MCSWAIN, JR., MD REINHOLD MUNKER, MD Departments DAVID MUSHATT, MD JOSEPH NADELL, MD D. Luke Glancy, MD 123 ECG OF THE MONTH HAROLD R. NEITZSCHMAN, MD Rehan Z. Ali, MD ECG in a 52-Year-Old Man With a Dilated Cardiomyopathy STEVE NELSON, MD NORA OATES, MD Shiva Nagalingam, BS, BA 125 RADIOLOGY OF THE MONTH DONALD PALMISANO, MD, JD, FACS Mandy Weidenhaft, MD Recurrent Knee Pain in a Young Athlete PATRICK W. PEAVY, MD ROBERTO QUINTAL, MD Shane G. Guillory, MD 129 CLINICAL CASE OF THE MONTH RAOULT RATARD, MD, MS, MPH & TM Matthew D. Jordan, DO A 44-Year-Old Woman With Jaundice and Abdominal Pain ROBERT RICHARDS, MD Bradley M. Spieler, MD DONALD RICHARDSON, MD Matthew L. Safley, DO FRANK A. RIDDICK, JR., MD John J. Hutchings, MD WILLIAM C. ROBERTS, MD Leslie A. Saketoo, MD DONNA RYAN, MD Fred A. Lopez, MD, FACP JERRY ST. PIERRE, MD CHARLES SANDERS, MD Christin Tsao, MD 134 PATHOLOGY IMAGE OF THE MONTH OLIVER SARTOR, MD Robin R. McGoey, MD Black Thyroid CHARLES SCHER, MD RICHARD SPECTOR, MD JACK P. STRONG, MD PRAMILLA N. SUBRAMANIAM, MD KEITH VAN METER, MD DIANA VEILLON, MD HECTOR VENTURA, MD CHRIS WINTERS, MD GAZI B. ZIBARI, MD Journal of the Louisiana State Medical Society

Subcutaneous Fat Necrosis of the Newborn Associated With Hypercalcemia After Therapeutic Hypothermia

Zhuang Feng, MD, PhD; Baofeng Guo, MD; Zhenzhen Zhang, MD, MPH

Subcutaneous fat necrosis of the newborn (SCFN) is a rare, benign, and self-limiting panniculitis of neonates that presents in the first few weeks of life and is most commonly associated with birth asphyxia and meconium aspiration. There have been few case reports of SCFN following therapeutic hypothermia. With the increasing use of therapeutic whole-body hypothermia, SCFN may become more prevalent. The differential diagnosis of SCFN can be broad, and clinicopathologic correlation is essential to make the correct and timely diagnosis. Clinicians should be aware of this rare disease and its potential serious complication hypercalcemia.

CLINICAL FEATURES onset of skin lesions.1,6,12 Hypercalcemia as a complication of SCFN has been seen in 20%-69% of patients in previous case Subcutaneous fat necrosis of the newborn (SCFN) is a series.1,2,12 Strohm et al. reported hypercalcemia was seen in rare, benign, and self-limiting panniculitis of neonates that 8 (67%) of 12 SCFN patients after therapeutic hypothermia.8 presents in the first few weeks of life. It mainly affects term Clinically, hypercalcemia manifests from asymptomatic to and post-term neonates. Neonatal risk factors include hy- irritability, weight loss, hypotonia, lethargy, poor feeding, poxia, meconium aspiration, sepsis, hypothermia, obstetric dehydration, and growth retardation.3,11,13 In severe cases, trauma, anemia, and thrombocytopenia; maternal risk factors metastatic calcification occurs in kidney, myocardium, major include gestational diabetes, preeclampsia, smoking, and vessel, liver, and brain.1,8,12 family history of thrombosis.1,2 Cold exposure is a known risk factor for SCFN. As therapeutic hypothermia has been becom- PATHOLOGIC FINDINGS ing a routine protocol for hypoxic ischemic encephalopathy (HIE) in neonatal intensive care units, SCFN as a complica- The diagnosis of SCFN is based on clinicopathologic tion of whole-body cooling has been increasingly reported correlation and histopathologic examination of skin punch in the past several years.3-8 Studies reporting its incidence are biopsy. SCFN characteristically shows a lobular panniculitis limited. In a study by Strohm et al., 12 (1%) of 1,239 newborns with a dense infiltrate of lymphocytes, histiocytes, multi- with therapeutic whole-body hypothermia developed SCFN.8 nucleated giants cells and occasional eosinophils, and radially Shankaran et al. reported 1 (1%) of 102 newborns with thera- arranged needle-shaped clefts in adipocytes and histiocytes.14 peutic whole-body hypothermia developed SCFN.9 The needle-shaped clefts represent triglyceride crystals that SCFN usually presents as circumscribed, erythematous, are extracted during specimen processing; the crystals are indurated nodules and plaques on fat-bearing areas such as derived from stearic and palmitic acids, normal components face, chest, back, buttocks, arms, and thighs; fluctuant skin of neonatal subcutaneous adipose tissue. In late stage of the lesion was rarely reported.6 The skin lesions are often pain- disease, septal fibrosis and calcification can be seen in the less and not warm to palpation. Pain was seen in 25% of fat lobules. patients in one case series.1 The skin lesions usually appear Fine-needle aspiration and touch imprint cytology of 2-10 days after the completion of cooling therapy.3,4,6,7,10,11 drainage material have been used as alternative tools for The skin lesions usually resolve spontaneously in weeks to diagnosis in few case reports.15 Aspiration and drainage can months, but hematoma formation requiring skin debridement provide quick and less invasive evaluation, but the sensitiv- and grafting was rarely reported.8 Complications of SCFN ity is limited compared to skin biopsy. Cytology findings include dyslipidemia, hypoglycemia, thrombocytopenia, consist of fat droplets containing radially arranged refractile and hypercalcemia.1,5 The most serious complication, hy- needle-shaped crystals in a background of inflammatory percalcemia, may occur several days to six months after the cells, including lymphocytes, histiocytes, and multinucleated

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giant cells, with or without calcifications. The background and absence of adipocyte necrosis and calcification. Unlike appearance may range from scanty inflammation with no SCFN, which is localized and self-limiting with an excellent significant necrosis of adipocytes to numerous inflammatory prognosis, sclerema neonatorum rapidly generalizes and has cells with dirty necrotic background, depending on the stage a poor prognosis with a mortality rate of 75%. The presence of of the disease.15 needle-shaped clefts is rather a nonspecific feature for SCFN and sclerema neonatorum, and hence, clinical presentation DIFFERENTIAL DIAGNOSIS and degree of inflammation are more important for diagnosis. Scleredema is a rare and self-limiting skin condition affect- The differential diagnosis of SCFN can be broad, and ing primarily preterm neonates in the first week of life. The clinicopathologic correlation is essential to make the correct risk factors of scleredema include cold injury, dehydration, and timely diagnosis so that appropriate measures can be diarrhea, vomiting, and infection. Clinically, scleredema taken to prevent the potential serious complication hyper- manifests as generalized firm pitting edema more commonly calcemia.14 seen in lower extremities. Histopathologically, scleredema When fluctuant nodules or skin rashes are present, is characterized by a lobular panniculitis with inflammation especially in critically ill or immunocompromised patients, and marked edema of skin and subcutaneous tissue without infectious etiology such as bacterial cellulitis, toxic shock syn- needle-shaped clefts and adipocyte necrosis. The prognosis drome, abscess, and erysipelas should be ruled out first. Skin of scleredema is good, and skin lesions heal spontaneously and subcutaneous infection generally manifests in warmth, with supportive care. swelling, and pain of the lesion, whereas SCFN remains Poststeroid panniculitis is a rare panniculitis occurring in normothermic to palpation. Histopathologically, infection of neonates who had an abrupt taper or sudden withdrawal of skin and subcutaneous tissue can show mostly neutrophilic high-dose systemic corticosteroids therapy. Clinically, post- lobular panniculitis or suppurative granulomas, which may steroid panniculitis presents as erythematous nodules on the require special stains (Gram, periodic acid-Schiff, acid-fast cheek and chin within days to weeks after the withdrawal of stain) to identify pathogenic microorganisms. Cultures of corticosteroids. Histopathologically, poststeroid panniculitis skin lesions may be necessary if special stains fail to detect can mimic SCFN by displaying a mixed inflammation of less pathogens and clinical suspicion for infection remains high. intensity, as well as needle-shaped clefts in adipocytes and Needle-shaped clefts are generally absent in adipocytes. histiocytes. Skin lesions due to infection usually resolve with systemic antibiotic therapy. PATHOGENESIS Cold panniculitis is inflammation of subcutaneous adipose tissue caused by direct exposure to cold. The clinical appear- The pathogenesis of SCFN and hypercalcemia is unclear. ance of cold panniculitis may overlap with early stage SCFN. It has been suggested that perinatal events, such as birth as- It usually has no maternal factors and tends to occur within phyxia or hypothermia, can shunt blood from peripheral skin 72 hours of cold exposure. Clinically, it usually presents as and subcutaneous tissue to central vital organs and result in red-blue indurated plaques or nodules. Histopathologically, subcutaneous stresses, e.g. hypoperfusion and hypoxemia, cold panniculitis is a lobular panniculitis with nonspecific which in turn lead to injury and crystallization of adipocytes, inflammatory infiltrate of lymphocytes and histiocytes, inflammation, and granulomatous reaction. Normal adipose most prominent at the dermosubcutaneous junction in the tissue contains triglycerides in a variable proportion of satu- fat lobules and without needle-shaped clefts and adipocyte rated and unsaturated fatty acids. The neonatal adipose tissue necrosis. Cold panniculitis generally resolves spontaneously has a higher ratio of saturated to unsaturated fatty acids than after further cold exposure is avoided. the adult counterpart, which determines a higher melting Sclerema neonatorum is a very rare panniculitis affecting point and a lower solidification point of the adipose tissue. primarily ill preterm neonates in the first week of life. Unlike These unique features predispose neonatal adipose tissue SCFN, which has aforementioned risk factors, sclerema neo- to an increased risk for crystallization on exposure to stress natorum usually has no maternal factors with an uneventful factors such as hypothermia. delivery and is often associated with congenital anomalies, The most popular hypothesis of hypercalcemia in SCFN serious respiratory illness, and sepsis. Sclerema neonatorum is the extrarenal production of 1, 25-(OH)2D3, leading to manifests as diffuse hardening of the skin - sparing soles, increased intestinal absorption of calcium. SCFN can ex- palms, and genitalia - which firmly attaches to the underneath hibit a strong expression of 1a-hydroxylase in inflammatory muscle and bone, leading to impaired feeding and breath- infiltrate, suggesting that 1, 25-(OH)2D3 may be produced ing; whereas SCFN presents as circumscribed hardening of by macrophages in subcutaneous granulomas.1 However, the skin, which moves freely over the underneath muscle Burden et al. showed that elevated serum 1, 25-(OH)2D3 was and bone. Histopathologically, sclerema neonatorum is observed in only one out of four patients.2 Therefore, other characterized by thickening of the connective tissue septa possible mechanisms such as activation of osteoclasts and of the subcutaneous fat; absent to sparse inflammatory in- enhanced bone calcium turnover resulting from elevated filtrate of lymphocytes, histiocytes and multinucleate giant prostaglandin E2 may also play a role in the pathogenesis cells; radially arranged needle-shaped clefts in adipocytes; of hypercalcemia.

98 J La State Med Soc VOL 166 May/June 2014 TREATMENT AND PROGNOSIS 2. Burden AD, Krafchik BR. Subcutaneous fat necrosis of the newborn: a review of 11 cases. Pediatric dermatology. Sep-Oct 1999;16(5):384- SCFN is usually treated symptomatically. Painful lesions 387. can be managed with acetaminophen or opiate analgesia such 3. Akcay A, Akar M, Oncel MY, et al. Hypercalcemia due to as morphine; refractory cases can add short-term predniso- subcutaneous fat necrosis in a newborn after total body cooling. 10,13 Pediatric dermatology. Jan-Feb 2013;30(1):120-123. lone that has a synergistic effect with morphine. Tran et 4. Hogeling M, Meddles K, Berk DR, et al. Extensive subcutaneous fat al. (2003) showed that aspiration of skin lesions may be used necrosis of the newborn associated with therapeutic hypothermia. to relieve pain and skin breakdown. Hypercalcemia can be Pediatric dermatology. Jan-Feb 2012;29(1):59-63. managed by conservative and symptomatic treatment such as 5. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis low calcium and vitamin D formula, intravenous hydration, PG. Cooling for newborns with hypoxic ischaemic encephalopathy. and loop diuretics. Severe cases can be treated with corti- Cochrane Database Syst Rev. 2013;1:CD003311. costeroids, bisphosphonate, and calcitonin. Serum calcium 6. Oza V, Treat J, Cook N, Tetzlaff MT, Yan A. Subcutaneous fat levels should be monitored weekly or biweekly for up to six necrosis as a complication of whole-body cooling for birth asphyxia. Archives of dermatology. Aug 2010;146(8):882-885. months or until the resolution of fat necrosis. Filippi et al. 7. Sivanandan S, Rabi Y, Kamaluddeen M, Akierman A, Lodha (2012) proposed that using a cooling blanket in an automatic A. Subcutaneous fat necrosis as a complication of therapeutic “gradient variable mode,” where the circulating water was hypothermia in a term neonate. Indian journal of pediatrics. May maintained at minimal change in temperature along with a 2012;79(5):664-666. special nursing protocol to change position of neonates every 8. Strohm B, Hobson A, Brocklehurst P, Edwards AD, Azzopardi D. three hours by alternating pronation/supination during cool- Subcutaneous fat necrosis after moderate therapeutic hypothermia ing, may reduce the risk of developing SCFN.16 Therefore, it in neonates. Pediatrics. Aug 2011;128(2):e450-452. is prudent to change the skin contact site of cooling device 9. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body more frequently and avoid direct pressure of cooling device hypothermia for neonates with hypoxic-ischemic encephalopathy. The New England journal of medicine. Oct 13 2005;353(15):1574-1584. against skin to minimize subcutaneous stress. 10. Woods AG, Cederholm CK. Subcutaneous fat necrosis and whole- SCFN is generally self-limiting with an excellent prog- body cooling therapy for neonatal encephalopathy. Advances in nosis. Skin lesions usually resolve spontaneously in weeks to neonatal care : official journal of the National Association of Neonatal months without long-term sequelae, and most cases require Nurses. Dec 2012;12(6):345-348. only conservative and symptomatic treatment. Previous case 11. Zifman E, Mouler M, Eliakim A, Nemet D, Pomeranz A. series demonstrated good prognosis even when associated Subcutaneous fat necrosis and hypercalcemia following therapeutic with hypercalcemia;1,2,8 however, SCFN complicated by hy- hypothermia--a patient report and review of the literature. Journal percalcemia can be fatal if left untreated.12 of pediatric endocrinology & metabolism : JPEM. Nov 2010;23(11):1185- 1188. 12. Norwood-Galloway A, Lebwohl M, Phelps RG, Raucher H. CONCLUSIONS Subcutaneous fat necrosis of the newborn with hypercalcemia. Journal of the American Academy of Dermatology. Feb 1987;16(2 Pt SCFN is a rare, benign and self-limiting panniculitis of 2):435-439. neonates. It can present as fluctuant lesions or with concur- 13. Wiadrowski TP, Marshman G. Subcutaneous fat necrosis of the rent infection, which may result in delayed diagnosis. The newborn following hypothermia and complicated by pain and differential diagnosis of SCFN can be broad, and clinicopatho- hypercalcaemia. The Australasian journal of dermatology. Aug logic correlation is essential to make the correct and timely 2001;42(3):207-210. 14. Requena L, Sanchez Yus E. Panniculitis. Part II. Mostly lobular diagnosis. With the increasing use of therapeutic whole-body panniculitis. Journal of the American Academy of Dermatology. Sep hypothermia, SCFN may become more prevalent. Physicians 2001;45(3):325-361; quiz 362-324. should be aware of this uncommon disease because of its 15. Schubert PT, Razack R, Vermaak A, Jordaan HF. Fine-needle potential serious complication. The patient should be moni- aspiration cytology of subcutaneous fat necrosis of the newborn: tored closely for skin involvement because skin lesions can the cytology spectrum with review of the literature. Diagnostic appear several days after the completion of cooling therapy. cytopathology. Mar 2012;40(3):245-247. The patient should be followed weekly or biweekly for serum 16. Filippi L, Catarzi S, Padrini L, et al. Strategies for reducing the calcium levels until skin lesions resolve, because hypercal- incidence of skin complications in newborns treated with whole- cemia may occur weeks to six months after the onset of skin body hypothermia. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, lesions. The parents should be educated with the signs and the Federation of Asia and Oceania Perinatal Societies, the International symptoms of SFCN and hypercalcemia. Society of Perinatal Obstet. Oct 2012;25(10):2115-2121. REFERENCES

1. Mahe E, Girszyn N, Hadj-Rabia S, Bodemer C, Hamel-Teillac D, Dr. Feng is with the Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans. Dr. Guo is with De Prost Y. Subcutaneous fat necrosis of the newborn: a systematic the Department of Emergency Medicine, China-Japan Union Hospital evaluation of risk factors, clinical manifestations, complications of Jilin University, Changchun, China. Dr. Zhang is with the Department The British journal of dermatology and outcome of 16 children. . Apr of Epidemiology and Biostatistics, Michigan State University, East 2007;156(4):709-715. Lansing, Michigan.

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Juvenile Ossifying Fibroma of the Middle Turbinate

John Carter, MD; Ryan Winters, MD; Christina Yang, MD; Hugo St. Hilaire, DDS, MD; Kimsey Rodriguez, MD

Juvenile ossifying fibroma is a rare, benign tumor that may present in the sinonasal area but has never been described arising from the middle turbinate. The lesion’s locally aggressive behavior and close proximity to orbit and anterior skull base create a significant challenge for the patient and practitioner. This is a case presentation of a 7-year-old female with an invasive recurrent juvenile ossifying fibroma arising from the middle turbinate.

INTRODUCTION CASE REPORT

Juvenile ossifying fibroma is a benign osseous neoplasm A 7-year-old female with an unremarkable medical that most commonly presents in the pediatric population history presented to the pediatric otolaryngology clinic at less than 15 years of age. These masses present in the with a 10-month history of gradually increasing proptosis craniofacial skeleton and are most often recognized in the and lateral displacement of the left eye. She had headaches, paranasal sinuses, maxilla, or orbit. In contrast to their adult seasonal allergies, and nasal obstruction but denied vision counterpart, ossifying fibroma, these lesions tend to be more changes, retro-orbital pain, or purulent rhinorrhea. Aside locally aggressive. Their nonspecific radiographic appear- from proptosis, ophthalmologic exam was normal. Clinical ance and locally invasive nature may create a challenge for exam via anterior rhinoscopy and nasal endoscopy revealed the practitioner. This is the first described case report of a clear secretions and markedly enlarged inferior turbinates juvenile ossifying fibroma of the middle turbinate. obstructing both nasal cavities. With decongestion, the left nasal exam was notable for a large, firm, mucosa-covered

Figure 1a: Computed tomography of the sinuses (coronal Figure 1b: Axial view highlights the involvement of the middle view, bone window). Left-sided mass (3.6 x 2.4 x 3.5 cm) with turbinate. a radiopaque focus at the anterior aspect of a concha bullosa, immediately opposite the ostium of an opacified maxillary sinus.

100 J La State Med Soc VOL 166 May/June 2014 Figure 2: T1-weighted coronal magnetic resonance, expansile lesion with significant homogenous enhancement. mass extending from the lateral nasal wall to the septum with obliteration of middle meatus. Computed tomography of the sinuses showed a left- sided mass (3.6 x 2.4 x 3.5 cm) with a radioopaque focus at the anterior aspect of a concha bullosa, immediately op- Figures 3a and 3b: Benign respiratory mucosa and areas posite the ostium of an opacified maxillary sinus (Figure of trabecular bone consistent with the trabecular variant of 1). T1-weighted coronal magnetic resonance imaging of juvenile ossifying fibroma. Occasional multi-nucleated giant the sinuses revealed a well-defined, expansile lesion with cells can be found within a stroma of plump fibroblasts. significant homogenous enhancement demonstrated in its Hematoxylin and eosin stain at 10x and 40x magnification, respectively. inferior portion. Lateral displacement of the lamina papy- racea and left eye and opacification of the left maxillary and and is thought to arise from the periodontal membrane, sur- ethmoid sinuses were demonstrated (Figure 2). The patient rounding tooth roots, and most often presents with painless underwent endoscopic surgical removal of the lesion. swelling of the mandible or incidental finding on routine Histopathology revealed benign respiratory mucosa and dental radiographs. By contrast, juvenile ossifying fibroma areas of trabecular bone consistent with juvenile ossifying (JOF) most often originates outside the tooth root in the fibroma (Figures 3a, 3b). The patient experienced improve- maxilla, paranasal sinuses, or orbit.1,3 This case presented ment of symptoms initially; however, the lesion recurred within the middle turbinate in an apparent concha bullosa. three months later. Craniofacial resection via combined There are no previously reported cases of JOF arising from bicoronal and Weber-Ferguson approaches was performed a concha bullosa or middle turbinate. There have only for definitive resection with good result. been two previously described cases of OF arising from the middle turbinate.4,5 DISCUSSION JOF is histologically similar to OF, differentiated from the latter by its more locally aggressive behavior, higher rate A variant of ossifying fibroma (OF) was first described of recurrence (30%-58%), and early age of onset (most often as a cemento-ossifying fibroma by Menzel in 1872; in 1927, between 5 and 15 years of age, mean 11.8). The aggressive Montgomery first used the term ossifying fibroma.1,2 OF nature of these lesions tends to represent their proximity to are benign tumors that can originate anywhere in the cra- structures, such as the orbit and anterior skull base rather niofacial skeleton. OF demonstrates female predominance

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than a true difference in tumor biology.3,6,7 JOF are character- 7. Slootweg PJ, Panders AK, Koopmans R, Nikkels PG. Juvenile ized by fibrocellular stroma of spindle- or stellate-shaped ossifying fibroma. An analysis of 33 cases with emphasis on cells with bony trabeculae, with or without osteoblastic histopathological aspects. J Oral Pathol Med. 1994 Oct;23(9):385-8. rimming, and lacking cementicles or a formal capsule. Bony 8. Williams HK, Mangham C, Speight PM. Juvenile ossifying fibroma. An analysis of eight cases and a comparison with other trabeculae vary in size and often are a combination of woven fibro-osseous lesions. J Oral Pathol Med. 2000 Jan;29(1):13-18. and lamellar components. The two main histologic subtypes 9. White SC, Pharoah MJ. Oral radiology principles and interpretation. 2,3,7,8 of JOF are trabecular (WHO type) and psammomatoid. 5th ed. St. Louis, MO: Mosby; 2004: 498–501. Ossifying fibromas contain similar fibrocellular stroma 10. Yang HY, Zheng LW, Luo J, Yin WH, Yang HJ, Zwahlen RA. and are characterized by osteoblastic rimming due to rapid Psammomatoid juvenile cemento-ossifying fibroma of the maxilla. growth. By contrast, fibrous dysplasia is characterised by J Craniofac Surg. 2009 Jul;20(4):1190-2. fibrous stroma with loose myxomatous areas, a good blood supply, feathery irregular-shaped trabeculae of immature “woven” bone (“Chinese character” shapes), and a poorly- Dr. Carter is with the Tulane University Department of Otolaryngology defined periphery.2,5,8 - Head and Neck Surgery in New Orleans. Dr. Winters is with the Radiographically, OF lesions are monostotic and well Department of Otolaryngology and Communication Sciences, State circumscribed.4 They appear osteolytic and progess to a University of New York – Upstate Medical University in Syracuse, mixoid appearance. Lesions that contain greater amounts New York. Dr. Yang with the Department of Pediatric Otolaryngology Head & Neck Surgery, Cincinnati Children’s Hospital Medical Center in of cementum may contain additional irregular radiopaque Cincinnati, Ohio. Dr. St. Hilaire is with the Louisiana State University or radiolucent areas. As is the case with our presentation, Division of Plastic and Reconstructive Surgery in New Orleans. Dr. these lesions may exhibit cortical expansion and bony Rodriguez is the with the Ochnser Health System Department of thinning.2,9,10 However, these imaging characteristics are Otolaryngology - Head and Neck Surgery in New Orleans. relatively nonspecific in appearance and make preoperative diagnosis based on imaging alone difficult. Due to potential involvement of crucial adjacent structures and high recurrence rate, management of OFs in the paranasal sinuses and turbinates is surgical. These lesions do not tend to metastasize.4 However, radiotherapy can induce malignant transformation (0.4%-44% increased risk).1,4 Several approaches have been described, including simple curettage, functional endoscopic sinus surgery, a sublabial Caldwell-Luc type approach, and even radical maxillec- tomy.3,6,7,10 The main goals of surgery are to achieve complete resection while preserving cosmesis and function of the eye. In conclusion, juvenile ossifying fibroma is a locally destructive neoplasm of the pediatric population. Early recognition of this entity and complete surgical excision of these lesions can achieve promising results.

REFERENCES

1. Gondivkar SM, Gadbail AR, Chole R, Parikh RV, Balsaraf S. Ossifying fibroma of the jaws: Report of two cases and literature review. Oral Oncol. 2011 Sep;47(9):804-9. 2. Hamner JE, Scofield HH, Cornyn J. Benign fibro-osseous jaw lesions of periodontal membrane origin: An analysis of 249 cases. Cancer. 22;1968(22):861–878. 3. Hakeem AH, Hakeem IH. Intraoral Sublabial Approachfor Anterior Skull Base Juvenile Ossifying Fibroma. J Craniofac Surg. 2011 Sep;22(5):1976-7. 4. Caylakli F, Buyuklu F, Cakmak O, Ozdemir H, Ozluoglu L. Ossifying fibroma of the middle turbinate: a case report. Am J Otolaryngol. 2004 Sep-Oct;25(5):377-8. 5. Galvan O, Gassner EM, Neher A, Gunkel AR. Fibro-osseous lesion of the middle turbinate: ossifying fibroma or fibrous dysplasia? J Laryngol Otol. 2007 Dec;121(12):1201-3. 6. Bowyer JD, Majid MA, Ah-Fat F, Kaye SB, Kokai GK, May PL, McCormick M. Giant cemento-ossifying fibroma of the maxilla causing proptosis in a young patient. J Pediatr Ophthalmol Strabismus. 2001 Nov-Dec;38(6):359-62.

102 J La State Med Soc VOL 166 May/June 2014 Emerging Causes of Superficial and Invasive Infections Following Marine Injuries and Exposures

James H. Diaz, MD, MPH & TM, DrPH, FCCM, FACMT

Soft tissue bacterial infections following aquatic animal bites, stings, and minor injuries occur commonly and usually on the extremities in fishermen and beachgoers worldwide after freshwater and saltwater exposures. Louisiana has more tidal, saltwater, and brackish water shorelines (more than 7,000 miles) than any other state, including Alaska and Hawaii. As a result, Louisiana residents are often exposed to marine pathogens when fishing or working offshore or when enjoying Louisiana’s miles of shorelines. Although many species of bacteria have been isolated from marine wounds, superficial soft tissue and invasive infections following marine injuries and exposures are most commonly caused by a small number of bacterial species, including Aeromonas hydrophila, Edwardsiella tarda, Erysipelothrix rhusiopathiae, Mycobacterium marinum, and Vibrio vulnificus. In addition to these species, several other aquatic bacteria have recently been identified as emerging causes of superficial and invasive infections following marine injuries and exposures, including marine mammal (dolphins and seals) Brucella species, Chromobacterium violaceum, Comamonas species, Shewanella algae, and Streptococcus iniae. The objectives of this review are to describe the epidemiology, presenting clinical manifestations, diagnostic and treatment strategies, and outcomes of both the superficial and the deeper invasive infections caused by the newly emerging marine bacterial pathogens.

Soft tissue bacterial infections following aquatic animal nas species, Shewanella algae, and Streptococcus iniae. The bites, stings, and minor injuries occur commonly and usu- objectives of this review are to describe the epidemiology, ally on the extremities in fishermen and beachgoers world- presenting clinical manifestations, diagnostic and treatment wide after freshwater and saltwater exposures. Although strategies, and outcomes of both the superficial and the Louisiana’s shorelines are rapidly retreating today from deeper invasive infections caused by the newly emerging levee projects, saltwater intrusions, and hurricane storm marine bacterial pathogens. surges, Louisiana has more tidal, saltwater, and brackish water shorelines (more than 7,000 miles) than any other MATERIALS AND METHODS state, including Alaska and Hawaii. As a result, Louisiana residents are often exposed to marine pathogens when Initially, several search engines were queried for refer- fishing or working offshore or when enjoying Louisiana’s ences using all keywords listed as medical subject heading miles of shorelines. (MESH) words for searches. The keywords included: marine Although many species of bacteria have been isolated injuries, marine animal injuries, marine infections, aquatic from marine wounds, superficial soft tissue and invasive infections; marine bacteria; fish pathogens; aquaculture- infections following marine injuries and exposures are most related fish infections; marine mammal pathogens. The commonly caused by a small number of bacterial species, sources of US cases of superficial and invasive infections including Aeromonas hydrophila, Edwardsiella tarda, Erysip- following marine injuries and exposures were provided by elothrix rhusiopathiae, Mycobacterium marinum, and Vibrio peer-reviewed, published case reports and series, descrip- vulnificus. Of the causative marine pathogens, the most seri- tive studies, case-control studies, and Morbidity Mortality ous and often fatal invasive infections are caused by Vibrio Weekly Reports (MMWR) published by the United States vulnificus. In addition to these species, several other aquatic (US) Centers for Disease Control and Prevention (CDC). bacteria have recently been identified as emerging causes of Infections were classified as superficial (abscess), spreading superficial and invasive infections following marine injuries (cellulitis, lymphangitis), and invasive (arthritis, tenosynovi- and exposures, including marine mammal (dolphins and tis, osteomyelitis, metastatic abscesses, e.g., neurobrucello- seals) Brucella species, Chromobacterium violaceum, Comamo- sis). Bacterial species were classified by Gram staining status,

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Table 1: Representative marine pathogens and their antiobiotic susceptibilities Bacteria Antibiotic susceptibilities Gram-positive bacteria

Erysipelothrix rhusiopathiae Amoxicillin, piperacillin-taxobactam, erythromycin, doxycycline, aminoglycosides

Streptococcus iniae Amoxicillin, piperacillin-tazobactam, cephalosporins Gram-negative bacteria

Aeromonas hydrophila Third-generation cephalosporins, second-generation quinolones, resistant to penicillins and first-generation cephalosporins Gram-negative marine mammal Brucella spp.

B. cetaceae (dolphin-porpoise strain) Tetracyclines (doxycycline) + rifampin or trimethoprim- B. pennipediae (seal strain) sulfamethoxazole + rifampin

Chromobacterium violaceum Aminoglycosides, carbapenems, tetracyclines, trimethoprim-sulfamethoxazole, resistant to penicillins and cephalosporins

Comamonas spp. C. acidovorans Piperacillin-tazobactam, quinolones, aminoglycosides, C. terrigena third-generation cephalosporins C. testosteroni Edwardsiella tarda Aminoglycosides, cephalosporins, quinolones, teracyclines (doxycycline) Morganella morganii Carbapenems, cefepime, ciprofloxacin Pseudomonas aeruginosa Piperacillin-taxobactam, antipseudomonal cephalosporins, carbapenems, quinolones, aminoglycosides Shewanella spp. Aminoglycosides, quinolones, third generation S. algae cephalosporins, resistant to penicillins and first- and S. putrefaciens second-generation cephalosporins Gram-negative marine vibrios

Vibrio vulnificus Doxycycline + ceftazidime or quinolone; or cefotaxime + quinolone

Vibrio carchariae Antibiotics are not usually indicated for self-limited Vibrio Vibrio parahemolyticus gastroenteritis Marine acid-fast mycobacteria

Mycobacterium marinum (causes fish tank granuloma) Clarithromycin + ethambutol, rifampin

M. fortuitum Rifampin + streptomycin M. terrae M. ulcerans (causes Buruli ulcer following soil and/or stagnant water-contaminated wounds)

104 J La State Med Soc VOL 166 May/June 2014 Figure 1: A Shewanella haliotis severe soft tissue infection developed in the left leg of a 52-year-old female who had undergone orthotopic liver transplantation six months earlier and had handled fresh seafood in a market a week before (A, black arrow). Progressive, painful swelling of the left leg created a compartment syndrome with the loss of distal pulses and required emergent surgical decompression by fasciotomy (B). Two sets of blood cultures and fluid cultures from the left leg confirmed S. haliotis infection in an immunocompromised patient.13 antibiotic susceptibilities, and biochemical and molecular intracerebral lesions; one patient in New Zealand with spinal signatures (Table 1). osteomyelitis; and one veterinary laboratory worker with a mild form of brucellosis.2,4 NEWLY EMERGING CAUSES OF MARINE The diagnosis of brucellosis can be by slow-growing INFECTIONS culture from blood or biopsies, serological demonstration of Brucella antibodies (ELISA) for the more commonly en- Marine Mammal Brucella Species countered strains, and PCR assays for separation and specia- Brucellosis, or undulant fever, is a zoonotic infectious tion of the terrestrial and marine mammal strains. Invasive disease caused by several species-specific strains of Brucella, brucellosis and neurobrucellosis will require prolonged which are small, gram-negative, non-motile, non-spore- treatment (2-12 months) with a combination of intravenous forming, rod-shaped coccobacilli. Brucellosis is rare in the rifampin, doxycycline, and gentamicin for a week or more United States, with an average of 113 cases reported to the followed by six or more weeks of oral doxycycline and 1 CDC annually over the period 2000-2009.1 Most cases in rifampin. For persons exposed to stranded marine mam- the United States are caused by consuming unpasteurized mals or their carcasses, a three-week course of antimicrobial milk or cheese from infected cattle (B. abortus) or goats (B. prophylaxis with oral doxycycline and rifampin has been melitensis), hunting feral swine (B. suis), and occupational recommended by the CDC in addition to symptom surveil- 1 exposures among laboratory workers handling Brucella lance with daily fever checks for 24 weeks. For children species.1,2 New zoonotic reservoirs of Brucella strains have and others who cannot take doxycycline, a three-week now been identified in pinnipeds (seals, sea lions, and course of trimethoprim-sulfamethoxazole and rifampin is 1 walruses) and cetaceans (dolphins, porpoises, and whales), recommended. collectively referred to as marine mammal Brucella species On October 27, 2011, six months after the Deepwater and tentatively classified as B. pinnepediae and B. cetaceae, Horizon BP oil spill off the Louisiana coast in April 2010, respectively.2 Seroprevalence studies have now identified the National Oceanic and Atmospheric Administration marine mammal Brucella species strains in both seals and (NOAA) confirmed that 5 of the 21 tested bottle-nosed porpoises stranded and dying along the New England dolphins among the 580 dolphins that died in the northern Coast.3 In humans, brucellosis can cause fever, febrile sweat- Gulf of Mexico in 2010-2011 had marine mammal brucel- 5 ing, headache, weakness, myalgia, back pain, and rarely, losis. NOAA scientists concluded that severe environ- invasive granulomatous disease in bone, liver, and the cen- mental stress, including crude oil exposures, could have tral nervous system (neurobrucellosis).2 Four human cases compromised the animal’s immune systems, making them of marine mammal brucellosis have been reported since more susceptible to a zoonotic infectious disease common 5 2001 with two cases in males from coastal Peru treated in in marine mammals. As a result, the NOAA advises that the United States for neurobrucellosis with granulomatous anyone who encounters a stranded or dead dolphin in the

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Gulf of Mexico region not touch the animal, keep all pets Comamonas species could be human gastrointestinal tract away from the animal, and notify the NOAA immediately commensals.10 In seven cases, there were no predisposing at 1-877-942-5343.5 All persons who handle stranded marine factors, with the exception of one case following a tiger bite.10 mammals or who participate in autopsies on their carcasses Comamonas peritonitis occurred in eight cases, endocarditis should be educated as to the potential risks of marine mam- in two cases, and one in an intravenous drug abuser.10 mal brucellosis and use personal protective equipment, Smith and Gradon reported a case of Comamonas sepsis including respirators.1,5 in a previously healthy 89-year-old man who slept next to a tropical fish tank in which fish had started to die rapidly, Chromobacterium violaceum turning the tank water opaque and malodorous.10 The pa- Chromobacterium violaceum is an aerobic, gram-negative tient presented with sore throat, myalgia, fever, and had two bacillus, and a saprophyte found in soil and water in tropical sequential positive blood cultures for Comamonas species and subtropical regions worldwide.6 The organism grows sensitive to all antibiotics tested.10 The patient was treated rapidly on ordinary culture media and is typically first with levofloxacin, and his condition rapidly stabilized identified by the violet-color of its colonies.6 Non-pigmented without sequelae.10 Since the patient denied any physical strains of C. violaceum are less commonly found than pig- contact with his son’s fish tank, the authors concluded that mented strains, but do co-exist with pigmented strains and the most likely source of infection was by inhalation and can cause mixed infections.7 Although widely distributed, C. recommended that Comamonas bacteremia be considered violaceum is a low-grade pathogen and causes few infections, in the differential diagnosis of sepsis in patients who are with most reported from the southeastern US with high case tropical fish tank enthusiasts.10 fatality rates, especially in the immunocompromised.8 In 1982, Macher and colleagues reported 12 cases of C. viola- Shewanella species ceum infections in the United States in patients with chronic Shewanella species are saprophytic gram-negative bac- granulomatous disease - seven of whom died of invasive teria that are distributed in temperate regions worldwide septicemia 7 days to 15 months after initial infections.9 The and are part of the normal microflora of the marine environ- portal of entry for C. violaceum is typically a break in the ment like Aeromonas hydrophila, Erysipelothrix rhusiopathiae, skin from an insect bite, laceration, or fish bite, followed by and Vibrio vulnificus.11-13 There are more than 50 species of exposure to brackish or stagnant water. An ulcerated skin Shewanella, all of which produce yellowish-brown mucoid lesion with a bluish purulent discharge develops at the initial colonies that emit hydrogen sulfide in culture.11-13 Several injury site with regional swelling usually on an extremity. Shewanella species have been recently recognized as emerg- Within days, invasive septicemia may occur, especially in ing causes of soft tissue and invasive infections after seawa- the immunocompromised, with high fevers and dissemi- ter exposures, including S. algae, S. haliotis, S. putrefaciens, nated macular skin lesions that progress to abscesses. Ab- and S. xiamenensis.13 The most common clinical manifesta- scesses may also occur in bone and in the liver. The organism tions of Shewanella infections are deep ulcers associated is susceptible to aminoglycosides, quinolones, tetracyclines, with hemorrhagic bullae, usually on the lower extremities, imipenem, and trimethoprim-sulfamethoxazole but resistant otitis externa, otitis media, and bacteremia.11-13 Non-healing to penicillins and cephalosporins.8 Due to high case fatality ulcers have resulted in necrotizing fasciitis, compartment rates, treatment of suspected C. violaceum infections should syndromes requiring decompressive fasciotomies, and begin immediately with drainage of all purulent abscess osteomyelitis (Figure 1).11-13 Shewanella septicemia has been collections and combined intravenous antibiotic therapy. A associated with endocarditis and meningitis.11-13 Shewanella high index of suspicion for C. violaceum infections should be pneumonia, cholecystitis, and peritonitis have been reported maintained in all cases with a rapid progression from an ul- following aspiration or ingestion of seawater.12 Besides sea- cerated lesion in a soil- or water-contaminated minor wound water exposure and ingestion of raw seafood, other common followed by sepsis, widespread cutaneous involvement, risk factors for Shewanella infections have included minor and liver abscesses. Rapidly growing violet-pigmented trauma or lacerations in marine environments, pre-existing colonies on blood or MacConkey agar are diagnostic of the lower extremity ulcers, and immunocompromise.13 Wagner pigmented strains of C. violaceum. and colleagues reported a case of S. algae-infected chronic leg ulcers in a 52-year-old female with autoimmune vascu- Comamonas species litis and myasthenia gravis seven months after returning Comamonas species are flagellated, gram-negative, rod- from a Mediterranean vacation during which she reported shaped bacteria that form characteristic pink-pigmented frequently bathing in the surf.11 Poovorawan and colleagues colonies on ordinary culture media.10 Like C. violaceum, reported another recent case of severe S. haliotis soft tissue Comamonas species are widely distributed in nature in infection in the left lower leg with compartment syndrome soil and water but rarely cause human infections, with 24 in a 52-year-old female from Bangkok who had undergone cases reported to date and a case fatality rate of 12.5%.10 Of orthotopic liver transplantation six months previously the 24 reported human cases, eight cases were associated and reported frequent handling of fresh saltwater fish in with appendicitis or perforated appendix, suggesting that a seafood market (Figure 1).13 In a descriptive analysis of

106 J La State Med Soc VOL 166 May/June 2014 16 Shewanella cases in Martinique and another 239 cases hours of their injuries.15 Most of the fish species identified reported in the literature over a 14-year period, 1997-2012, were tilapia commonly used in Asian cuisine.15 The median Vignier and co-investigators noted that 79% of patients had age of the case-patients was 67 years (range 40-80 years); the predisposing risk factors for Shewanella infections - 53% of female-to-male ratio was 2:1; and all patients were of Asian patients had a skin or mucosal portal of entry, and 44% of descent.15 Four patients had chronic underlying diseases, cases reported prior marine exposures.12 The case fatality including diabetes, chronic renal failure, rheumatic heart rate was 13% in their case series.12 disease, and osteoarthritis.15 In all 11 cases, invasive S. iniae The diagnosis of Shewanella infections can be established infection was culture-confirmed; and S. iniae isolates from by positive blood or lesion aspirate cultures, but the specia- nine of these cases were identical by pulsed-field gel electro- tion of Shewanella causative strains will require molecular phoresis (PFGE) and also matched PFGE-identified S. iniae characterization by PCR.12 Most species are sensitive to isolates obtained from the surface and brains of infected a broad range of antibiotics, including aminoglycosides, tilapia from local aquaculture farms.15 In all cases, the S. third-generation cephalosporins, and quinolones. S. algae iniae isolates were sensitive to a broad range of antibiotics, is resistant to penicillins and first- and second-generation including aminoglycosides, cephalosporins, macrolides, cephalosporins.11,12 For invasive infections, especially in penicillins, and trimethoprim-sulfamethoxazole.15 All pa- immunosuppressed patients, most authorities recommend tients were admitted to hospitals, treated with parenteral two weeks of intravenous antibiotic therapy with third- antibiotics, and responded to antibiotic therapy within two generation cephalosporins combined with either aminogly- to four days.15 The investigators concluded that most pa- cosides or quinolones, followed by two to three weeks of tients had been inoculated with S. iniae in association with oral antibiotic therapy.11-13 Early surgical consultation is also minor injuries received during preparation of fresh fish, recommended for drainage of bullous lesions, debridement especially tilapia, and recommended that precautionary of ulcers, and monitoring for potential extremity compart- measures be taken, especially by immunocompromised ment syndromes requiring decompressive fasciotomies elderly patients, when handling whole, uncooked fish to (Figure 1). prevent S. iniae infections.15

Streptococcus iniae GENERAL MANAGEMENT OF MARINE INJURIES Streptococcus iniae, a gram-positive, B-hemolytic streptococcus unassigned to a Lancefield Group, was first Even minor abrasions and lacerations sustained in identified in 1976 as the cause of subcutaneous abscesses marine environments should be considered potentially in Amazon freshwater dolphins in US aquariums.14 Often contaminated with common marine microbes, such as Vibrio misidentified as S. viridians, S. iniae has emerged as a major species. Following any specific detoxification measures, such fish pathogen capable of causing epizootic outbreaks of as hot water immersion for stingray injuries or topical acetic invasive streptococcal disease in farm-raised fish.15 S. iniae acid for fire coral and jellyfish stings, all wounds should initially colonizes the surface of the fish, causing cellulitis be irrigated with a sterile diluent solution, if possible, such which can be complicated by invasive meningoencephalitis as normal saline. Crushed or devitalized tissues should be with 30%-50% mortality in affected aquaculture ponds.15 excised by sharp dissection under local anesthesia or pe- Commercially devastating outbreaks have now been re- ripheral nerve blocks. Foreign bodies should be removed. ported worldwide in other farm-raised fresh and saltwater Diagnostic imaging is often indicated, especially in punc- fish species, including coho salmon, rainbow trout, tilapia, ture wounds, to exclude retained foreign bodies. Potential and yellowtail.15 constriction bands, such as bracelets, rings, and watches, The first human cases of S. iniae invasive infections were should be removed from the injured extremity and base- reported from the Toronto area in 1996, when a cluster of line extremity circumference measurements taken in the four cases in patients of Asian descent who had recently pre- event of swelling from necrotizing fasciitis and compart- pared fresh, whole farm-raised fish was reported to public ment syndromes. Sequential surgical debridements will be health authorities.15 Three of these patients had bacteremic indicated in many cases - in all cases of necrotizing fasciitis cellulitis of the hands secondary to soft tissue injuries that - and following fasciotomies for compartment syndromes. occurred during the preparation of fresh fish obtained from Most wounds should be left open or packed open to heal wet markets; and the fourth patient had S. iniae sepsis with by secondary intention. Delayed primary closures may be arthritis, meningitis, and endocarditis.15 During a follow- indicated for potentially disfiguring facial wounds. Tetanus up, one-year surveillance investigation, Weinstein and col- prophylaxis is indicated for all marine wounds. leagues identified 11 patients with invasive S. iniae infections with cellulitis of the hands in eight cases, endocarditis in one GENERAL MANAGEMENT OF CONTAMINATED case, and either arthritis or cellulitis in the remaining cases.15 MARINE WOUNDS All of the patients had recently handled live or freshly killed fish, and eight patients suffered percutaneous injuries while Grossly contaminated or infected wounds and all preparing the fish and developed cellulitis within 16-24 puncture wounds should be cultured, and the microbiology

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laboratory should be notified in advance that special culture spp. Emerg Infect Dis 2003; 9: 485-488. media and stains will likely be required, such as sodium- 3. Maratea J, Ewalt DR, Frasca S, et al. Evidence of Brucella sp. enriched media for Vibrio species and acid-fast stains/cul- infection in marine mammals stranded along the coast of southern tures for marine aquatic mycobacteria. With the exception New England. J Zoo Wildlife Med 2003; 34: 256-261. 4. McDonald WL, Jamaludin R, Mackereth G, et al. Characterization of minor marine wounds demonstrating localized cellulitis of Brucella sp. strain as a marine mammal type despite isolation or spreading erysipeloid-type reactions, most other marine from a patient with spinal osteomyelitis in New Zealand. J Clin infections and all gram-negative and mycobacterial marine Microbiol 2006; 44: 4363-4370. infections will require therapy with antibiotic combinations.1 5. United States Department of Commerce. National Oceanographic Streptococcus iniae infections are characterized by impetigo and Atmospheric Administration. NOAA finds bacterial and cellulitis, and Erysipelothrix rhusthopathiae infections infection as a cause of death for five northern Gulf dolphins; cause erysipeloid manifestations. These infections may investigation continues. Available at www.noaanews.noaa.gov/ be treated empirically with single antibiotics, specifically stories2011/20111027_dolphins.html 6. Petrillo VF, Severo V, Santos MM, Edelweiss EL. Recurrent penicillins or macrolides in cases of penicillin allergy, until infection with Chromobacterium violaceum: first case report culture and antibiotic susceptibility results are reported. from South America. J Infect 1984; 9: 167-169. In all suspected cases of M. marinum infection, clini- 7. Yang CH. Nonpigmented Chromobacterium violaceum cians will need to pursue confirmation by culture and bacteremic cellulitis after a fish bite. J Microbiol Immunol Infect begin combined antibiotic therapy with clarithromycin 2011; 44: 401-405. and ethambutol.11,12 Persons who are immunosuppressed 8. Midani S, Rathore M. Chromobacterium violaceum infection. or have cirrhosis, hepatitis, uremia, hemosiderosis, or other South Med J 1998; 91: 464-466. iron-retaining conditions, are at higher risks for invasive 9. Macher AM, Casale BT, Fauci AS. Chronic granulomatous disease Vibrio infections with the highest case fatality rates. They of childhood and Chromobacterium violaceum infections in the South Eastern United States. Ann Intern Med 1982; 97: 51-52. also should be empirically covered with combinations of 10. Smith MD, Gradon JD. Bacteremia due to Comamonas species third-generation cephalosporins (ceftazidime) and tetra- associated with exposure to tropical fish. South Med J 2003; 96: cyclines (doxycycline), fluoroquinolones and tetracyclines, 815-817. or aminoglycosides and trimethroprim-sulfamethoxazole. 11. Wagner N, Otto L, Podda M, et al. Travel-related chronic The clinical microbiology laboratory should be consulted hemorrhagic leg ulcer infection by Shewanella algae. J Travel Med frequently, and all definitive antibiotic therapy should 2013; 20: 262-264. be based on precise pathogen identification by culture or 12. Vignier N, Barreau M, Olive C, et al. Human infection with molecular signature and antibiotic susceptibility testing. Shewanella putrefaciens and S. algae: Report of 16 cases in Martinique and review of the literature. Am J Trop Med Hyg 2013; 89: 151-156. CONCLUSIONS AND RECOMMENDATIONS 13. Poovorawan K, Chatsuwan T, Lakananurak N, et al. Shewanella haliotis associated with severe soft tissue infection, Thailand, 2012. Clinicians should maintain a high index of suspicion Emerg Infect Dis 2013; 19: 1019-1021. regarding potentially catastrophic bacterial infections, 14. Pier GB, Madin SH. Streptococcus iniae sp. nov., a beta-hemolytic especially Vibrio vulnificus and Chromobacterium violaceum streptococcus isolated from an Amazon freshwater dolphin, Inia infections, following marine injuries and exposures. Patients geoffrensis. Int J Syst Bacteriol 1976; 26:545-553. with well-known risk factors for marine infections, including 15. Weinstein MR, Litt M, Kertesz DA, et al. Invasive infections due to a fish pathogen, Streptococcus iniae. N Engl J Med 1997; 337: those with suppressed immune response mechanisms, liver 589-594. disease, alcoholism, diabetes, chronic renal disease, AIDS, and cancer, should be cautioned about the risks of marine infections through exposures to marine animals, seawater, the preparation of freshly-killed seafood, and the ingestion Dr. Diaz is Professor and Head of Environmental and Occupational of seawater or consumption of raw or undercooked seafood, Health Sciences in the School of Public Health and Professor of Anesthesiology in the School of Medicine at Louisiana State University especially oysters. All persons who handle stranded marine Health Sciences Center in New Orleans. mammals, such as bottle-nose dolphins common in the northern Gulf of Mexico, or who participate in necropsies on their carcasses should be educated as to the potential risks of marine mammal brucellosis and the use of personal protective equipment, including respirators.

REFERENCES

1. United States Centers for Disease Control and Prevention (CDC). Human exposures to marine Brucella isolated from a harbor porpoise—Maine, 2012. Morb Mort Week Rep 61: 461-463. 2. Sohn AH, Probert WS, Glaser CA, et al. Human neurobrucellosis with intracerebral granuloma caused by marine mammal Brucella

108 J La State Med Soc VOL 166 May/June 2014 The Association Between the Medical Home and Pediatric Developmental Screening Among US Children Five Years and Younger: Results From the 2007 National Survey of Children’s Health

Nicole Richmond, MPH; Tri Tran, MD, MPH; Susan Berry, MD, MPH

Objectives: The medical home is associated with key healthcare services. We assessed its association with the pediatric developmental screening among United States (US) children < five years.

Methods: The 2007 national survey of children’s health data was analyzed using state clusters, and pediatric developmental screening probability was modeled as a function of the medical home.

Results: Only 19.5% of US children received pediatric developmental screening, and crosstabs showed a null medical home association. Based on medical home status, adjusted state models showed much variation in pediatric developmental screening odds. A random intercept and slope model had the best fit. The medical home increased pediatric developmental screening odds by 24% (1.10, 1.38).

Conclusions: The pediatric developmental screening rate and the medical home association are partially influenced by an individual’s state. A multilevel model including state level predictors will help illuminate factors that promote healthcare service acquisition. This knowledge will enhance policy development in public and private sector health programs.

INTRODUCTION well-child visit. The rationale illuminates the hidden nature of DD. Symptoms or characteristics are often intertwined The adage “an ounce of prevention is worth a pound with nervous system plasticity, and thus, screening ideally of cure” can be interpreted in countless ways given context. occurs during critical periods of development (9, 18, and 30 In the milieu of infectious disease, public health practitio- months old).1 This longitudinal evaluation method helps ners might focus on timely administration of vaccinations to assess the duration, intensity, and accumulation of child to inoculate a populace, thereby creating herd immunity. and family risk factors that may have a temporal influence In the context of chronic disease such as birth defects, it is toward imparting phenotypic aberrations in normal devel- not incidence that is prevented but rather an increase in opment. As such, the AAP policy highlights the need for prevalence with the aim to minimize long-term sequelae pediatric developmental screening (PDS) using standard- and corresponding incidence of co-morbidities. In one sce- ized tools to detect veiled aberrations in development. nario, eradication of onset is the goal, while for the latter, Research supports PDS use. A study by Voigt and col- it is reduction of deleterious consequences. However, both leagues found a strong association between DD and parent- capture the same sentiment: early detection and interven- ing stress (assessed by parents’ evaluation of developmental tion will impart a greater impact on population health than status (PEDS)).2 However, few clinicians implement PDS, treatment alone. as reflective of the slight change in PDS rates: between 2002 A 2006 American Academy of Pediatrics (AAP) policy and 2009, PDS went from 23% to roughly 48%.3 Likewise, in outlines the pivotal role of the pediatrician to conduct age- 2002, 71% said they relied solely on clinical judgment, and specific developmental delay (DD) surveillance as part of the fewer (66%) reported the same in 2009.3 One likely reason

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Table 1: Study sample demographic characteristics, National Survey of Children’s Health 2007 (N=22,270) Characteristic %a(n) 95% CI Pediatric development screening status Yes, received 19.5 (4,310) 18.3, 20.8 Medical home status Yes, care meets medical home criteria 63.0 (14,415) 61.3, 64.6 Sex Male 51.5 (11,512) 49.9, 53.2 Age 10 - 12 months 3.5 (775) 3.0, 4.1 1 year 20.3 (4,595) 19.0, 21.6 2 years 17.3 (3,722) 16.1, 18.6 3 years 19.0 (4,393) 17.7, 20.3 4 years 19.4 (4,457) 18.1, 20.7 5 years 20.6 (4,328) 19.2, 22.0 Race White 72.4 (20,906) 70.8, 73.9 Black 14.6 (16,143) 13.5, 15.7 Multiple races 6.7 (1,391) 5.8, 7.8 Other 6.4 (1,272) 5.5, 7.3 Ethnicity Hispanic 22.0 (3,252) 20.3, 23.8 Child with special healthcare need Yes, CSHCN 13.2 (3,017) 12.2, 14.2 Health insurance status Public Insurance (Medicaid/SCHIP) 34.1 (5,696) 32.5, 35.8 Private Insurance (employer/self) 58.3 (14,976) 56.6, 60.0 Uninsured 7.6 (1,394) 6.76, 8.6 Highest educational level of household member Greater than high school 53.3 (13,913) 51.6, 55.0 Household % federal poverty level 200% or above 61.2 (14,682) 59.4, 63.0 Household structure Two-parent (biologic/adopted) 77.3 (17,706) 75.9, 78.7 Two-parent (stepfamily) 2.8 (426) 2.2, 3.5 Single mother - no father present 16.4 (3,097) 15.2, 17.6 Other 3.6 (930) 3.0, 4.2 Census bureau region of child’s resident state South 38.2 (7,572) 36.7, 39.7 Northeast 15.9 (3,791) 15.0, 16.8 Midwest 21.6 (5,168) 20.6, 22.6 West 24.4 (5,739) 22.7, 26.2

Abbreviations: CI=confidence interval; N=study population size; n=sample size; SCHIP=state children’s health insurance program; CSHCN=children with special healthcare needs.

a“Percent” refers to the population-weighted estimate.

110 J La State Med Soc VOL 166 May/June 2014 for this is the use of standardized parent questionnaires services the “pediatric healthcare professional is the most that are shown to be more sensitive with DD detection than appropriate healthcare consultant, coordinator, and source pediatrician clinical judgment alone.4 of referral” (and) “regardless of the pediatric healthcare What may explain pediatricians’ low buy-in with formal setting, this care can be provided in accordance with the tools is the nominal training received on child development precepts of the MH.”9 Moreover, the role of the MH provider and psychology, early education, and the system of services with regards to early intervention is to first conduct a PDS.9 for children with special healthcare needs (CSHCN).5 Hypo- It is with this background in mind that we aim to answer thetically, if a patient is identified with a delay, the chasm the following: what is the association between the MH and in knowledge on how to link families to community-based PDS among US children five years and younger? services may appear daunting to the provider, thus affecting the family’s efficacy to navigate the service system. In an METHODS effort to address the sparse training, Bauer et al. conducted a pediatric resident education intervention to improve The 2007 national survey of children’s health (NSCH) screening knowledge and referral self-efficacy to increase is a cross-sectional, complex, randomly sampled survey PDS rates.6 The intervention improved rates by roughly that provides both national and state estimates on the 90% and also found a greater increase in PDS knowledge prevalence of child health indicators and service system for first-year residents versus third-year residents, despite use.10 Survey respondents are the primary guardian of a ran- similar baseline knowledge.6 domly selected child from a randomly selected household. The medical home (MH) defines the pivotal role of Households are contacted through random digit dialing the pediatrician in the provision of culturally competent, methodology. The 2007 NSCH was conducted between compassionate, coordinated, and comprehensive primary April 2008 and July 2008, encompassed 91,642 interviews, care and is a model that has been shown to reduce dispari- and resulted in an overall weighted response rate of 46.7%.10 ties for access and need.7 Romaire and Bell used medical Sampling weights reflect the total US child population. A expenditure panel survey data and found that children more comprehensive description of the survey methodology (<17 years) with an MH had greater odds for general health is detailed elsewhere.10 Because children <10 months or >5 screening and anticipatory guidance on healthy behaviors.8 years at the time of the survey were not assessed for PDS, In 2007, the AAP recommended that for early intervention our study is limited to those between these ages (n=27,566).

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Pediatric developmental screening Statistical analyses The PDS survey question is: “Sometimes a child’s doctor SAS-Callable SUDAAN v. 9.1 was used to account for or other healthcare provider will ask a parent to fill out a the complex sampling design of NSCH data in order to questionnaire at home or during their child’s visit. During estimate weighted percentages, odds ratios (OR), and 95% the past 12 months, did a doctor or other healthcare provider confidence intervals (CI) with proper standard errors so have you fill out a questionnaire about specific concerns or that parameters reflect population estimates. Preliminary observations you may have about [child]’s development, descriptive analyses assessing the PDS rate and the MH-PDS communication, or social behaviors?”10 association in covariate-adjusted models for each state were If the response was affirmative and based on the child’s done to determine if multilevel logistic regression models age (10-23, 24-71 months), two questions were asked to de- (MLM) were appropriate for this study. Clusters for this lineate false positives. If both the initial and two follow-up study are states (n=51). Two-level MLMs were conducted questions were answered “yes,” then the child is defined to determine the overall MH-PDS association controlling for to have received PDS. If any of the three questions was covariates. The MLM framework (Figure 1) outlines how answered “no,” the child is defined to have not received level-2 influences the level-1 MH-PDS association. Mplus PDS (n=22,270). v.6.0 was used to build three MLMs sequentially tested for goodness-of-fit. The reduced null model did not include MH Medical home and covariates. The random intercept model included MH The MH is a composite of 21 questions that operation- with covariates and assumed that PDS prevalence varied alizes five model domains: 1) personal doctor or nurse; 2) but the MH-PDS association did not differ by state. The usual source of care; 3) access to needed referrals; 4) fam- final random intercept and random slope model expanded ily-centered care; and 5) care coordination.10 The MH was on the second but assumed the MH-PDS association varied dichotomized into a response of “yes” or “no” (n = 26,694). by state. All covariates were assumed to have fixed effects, meaning confounding on the MH-PDS association did not Covariates vary by state. Akaike’s and Bayesian’s information criteria CSHCN encompass children with a broad spectrum of and likelihood-ratio tests were used to evaluate model fit. health needs defined as meeting one or more of the follow- The intra-class correlation coefficient (ICC) measures the ing chronic conditions for 12 or more months: (1) currently percent of variability of the PDS between states. To improve need prescription medication; (2) need more medical care, parameter estimate accuracy, the raw sampling weight was mental health, or educational services than a typical child; scaled by applying scaling method A as suggested by Aspa- (3) are limited in the ability to do things; (4) need physical, rouhov and yields new weights that add up to the cluster occupational, or speech therapy; and (5) have any kind of sample size. This method is particularly recommended emotional, developmental, or behavioral problem for which when the cluster size is greater than 20.12 Because of study he/she needs treatment or counseling.10 CSHCN status inclusion criteria, a zero-weight approach was applied to the was modeled as “yes” or “no” (n=27,566). Ethnicity was new weight so ineligible children (n=5,296) were excluded dichotomized, Hispanic or non-Hispanic (NH) (n=27,260). from analysis with a designated zero weight prior to MLM Race was grouped as: White, Black, Other, and Multiple building. As subpopulations are nested above the cluster races (n=25,814). Other merged Asian, Native American, level, the zero-weight approach is deemed an appropriate Alaskan Native, Native Hawaiian, or Pacific Islander into method for MLM subpopulation analyses. Alpha was set at one group. Household federal poverty level (FPL) is binary: 0.05 for statistical significance. less than or equal to 200% or greater than 200% based on the average Medicaid household income eligibility criteria RESULTS (n=25,125). The highest educational level of any household member is binary: < high school or > high school (n=27,290). Our study captured 81% (n=22,270) of the five years Primary health insurance was grouped: public (Medicaid), and younger child population. Of this, a fraction (19.5%) private (employer or self-insured), or currently uninsured received a PDS (Table 1), whereas, almost two-thirds (63%) (n=27,271). Family structure is: two-parent (biologic or report a MH. A majority (58.3%) is privately insured, and adoptive), two-parent (stepparent), single-mother, and 13.2% are CSHCN. About one-fifth are Hispanic (22%) and other (n=27,414). The 50 states and DC were categorized as: 72.4% white. Educational attainment was equally distrib- South, Northwest, Midwest, and West (n=27,566). Lastly, uted, as was sex and age (given the inclusion criteria only the child’s age at the time of the survey (10 months to 5 children less than one year represented a comparatively years) (n=27,566), and sex (male or female) (n=27,547) were smaller fraction of the study sample). More than 75% reside included. Missing values and responses of either “don’t in two-parent (biologic/adopted) families, 61.2% live at or know” or “refused” were coded as missing (n-missing range: above 200% FPL, and nearly 40% are from the South. A 19 - 2,441). comparable proportion of children with or without a MH received a PDS (20.4% vs. 18.4%, respectively) (Table 2). Only significant confounders were included in the adjusted models (age, insurance, race, CSHCN, family structure, and

112 J La State Med Soc VOL 166 May/June 2014 Table 2: Pediatric developmental screening associations, National Survey of Children’s Health 2007 (N=22,270) Received a Pediatric Developmental Screening (n=4,310) Characteristics %a (n) 95% CI P valueb Medical home status Yes, care meets medical home criteria 20.4 (2,891) 18.8, 22.0 0.14 No, care does not meet medical home criteria 18.4 (1,318) 16.6, 20.5 Sex Male 19.8 (2,252) 18.1, 21.7 0.62 Female 19.2 (2,055) 17.6, 21.0 Age 10-12 months 267 (184) 20.3, 34.2 <0.01 1 year 22.5 (1,096) 20.1, 25.1 2 years 22.0 (790) 18.9, 25.4 3 years 17.7 (804) 15.2, 20.6 4 years 17.2 (718) 14.5, 20.4 5 years 17.1 (718) 14.7, 19.9 Race White 18.7 (3,081) 17.4, 20.2 0.04 Black 24.4 (432) 21.0, 28.2 Multiple races 20.6 (287) 15.0, 27.6 Other 20.8 (248) 16.2, 26.2 Ethnicity Hispanic 19.1 (659) 16.1, 22.6 0.73 Child with special healthcare need Yes, CSHCN 23.9 (756) 20.9, 27.2 <0.01 No, non-CSHCN 18.9 (3,554) 17.6, 20.2 Health insurance status Public Insurance (Medicaid/SCHIP) 23.6 (1,297) 21.2, 26.2 <0.01 Private Insurance (employer/self) 17.8 (2,735) 16.4, 19.3 Uninsured 14.9 (234) 11.4, 19.1 Highest educational level of a household member High school or less 21.1 (1,637) 19.1, 23.3 0.03 Greater than high school 18.3 (2,645) 16.9, 19.9 Household % federal poverty level Less than 200% 21.9 (1,290) 19.7, 24.2 0.02 200% or above 18.8 (2,697) 17.2, 20.4 Household structure Two-parent (biologic/adopted) 19.0 (3,374) 17.6, 20.4 0.05 Two-parent (stepfamily) 17.8 (85) 12.0, 25.5 Single mother - no father present 23.6 (675) 20.4, 27.0 Other 16.8 (157) 12.3, 22.4 Census bureau region of child’s resident state South 22.1 (1,521) 20.1, 24.2 <0.01 Northeast 13.0 (582) 11.1, 15.2 Midwest 22.2 (1,067) 20.3, 24.3 West 17.4 (1,140) 14.6, 20.7

Abbreviations: CI=confidence interval; N=study population size; n=sample size; SCHIP=state children’s health insurance program; CSHCN=children with special healthcare needs. a“Percent” refers to the population-weighted estimate. bOne-sided P values are computed using Wald Chi-square tests.

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Table 3: Pediatric developmental screening receipt and adjusted odds ratios by child’s state of residence, National Survey of Children’s Health 2007 (N=22,270) State %a aORb 95% CI Logit model n Alaska 20.7 1.54 0.77, 3.07 411 Alabama 12.1 0.99 0.38, 2.58 371 Arkansas 15.9 0.84 0.36, 1.96 342 Arizona 17.3 1.93 0.74, 5.04 356 California 14.0 1.53 0.41, 5.62 331 Colorado 25.9 1.52 0.71, 3.25 371 Connecticut 16.6 1.06 0.50, 2.25 383 District of Columbia 14.3 0.55 0.29, 1.04 425 Delaware 10.9 1.15 0.44, 3.00 336 Florida 17.1 0.97 0.33, 2.85 374 Georgia 22.7 1.63 0.81, 3.27 447 Hawaii 27.2 1.04 0.51, 2.14 416 Iowa* 18.7 2.272 1.15, 6.45 406 Idaho 18.1 0.80 0.38, 1.67 383 Illinois 21.1 0.80 0.41, 1.55 406 Indiana 19.4 1.50 0.63, 3.60 404 Kansas 24.7 1.23 0.63, 2.41 380 Kentucky 15.5 0.77 0.35, 1.71 382 Louisiana 28.7 1.56 0.74, 3.29 422 Massachusetts 16.4 0.75 0.31, 1.82 401 Maryland 22.3 1.13 0.55, 2.31 358 Maine* 21.5 2.15 1.11, 4.17 403 Michigan 18.2 0.70 0.31, 1.59 380 Minnesota* 41.6 0.44 0.23, 0.85 413 Missouri 19.0 1.69 0.71, 4.04 427 Mississippi* 20.0 2.29 1.01, 5.20 436 Montana 16.7 1.25 0.56, 2.77 383 North Carolina 47.0 1.39 0.71, 2.69 392 North Dakota 17.6 1.38 0.70, 2.72 379 Nebraska 18.8 0.86 0.37, 1.99 387 New Hampshire 18.1 1.13 0.55, 2.32 345 New Jersey* 12.7 5.98 2.38, 15.02 418 New Mexico* 29.6 3.58 1.37, 9.36 308 Nevada 18.6 1.81 0.73, 4.50 380 New York 11.7 0.56 0.25, 1.27 354 Ohio 20.8 0.66 0.27, 1.63 384

114 J La State Med Soc VOL 166 May/June 2014 Oklahoma 20.8 1.11 0.58, 2.12 408 Oregon 13.5 1.23 0.49, 3.12 372 Pennsylvania 10.7 0.96 0.32, 2.92 375 Rhode Island* 14.5 0.37 0.16, 0.87 324 South Carolina 19.1 1.39 0.72, 2.68 425 South Dakota 18.8 1.84 0.84, 4.01 381 Tennessee 29.0 0.81 0.43, 1.55 411 Texas* 19.2 3.17 1.27, 7.88 370 Utah* 20.6 3.58 1.43, 8.95 457 Virginia 18.2 1.24 0.55, 2.80 418 Vermont 17.9 1.04 0.44, 2.45 356 Washington 25.6 1.54 0.70, 3.39 390 Wisconsin 25.9 1.13 0.57, 2.22 391 West Virginia* 31.9 2.77 1.52, 5.07 409 Wyoming 20.2 1.27 0.60, 2.65 415

Abbreviations: CI=confidence interval; N=study population size; n=sample size; aOR=adjusted odds ratios.

a“Percent” refers to the population-weighted estimate. *One-sided P value <0.05 using Wald Chi-square tests. bModels adjusted for age, insurance, race, special healthcare need, and family structure. region of residence). The PDS prevalence varied by state, despite a steady disability rate (18.7%).13 The increase may and covariate-adjusted logit models indicate significant reflect CSHCN who are reaching adulthood due to medical variation (Table 3); we therefore proceeded with MLMs. advances over the past 30 years.14 Despite the improvements Adjusted MLMs indicate the random intercept and random in life expectancy and chronic disease management, adults slope model fit best (Table 4); subsequently, both the PDS with disabilities face disproportional social challenges. The and the MH-PDS association varied by state. Based on this 2010 census showed 20% of severely disabled adults were model, children whose care meets MH criteria have 1.24 employed in the 24 months prior to the survey versus 54.8% greater odds of having received a PDS compared to those (non-severe) and 61.1% (not disabled).13 Also, persistent without MH care (adjusted OR: 1.24; 1.10, 1.38). The percent poverty (24 months) was experienced differentially: 11% of variability in the PDS prevalence between states is 4% of severely disabled, 4.9% of non-severe, and 3.8% of non- (ICC = 0.04). disabled.13 Perhaps by considering the lack of PDS as a proxy for delayed DD diagnosis rather than an indicator of services DISCUSSION provided, the urgency for understanding the mechanisms for why children are not receiving necessary screenings Population Distribution Implications may be greater. Indeed, from this perspective, research is This is the first study to date that has examined the not constrained to defend the need for increased PDS to MH-PDS association accounting for the influence of a child’s inform health policy but only to highlight a connection: the resident state. Our work indicates that a nominal fraction of rate of adult disability is constant, and this parallels the rate US children have received a PDS in the 12 months prior to for delayed DD diagnosis (PDS) and subsequent acquisition the survey. Greater than 80%, or about 15.9 million out of the of early intervention services. total 19.9 million US children between 10 months and 5 years of age, did not meet PDS criteria. Given the reliability of the State and Federal Health Policy Implications - survey, we presume a substantial number of young children Health Insurance Disparities at risk for DD have missed an important opportunity for We found PDS odds were higher in children with an early intervention. Looking ahead, the marginal PDS rate MH than without. This was expected given the AAP policy may forecast changes in the distribution of adult disability outlines a fundamental service for an MH provider is to indicators over the next few decades. Between 2005 and conduct a PDS. We found the MH-PDS association remained 2010, there was an increase of 2.2 million disabled US adults, after accounting for identified confounders. Among these

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Table 4: Adjusted odds ratios for receipt of developmental screening as a function of having a medical home among US children five years and younger, National Survey of Children’s Health 2007 (N=22,270) Null Random intercept Random intercept and slope P value aORa,c (95% CI) P valueb aORa,c (95% CI) P valueb 1.25 (1.11-1.39) 0.001 1.24 (1.10-1.38) 0.002 Variance 0.142 0.001 0.120 0.002 0.138 0.010 ICC 0.041 0.035 0.040 DF 2 21 22 AIC 22,092.11 19,935.24 19,901.51 BIC 22,108.13 20,101.56 20,075.74 Likelihood ratio tests Log likelihood -11,044.06 -9,946.62 -9,928.75 Devianced 2,194.88 35.74 DF 2 19 1 half P value 0.0000 0.0117

Abbreviations: CI=confidence interval; N=study population size; n=sample size; aOR=adjusted odds ratios; ICC=intra-class correlation coefficient; DF=degrees of freedom; AIC=Akaike’s information criterion; BIC=Bayesian’s information criterion.

aAdjusted odds ratios and corresponding 95% CI refer to the population-weighted estimate. bTwo-sided P value <0.05 are computed using Wald Chi-square tests. cModels adjusted for age, insurance, race, special healthcare need, family structure, and census bureau region. dDeviance is the computed difference in log likelihood values obtained with MLR estimators.

confounders, was insurance type. Public health insurance State and Federal Health Policy Implications - coverage increased PDS odds by 36% compared to private Racial Disparities and by 30% compared to the uninsured. This may reflect Another significant confounder was race. This is an the Medicaid Early Periodic Screening, Diagnosis, and important confounder that is related to state residence and Treatment Program.15 It may also indicate that clinicians adult quality of life. For example, the 2010 census disability consider Medicaid-covered children at high risk for poorer age-adjusted rates reveal racial differences: NH-Black 22.3 health outcomes and subsequently are more inclined to versus NH-White 17.6.13 These rate differences suggest provide PDS. Another theory is that private carriers sel- that all things being equal, a higher disability burden is dom pay or inadequately reimburse for PDS, something experienced among NH-Black adults. Linked to this, is of concern for privately owned clinics given the extended disproportionately greater public health capacity and fund- office visit required to provide PDS.3 However, we may ing requirement on southern states, which have the highest see such disparities minimized as a result of the preventive concentration of the nation’s NH-Black population. This health service stipulations outlined in the affordable care infrastructure demand is more taxing given the relatively act (ACA).16 For example, health plans must cover 25 pre- low wealth of these states, distribution of other compet- ventive health services for children at no additional charge ing health indicators, and higher proportion of publically (copayment, coinsurance, or unmet yearly deductible) to funded healthcare coverage. The ACA may again provide the insured.16 Among these 25, are five behavioral assess- the tools to decrease racial disparities through the inclusion ments organized to occur during specified age periods and of the patient navigator program.17 Also referred to as patient two autism screenings: one at 18 months and another at 24 advocacy, the goals of this program are to reduce healthcare months, developmental screenings for children under three disparities; increase access to care; improve health outcomes, years of age, and other salient development evaluations.16 particularly for chronic diseases; and assist patients with As a result of the mandate, the PDS policy has moved from navigating the complex system of healthcare services.17 Such “best practice” under AAP to an assurance as part of a child/ a program is in concert with the MH model. family’s healthcare coverage.1,16

116 J La State Med Soc VOL 166 May/June 2014 State and Federal Health Policy Implications - Disabilities, Section on Developmental Behavioral Pediatrics, State Disparities Bright Futures Steering Committee, Medical Home Initiative Our study also revealed the role of resident state as a for Children With Special Health Care Needs Project Advisory separate entity that influences health. The mechanisms for Committee. Policy statement: Indentifying Infants and Young Children With Developmental Disorders in the Medical Home: An this were not tested, but research has shown that includ- algorithm for Developmental Surveillance and Screening. Pediatr. ing cluster level characteristics in MLMs are helpful with 2006; 118(1):405-420. identifying the policy or the context that shapes individual 2. Voigt RG, Johnson SK, Mellon MW, et al. Relationship Between behavior.18 For example, by including the proportion of Parenting Stress and Concerns Identified by Developmental children covered by private health insurance, model results Screening and Their Effects on Parental Medical Care-Seeking may reveal policy mechanisms associated with each state’s Behavior. Clin Pediatr. 2009;48(4):362-368. insurance commission. Or perhaps investigators may find 3. Radecki L, Sand-Loud N, O’Connor KG, et al. Trends in the Use a state-level interaction between the proportion of privately of Standardized Tools for Developmental Screening in Early owned pediatric clinics and privately insured children that Childhood: 2002-2009. Pediatr. 2011;128(1):14-19. 4. Rydz D, Srour M, Oskoui M, et al. Screening for Developmental explains part of the MH-PDS association. In this sense, we Delay in the Setting of a Community Pediatric Clinic: A may hypothesize the lack of a PDS mandate by private Prospective Assessment of Parent-Reported Questionnaires. insurers prohibits clinics from providing the screening. Pediatr. 2006;118(4):e1178-e1186, ppe1184. Additionally, such cluster-level characteristics may indicate 5. Pinto-Martin JA, Dunkle M, Earls M, et al. Developmental Stages of disparities as a function of the wealth of the state. For ex- Developmental Screening: Steps to Implementation of a Successful ample, we may find that private insurance policy for CSHCN Program. Am J Public Health. 2005;995(11):1928-1932. is disproportionately less comprehensive in southern than 6. Bauer SC, Smith PJ, Chien AT, et al. Educating Pediatric Residents in northern states, and this may account for a proportion of About Developmental and Social-Emotional Health. Infant Young Child. 2009; 22(4):309-320. the individual level variation in MH outcomes according to 7. American Academy of Pediatrics, Medical Home Initiatives the child’s health insurance type and race/ethnicity. for Children With Special Health Care Needs Project Advisory Committee. Policy statement: The Medical Home. Pediatr. Strengths and Limitations 2002;110(1):184-186. Discussion of any inferences must be assessed in the 8. Romaire MA, Bell JF. The medical home, preventive care context of limitations due to unaccounted biases. Individual screenings, and counseling for children: Evidence from the medical level observations are based on respondent knowledge, expenditure panel survey. Acad Pediatr. 2010:10(5); 338-345. recollection, and interpretation of survey questions. Hence, 9. American Academy of Pediatrics, Council on Children with Disabilities, Policy Statement: Role of the Medical Home in Family- information biases may exist (social and recall) and of im- Centered Early Intervention Services. Pediatr. 2007;120(5):1153- portance, is having a parent respondent versus a medical 1158. record abstraction. Compared to doctors, parents report a 10. Blumberg SJ, Foster EB, Frasier AM, et al. Design and Operation lower PDS rate.19 The cross-sectional complex study design of the National Survey of Children’s Health, 2007. National Center limits causal inferences. Analytical methods provided cor- for Health Statistics. Vital Health Stat. 2012;1(55). rected standard errors and further enhanced parameter 11. Snijders TAB, Bosker RJ. Multilevel analysis, an introduction to inference precision as we applied appropriate weights for basic and advanced multilevel modeling. Thousand Oaks, CA: SAGE the subsample and improved exactness for estimates by fit- Publications Ltd; 2003. 12. Carle AC. Fitting multilevel models in complex survey data ting standard error adjustment. Despite the relatively low with design weights: Recommendations. BMC Med Res Methodol. ICC, this type of analysis is deemed appropriate as “even a 2009;9(49). very weak ICC can substantially deflate standard errors of 13. Brault, MW. Americans With Disabilities: 2010 Current regression coefficients,” and thus, MLMs are appropriate Population Reports. Washington, DC: US Census Bureau; 2012; when data is clustered so that standard errors are accounting P70-131 certified as of 07/2012. (accessed 2 October, 2012). and hence, the between-cluster variation.20 14. Reiss J, Gibson R. Health care transition: Destinations unknown. Pediatr. 2002;110(6):1307-1314. 15. US Centers for Medicare & Medicaid Services, Early and Periodic CONCLUSION Screening, Diagnosis, and Treatment certified as of 12/11/2013. (accessed 11 December, 2013). theoretical interpretation of how and why healthcare models 16. U.S. Centers for Medicare & Medicaid Services certified as of within a given context can influence individual health. State 12/11/2013. < https://www.healthcare.gov/what-are-my- and private sector health programs may then benefit from preventive-care-benefits/#part=3> (accessed 10 December, 2013). this research as an aid in developing context relevant policy. 17. American Medical Association certified as of 2012. (accessed 10 December, 2013). REFERENCES 18. Marmot M. Multilevel Approaches to Understanding Social Determinant. In: Berkman LF, Kawachi I (editors). Social 1. American Academy of Pediatrics, Council on Children with

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Epidemiology. New York, NY: Oxford University Press; 2000:349- 367. 19. Halfon N, Regalado M, Sareen H, et al. Assessing Development in the Pediatric Office. Pediatr. 2004;113;1926-1933. 20. Bicknel R. Multilevel Analysis for Applied Research: It’s Just Regression. New York, NY: Guilford Press 2007.

Ms. Richmond is a Professional Research Assistant with the University of Colorado Denver School of Medicine. Drs. Tran and Berry are with the Louisiana State University Health Sciences Center, School of Medicine, Department of Pediatrics and the Louisiana Department of Health and Hosptials, Office of Public Health, Center for Preventive Health, Children’s Special Health Services Program in New Orleans.

118 J La State Med Soc VOL 166 May/June 2014 Hounsfield Unit Changes Over Time in Contusions of the Brain

Kevin Moore II; Addison Willett; Eduardo Gonzalez-Toledo, MD, PhD; Asser Youssef, MD, FACS, FICS

In the United States, traumatic brain injuries are an important cause of death and disability, often with significant financial and legal consequences. Although it is generally accepted by neuroradiologists that the density of cerebral contusions decreases over time, previous research has not addressed this phenomenon directly. In the current study, we reviewed charts of patients who had suffered cerebral contusions and had at least two subsequent computed tomography scans in order to determine whether Hounsfield Units, a measure of density, decreased over time. We found that 100% of contusions decreased in Hounsfield Units over time. In addition, we found that the rate of decrease in density appears to be higher in the first 100 days after the injury. These findings are especially applicable in the area of forensics. For example, they could be used to determine the relative age of two separate brain contusions in the same patient.

INTRODUCTION one follow-up CT scan of the brain were included. The total number of patients included was 31, and there were 83 Trauma is well known to be a major cause of loss of total CT scans obtained from these patients. The number of life and disability in the United States. According to the scans per patient ranged from two to nine. Using the Osiris National Trauma Institute, trauma accounts for 47% of all program, we sampled the contusion using the slice with deaths in people under age 44, making it the number one the greatest apparent area of injury. We then calculated the killer in this age group.1 Traumatic brain injuries (TBI) are a average HU value of the contusion, repeated the process major contributor to death and disability in trauma victims, for any subsequent scans, and compared the values to see with the Centers for Disease Control (CDC) estimating that whether the average HU decreased over time. We also approximately 1.7 million TBIs occur every year.2 Cerebral used statistical software to determine whether there was contusion is a common type of TBI that can result from a a significant correlation between the time elapsed and the variety of traumatic etiologies and can result in a wide range HU. Furthermore, we investigated whether the correlation of disabilities, depending on location and severity. differed when considering different time periods relative Computed tomography (CT) scans are commonly used to the initial scan. to assist in evaluating trauma patients once the primary survey has been completed. In CT scans, the Hounsfield RESULTS Unit (HU) is used as a measure of the relative density of a certain area of tissue. It is generally well accepted among The average HU value decreased over time in 100% neuroradiologists that the HU (and therefore density) of of the contusions (n=31). There was also a correlation be- cerebral contusions decreases over time. However, it has tween HU and time elapsed when all scans were analyzed not been well characterized in previous research whether together (R=-.533, N=83, P<.001) When the average HU HUs change predictably over time in cerebral contusions. was correlated with time elapsed for scans <100 days after This study aims to determine whether the HUs decrease as the initial scan, the strength of the negative correlation the wound ages. increased. (R=-.603, N=51, P<.001). The correlation also increased when the first scan (time elapsed = 0 days) was MATERIALS AND METHODS omitted (R=-0.712, N=36, P<.001). At time periods greater than 150 days, there was no significant correlation (R -.201, In this IRB-approved retrospective chart review, we N=14, P=.491). The average HU of the initial scans ranged analyzed 1,674 records of patients admitted to the ICU from 11.8 to 54.3, with o=10.81. with traumatic head injuries that had at least one CT scan of the brain. Patients with cerebral contusions and at least

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DISCUSSION

The results of this study support our hypothesis and show that the average HU of cerebral contusions tends to decrease over time. When all scans are considered, it appears that the rate of decay of HU is higher initially, but that it levels off after a period of time (see Figure). The fact that there was a significant correlation between HU and time elapsed during the first 100 days but no correlation after the first 100 days supports this idea. However, there is a noticeable variation in the HU values from the initial scans of the patients, which is a potential confounding factor. This may be why the correlation becomes even stronger when the initial scans are omitted. There are two likely reasons for this variation: differences in the time period between the actual injury and the initial scan and variations in baseline brain density between Figure: When all scans are considered, there is a significant correlation between individuals.3 the average HU of the contusion area and the time elapsed. It appears that there is a lower rate of decrease in HU as the overall time interval increases. This study supports the idea that the relative age of cerebral contusions can be REFERENCES differentiated, to a certain extent, using the HU values in the area of the contusions. This concept could be applicable 1. National Trauma Institute. Trauma statistics, updated April in a number of settings, but it could be especially important 2012. (accessed 9/15/2013). patient claims a contusion that is actually an old injury was 2. Centers for Disease Control and Prevention, Traumatic Brain caused by a recent accident, an abnormally low HU value Injury (TBI): Incidence and distribution, 2004. in the area of the contusion could indicate that the recent 3. Cala et al. Brain density and cerebrospinal fluid space size: CT accident did not cause the contusion. for normal volunteers. American Journal of Neuroradiology. 1981 The current study is limited by a relatively small sample Jan-Feb;2(1):41-7. size, as well as the abovementioned variation in baseline brain density. Future studies could attempt to better control for these factors. Taking into account the time between Mrs. Moore II and Willett are Medical Students at Louisiana the injury itself and the initial scan could result in a more State University School of Medicine in Shreveport. Dr. Toledo is a accurate assessment of the early changes in density of the Professor of Radiology, Neurology, and Anesthesiology and Director of Neuroradiology and Research at LSU School of Medicine in Shreveport. contusions. A larger study that controls for these factors Dr. Youssef is Assistant Professor of Surgery at LSU School of Medicine could also further elucidate the overall relationship between in Shreveport. time and density of cerebral contusions.

120 J La State Med Soc VOL 166 May/June 2014 LSUHSC Department of Medicine White Coat Ceremony Address, 2014

D. Luke Glancy, MD

Let me congratulate each of the White Coat recipients on 3. KNOW HOW THE BODY WORKS. This seems axi- having successfully completed medical school, no small ac- omatic, but relating your patient’s findings to the anatomy, complishment, and on having secured a first-rate residency physiology, biochemistry, and pathology that you studied appointment that will allow you to continue the life-long so intensely a few years ago is not always easy. All signs learning process that is a requisite for being a successful and symptoms, however, have pathophysiologic bases, and physician. The intellectual rigor that medicine demands defining these will facilitate both diagnosis and treatment. and the opportunity to continue to learn are two of the chief joys of this, the noblest of professions. Each of us has had 4. TAKE NOTHING FOR GRANTED (TRUST BUT outstanding mentors, and hopefully, we will have more. I VERIFY). When one of your colleagues or a referring physi- suspect that you will find, as I have, that mentoring comes cian tells you about a patient or you read his or her evalua- not only from professors, but also from your fellow house tion in the medical record, start by believing the information officers and, most importantly, from your patients. because he or she often is correct and is never intentionally trying to mislead you. Just remember that because most of The patient, of course, is at the center of our world. What us run diagnostic algorithms the same way, if you believe an honor it is to be entrusted with caring for our fellow hu- all that you are told, you will come to the same diagnosis man beings! It is an awesome responsibility that teaches us as the referring physician. It is better to take your own his- not only about disease processes, but about human nature tory, do your own physical exam, and examine the pertinent and coping with adversity. Nothing is more rewarding laboratory data yourself. You will then often have a different than helping a patient through a life-threatening illness, data set, consequently run a different algorithm, and arrive and nothing is more humbling than not being able to do so. at a different diagnosis. All of this may require getting out of bed and going to the hospital in the middle of the night, Now, if you will indulge me, I’d like to discuss a half but the trip is worth the inconvenience. dozen precepts that I have found helpful in increasing the number of salutary medical experiences and in keeping the 5. BECOME A DIAGNOSTIC EXPERT. There is prec- number of unwholesome ones to a minimum. I must admit edent for this. Early in the 20th century, internists were that I learned many of these rules by violating them, usually often known as diagnosticians. Regardless of one’s specialty, a most unpleasant experience. however, optimal treatment depends on a precise diagnosis. Much intellectual effort is appropriately devoted to devel- 1. TREAT EVERYONE WITH RESPECT. This includes oping and learning treatment guidelines. All such effort, your patients, whether they are governors, archbishops, in- however, presupposes an accurate diagnosis. Remember digent persons, or prisoners. This also applies to all of your the role of the history and the physical exam, which often co-workers from the chief of the service to the janitor. An either make the diagnosis or suggest which of our more air of superiority serves no useful purpose and is often an sophisticated tests will. The ability to take a history and do impediment to the success of any endeavor. In this regard, a physical exam is always available. The H and P are non- the nurses are your special partners in the care of patients invasive, cost only some of your time, and can be repeated and deserve special respect. as often as is necessary.

2. ALWAYS CARRY YOUR SHARE OF THE LOAD. 6. THE BUSINESS OF MEDICINE IS IMPORTANT, BUT And if you are asked to carry more than your share, do so IS NEVER PRIMARY. Virtually all physicians, especially in without grumbling. All of us occasionally need help, and the United States, make a good living, but our bottom line is your time will come. In the same spirit of collegiality, don’t not the bottom line of the profit and loss statement, but the worry about who gets credit for the life-saving diagnosis. bottom line of whether we have served our fellow humans The important thing is that it was made. well in the most important way imaginable, i.e. by helping them stay alive and well. Judge Elbert Tuttle put business

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and the professional person in perfect perspective when he said to graduates of the professional schools at Emory University, “So do not try to set a price on yourselves ... Rather be reckless and spendthrift, pouring out your talent to all to whom it can be of service! Like love, talent is useful only in its expenditure, and it is never exhausted. Certain it is that man must eat, so set what price you must on your service. But never confuse the performance, which is great, with the compensation, be it money, power, or fame, which is trivial.”1

I envy you as you don your white coats and move on in your medical careers. I have enjoyed my career immensely and would welcome the opportunity to do it again. But I have had my turn, and it is time to let you enthusiastic young physicians have your turn to advance medicine beyond where my generation leaves it. Godspeed to each of you.

REFERENCE

1. Tuttle E P Sr. Heroism in war and peace. Emory UQ 1957; 13:129-130.

Dr. Glancy is a Professor and Dr. Ali is a former Fellow in the Sections of Cardiology, Departments of Medicine, Louisiana State University Health Sciences Center and the Interim LSU Hospital, New Orleans.

122 J La State Med Soc VOL 166 May/June 2014 ECG of the Month

ECG in a 52-Year-Old Man With a Dilated Cardiomyapathy

D. Luke Glancy, MD; Rehan Z. Ali, MD

Figure: ECG in a 52-year-old man with a dilated cardiomyopathy.

What is your diagnosis?

Explication is on page 124.

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DIAGNOSIS: Atrial tachycardia (214/min) with atrioventricular (AV) block and complete AV dissociation from junctional tachycardia (140/min), together with repolarization changes of digitalis, suggest digitalis toxicity.

The P waves of the atrial tachycardia are directed inferiorly. P waves and QRS complexes occur regularly and independently with no evidence of anterograde or retrograde conduction. The rounded sagging of the ST segments, with short QT intervals (0.26 s) and low T waves, is typical of digitalis effect, and digitalis excess is known to produce both conduction abnormalities and tachyarrhythmias in patients with cardiac disease.1 Thus, although every arrhythmia caused by digitalis may occur in its absence, few of them suggest digitalis toxicity as strongly as this double tachycardia with AV dissociation in a man taking the drug.

REFERENCE

1. Wellens HJJ, Conover MB. The ECG in Emergency Decision Making. Philadelphia: WB Saunders;1992:139-159.

124 J La State Med Soc VOL 166 May/June 2014 Radiology Case of the Month

Recurrent Knee Pain in a Young Athlete

Shiva Nagalingam, BS, BA; Mandy Weidenhaft, MD

A 22-year-old male collegiate basketball player with a history of right knee pain presents with pain and swelling of his right knee. Physical exam reveals local swelling and tenderness over the right proximal tibial-fibular joint.

Figure 1: Frontal radiograph of the knee, which demonstrates Figure 2: A lateral radiograph of the knee, which demonstrates a 2.2 x 1.7 cm rounded calcific density (black arrow) overlying the density (black arrow) and confirms it’s location within the the right tibiofibular joint. tibiofibular joint.

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Figure 3: Oblique radiograph of the knee. In this figure, Figure 4: A coronal proton density MR with fat suppression the tibiofibular joint space is better demonstrated. The obtained at the level of the posterior tibia and fibular head rounded density is again identified (black arrow). Also note demonstrates a mixed intensity lesion (black arrow) within degenerative osteophytosis of the superior aspect of the fibular the tibiofibular joint adjacent to the synovium. Signal head (white arrow). characteristics confirm that this is an ossification and not simply a calcification. A linear area of hyperintensity within the joint space represents a small joint effusion (white arrow). Also noted is high signal intensity within the fibular head (white arrowhead) indicative of edema, consistent with a bone bruise. This patient also had a sprain of the tibialis posterior tendon, not shown.

126 J La State Med Soc VOL 166 May/June 2014 considerations of synovial osteochondromatosis in the knee include pigmented villonodular synovitis, osteoarthritis, chondrosarcoma, osteochondroma, osteochondritis dissecans, and fracture with an avulsed fragment.1,2 Synovial osteochondromatosis is a benign intrasynovial process caused by nodular proliferation of the synovial membrane. Fragments can break off of the synovial surface within the joint. These bodies can grow, calcify, and ossify within the periarticular synovial fluid. The condition can occur in a primary or secondary form, but the etiologies are not specifically known. The primary form occurs as ectopic cartilage within synovial fluid without identifiable joint pathology. A secondary form can develop in a setting of preexisting joint pathology, including osteoarthritis, rheumatoid arthritis, osteochondritis dissecans, neuropathic osteoarthropathy, osteonecrosis, or fracture. Etiology of the second form is based on fragment production by the underlying disease process.2 With the primary etiology, the knee is the joint that is most often affected, comprising 60%-70% of cases. Other sites that can commonly be affected include the shoulder, the elbow, and the hip. The process appears to occur in three phases: initial active intrasynovial disease without loose bodies, a transitional phase with osteochondral nodules on the synovial membrane and free bodies in the cavity, and finally a quiescent disease state with mulitiple free intrasynovial osteochondral bodies.3 Transformation to malignancy is rare. Cases have been reported of coexisting chondrosarcoma, but a causal relationship has not been established. Osteochondromatosis does appear to have a predilection for knees with a history of repeat minor trauma and/or Figure 5: A coronal proton density MR with fat suppression image. It was obtained more anteriorly than Figure 4. It degenerative joint disease. Whether trauma or degenerative demonstrates an abormal high signal along the lateral aspect of disease contribute to the proliferation of synovial nodule or 4 the proximal tibia (black arrow) and medial femoral condyle to their fragmentation is not known. (white arrow), again consistent with edema due to bone Patients with synovial osteochondromatosis often com- bruise. plain of chronic, progressive, monoarticular pain, and swelling exacerbated by physical activity. Mechanical symptoms RADIOLOGIC DIAGNOSIS: This is a case of osteochon- can also present, including limited range of motion, grating, dromatosis of the proximal tibiofibular joint with associated bone and joint locking. Medical therapy with non-steroidal, anti- bruise and degenerative osteophytosis. inflammatory drugs can provide some relief, depending on the degree of nodule proliferation, size and characteristics DISCUSSION of the free bodies, and the physical stress placed upon the joint. Surgical excision of free bodies within the joint space Synovial osteochondromatosis is an uncommon condi- is also an appropriate intervention, with partial or total 3 tion caused by synovial metaplasia that generates multiple synovectomy depending on the degree of recurrence. calcified periarticular bodies. The lesion commonly presents The classic radiographic appearance of synovial os- as monoarticular joint pain and swelling in patients who re- teochondromatosis is multiple, spheroid, calcified masses late a history of several years of such symptoms. It presents within the joint cavity. The bodies tend to have a “popcorn more commonly in males than females by a factor of between ball” appearance characteristic of calcified cartilage. Joint two and four. While individuals of any age can be affected, effusion and degenerative changes are frequently noted as it is most often diagnosed in persons aged 20 to 50 years. well. Serial imaging studies may reveal changes in numbers Current medical therapy is centered around non-steroidal and sizes of masses, as some of the calcified bodies grow anti-inflammatory drugs, while surgical treatment consists and other are reabsorped into the synovial membrane. Lack primarily of arthroscopic examination and excision of loose of calcification or ossification of free bodies renders them bodies from the joint space with limited synovectomy of relatively lucent, with opacity similar to water. It is worth the affected synovium. Important differential diagnostic noting that the dynamic nature of the fragmented nodules can lead to normal findings in a patient with osteochon-

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dromatosis. Computed tomography (CT) scanning also can only be used for identification of calcified loose bodies; it cannot provide visualization of unmineralized fragments.5,6 The best modality for visualizing synovial osteochondromatosis is magnetic resonance imaging (MRI). MRI imaging may be diagnostic, even when calcification is minimal or absent, because uncalcified bodies of cartilage appear characteristically lobulated. They also appear isointense or slightly stronger in intensity than muscle tissue on T1- and T2-weighted images. Signal intensity correlates with the quantity of calcium present in the nodule. The degree of composing cellular component compared to acellular hyaline matrix and the quantity of calcium present in the nodules correlates with the signal intensity. Gadolinium enhancement can also be added to increase the sensitivity of the scan and assist in identifying lesions. MRI may also reveal areas of high signal intensity consistent with synovial thickening and joint effusion. Plain radiographs are useful adjuncts to MRI when the presence of calcification is am- biguous. Still, further evaluation can be achieved via nuclear imaging; lesions induce increased radionuclide uptake on technetium-99m bone scans in affected areas.7-9

REFERENCES

1. Mussey RD, Henderson MS. Osteochondromatosis. J Bone Joint Surg Am 1949;31:619-627. 2. Bearcroft PPW. Joint Disease. In: Adam A, Dixon AK, Grainger RG, Allison DJ, eds. Grainger & Allison’s Diagnostic Radiology. Churchill Livingstone 2007. 3. Milgram JW. Synovial osteochondromatosis: a histopathological study of thirty cases. J Bone Joint Surg Am 1977;59:792-801. 4. Murphey MD, Vidal JA, Fanburg-Smith JC, Gajewski DA. Imaging of Synovial Chondromatosis with Radiologic-Pathologic Correlation. RadioGraphics 2007;27:1465-1488. 5. Sheldon PJ, Forrester DM, Learch TJ. Imaging of Intra-articular Masses. RadioGraphics 2005;25:105-119. 6. Ryan RS, Harris AC, O’Connell JX, Munk PL. Synovial osteochondromatosis: the spectrum of imaging findings. Australasian Radiology 2005;49:95-100. 7. Winalski CS, Foldes K, Gravallese EM, et al. Synovial membrane disorders. Magn Reson Imaging 1999;2:1079-1096. 8. Cohen EK, Kressel HY, Frank TS, Fallon M, Burk DL, Dalinka MK, Schiebler ML. Hyaline Cartilage-Origin Bone and Soft-Tissue Neoplasms: MR Appearance and Histologic Correlation. Radiology 1988;167:477-481. 9. Frick MA, Wenger DE, Adkins M. MR Imaging of Synovial Disorders of the Knee: An Update. Radiol Clin N Am 2007;45:1017- 1031.

Ms. Nagalingam is a Medical Student at Tulane School of Medicine in New Orleans. Dr. Weidenhaft is a second-year Radiology resident at Tulane University Health Sciences Center in New Orleans

128 J La State Med Soc VOL 166 May/June 2014 Clinical Case of the Month

A 44-Year-Old Woman With Jaundice and Abdominal Pain

Shane G. Guillory, MD; Matthew D. Jordan, DO; Bradley M. Spieler, MD; Matthew L. Safley, DO; John J. Hutchings, MD; Leslie A. Saketkoo, MD; Fred A. Lopez, MD, FACP

INTRODUCTION ties in her routine lab work, the patient was told to present to the emergency department for further workup. Primary biliary cirrhosis (PBC) is an autoimmune Vital signs at the time of presentation were only notable disease of the liver. It is characterized by a T-cell-mediated for a pulse of 100 beats per minute and a temperature of 99.0 attack of the small, intrahepatic bile ducts. The exact etiology degrees Fahrenheit. Head and neck examination revealed is unknown, but it is thought to be a result of a combina- sublingual icterus, as well as scleral icterus bilaterally. Ab- tion of genetic predisposition and environmental factors.1 dominal examination revealed mild tenderness to palpation The vast majority of patients affected by PBC are women.2 in the epigastric region, as well as the right upper quadrant The natural history of the disease varies by patient, but it is without rebound or guarding. A Murphy’s sign was absent. generally thought to be a chronic, progressive disease that The liver edge was palpated at 12 cm below the right costal carries a high mortality rate if not treated definitively with margin, and the spleen was palpated at 3 cm below the left liver transplantation.3 The diagnosis of PBC is made with costal margin. Spider angiomata were noted in two spots the combination of clinical findings and laboratory data, on the right forearm, one spot on the left lower leg, and including antimitochondrial antibodies. The diagnosis can one spot on the back. Palmar erythema was noted as well. also be further confirmed with a liver biopsy. We present Initial laboratory workup revealed an elevated total a case of a woman who presented with abdominal pain, bilirubin of 4.7 mg/dl (<1.3 mg/dl), alkaline phosphatase jaundice, and significant weight loss and was diagnosed of 795 U/L (20-120 U/L), GGT of 1,199 U/L (<55 U/L), with PBC based on autoantibody testing and liver biopsy. AST of 318 U/L (<46 U/L), and ALT of 289 U/L (<46 U/L). We also present a review of the epidemiology, etiology, Erythrocyte sedimentation rate was mildly increased at clinical findings, diagnosis, and treatment options for PBC. 22 mm/hr (0-20 mm/hr). Total cholesterol was 554 mg/ dl (<200 mg/dl), triglyceride level was 923 mg/dl (<150 CASE PRESENTATION mg/dl), and LDL level was 344 mg/dl (<130 mg/dl). An acute hepatitis panel was performed and was negative. An A 44-year-old woman with a past medical history of ammonia level was elevated at 72 Umol/L (9-35 Umol/L). cholelithiasis, status-post cholecystectomy three years prior, Urine drug screen and salicylate levels were not abnormal. presented to her primary care physician complaining of Imaging at the time of admission included a right up- progressively worsening right-sided abdominal pain of per quadrant ultrasound that revealed an enlarged liver at two months duration. She described the pain as “heavy,” approximately 25 cm in sagittal dimension with no focal located throughout the right side of her abdomen, 5/10 in hepatic abnormality, an enlarged spleen at approximately intensity, and progressively worsening throughout the day. 15.7 cm in sagittal dimension, normal flow in the portal She reported that the pain was exacerbated by lying on her vein, and an enlarged 2.3 cm lymph node near the porta right side. She did admit to occasional radiation to her back hepatis. The gallbladder was surgically absent. The com- and flank on the right side. The pain was not associated mon bile duct was noted to be normal, and no masses or with eating. She also denied any nausea, vomiting, diar- free fluid were appreciated. Computed tomography of the rhea, melena, hematochezia, dysphagia, decreased appetite, abdomen on the day of admission confirmed the findings or pruritis. Review of systems was otherwise positive for of the abdominal ultrasound (Figures 1, 2). A routine chest a 35-pound, unintentional weight loss over the prior three radiograph revealed no acute cardiopulmonary process. months. After her primary care physician noted abnormali- A rheumatologic workup was pursued. While anti-

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nuclear antibody levels were negative, the anti-mitochondrial antibody level was elevated at 26.5 units (<20 units). C-ANCA, P-ANCA, alpha- 1-antitrypsin level, transferrin, ceru- loplasmin, and AFP were all normal. An outpatient liver biopsy was performed to further confirm the suspected diagnosis of PBC. The results revealed severe portal lymphocytic and granulomatous inflammation with small interlobular duct ductopenia/destruction and extensive periportal necroinflammatory changes, consistent with early-stage primary biliary cirrhosis (Figures 3, 4).

DISCUSSION

Primary biliary cirrhosis (PBC) is a progressive autoimmune disease that primarily affects women. Of the estimated 9,232 cases of PBC in the Figure 1: Axial contrast-enhanced CT demonstrates hepatosplenomegaly with an United States in 1996, 88.7% occurred 4 enlarged periportal lymph node (arrow), which measures greater than one centimeter in in females. Autoimmune-mediated maximal short axis diameter. destruction of intrahepatic bile ducts eventually leads to bile flow obstruction, hepatic fibrosis, cirrhosis, and eventual liver failure. The exact etiology continues to be a subject of investigation, but it is described by Gershwin and Mackay to be a combination of genetic predisposition and underlying environmental factors.5 Selmi et al. also suggest a genetic component by showing that the concordance of PBC in monozygotic twins is about 63%.1 Based on a systematic review of epidemiologic studies published by Boonstra et al. in the Journal of Hepatology in 2012, worldwide incidence rates of PBC range from 0.33-5.8 per 100,000 and prevalence rates range from 1.91-40.2 per 100,000.6 Due to improved awareness and diagnosis earlier in the clinical course, 50-60% of patients are asymptomatic at the time of diagnosis.7 The most common symptoms seen in PBC are fatigue and pruritis.8 Pruritis is Figure 2: Coronal contrast-enhanced images show hepatosplenomegaly with the liver estimated to occur in 25%-75% of pa- and spleen measuring 28 and 23 centimeters in maximal craniocaudal dimensions, tients with PBC. It can often precede respectively. the actual diagnosis by several years, highlighting the need to consider PBC in any patient with pruritis that is not associated with a rash.8 The

130 J La State Med Soc VOL 166 May/June 2014 Figure 3: Image (left) shows a portal bile duct with lymphocytic infiltration of the epithelium and severe chronic inflammation in the surrounding tissue.

Figure 4: This image (below) reveals poorly formed granumlomas, with multiple epitheloid histocytes, within the portal triads and surrounding severe chronic inflammation.

pruritis in PBC is thought to be directly related to cholestasis, As in this case, primary biliary cirrhosis will often decreased bile excretion, and subsequent accumulation of manifest with nonspecific findings on ultrasonography bile in the plasma and tissues. Fatigue is the most consistent and CT. Common imaging findings include signs of portal symptom of PBC, occurring in about 70%-80% of patients.8 hypertension, including splenomegaly, ascites, and varices. The exact etiology is still unknown, but peripheral muscle Hepatomegaly is also often present, particularly in earlier fatigablilty9 and autonomic dysfunction10 as mechanisms phases of the disease. Enlarged upper abdominal lymph have been proposed. Less common symptoms may include nodes, which can enhance, are also a common finding.12 Sicca Syndrome (dry eyes and mouth), cutaneous calcinosis, MRI can have improved specificity, particularly in later Raynaud’s phenomenon, and dysphagia, as PBC can be as- stages of the disease, manifesting a periportal halo sign. sociated with other autoimmune diseases such as Sjogren’s This sign is characterized by low T1 and T2 signal intensity syndrome and scleroderma.2 The physical exam is often in a periportal distribution without mass effect. The sign normal in the asymptomatic patient. Skin hyperpigmenta- reflects periportal parenchymal loss adjacent to regeneration due to melanin deposition may be seen earlier in the tive nodule formation. Aside from diagnostic utility, cross course, while jaundice is a late manifestation. Hepatomegaly sectional imaging can also be used for screening for hep- is found in about 70% of patients, and splenomegaly may tocellular carcinoma, as these patients a carry an increased develop as the disease progresses.2 risk (~5%).13,14 The diagnosis of PBC should always be considered in The classic findings on liver biopsy of patients with the setting of cholestasis after the exclusion of other liver PBC is asymmetric destruction of the bile ducts within the diseases. Most patients have a significantly elevated alkaline portal triads.2 Patients are further classified into stages (i.e., phosphatase with milder elevations in the aminotransferas- stage one through four) based on the degree of destruction es.11 The degree of alkaline phosphatase elevations generally and the number of bile ducts involved. Stage 1 is inflamma- correlates with the severity of ductopenia and inflammation. tion localized to the portal triads, while stage 4 represents As the disease progresses, a rise in serum bilirubin, along end-stage liver disease.2 In 2009, The American Association with a decrease in serum albumin and platelets, may signal for the Study of Liver Diseases (AASLD) published recom- the development of cirrhosis and portal hypertension. Se- mendations for the diagnosis of PBC.11 The diagnosis can rum cholesterol levels are often markedly elevated as well.11 be made if any two of the following three criteria are met: While anti-nuclear antibody (ANA) is only positive in ap- • Biochemical evidence of cholestasis based mainly proximately 70% of patients with PBC12, anti-mitochondrial on alkaline phosphatase elevation antibody (AMA) is found in nearly 95% of cases.11 • Presence of AMA

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• Histologic evidence of nonsuppurative destruc- suspected in any patient with unexplained cholestasis or tive cholangitis and destruction of interlobular pruritis. Timely diagnosis and early referral to a specialist bile ducts is imperative for these patients. The only FDA-approved therapy for PBC is ursodeoxycholic acid (UDCA).11 Several studies have supported REFERENCES the usefulness of UDCA in slowing the progression of liver failure and improving mortality rates.15 UDCA is indicated 1. Selmi C, Mayo M, Bach N, et.al. Primary Biliary Cirrhosis in for any patient with PBC and abnormal liver chemistries, Monozygotic and Dizygotic Twins: Genetics, Epigenetics, and regardless of stage. Appropriate dosing of UDCA is para- Environment. Gastroenterology 2004; 127: 485-492. mount, as studies have shown superior results with a dose 2. Kaplan M and Gershwin M. Medical Progress: Primary Biliary Cirrhosis. N Engl J Med 1996; 353; 12: 1261-1273. of 13-15 mg/kg/day when compared to either a lower or 16 3. Boyer J, Shockcor W, and Mahl T. The Natural History of Primary higher dose. Some of the other medications that have been Biliary Cirrhosis. Trans Am Clin Climatol Assoc. 1992; 103: tested as a single agent in the treatment of PBC include 157–163. chlorambucil, penicillamine, cyclosporine, corticosteroids, 4. Jacobson D, Gange S, Rose N, et al. Epidemiology and Estimated azathioprine, mycophenolate mofetil, thalidomide, metho- Population Burden of Selected Autoimmune Diseases in the trexate, malotilate, and colchicine. None of the above-men- United States. Clinical Immunology and Immunopathology 1997; tioned medications have been shown to be of benefit, either Vol. 84, No. 3, 223-243. as single-agent treatments or in combination with UDCA.11 5. Gershwin, M and Mackay, I. The Cause of Primary Biliary Treatment of the major symptoms of PBC, including fatigue Cirrhosis: Convenient and Inconvenient Truths. Hepatology 2008; Vol. 47, No.2. and pruritis, is also often a focus of management. At this 6. Boonstra K, Beuers U, and Ponsioen C. Epidemiology of Primary time, there is no recommended therapy for fatigue in PBC. Sclerosing Cholangitis and Primary Biliary Cirrhosis: A Systematic The selective serotonin reuptake inhibitor, fluoxetine, has Review. Journal of Hepatology 2012; vol. 56, 1181-1188. not shown any improvement of fatigue in the setting of PBC, 7. Prince M, Chetwynd A, Craig W, et al. Asymptomatic Primary while modafinil, a medication used for excessive daytime Biliary Cirrhosis: Clinical Features, Prognosis, and Symptom sleepiness, has shown some benefit.11 Pruritis in PBC is not Progression in a Large Population Cohort. Gut 2004; 53: 1216. generally relieved by UDCA. The AASLD recommends 8. Bergasa N, Mehlman J, and Jones E. Pruritis and Fatigue in Primary that bile acid sequestrants be used as a first-line treatment Biliary Cirrhosis. Clinical Liver Disease. 2003. Vol.7, 879-900. 9. Goldblatt J, James O, and Jones D. Grip Strength and Subjective for pruritis, followed by rifampicin, oral opiate antagonists, 11 Fatigue in Patients with Primary Biliary Cirrhosis. JAMA 2001; or sertraline for refractory cases. Outcomes for liver trans- 285 (17): 2196-7. plantation in patients with PBC are generally more favorable 10. Newton J, Davidson A, Kerr S, et al. Autonomic Dysfunction than transplants for other indications. Transplantation also in Primary Biliary Cirrhosis Correlates with Fatigue Severity. improves fatigue, pruritis, and bone disease in PBC.11 Timing European Journal of Gastroenterology and Hepatology. 2007; 19: of transplantation is key and can be better determined by 125-132. using one of several prognostic formulas. One of the most 11. Lindor K, Gershwin M, Poupon R, et al. Primary Biliary Cirrhosis: widely used, the Mayo model, takes into account several AASLD Practice Guidelines. Hepatology. July 2009: 291-304. factors, including serum bilirubin level, serum albumin 12. Blachar A, Federle M, and Brancatelli G. Primary Biliary Cirrhosis: Clinical, Pathologic, and Helical CT Findings in 53 Patients. level, age, prothrombin time, and presence or absence of Radiology 2001; 220: 329-336. 17 peripheral edema. In combination with the Mayo model, 13. Wenzel J, Donohoe A, Ford K, et al. MR Imaging Findings and the Model for End-Stage Liver Disease (MELD) is also used Description of MR Imaging Periportal Halo Sign. American to guide timing of liver transplantation. Up to 20%-25% of Journal of Roentgenology. 2001; 176: 885-889. patients who undergo transplantation for PBC will have 14. Knowlton J, Taylor A, Reichelderfer M, et al. Imaging of recurrent disease in 10 years; however, cyclosporine-based Biliary Tract Inflammation: An Update. American Journal of immunosuppression appears to reduce recurrence risk.18 Roentgenology. 2008; 190: 984-992. In conclusion, PBC is a progressive, autoimmune dis- 15. Lindor K, Therneau T, Jorgensen R, et al. Effects of Ursodeoxycholic Acid on Survival in Patients with Primary Biliary Cirrhosis. ease of the liver seen primarily in women. It is diagnosed Gastroenterology. 1996; 110: 1515-1518. based on a combination of clinical findings and laboratory 16. Angulo P, Dickson E, Therneau T, et al. Comparison of Three data, with elevation of alkaline phosphatase and the pres- Doses of Ursodeoxycholic Acid in the Treatment of Primary Biliary ence of AMA being the hallmarks. The most consistent Cirrhosis: A Randomized Trial. Journal of Hepatology 1999; 30: symptoms of PBC are fatigue and pruritis. Skin hyper- 830-835. pigmentation due to melanin deposition may also be seen 17. Weisner R, Porayko M, Dickson R, et al. Selection and Timing of early in the course, while jaundice is a late presentation. Liver Transplantation in Primary Biliary Cirrhosis and Primary Per the AASLD practice guidelines, the diagnosis is largely Sclerosing Cholangitis. Hepatology. 1992; vol. 16: 1290-1299. based on biochemical evidence of cholestasis, presence of 18. Charatcharoenwitthaya P, Pimentel S, Talwalkar J, et al. Long- term Survival and Impact of Ursodeoxycholic Acid Treatment for AMA, and liver biopsy. The only FDA-approved medica- Recurrent Primary Biliary Cirrhosis After Liver Transplantation. tion for treatment of PBC is UDCA, which has been shown Liver Transplantation 2007; 13:1236-1245. to improve survival. Liver transplantation is a definitive treatment with overall favorable outcomes. PBC should be

132 J La State Med Soc VOL 166 May/June 2014 Dr. Guillory is a Chief Resident of the Internal Medicine Program in the Department of Medicine at Louisiana State University Health Sciences Center in New Orleans. Dr. Jordan is a second-year Resident in Internal Medicine in the Department of Medicine at LSUHSC-New Orleans. Dr. Spieler is an Assistant Professor in the Department of Radiology at LSUHSC-New Orleans. Dr. Safley is a Chief Resident of the Department of Pathology at LSUHSC-New Orleans. Dr. Hutchings is an Assistant Professor in the Department of Gastroenterology at LSUHSC-New Orleans. Dr. Saketkoo is an Assistant Professor in the Department of Rheumatology; Scleroderma and Sarcoidosis Patient Care and Research Center Director; and Associate Director of the Rheumatology Fellowship at LSUHSC-New Orleans. Dr. Lopez is the Richard Vial Professor and Vice Chair for Education in the Department of Medicine at LSUHSC-New Orleans.

J La State Med Soc VOL 166 May/June 2014 133 Journal of the Louisiana State Medical Society Pathology Image of the Month

Black Thyroid

Christin Tsao, MD; Robin R. McGoey, MD

A 54-year-old Caucasian male had a witnessed collapse on the street. He was transported to the emergency department and subsequently pronounced dead. An unlimited autopsy examination was conducted under authorization of the coroner. Medical record review later revealed that the decedent had a history of alcohol abuse, chronic obstructive pulmonary disease, congestive heart failure, and chronic osteomyelitis treated by minocycline 100 mg twice daily. Autopsy revealed the cause of death to be ruptured gastroesophageal varices with nearly one liter of recent hemorrhage in the stomach and gastrointestinal tract. Other findings compatible with a history of alcoholism included hepatosplenomegaly, hepatic steatosis, and early bridging fibrosis. The decedent’s thyroid was multinodular and enlarged at 50 gm. The thyroid gland, in its entirety, is shown below with serial sections made longitudinally through the gland capsule to reveal the underlying parenchyma.

Figure 1: Gross image of the thyroid gland eviscerated at autopsy, serially sectioned longitudinally, that shows charcoal black pigmentation of the gland parenchyma extending full thickness from the capsular surface.

What is the diagnosis in this thyroid gland and what is the likely cause?

134 J La State Med Soc VOL 166 May/June 2014 DIAGNOSIS: Black thyroid syndrome, a.k.a. Melanosis as a potential marker for thyroid carcinoma. In one such Thyroidi due to Minocycline therapy 2001 study of 28 reported MIBT cases by Birkedal et al.,11 of the MIBT patients (39%) also had papillary carcinoma.5 DISCUSSION With an additional case of MIBT, in conjunction with papillary carcinoma to report, Bruins et al., in 2007, make the Minocycline-induced black thyroid (MIBT) is a rare comparative remark that the observed incidence of thyroid condition that was first described in 1967 by Benitz et al. cancer in MIBT patients approached 40% while the observed in the thyroidal tissues of laboratory animals.1 It was not incidence of thyroid cancer in the general population ap- documented in the thyroid glands of humans until nearly proximated 0.003% or 3/100,000.10 In 2010, six additional 10 years later when Attwood et al. reported a single case patients with MIBT and carcinoma were added to the litera- at autopsy in a man with bronchiectasis and emphysema ture, leading to published recommendations that clinicians treated antemortem with twice daily minocycline for one attend differently to thyroid glands with black pigmentation. year.2 A tetracycline-derived, semisynthetic broad-spectrum Recommendations also endorsed a more comprehensive antibiotic, minocycline was first used clinically in 1967. It is pathologic examination of MIBT thyroidectomy specimens, used most commonly to treat long-term acne vulgaris but including submission of a greater number of blocked sec- also can be used to treat other bacterial infections such as tions per specimen for histopathology.11,12 And finally in pneumonia, urinary tract infections, skin infections, and 2011, in an effort to establish the malignant potential of black methicillin-resistant Staphylococcus aureus infections as may thyroid syndrome, Kandil et al. conducted a retrospective be seen in osteomyelitis.3 Pigmentation as a side effect of chart review of more than 400 patients who underwent minocycline therapy has not only been seen in the thyroid thyroid surgery for nodular lesions. The authors calculated gland but has also been documented in the skin, oral mucosa, a 15% incidence of MIBT (63/433) and found significantly bone, nail beds, heart valves, and teeth.4,5 Since the original more malignancy in the MIBT group than the non-MIBT MIBT publication, the literature cites approximately 60 total group [50.8% vs. 29.8%, p<0.002]. Conversely, benign le- cases, some following minocycline exposures as short as 12 sions were statistically more likely in the non-MIBT group days in duration.6 than those with black thyroid syndrome.12 Pathologic examination of a MIBT reveals characteristic The current case demonstrates the classic features of gross features, including the eponymous charcoal black minocycline-induced black thyroid syndrome (MIBT), coloring in a full-thickness distribution from the capsular sometimes known as a Melanosis thyroidii. Histology was layer throughout the entire thyroid parenchyma. Neither characteristic, and iron stains were negative. There was gland enlargement (goiter) nor nodularity of the thyroid is no evidence of malignancy on multiple histologic sections specifically associated with the pigment deposition. Histol- submitted. The diagnosis was made incidentally at the ogy reveals intracytoplasmic accumulation of “dust like” time of autopsy. There is currently an additional need for granules most often within follicular epithelial cells or tissue case reporting of MIBT in order to establish any causal link macrophages. The differential diagnosis includes iron and between pigmentation and the development of malignancy. ochronotic pigment depositions. Iron accumulation within A longtime believed harmless phenomenon, MIBT should the thyroid can be seen in patients with hemosiderosis ei- be reconsidered by clinicians across disciplines as further ther due to primary or secondary hemochromatosis. Iron, mechanisms of possible carcinogenesis are explored. In the however, typically manifests grossly as a ruddy or maroon meantime, the current literature supports a more thorough discoloration and will stain positively with iron stains such pathologic examination of these surgical specimens than as Prussian blue. Ochronotic pigment is a black-appearing once previously recommended. pigment that accumulates in tissue in association with the autosomal recessive condition of ochronosis. It, however, ACKNOWLEDGEMENTS displays refractile properties under polarized light and has yet to be published within the thyroid gland.7 The authors would like to gratefully acknowledge the The nature of the black pigment in MIBT remains de- support of the Orleans Parish Coroner’s Office: Dr. Frank bated. Considerations have included lipofuscin, melanin, Minyard and Chief Investigator John Gagliano for providing neuromelanin, a melanin-like substance, or simply oxida- the case material for this report. tive byproducts of minocycline.8 Several mechanisms for the accumulation of black pigment in thyroid tissue have REFERENCES been hypothesized, but the most reliable consensus seems to center around the fact that minocycline is a competitive 1. Benitz KF, Roberts GK, Yusa A. Morphologic effects of minocycline inhibitor of thyroid peroxidase and thereby, becomes itself in laboratory animals. Toxicol Appl Pharmacol 1967;11:150–170. oxidized.6,9 2. Attwood HD, Dennett X. A black thyroid and minocycline Clinically, MIBT has long been thought to be a harmless treatment. Br Med J 1976;2:1109–1110. 3. http://www.nlm.nih.gov/medlineplus/druginfo/meds/ phenomenon without clinical ramifications. However, in a682101.html (Accessed March 14, 2014) some recent literature reviews, MIBT has been suggested 4. Treister NS, Magalnick D, Woo SB. Oral mucosal pigmentation

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secondary to minocycline therapy: report of two cases and a review 10. Bruins NA, Oswald JE, Morreau H, et al. Papillary thyroid of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod carcinoma in a patient with sarcoidosis treated with minocycline. 2004;97(6):718-25. Neth J Med. 2007;65:185–187. 5. Birkedal C, Tapscott W J, Giadrosich K, et al. Minocycline-induced 11. Kandil E, Abdel Khalek M, Alabbas H, et al. Black thyroid black thyroid gland: medical curiosity or a marker for papillary associated with thyroid carcinoma. Int J Endocrinol. 2010;article cancer? Curr Surg 2001;58(5):470–471. ID 681647, 3 pages. 6. Miller BT, Lewis C, Bentz BG. Black thyroid resulting from short- 12. Kandil E, Khalek MA, Ibrahim WG, et al. Papillary thyroid term doxycycline use: case report, review of the literature, and carcinoma in black thyroids. Head Neck. 2011;33(12):1735-8. discussion of implications. Head Neck 2006;28:373–377. 7. Nikiforov, Yuri, Paul W. Biddinger, and Lester D.R. Thompson. Diagnostic Pathology and Molecular Genetics of the Thyroid. Philadelphia: Wolters Kluwer Health/Lippincott Williams & In the Department of Pathology at the Louisiana State University School Wilkins, 2012. 97-98. of Medicine in New Orleans, Dr. Tsao is a second-year Pathology 8. Veinot JP, Ghadially FN. Melanosis thyroid. Ultrastruct Pathol Resident and Dr. McGoey is an Associate Professor of Pathology and Residency Program Director. 1998;22(5):401-6. 9. Taurog A, Dorris ML, Doerge DR. Minocycline and the thyroid: antithyroid effects of the drug, and the role of thyroid peroxidase in minocycline-induced black pigmentation of the gland. Thyroid 1996;6(3):211-9.

136 J La State Med Soc VOL 166 May/June 2014 Editor Volume 166, Number 4 • July/August 2014 Established 1844 D. LUKE GLANCY, MD

Associate Editor L.W. JOHNSON, MD

BOARD OF TRUSTEES Chair, GEOFFREY W. GARRETT, MD Vice Chair, K. BARTON FARRIS, MD Secretary/Treasurer, RICHARD PADDOCK, MD ANTHONY P. BLALOCK, MD D. LUKE GLANCY, MD LESTER W. JOHNSON, MD FRED A. LOPEZ, MD Featured Articles EDITORIAL BOARD MURTUZA J. ALI, MD RONALD AMEDEE, MD Rami N. Khouzam, MD, FACC, FACP, FASNC, 138 Showers of Emboli From a Large Aortic Root Thrombus SAMUEL ANDREWS, II, MD FASE, FSCAI BOB BATSON, MD Laura Salama, MD EDWIN BECKMAN, MD Mohamad Khaled Soufi, MD GERALD S. BERENSON, MD Alim Khandekar, MD C. LYNN BESCH, MD Saleem Al-Mawed, MD JOHN BOLTON, MD MICHELLE BOURQUE, JD Camille Thelin, MS, MD 143 Primary Clear Cell Adenocarcinoma of the Colon: A Case Report and JAMES N. BRAWNER, III, MD Caroline R. Alquist, MD, PhD Review BRETT CASCIO, MD Lee S. Engel, MD, PhD QUYEN CHU, MD Tracy Dewenter, MD WILLIAM PATRICK COLEMAN III, MD GUSTAVO A. COLON, MD Sarah Castillo-Jorge, MD 149 Calvarial Plasmacytoma, an Unusual Manifestation of Multiple RICHARD COULON, MD Christian Fauria-Robinson, MD Myeloma LOUIS CUCINOTTA, MD Enrique Palacios, MD, FACR VINCENT A. CULOTTA, JR., MD Jeremy Nguyen, MD JOSEPH DALOVISIO, MD Ronnie Self II, MD, MS NINA DHURANDHAR, MD Philip Daroca, MD JAMES DIAZ, MD, MPH & TM, Dr. PH JOHN ENGLAND, MD James H. Diaz, MD, MPH&TM, DrPH 154 Delusional Infestations: Case Series, Differential Diagnoses, and JULIO FIGUEROA, MD Lee T. Nesbitt Jr., MD Management Strategies ELIZABETH FONTHAM, MPH, Dr. PH EDWARD FOULKS, MD Anil Nanda, MD 160 Surgical Management of Middle Cerebral Artery Aneurysms HENRY G. HANLEY, MD Sudheer Ambekar, MD ELIAS B. HANNA, MD Mayur Sharma, MD LYNN H. HARRISON, JR., MD ROBERT HEWITT, MD Susanne Straif-Bourgeois, PhD, MPH 168 Firearm-Related Mortality, Louisiana 1999-2010 MICHAEL HILL, MD Raoult Ratard, MD, MS, MPH&TM LARRY HOLLIER, MD JOHN HUNT, MD Sabrina L. Noah 175 Protecting the Private Practice of Medicine: We Need More Data BERNARD JAFFE, MD NEERAJ JAIN, MD TRENTON L. JAMES, II, MD STEPHEN KANTROW, MD KEVIN KRANE, MD MAUREEN LICHTVELD, MD, MPH FRED A. LOPEZ, MD F. BROBSON LUTZ, JR., MD DAVID MARTIN, MD JORGE A. MARTINEZ, MD, JD ELIZABETH MCBURNEY, MD ELLEN MCLEAN, MD NORMAN E. MCSWAIN, JR., MD Departments REINHOLD MUNKER, MD DAVID MUSHATT, MD Stephanie C. El Hajj, MD 176 ECG OF THE MONTH JOSEPH NADELL, MD Curley J. Bordelon, MD Out-of-Hospital Cardiac Arrest HAROLD R. NEITZSCHMAN, MD D. Luke Glancy, MD STEVE NELSON, MD NORA OATES, MD Arielle Bauer 179 RADIOLOGY OF THE MONTH DONALD PALMISANO, MD, JD, FACS David Manning, MD 55-Year-Old Female With Shortness of Breath and Cough PATRICK W. PEAVY, MD Harold Neitzschman, MD, FACR, FACNM, FAAP ROBERTO QUINTAL, MD RAOULT RATARD, MD, MS, MPH & TM Carl Mickman, MS 182 CLINICAL CASE OF THE MONTH ROBERT RICHARDS, MD Carrie Caruthers, MD A 44-Year-Old HIV-Infected Man With Right-Shoulder Swelling DONALD RICHARDSON, MD Jaclyn Spiegel, MD FRANK A. RIDDICK, JR., MD Ron Schiro, BS WILLIAM C. ROBERTS, MD Joanne Maffei, MD DONNA RYAN, MD Charles V. Sanders, MD JERRY ST. PIERRE, MD Fred A. Lopez, MD CHARLES SANDERS, MD OLIVER SARTOR, MD Christin Tsao, MD 188 PATHOLOGY IMAGE OF THE MONTH CHARLES SCHER, MD Louise Thomas Black Esophagus Detected at Autopsy in a Patient With Abdominal RICHARD SPECTOR, MD Robin R. McGoey, MD Pain and Bloody Diarrhea JACK P. STRONG, MD PRAMILLA N. SUBRAMANIAM, MD KEITH VAN METER, MD DIANA VEILLON, MD HECTOR VENTURA, MD CHRIS WINTERS, MD GAZI B. ZIBARI, MD Journal of the Louisiana State Medical Society

Showers of Emboli From a Large Aortic Root Thrombus

Rami N. Khouzam, MD, FACC, FACP, FASNC, FASE, FSCAI; Laura Salama, MD; Mohamad Khaled Soufi, MD; Alim Khandekar, MD; Saleem Al-Mawed, MD

It is rare to find aortic root thrombi in the absence of aortic root aneurysm or extensive aortic atherosclerosis. Up to this date, only a few cases have been reported. The etiology has been mainly attributed to hypercoagulable disorders. Herein, we present a case of a large thrombus obliterating the aortic root in a patient presenting with acute abdominal pain and noted to have showers of emboli to the kidneys. Hypercoagulable workup failed to reveal any congenital or acquired clotting disorder. The thrombus was thought to have developed spontaneously, and was removed surgically. Two months later, however, she had an arterial clot in the left popliteal artery that was removed surgically. The patient was seen for follow-up three and six months later and was stable with no complaints.

This case highlights the importance of considering the ascending aorta as a source in cases of systemic embolization. In addition, the different diagnostic options, management protocols, and potential complications are discussed.

CASE PRESENTATION (N: 84-125%), protein C: 150% (N: 74-161%), protein S: 56% (N: 47-134%), activated protein C resistance: 2.5 (N: >2.1), A 43-year-old African-American woman with a past and normal Factor V leiden. Homocysteine level was normal: medical history of hypertension and diabetes mellitus, 9.8 mmol/L (N <12 mmol/L). Lupus anticoagulant profile presented to the emergency room with severe right lower was negative; anticardiolipin antibody IgG: 1.8 GPL units quadrant abdominal pain, nausea, and vomiting. Com- (N: 0-9.9 GPL units), IgM: 0.7 MPL (N: 0-9.9 MPL), and anti- puted tomography (CT) of the abdomen and pelvis with beta 2 glycoprotein1 was within normal range: IgG: 0.6 U/ contrast showed multiple wedge-shaped foci of diminished ml (N: 0-9.9 U/ml). Russel Viper Venom time: 36.1 sec (N: enhancement in the lower pole of the right kidney, highly 32.2-40.1). Cytoplasmic antineutrophil cytoplasmic antibod- suspicious for renal infarcts. An incidental finding of a mass ies (c-ANCA): 0.61 (N: 0-0.79), Anti-dsDNA antibodies: 6 (N: of low density appeared above the aortic valve. Computed 0-24.9), and Anti-Smith: 178 (N: 90-180)]. She had normal tomographic (CT) scan of the chest with contrast (Figure 1) CBC: Hb: 14.1 g/dL (N: 11.5-14.8 g/dL), Hct: 43.1 % (N: revealed a filling defect measuring 1.1 x 1.4 x 2.1 cm in the 34.6-43.8%), WBC: 12,400/mcL (N: 4,200-10,200/mcL), and proximal ascending aorta. The mass appeared to be local- Platelet count: 326,000/mcL (N: 150,000-400,000/mcL). She ized to the aortic root. The other cardiac valves were normal. had dyslipidemia: triglycerides: 276 mg/dL (N <150 mg/ There were no other filling defects within the ventricles or dL), total serum cholesterol: 187 mg/dL (N: <200 mg/dL), atria. The heart was normal in size. HDL: 33 mg/dL (N: 40-60 mg/dL), and LDL: 131 mg/dL Transesophageal echocardiography (Figures 2 and 3) (N: <100 mg/dL). was done to confirm the presence of a large mass almost The patient denied smoking and drug use. She had no obliterating the aortic root. The mass was not attached to history of atrial fibrillation, deep venous thrombosis (DVT), the aortic valve leaflets. The left ventricular ejection fraction or any other thrombus formation. She had an elevated Body was normal (>55%). Mass Index (BMI) of 33.4 (height: 157.5 cm, weight: 82.8 kg). A hematological consult was obtained after the patient There was no family history of coagulation or bleeding dis- was started on heparin. An extensive workup for coagulopa- orders. Her medications included atorvastatin, metoprolol, thy/hypercoagulable status and autoimmune disorders was and hydrochlorothiazide, and she denied the use of any oral negative. The workup revealed the following results: plasma contraception. Both diagnoses of HTN and DM were made fibrinogen: 320 mg/dl (N: 145-348 mg/dl), prothrombin prior to the initial presentation, and her diabetic control was G20210A genotype analysis: normal, antithrombin III: 109% suboptimal: HbA1C was 7.3% (N: 4.8-6%)

138 J La State Med Soc VOL 166 July/August 2014 Figure 1: Sixty-four-slice computed tomographic scan of the chest with contrast showing a filling defect (dark grey), with contrast around it (white), in the aortic root/proximal ascending aorta.

Sternotomy with removal of a large aortic thrombus measuring 1.4 x 1.9 x 0.7cm (Figure 4) was performed on cardiopulmonary bypass under moderate hypothermia. Figure 2: Transesophageal echocardiogram (TEE), upper The aorta was inspected with an epi-aortic echo and then esophageal view, 120o, longitudinal, showing a large mass cross-clamped beyond the visible thrombus. Transverse in the ascending aorta, just distal to the aortic valve but not aortotomy was then performed to inspect and remove the attached to it. thrombus. The patient was rewarmed and weaned off bypass. During surgical aortic thrombectomy, the aortic valve plaque.1,2 The descending aorta and the distal arch are the and root were noted to be normal, and the mass was non- most common locations of aortic thrombi; whereas the as- infiltrating. There were no signs of atherosclerotic disease cending aorta is the site of aortic thrombus in only 5% of the or aneurysmal dilation of the aortic root. The macroscopic cases.6 Aortic root thrombus is rare in an apparently normal, and microscopic examination of the specimen confirmed non-aneurysmal, non-atherosclerotic aorta.2,6-10 it to be a thrombus. Warfarin sodium was started with a The etiology of thrombus formation in a macroscopi- target INR of 2-3. cally normal aorta is not well understood and has been The patient had an uncomplicated early postoperative attributed to various hypercoagulable disorders, including course. Two months later, however, she complained during combined protein C and protein S deficiency,1,7,10,11 elevated a follow-up visit of claudication of the left calf and the ankle- levels of clotting factor VIII, antithrombin III deficiency,7 brachial index was <0.9. Her INR was >2. A CT angiogram of polycythemia vera,7 essential thrombocythemia,12 hyperho- the abdominal aorta and lower extremities revealed a filling mocysteinaemia,13 increased fibrinogen,4 as well as autoim- defect in the distal popliteal artery, resulting in diminished mune diseases with hypercoagulable states, e.g., systemic distal flow. An arteriogram (Figure 5) percutaneous An- lupus erythematosus,14 antiphospholipid syndrome,10,11 and gioJet thrombectomy, and balloon angioplasty were only vasculitis.10,11 It has also been associated with malignan- partially successful in removing the organized thrombus. cy,1,6,11 hematologic disorders,1,6 exogenous steroid,1,6,15 and Left femoral-popliteal bypass surgery was then performed estrogen use,4,6,16,17 primary endothelial disorders,1,6,11 blunt successfully. A CT arteriogram revealed no residual aortic aortic injury,6 heparin-induced thrombocytopenia,1,11,18-20 as root thrombus. well as iatrogenic causes.11 Generalized hypercoagulation When seen three and six months later, the patient had and vascular endothelial disorders have been proposed to no symptoms. be the most important factors for aortic mobile thrombus formation.6 DISCUSSION Aortic thrombus is usually suspected after the occurrence of a peripheral,3,4,10,11,21,22 cerebral,3,9,12,14,23-25 or visceral Aortic thrombi usually present as emboli from the thrombotic event.1 Myocardial infarction has been reported cardiac chambers or as a thrombus on an atherosclerotic as its first presentation.2,23 Aortic thrombus in the ascending

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Figure 3: Transesophageal echocardiogram (TEE), upper esophageal view, 180o, transverse, confirming the large mass almost completely occluding the ascending aortic root.

Figure 4: Large (1.4 x 1.9 x 0.7 cm) thrombus surgically removed from the aortic root.

aorta however, is considered to be an uncommon source of disorders was negative. The absence of any constitutional embolism,2,6,9 and the most frequent cause of embolism from symptoms and the normal blood tests make any malignant an aortic source is caused by thrombus superimposed on or hematologic disorder a very low possibility. an atherosclerotic aortic plaque.2,6 Peripheral and visceral Thromboembolic events in a normal aorta causing emboli most commonly result from cardiac dysfunction, systemic embolism in a relatively young patient have been such as atrial fibrillation, myocardial infarction, endocar- reported in the literature.2,4,13-15,23,25 However, in these cases ditis, ventricular aneurysms, and prosthetic heart valves. there was usually a plausible etiology. Either the patients The most frequent non-cardiac sources are thrombus within were taking oral steroidal medications,15 were heavy ciga- proximal aneurysms, ulcerated atherosclerotic plaques, dis- rette smokers,2,15 were on estrogen therapy,4 had hyperho- sections, penetrating ulcers, and traumatic lesions.2,11 mocysteinaemia13 or systemic lupus erythematosus,14 or In our case, the etiology of thrombus formation was not were taking synthetic progasterons.2 identified. A workup for hypercoagulable and auto-immune Transesophageal echocardiography (TEE),8,22 computed

140 J La State Med Soc VOL 166 July/August 2014 Figure 5: Arteriogram showing a filling defect in the distal left popliteal artery (arrow), obstructing flow at its bifurcation into the tibioperoneal trunk and anterior tibial artery.

tomography,26 and magnetic resonance imaging,8 remain the atherosclerotic aorta are rare. The pathogenesis may be diagnostic tools of choice in the diagnosis of aortic thrombus. multifactorial,6 and hypercoaguability may well play a role, The management of aortic root thrombosis is contro- even when standard coagulation studies are normal. versial.6,9,11,27 Therapeutic strategies are influenced by the The rarity of the lesions and difficulty in diagnosis have localization of the thrombus, the co-morbidities of the pa- precluded accurate determination of the natural history and tient, and the physician’s preferences.27 Treatment options optimal treatment of this disease. To date, there are no data include systemic anticoagulation therapy alone, throm- to advocate or to refute the use of anticoagulation prior to bolytic therapy,17 surgical removal of the thrombus with/ thrombectomy in these cases. Management should include without graft replacement, and endovascular stent-grafting. long-term therapy with warfarin sodium and imaging sur- Oral anticoagulation is generally considered a first- veillance to avoid further embolization.9,27 line management, unless warfarin is contraindicated or there are repetitive embolic events.9,11 Several cases have REFERENCES demonstrated successful resolution of mobile aortic thrombi without further emboli with long-term oral anticoagu- 1. Onwuanyi A, Sachdeva R, Hamirani K, Islam M, Parris R. Multiple lants.10,23,28 Thrombectomy is indicated in cases of contrain- aortic thrombi associated with protein C and S deficiency. Mayo dication to anticoagulation, mobile thrombus,11 or recurrent ClinProc 2001;76:319-322. embolic events.6,9,11,29,30 An aggressive surgical approach is 2. Bruno P, Massetti M, Babatasi G, Khayat A. Catastrophic consequences of a free floating thrombus in ascending aorta. Eur recommended in the low-risk patient to prevent cerebro- J Cardiothorac Surg 22,30 . 2001 Jan;19(1):99-101. vascular accidents and further peripheral embolization. 3. Zavala JA, Amarrenco P, Davis SM, Jones EF, Young D, Macleod Some reports suggest repeat TEE two weeks after starting MR, Horky LL, Donnan GA. Aortic arch atheroma. Int J Stroke. oral anticoagulation, when incomplete resolution of the 2006 May;1(2):74-80 thrombus might warrant surgical intervention, especially 4. Malyar NM, Janosi RA, Brkovic Z, Erbel R. Large mobile thrombus in young patients.9 Some authors have advocated the use of in non-atherosclerotic thoracic aorta as the source of peripheral an endovascular stent-graft (SG) whenever possible6,11,27 be- arterial embolism. Thromb J. 2005 Nov 29;3:19. cause the less invasive procedure may reduce perioperative 5. Laperche T, Laurian C, Roudaut R, Steg PG: Mobile thromboses morbidity and mortality.6 Although anticoagulation seems to of the aortic arch without aortic debris. A transesophageal echocardiographic finding associated with unexplained arterial be preferred over a surgical approach in many cases, there embolism. The Filiale Echocardiographie de la Societe Francaise 1,10 are reported complications of anticoagulation. de Cardiologie. Circulation 1997, 96(1):288-294 6. Piffaretti G, Tozzi M, Mariscalco G, Bacuzzi A, Lomazzi C, Rivolta CONCLUSION N, Carrafiello G, Castelli P. Mobile thrombus of the thoracic aorta: management and treatment review. Vasc Endovascular Surg. 2008 Thromboembolic events from a non-aneurysma, non- Oct-Nov;42(5):405-11.

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7. Sanon S, Phung MK, Lentz R, Buja LM, Tung PP, McPherson in Silence! Mobile Thrombus in the Aortic Arch. Circulation 2010 DD, Fuentes F. Floating, non-occlusive, mobile aortic thrombus Dec 7;122(23):2456-8. and splenic infarction associated with protein C deficiency. J Am 26. Prothet J, Floccard B, Levrat A, Guillaume C, Faure A, Marcotte G, SocEchocardiogr. 2009;22:1419.e1-3. Allaouchiche B. Recurrent systemic embolism: look for a thrombus 8. Berneder S, Van Ingen G, Eigel P. Arch thrombus formation in in the thoracic aorta. Ann Fr AnesthReanim 2008;27:723-726. an apparently normal aorta as a source for recurrent peripheral 27. Martens T, Van Herzeele I, Jacobs B, De Ryck F, Randon C, embolization. ThoracCardiovascSurg 2006;54:548-549. Vermassen F. Treatment of symptomatic mobile aortic thrombus. 9. Choukroun EM, Labrousse LM, Madonna FP, Deville C. Mobile Acta Chir Belg 2010 May-Jun;110(3):361-4. thrombus of the thoracic aorta: diagnosis and treatment in 9 cases. 28. Pasierski T, Jasek S, Firek B, Przybylski A, Szwed H, Sadowski Z. Ann VascSurg 2002;16:714-722. Resolution of an aortic mobile mass with anticoagulation without 10. Dhillon P, Murdoch D, Jayasinghe R, Niranjan S. A Case of evidence of arterial embolism. Clin Cardiol 1996 Feb;19(2):151-2. Mobile Aortic Arch Thrombus with Systemic Embolisation—A 29. Kolvekar SK, Chaubey S, Firmin R. Floating thrombus in the Management Dilemma. Heart Lung Circ. 2013 Oct 17. pii: S1443- aorta. Ann Thorac Surg 2001;72:925–7. 9506(13)01287-0. 30. Pagni S, Trivedi J, Ganzel BL, Williams M, Kapoor N, Ross C, 11. Tsilimparis N, Hanack U, Pisimisis G, Yousefi S, Wintzer C, Slater AD. Thoracic aortic mobile thrombus: is there a role for Rückert RI. Thrombus in the non-aneurysmal, non-atherosclerotic early surgical intervention? Ann ThoracSurg 2011;91:1875-1881. descending thoracic aorta--an unusual source of arterialembolism. Eur J Vasc Endovasc Surg. 2011 Apr;41(4):450-7. 12. Hino H, Terasaki T, Hashimoto Y, Hara Y, Uchino M.Cerebral infarction associated with mobile thoracic ascending aortic Drs. Khouzam and Salama are with the Department of Medicine, thrombus in a patient with essential thrombocythemia. Rinsho Division of Cardiovascular Diseases, University of Tennessee Health Shinkeigaku. 1999 Jul;39(7):705-10. Science Center in Memphis, Tennessee. Dr. Soufi is with St. Vincent Hospital in Cleveland, Ohio. Dr. Khandekar is with the Department 13. Slabbekoorn M, Henneman OD, Geelhoed-Duijvestijn PH, of Surgery, Division of Cardiovascular Surgery, University of Tennessee Veldkamp RF. Mural aortic thrombus and peripheral embolisation Health Science Center in Memphis, Tennessee. Dr. Al-Mawed is with in a patient with Hyperhomocysteinaemia. Neth J Med. 2006 Damascus University, Faculty of Medicine in Syria Jan;64(1):20-2. 14. Hanson JA, Lloyd ME, Hughes R. Aortic root thrombus causing stroke in a patient with systemic lupus erythematosus. Scand J Rheumatol. 1994;23(3):156-8. 15. Perler BA, Kadir S, Williams GM: Aortic mural thrombus in young women: premature arteriosclerosis or separate clinical entity? Surgery 1991, 110(5):912-916. 16. Dee W, Geibel A, Kasper W, Konstantinides S, Just H: Mobile thrombi in atherosclerotic lesions of the thoracic aorta: the diagnostic impact of transesophageal echocardiography. Am Heart J 1993, 126(3 Pt 1):707-710 17. Hausmann D, Gulba D, Bargheer K, Niedermeyer J, Comess KA,Daniel WG: Successful thrombolysis of an aortic-arch thrombus in a patient after mesenteric embolism. N Engl J Med 1992,327(7):500-501. 18. Collins D, Moloney MA, O’Donnell D, Brophy D, Sheehan SJ. Acute aortic occlusion in a patient with heparin-induced thrombocytopenia treated by thrombectomy. Ir J Med Sci 2012 Sep;181(3):397-400. 19. Chan SM, Millward SF. Heparin-associated thrombocytopenia with thrombosis presenting as large thrombi in the aorta. AJR Am J Roentgenol 1998;170(2):354-6. 20. Antecol DH,Walley VM, Chan KL. Massive acute thrombosis of the descending thoracic aorta in heparin-associated thrombocytopenia and thrombosis. J Am Soc Echocardiogr 1994;7:550-2. 21. O’Sullivan J, Kerins D, Vaughan C. Massive thrombus in the aortic arch: a 59-year-old lady with an unknown familial predisposition to vascular thrombosis. Eur J Echocardiogr 2008 Jan;9(1):178-80. 22. Lozano P, Gomez FT, Julia J, M-Rimbau E, Garcia F. Recurrent embolism caused by floating thrombus in the thoracic aorta. Ann Vasc Surg 1998 Nov;12(6):609-11. 23. Jaafari A, Benyoussef S, Selmi K, Boukhriss B, Boujneh MR. Myocardial infarction associated with stroke revealing a thrombus of the ascending aorta. Ann Cardiol Angeiol (Paris) 2004 Mar;53(2):105-8. 24. Loiselle A, Agrwal N, Ingall TJ, Chaliki HP. Aortic tumor or mobile thrombus? Echocardiography 2010 Feb;27(2):E21-2 25. Park YH, Chun KJ, Kim JS, Song SG, Han DC, Kim J, Kim JH. Hail

142 J La State Med Soc VOL 166 July/August 2014 Primary Clear Cell Adenocarcinoma of the Colon: A Case Report and Review

Camille Thelin, MS, MD; Caroline R. Alquist, MD, PhD; Lee S. Engel, MD, PhD; Tracy Dewenter, MD

A case of primary clear cell adenocarcinoma of the colon, a rare oncologic variant, was diagnosed in a 25-year- old man who presented with partial bowel obstruction. To understand better the pathology of this neoplasm, a retrospective review of Entrez PubMed entries describing primary clear cell adenocarcinoma of the colon and/or rectum was performed. Only 13 previous cases of primary clear cell adenocarcinoma of the colon and/or rectum have been reported, with an average presentation age of 57 years and generally afflicting the descending colon of men. Herein we present a case occurring in the distal ascending colon of the youngest patient in the literature to date. Our patient’s diagnosis is rare in occurrence, location, and age of onset.

INTRODUCTION He reported only occasional, but not recent, non-steroidal, anti-inflammatory drug use for pain. He denied any tobacco Primary clear cell adenocarcinoma of the colon is an or illicit drug use, but a social history review was positive uncommon oncologic diagnosis. A review of Entrez PubMed for the occasional alcoholic beverage. His family history was publications revealed 13 previously reported cases.1-13 relevant for one grandfather with colon cancer of unknown Herein, we describe the 14th and youngest patient with this type or age of onset. diagnosis reported in the literature to date: a 25-year-old Physical exam revealed unremarkable vital signs, aside man with stage IV primary clear cell adenocarcinoma of the from a slight tachycardia and the appearance of mild dis- distal ascending colon. comfort. Abdominal distention and decreased bowel sounds in all four abdominal quadrants, without tinkles or rushes, CASE REPORT were noted. Mid-epigastric and right-upper quadrant (RUQ) tenderness to palpation, without guarding or rebound, also A 25-year-old man presented to the emergency depart- was noted. ment with abdominal discomfort and distention, nausea, A complete blood count and comprehensive metabolic and several episodes of bilious vomiting for two weeks. profile were normal except for mild hyponatremia (133 Bilious emesis and abdominal pain was not associated with mEq/L). A carcinoembryonic antigen (CEA) level was el- any specific foods, medicines, or positions. His last bowel evated (12.3 ng/mL). A CT scan of the abdomen and pelvis movement had occurred more than one week prior and was found a mass-like thickening at the hepatic flexure, as well described as “foamy,” but flatus had continued. The review as dilated small bowel (>4 cm) and large bowel proximal of systems was negative for diarrhea, melena, hematochezia, to the mass (Figure 1A). Scattered lymph nodes were seen hematemesis, or history of hemorrhoids. He also denied throughout the abdomen, but were most prominent adjacent any fevers, chills, prior hospitalizations, sick contacts, or to the area of thickening (Figure 1B). No other evidence of recent travel history. malignancy was evident on the CT scan. Prior to coming to our institution, he had visited two He underwent an exploratory laparotomy with right different emergency rooms with the same complaints and hemicolectomy and was found to have a partial large bowel was discharged from each with a diagnosis of gastroenteritis. obstruction secondary to a stenotic tumor mass at the distal A computed tomography (CT) scan of the abdomen and ascending colon/hepatic flexure. An ileocolonic anastamosis pelvis was performed during one of these visits. The scan was performed at this time. was unavailable to our institution; however, he reported be- Surgical pathology evaluation of the right hemicolecto- ing told that there was nonspecific thickening of the bowel my specimen revealed a circumferential mass (3 cm) within wall for which he should schedule a follow-up appointment the distal ascending colon which involved the full thickness with a general surgeon. of the colonic wall. The tumor extended into the pericolonic His past medical history was significant only for child- fat to abut the serosa. Dilation of the colon proximal to the hood asthma. He had no past surgical history or allergies. mass was noted, with flattening of the mucosal folds. Histo-

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Figure 1A and 1B: (A) Transverse plane image of a CT scan showing the mass-like thickening of the ascending colon (circled) with dilated large and small bowel proximal to the tumor. (B) Frontal plane image of a CT scan showing a 5 x 4 cm mass-like thickening within the hepatic flexure (circled) accompanied by adjacent fluid and scattered lymph nodes.

Figure 2: Clear cell adenocarcinoma tumor cells with abundant clear cytoplasm and well-defined cell borders. (Hematoxylin & Eosin stain, original magnification 200x)

logic sections showed a clear cell adenocarcinoma, circum- seen for CD10 and neuron specific enolase. Tumor cells were ferentially involving the colonic wall. The tumor cells were negative for vimentin, thyroid transcription factor 1, alpha pleomorphic with hyperchromatic, rounded to angular, inhibin, calretinin, alpha-fetoprotein, placental alkaline vesicular nuclei, some with prominent nucleoli, exhibiting phosphatase, chromogranin A, synaptophysin, and CD56. well-defined cell borders and containing abundant clear No other source of malignancy could be identified by CT, cytoplasm (Figure 2). Immunohistochemical stains revealed full-body positron emission tomography (PET) scan (Figure the tumor cells to be strongly and diffusely positive for cyto- 3), or additional biopsy sampling of the liver, stomach, and keratin 7. There was patchy moderate to strong staining for duodenum. The hemicolectomy margins were free of tumor. CDX2, CD15, and cytokeratin 20. Focal spotty positivity was One of 19 identified pericolonic lymph nodes was positive

144 J La State Med Soc VOL 166 July/August 2014 Figure 3: Whole body PET scan image demonstrating lack of alternate primary malignancy. Hypermetabolic activity is seen on the liver, anastomotic site (post-right hemicolectomy), and anterior abdominal surgical incision site, consistent with prior surgery and liver biopsy.

Figure 4: A lymph node containing clear cell adenocarcinoma tumor cells. (Hematoxylin & Eosin stain, original magnification 100x)

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Table 1: Reported Cases of Clear Cell Adenocarcinoma of the Colon and/or Rectum Case Authors (et Year Pt Pt Primary Treatment +Immuno- Metastatic Outcome # al.) Reported Age Sex Tumor histochemical Site Location Staining 1 Hellstrom2 1964 67 M Rectum Abdomino- PAS, D-PAS, Lymph One-year perineal Alcian blue node follow- resection up; no recurrence 2 Jewell3 1988 75 M Sigmoid Polypec- CEA, EMA, None Died six colon tomy, LMW-keratin weeks sigmoidec- after tomy diagnosis 3 Jewell3 1988 26 F Sigmoid Sigmoidec- CEA, EMA, None colon tomy LMW-keratin 4 Rubio5 1995 68 M Splenic Left PAS, CEA, Lymph Died flexure hemicolec- TPA node seven tomy months after diagnosis 5 Furman6 1999 Rectum PAS, D-PAS 6 McCluggage7 2001 65 F Recto- Anterior PAS, CA125, Liver sigmoid resection CK7, laminin, colon type IV collagen, Ber- EP4 7 Braumann8 2004 89 M Left Segmental CEA, EMA, None Died 20 flexure resection CK18, CK20 months after diagnosis 8 Mallik9 2005 36 F Rectum Abdomino- PAS, D-PAS, Lymph Lost to perineal EMA, Alcian node follow-up resection blue 9 Ko10 2007 62 M Sigmoid Low None colon anterior resection 10 Hao4 2007 37 M Descending Left PAS, CEA, Lymph One-year colon hemiocol- EMA node follow- ectomy up; no recurrence 11 Soga12 2008 71 F Sigmoid Polypec- PAS, CD10, None colon tomy CK20, p53, Ki67 12 Barisella13 2008 54 M Hepatic Total CEA, None flexure colectomy CK20, p53, B-catenin, hMLH, hMSH2

146 J La State Med Soc VOL 166 July/August 2014 13 Furuya1 2011 81 M Hepatic Right PAS, D-PAS, Lymph Died 12 flexure hemicolec- CEA, AFP, node months tomy EMA, CK omentum, after AE1/3, lung, diagnosis CK20, CD117, liver B-catenin 14 Thelin 2011 25 M Hepatic Right CK7, CD10, Lymph Died six flexure hemicolec- CK20, CDX2, node & months tomy and CD15, NSE omentum after chemo- diagnosis therapy for metastatic clear cell adenocarcinoma (Figure 4). showed an uncharacteristic staining pattern for a primary This diagnosis prompted two therapeutic cycles of colonic tumor exhibiting strong staining with CK7 but only capecitabine (1,000 mg morning dosage and 500 mg dos- focal positivity with CK20. Similarly, one of the 13 reported age, Monday through Friday) and oxaliplatin (85 mg/m2 cases in the rectosigmoid region also displayed diffuse every three weeks), in conjunction with oncology follow-up. strong positivity for CK7 without staining of CK20.7,14 Unfortunately, postoperative and oncological follow-up Morphologic similarities between the clear cell carcino- periods were complicated by a small bowel obstruction, mas arising at diverse sites and the uncommon occurrence of refractory to medical management. Several abdominal clear cell adenocarcinoma within the colon make it difficult nodules were identified during surgery to lyse abdominal to differentiate this variant of colonic adenocarcinoma from adhesions, which were later confirmed to be metastatic foci a metastatic process. In our case, the patient underwent by histology. Given his dismal prognosis, the patient rejected several full-body CT scans and a PET scan to rule out additional chemotherapy and irradiation in favor of pallia- metastatic disease to the colon from another source. These tive measures. He expired in hospice care six months after studies failed to identify any alternative primary origin for his initial diagnosis. No autopsy was performed. the malignancy, specifically excluding the more common sites of renal and prostate origin. DISCUSSION Prognosis is difficult to ascertain given the paucity of reported cases. Seven cases have unknown survival informa- Primary clear cell adenocarcinoma of the colon and tion.2,3,6,7,9,10,12,13 Two cases report no reoccurrence at one-year rectum is rare. This is the 14th reported case, according follow-up without further information.4 Outcomes from the to the results of the authors’ searches on PubMed (Table remaining five cases, including ours, have a mean survival I),1-13 and the youngest case ever reported. Previously, the of 10.2 months from diagnosis, suggesting this variant to average reported age at diagnosis was 56 years old. The be an aggressive cancer.4,5,8 Lymph node metastasis was re- ascending colon location is also unusual for primary clear ported in a total of five cases, including ours. Most patients cell adenocarcinomas, as 11 reported cases involve the left underwent surgical therapy, even in advanced age.8 colon.2-12 Thus, this patient’s specific tumor is not only rare Unfortunately, little is known about the incidence and in occurrence, but also in early age of onset and location. prognosis of primary colonic clear cell adenocarcinoma Clear cell adenocarcinomas usually occur in the kidney given the paucity of reported cases. No screening genetic and within tissues of Müllerian system derivation, such as analysis tests are currently recommended for detection of the lower urinary and female genital tracts; other less com- primary clear cell adenocarcinoma, a rare entity. The authors mon sites include the larynx, breast, pancreas, stomach, stress the importance of screening colonoscopies in the early biliary system, and colon.4,8-10 The histologic features of clear detection and intervention of colorectal cancers. While our cell adenocarcinomas include rounded or polygonal-shaped patient was too young to fall within the targeted age group cells with well-defined cell membranes and large amounts of of 50 years or older, nine of the previously cited cases may clear or granular cytoplasm, typically attributed to abundant have benefited from earlier identification and intervention. cytoplasmic glycogen.15,16 Morphologically, primary colonic With the increased availability of the electronic medical clear cell adenocarcinoma shares traits with the aforemen- record, advancements and accessibility of radiographic im- tioned and more common clear cell malignancies of the aging, and the growing spectrum of immunohistochemical uterus, kidney, and ovaries. Given the tumoral presentation stains, the identification of definitive cases of primary clear in a male, our differential included renal cell carcinoma, cell adenocarcinoma of the colon may increase. transitional cell carcinoma, and a clear cell adenocarcinoma of colonic or prostatic origin. ACKNOWLEDGEMENTS The typical immunohistochemical profile for adenocarcinomas arising within the colon is strong expression Special thanks to Dr. John Hutchings of the Department of CK20 without expression of CK7. The tumor in our case of Gastroenterology, Louisiana State University Health Sci-

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ences Center in New Orleans, LA. 9. Mallik AA, Katchy KC. Clear cell adenocarcinoma of the rectum. Med Princ Pract 2005;14:58-60. REFERENCES 10. Ko YT, Baik SH, Kim SH, et al. Clear cell adenocarcinoma of the sigmoid colon. Int J Colorectal Dis 2007; 22:1543-1544. 11. Soga K, Konishi H, Tatsumi N, et al. Clear cell adenocarcinoma 1. Furuya Y, Wakahara T, Akimoto H. Clear Cell Adenocarcinoma of the colon: A case report and review of literature. World J with Enteroblastic Differentiation of the Ascending Colon. J Clin Gastroenterol 2008; 14:1137-1140. Oncol 2011; 29:e647-9. 12. Barisella M, Lampis A, Perrone F, et al. Clear cell adenocarcinoma 2. Hellstrom HR, Fisher ER. Physaliferous Variant of Carcinoma of of the colon is a unique morphological variant of intestinal Colon. Cancer 1964; 17:259-263. carcinoma: Case report with molecular analysis. World J 3. Jewell LD, Barr JR, McCaughey WT, et al. Clear-cell epithelial Gastroenterol 2008; 14:6575-6577. neoplasms of the large intestine. Arch Pathol Lab Med 1988; 112:197- 13. Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 199. expression in epithelial neoplasms: A survey of 435 cases. Mod 4. Hao LS, Zhu X, Zhao LH, et al. Clear cell adenocarcinoma of Pathol 2000;13:962-972. colorectum: A case report and review of the literature. Acta 14. Odze RD and Goldblum JR (editors). Surgical Pathology of the GI Gastroenterol Belg 2007; 70:235-238. tract, Liver, Biliary Tract, and Pancreas, 2nd edition. Philadelphia: 5. Rubio CA. Clear cell adenocarcinoma of the colon. J Clin Pathol Saunders Elsevier; 2009: 613, 868. 1995; 48:1142-1144. 15. Rosai J. Rosai and Ackerman’s Surgical Pathology, 9th edition. New 6. Furman J and Lauwers GY. Clear cell change in colonic York: Mosby; 2004: 815. adenocarcinoma: An equally unusual finding. Histopathology 1999; 35:476-477. 7. McCluggage WG, Desai V, Toner PG, et al. Clear cell adenocarcinoma of the colon arising in endometriosis: A In the Department of Internal Medicine at Louisiana State University rare variant of primary colonic adenocarcinoma. J Clin Pathol Health Sciences Center in New Orleans: Dr. Thelin is a third-year 2001;54:76-77. Internal Medicine Resident and Dr. Engel is an Associate Professor 8. Braumann C, Schwabe M, Ordemann J, et al. The clear cell of Clinical Medicine and Associate Program Director of the Internal adenocarinoma of the colon: Case report and review of the Medicine Residency. In the Department of Pathology at LSUHSC- literature. Int J Colorectal Dis 2004; 19:264-267. New Orleans, Dr. Alquist is a third-year Pathology Resident, and Dr. Dewenter is an Assistant Professor of Pathology.

148 J La State Med Soc VOL 166 July/August 2014 Calvarial Plasmacytoma, an Unusual Manifestation of Multiple Myeloma

Sarah Castillo-Jorge, MD; Christian Fauria-Robinson, MD; Enrique Palacios, MD, FACR; Jeremy Nguyen, MD; Ronnie Self II, MD, MS; Philip Daroca, MD

The case presented is that of a 63-year-old female with an unusually large solitary calvarial plasmacytoma as an initial manifestation of a multiple myeloma. We were able to follow the progression of the disease clinically and with diagnostic imaging.

INTRODUCTION may progress to multiple myeloma.1 Primary amyloidosis and plasma cell leukemia can also present as an isolated Plasmacytomas are manifestations of plasma cell tu- lesion termed solitary plasmacytoma, which can present as mors that may arise in any part of the body from the plasma an intra- or extra-medullary tumor. Although rarely seen in cells in the bone marrow or from the mucosal surfaces when the head and neck, when encountered, they are described extramedullary. Gammopathy of unknown significance as extramedullary skull base lesions. However, medullary (MGUS), a condition that leads to moderately elevated plasmacytomas can and do arise from the skull. These levels of immunoglobulin protein in the blood, may be rapidly growing masses can present a diagnostic dilemma asymptomatic; but is precancerous and in rare instances, with significant co-morbidity and consequences for delayed

Figure 1: CT axial section in the upper portion of the calvarium. (Left) Soft tissue window and (Right) bone window revealed a large soft tissue mass arising from the calvarium in the left parietal region with significant bone erosion and remodeling.

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Figure 2: MR images: (Top row, left to right) axial T1W, axial DWI, coronal T2W. (Bottom row, left to right) images in axial, coronal, and sagittal, respectively, demonstrating an enhanced soft tissue mass in the left parietal region. diagnosis. Imaging (MR) revealed a 4.6 x 4.1 cm mass (Figure 2), suggesting a lesion arising from the calvarium or an extra-axial CASE PRESENTATION mass, such as a meningioma. A cerebral angiogram demonstrated the mass to be supplied primarily by the branches of A 63-year-old African-American female, with an ex- the left middle meningeal and superficial temporal arteries tensive past medical history that included schizophrenia, (Figure 3). substance abuse, diabetes, hypertension, and Hepatitis The patient was lost to follow-up and presented to the C presented to the surgery clinic with an enlarging mass emergency room six months later with signs and symptoms on the left posterior scalp parietal region. The mass was of meningitis. At that time, CT showed interval enlargement reportedly tender to palpation; cough or sneezing also of a left parietal extra-axial hyperdense mass now measuring precipitated local pain. 8.0 x 6.5 cm associated with bone destruction, calcifications, Initial imaging with Computed Tomography (CT) re- and areas suggestive of necrosis. MR demonstrated the vealed a large soft tissue mass appearing to arise from the mass to be arising from the calvarium, unchanged in signal calvarium with minimal moderate extrinsic mass effect on characteristics from the previous imaging studies but with the adjacent brain, (Figure 1) while Magnetic Resonance additional smaller lesions throughout the calvarium, further

150 J La State Med Soc VOL 166 July/August 2014 Figure 3: Digital subtraction angiography in anterior projection on the left demonstrating the mass in the left parietal region being supplied by meningeal branches from the left external carotid artery. (Left) arterial phase and (Right) capillary phase.

supporting the diagnosis of a multifocal, multiple myeloma. made on the basis of screening laboratory tests.3-7 Multiple A CT angiogram revealed the mass to be enhancing from myeloma is difficult to diagnose when it is manifested in the hyper-vascularity seen on the venous phase with associated head and neck as a solitary plasmacytoma, which is an un- areas of necrosis and calcifications of the adjacent tissues. common manifestation and simulates other head and neck The patient had a cardiac arrest and was later diagnosed neoplastic masses.3,4 Plasmacytomas may associate with or with endocarditis with severe aortic regurgitation and un- progress to multiple myeloma in up to 50% of patients.5, 6 derwent a valve replacement. Subsequently, the patient had They generally appear as a bone or soft tissue tumor with a partial resection of the calvarial plasmacytoma. A follow- mass effect, pain, weakness, fatigue, fever, and infection.5,7 up MR of the brain revealed additional lytic lesions in the Solitary intracranial plasmacytomas are rare, with only scat- left parietal region with no evidence of brain meningeal or tered cases having been reported in the literature.2 These parenchyma involvement. The patient underwent radia- lesions can arise from the calvarium, dura, and base of the tion therapy to the left parietal region and was enrolled in skull and may appear as benign lesions.4 In patients with the Southwest Oncology Group (SWOG) clinical trials and a primary calvarial mass, the lesion may generate focal placed on Zometa, Revlimid, and Decadron. The patient cerebral dysfunction. was then evaluated for Autologous Peripheral Blood Stem Calvarial lesions and most skull base plasmacytomas, Cell Transplantation (APBSCT), since her Karnofsky perfor- being intramedullary, have a greater chance of progressing mance status had improved to 90%. The patient continues to multiple myeloma than the dural-based lesions but less to be followed-up and remains stable at the time of this than extracranial extramedullary plasmacytomas. It has writing, six months from the identification of the calvarial been observed that all base of the skull infiltrating plasma- mass. cytomas were associated with multiple myeloma.8

DISCUSSION HISTOPATHOLOGY

Solitary intramedullary plasmacytoma may occur as Solitary plasmacytoma of bone (osseous plasmacytoma) a primarily focal entity or as the first presentation of a is a localized tumor consisting of monoclonal plasma cells systemic disease, such as multiple myeloma. Nearly 57% with an immunophenotypic pattern similar to plasma cell of patients with solitary plasmacytoma eventually develop myeloma. As such, plasmacytomas typically express CD79a, multiple myeloma.2 Although multiple myeloma generally CD138, and CD38 similar to normal plasma cells with aber- presents as a symptomatic multifocal process, some patients rant expression of CD56, suggesting a neoplastic process do not present overt manifestations, and the diagnosis is (67%-79% of cases) and a lack of CD19 reactivity (nearly all

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dex in the atypical plasma cells with proliferation indices ranging from 10% to 70%, depending on the area examined. Additionally in our case, plasma cells are negative for CD3, CD20, Lambda light chain, and cyclin D1.9

DIFFERENTIAL DIAGNOSIS AND IMAGING

Plasmacytoma may be similar to a meningioma, metastasis, sarcoma, chordoma, hemangiopericytoma, and giant cell tumor. Meningiomas can cause a similar high density peripheral lesion with homogeneous enhancement, and they exhibit adjacent dural reaction, so-called “dural tail.” A rare form of intraosseous meningioma can cause lytic bony changes with their blood supply, usually from the middle meningeal artery, while the blood supply of a plasmacytoma could be from the external carotid artery, mainly from superficial temporal branch and muscular branches of the vertebral artery.7-10 In multiple myeloma, plasmacytomas are purely lytic and have a clear margin with a narrow zone of transition to normal surrounding bone. The sharp borders, lack of bony sclerosis, and the paucity of periosteal reaction are Figure 4: 400x H&E sheet of plasma cells with occasional characteristic findings.5 On the other hand, plasmacytomas enlarged nuclei. often present as solitary intra- and extra-cranial masses that bridge the diploic site of origin.3 Solitary plasmacytomas are often large and well-advanced at the time of diagnosis. This is usually due to the fact that the mass is asymptomatic and the patient seeks no immediate care until the mass is sizeable, as in our case. Diagnostic imaging with CT and in particular, MR, is highly sensitive to delineate the lesion and its extension. On CT, the mass appears as an extra-axial lesion of high- attenuation with homogeneous contrast enhancement.11 On MR, the mass is consistent with a focal lesion involving the bone marrow; the signal intensity of the mass is similar to muscle on T1WI and iso- to hyperintense relative to muscle on T2WI.4 Larger tumors may show necrosis, destruction, and infiltration of the adjacent structures.11,12 In the assessment of solitary plasmacytoma, skeletal survey is beneficial to detect lytic lesions consistent with multiple myeloma and to monitor osteoblastic response to bone Figure 5: 100x CD138 plasma cells diffusely express CD138. destruction. Computed tomography may be more helpful in some areas to detect the extent of bone destruction, while MR cases). In addition to CD56, plasmacytomas may aberrantly may be useful to determine the bone marrow involvement, express CD117, CD20, CD52, CD10, and EMA.9 particularly in the spine. In this setting the lesions are low Our case shows a dense and diffuse atypical plasma cell in intensity and isointense on T1WI, hyperintense on T2WI 11,12 infiltrate consisting of a mixture of small normal appearing and enhanced in T1W with fat saturation. plasma cells and larger atypical occasionally pleomorphic plasma cells (Figure 4). The plasma cells are noted to both CONCLUSION infiltrate soft tissue with prominent areas of necrosis and involve bone of the intramedullary space. Immunohistochemi- We presented the imaging findings of an unusual large cal stains show a kappa-restricted plasma cell population solitary calvarial plasmacytoma as an initial manifestation with normal expression of CD138 (Figure 5), aberrant strong of multiple myeloma. We briefly discussed the clinical and expression of CD56 and diminished expression of CD79a. pathological findings, as well as the progression of this The Ki-67 immunostain shows a variable proliferation in- entity.

152 J La State Med Soc VOL 166 July/August 2014 REFERENCES

1. Multiple Myeloma Memorial Sloan-Kettering Cancer Center. http://www.mskcc.org/cancer-care/adult/multiple-myeloma. 2013. 2. Bertanha F, Boufelli G, Pires de Camargo, O, et al: Original Research Oncologic Progression of Bone Plasmacytomas to Multiple Myeloma. Clinics 2006; 61:139-46. 3. Meyer et at. Solitary Intramedullary Plasmacytoma of the Skull base mimicking aggressive meningioma. Skull Base Surgery 1997; 7: 101-105. 4. Vogl et al. MR Characteristics of Primary Extramedullary Plasmacytoma in the Head and Neck. AJNR Am J Neuroradiol 17:1349-1354, 1996. 5. Oliveira, Rodrigo; Reis Fabiano et. al. Plasmacytoma of the Head and Neck as initial presentation of multiple myeloma. Arq Neurosiquatr 2011; 69: 139-140 6. Cerase A, Tarantino A, Gozzetti A, Muccio CF, Gennari P, Monti L, Di Blasi A, Venturi C: Intracraneal involvement in plasmacytomas and multiple myeloma: A pictorial Essay. Neuroradiology 50:665- 674, 2008. 7. Scwartz et at. Association between Intracranial Plasmacytoma and Multiple Myeloma: Clinicopathological Outcome Study. Neurosurgery 49: 1039-1045, 2001. 8. Tanaka et al. Solitary Plasmacytoma of the Skull: a case report. Jpn J Clin Oncol 1998; 28: 626-630. 9. Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J., Vardiman J.W. (Eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon 2008. Pgs. 202–209. 10. Swerdlow SH; Campo E; Harris NL; Jaffe ES; Pileri SA; Stein H; Thiele J; Vardiman JW (Eds): WHO Classification of Tumours of Hematopoiectic and Lymphoid Tissue. IARC: Lyon 2008, 202-209. 11. Du Preez JH, Branca EP: Plasmacytoma of the skull: Case reports. Neurosurgery. 29:902-906, 1991. 12. Ooi et al. Radiologic Manifestations of Primary Solitary Extramedullary and Multiple Solitary Plasmacytomas. AJR 2006; 186:821-827. 13. Kilciksiz et al. A Review for Solitary Plasmacytoma of Bone and Extramedullary Plasmacytoma. The Scientific World Journal 2012: 1-6. Doi: 10.1100/2012/895765. 14. Ustuner et al. Plasmacytoma in a Patient with Light Chain Myeloma. Skull Base 2003; 13-3: 167-171.

Drs. Castillo-Jorge, Fauria-Robinson, Palacios, and Nguyen are with the Department of Radiology in the Tulane University School of Medicine in New Orleans. Drs. Self II and Daroca are with the Department of Pathology in the Tulane University School of Medicine in New Orleans.

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Delusional Infestations: Case Series, Differential Diagnoses, and Management Strategies

James H. Diaz, MD, MPH&TM, DrPH; Lee T. Nesbitt Jr., MD

Physicians are not infrequently consulted by distraught patients with delusions of infestation who believe that they are infested with external or internal parasites and describe a crawling sensation of bugs or worms on or under their skin. Internet search engines were queried with the keywords as search terms to examine the latest articles on delusional infestations in order to describe presenting manifestations, differential diagnoses, and effective management strategies. The demographic and behavioral features of delusional infestations have remained constant and include: (1) onset in well-educated, middle-aged adults who are pet owners; (2) production of purported specimens of causative parasites; (3) pesticide overtreatment of themselves, their households, and pets; (4) excessive cleaning or vacuuming of households; (5) intense anger and resentment directed at physicians failing to confirm their self-diagnoses; and (6) sharing delusional symptoms with spouses or relatives. Although some reports have suggested that cases of delusional infestation are increasing today in the tropics, most studies have confirmed a stable incidence over time and similar disorder demographics worldwide. However, management strategies for delusional infestations have changed significantly over time with second generation, atypical antipsychotics offering safer adverse effect profiles and better prognoses than earlier therapies with first generation, typical antipsychotics. The most effective management strategies for delusional infestations include empathetic history-taking and active listening to the patient, careful exclusion of true parasitoses, and a therapeutic regimen that includes a second generation neuroleptic agent.

In an era of Internet-assisted self-diagnoses and the strategies. The keywords included the following: parasit- return of bedbugs, physicians are not infrequently consulted osis, delusional; ectoparasitosis, delusional; infestations, by distraught patients who believe that they are infested delusional; Ekbom’s syndrome; acarophobia; and Morgel- with external or internal parasites, describe a crawling sen- lons disease. A representative series of cases, either from sation of bugs or worms on or under their skin, and often peer-reviewed scientific publications, or from the authors’ display a boxed specimen or blurred photo of the offend- own clinical practices are reported first. ing parasite. When other causes of infectious dysesthesias - such as scabies, cercarial dermatitis, and cutaneous larva RESULTS migrans - are excluded by physical examination or skin biopsy, and no treatable dermatoses are diagnosed, this con- Report of Cases dition is called delusional infestation, formerly delusional parasitosis. The objectives of this review are to present a Case 1 (Adapted from Meehan WJ et al. 2006)1 representative series of cases of delusional infestations and A 56-year-old female with a history of depression to recommend effective management strategies. presented with a two-month history of intensely pruritic sensations of “bugs that were crawling” on her posterior METHODS neck at her hairline. These sensations were resistant to topical therapy with antihistamines and corticosteroids. Internet search engines were queried with the keywords Physical examination demonstrated a localized plaque of as search terms to examine the latest scientific articles on self-excoriated nodules and papules. Microscopic exami- delusional infestations in order to describe a variety of nation of skin scrapings was negative for scabies mites or clinical and behavioral manifestations, develop a differential eggs, and a potassium hydroxide mount was negative for diagnosis, and recommend new and effective management any organisms or fungi. Intralesional triamcinolone was in-

154 J La State Med Soc VOL 166 July/August 2014 of pruritic crawling sensations in similar locations causing self-excoriations occurred in other family members in other areas of the residence. The physician treated his family with oral ivermectin and topical permethrin and the family’s pet dog with topical permethrin. The family then spent two nights in a hotel while their house was being pro- fessionally fumigated with a pyrethroid pesticide. On return to the household, the pruritic crawling sensations had improved but persisted. There was no further follow-up.

Case 3 (Author’s case) A 45-year-old nurse, who lived with two cats in an apartment whose carpets had been treated for carpet beetles, developed pruritic bite-like lesions with scratch marks on the anterior abdominal wall and breasts. Microscopic examination of skin scrapings and potassium hydroxide mounts demonstrated no evidence of scabies mites or eggs, or other arthropods, or fungi. Repeated examination of the two cats by a veterinarian demonstrated no Figure 1: The typical, self-limited, erythematous and papular rash evidence of ectoparasitic infections. After moving caused by multiple bites of European itch mites (Peymotes herfsi), which to another apartment in an old home with a base- are ectoparasites of leaf-rolling fly larvae. The microscopic mites fall ment, the patient reported fewer episodes of itching from tress or get carried by the wind causing community outbreaks of with topical antihistamine therapy until mice were intensely pruritic rashes in humans exposed outdoors during summer discovered and trapped in the basement and moths oak tree infestations. Source: Outbreak of pruritic rashes associated with were identified in her bedroom. Following control mites - Kansas, 2004. US Centers for Disease Control and Prevention. of the mice and moths by an exterminator, the itch- Month Morb Mort Week Rep 2005; 54: 952-55. No copyright permission ing and scratch marks improved again. Lastly, the required. The photo is courtesy of A. Broce and L. Zurek, Kansas State patient also reported excessively vacuuming of the University. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/ carpets and was later lost to follow-up. mm5438a3.htm.

2 jected into the largest nodule, and the patient was instructed Case 4 (Adapted from Donabedian H 2007) to apply a topical steroid cream twice daily to the affected A 51-year-old dog breeder whose dogs had been treated area and to complete a 10-day course of oral cephalexin for ectoparasites several months earlier reported to an infec- before returning for follow-up. At follow-up, the patient tious disease specialist that she had “worms crawling under was tearful and distraught and produced a specimen of a her skin” that occasionally exited her skin, jumped into her “bug” from her hairline, later identified as a dried pea. The nose or eyes, and then traveled to her brain causing severe patient was started on oral atypical antipsychotic therapy headaches. The physical examination and all laboratory tests with olanzapine, 5 mg/day, and demonstrated dramatic were negative, including a serologic test for leptospirosis. improvement and resolution of all symptoms at her one- Later, the patient produced a sealed plastic bag containing month follow-up appointment. round “worms” rolled in tissue paper. Microscopic examination demonstrated the “worms” to be inanimate, fiber-like matter. When a recommendation was made for psychiatric Case 2 (Author’s case) consultation and possible treatment with antipsychotic A physician and his wife experienced episodic crawl- medications, the patient accused the physician of being ing sensations on their faces, chests, and backs, especially totally uncaring of her suffering and completely ignorant at night, and developed an increasing number of pruritic, of her condition. The patient dismissed her physician and papular lesions in the same locations that became excoriated was lost to further follow-up. from scratching. Dermatoscopic examination of the lesions and microscopic examination of skin scrapings from the lesions revealed no evidence of scabies or mite infestations. DISCUSSION A pest extermination company examined the premises and The earliest reports of delusions of infestations were found no evidence of animal or arthropod infestation, and published in the late 19th century and attributed to Thi- a veterinarian found no evidence of ectoparasitic infection bierge, who reported cases of “acarophobia.”2 In 1938, on examination of the family’s pet dog. Later, the episodes

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recently, Freudenmann and Lepping have recommended a broader term, “delusional infestation,” rather than more disease-oriented descriptions, such as parasitosis and phobia.4 Approximately 5%-15% of patients with delusional infestations will exhibit delusions shared with a spouse or relative (folie à deux) or shared with more than one family member or close friend (folie partagé).5 The most common shared delusions are between husband and wife; between siblings, especially twins; or between a parent, usually the mother, and a son or daughter.2, 5 Patients with delusional infestations all harbor intense anger and resentment for physicians who do not quickly confirm their perceived infestations. They will dismiss their initial doctors quickly to seek other medical opinions from a variety of specialists ranging from dermatologists to internists and infec- Figure 2: The life cycle of several species of avian schistosomes of resident and migratory tious disease specialists.2 waterfowl whose eggs are passed in bird feces and hatch into ciliated miricidia that In 1992, Bourgeois and coauthors penetrate aquatic snail intermediate hosts. Infected snails later release infective cercariae reported a case of shared delusional into freshwater sources to penetrate the skin of definitive bird hosts or inadvertent or infestations between husband and dead-end hosts, such as man, causing self-limited, intensely pruritic cercarial dermatitis. wife (folie à deux) in which a 58-year- Source: US Centers for Disease Control and Prevention, DpDx Image Library. No old woman was institutionalized for copyright permission required. Available at http://www.dpd.cdc.gov/dpdx/HTML/ attempting to kill her general prac- CercarialDermatitis.htm. titioner who refused to confirm her Figure 3: The delusions.5 In some cases, patients typical, self-limited, with delusional infestations have intensely pruritic, killed their pets to rid themselves of papulovesicular rash their perceived delusions.2 of cercarial dermatitis All of the cases presented in or swimmer’s (duck this series have demonstrated the hunter’s) itch caused pathognomonic behavioral features by penetration of the and clinical manifestations of delu- skin by the cercariae sional infestations, including: (1) of avian (waterfowl) onset in well-educated, middle-aged schistosomes. Source: adults who are pet owners (Cases 2, US Centers for Disease 3, and 4); (2) production of purported Control and Prevention, specimens of causative parasites DpDx Image Library. No copyright permission in what is called the “matchbox required. Available sign” (Cases 1 and 4); (3) pesticide at http://www.dpd. overtreatment of themselves, their cdc.gov/dpdx/HTML/ households, and their pets with oral CercarialDermatitis.htm. (ivermectin) and topical (ivermectin, pyrethroids) insecticides (Cases 2 and 3); (4) excessive cleaning or vacuum- Karl Ekbom, a Swedish neurologist, described “delusions ing of their households (Case 3); (5) intense anger and of animals on the skin,” but his long German description resentment directed towards physicians failing to confirm was so cumbersome (Dermatozoenwahn) that the condition their self-diagnoses (Case 4); and (6) sharing delusional was called Ekbom’s syndrome instead until 1946, when symptoms with their spouses or partners in the folie à deux Wilson and Miller coined “delusion of parasitosis.”3 More phenomenon (Case 2), or with others in the folie partagé

156 J La State Med Soc VOL 166 July/August 2014 Table 1: The Differential Diagnosis of Delusional Infestations Infections Drug-induced Neurological Ectoparasitic infections: Prescribed medications: Parkinson’s disease Alzheimer’s disease Scabies (Sarcoptes scabiei) Ciprofloxacin Diabetic neuropathy Follicle (Demodex) mites Corticosteroids Morgellons disease (an unrecognized, Animal and plant mites Phenelzine self-diagnosed neuropsychological Body lice (Pediculus humanus corporis) Topiramate disorder characterized by delusional Pubic lice (Pthirus pubis) infestation) Trichotillomania (a compulsive urge to pull out and, in some cases, eat one’s own hair, usually on the scalp) Cutaneous larva migrans: Illicit drugs: Cerebrovascular disease:

Animal hookworms (Ancylostoma Cocaine Temporoparietal lobe infarcts braziliensis) Avian schistosomal cercarial dermatitis (swimmer’s itch or duck hunter’s itch) Miscellaneous infections:

Shingles (Herpes zoster) Hansen’s disease phenomenon (Case 2).1, 2 cal care for intensely pruritic, erythematous, papular rashes In addition, Case 4 demonstrated a unique variation of that were subsequently determined to be caused by multiple delusional infestation, now known as Morgellons disease bites from European itch mites (Peymotes herfsi) (Figure 1).9 or syndrome, by producing “round worms” rolled in paper These insect mites are ectoparasites of leaf-rolling fly larvae tissues.6 Morgellons disease is defined as an unrecognized that fall from oak trees or get carried by the wind and land medical and/or neuropsychiatric disorder in which embed- on people outdoors, causing summertime community out- ded fibers of cellulose or cotton from clothing or paper can be breaks of pruritic rashes.9 demonstrated microscopically in self-excoriated, intensely Another common cause of seasonal clusters of pruritic pruritic and self-excoriated skin lesions in patients suffering rashes may be caused by aquatic exposures to the infective from delusional infestations.6 stage cercariae of several avian schistosomes, or flatworms, In 1995, Trabert reported the results of his comprehen- that are released into freshwater lakes and rivers in the tens sive meta-analysis of 193 reports of delusional infestations of thousands by infected aquatic snail intermediate hosts in over 100 years that included 1,123 case-patients.7 The inci- a complicated life cycle (Figure 2). Cercarial dermatitis, or dence in Germany was 1.6 cases per million cases per year swimmer’s (duck hunter’s) itch, has occurred in seasonal with a mean age of case-patients of 57 years.7 The ratio of outbreaks in swimmers in freshwater lakes and rivers whose female-to-male cases was 1.4:1.0 for those under age 50 years resident or migratory waterfowl are infected with avian and 2.5:1.0 for those 50 years of age and older.7 Subsequent schistosomes (Figure 3). Lastly, several drugs; metabolic descriptive and analytical epidemiological investigations, disorder-associated peripheral neuropathies, especially dia- including our own small case series, have confirmed simi- betic neuropathy; and some neurodegenerative diseases, lar demographic characteristics.8 When Reilly and Batchlor especially Parkinson’s and Alzheimer’s diseases; can cause surveyed 386 dermatologists in the United Kingdom, 66% dysesthesias with bug-crawling skin sensations that mimic reported seeing at least one patient with delusional infesta- arthropod infestations (Table 1).1,2,10,11 tion within the past five years.8 Prior to the discovery of antipsychotic medications, Wil- The major differential diagnoses of delusional infesta- son and Miller reported a poor prognosis for patients with tion include true ectoparasitic infections and cutaneous delusional infestations with 82% of 51 reported patients hav- larva migrans, which must be ruled out initially by careful ing no change in their illnesses.3 However, by the 1990s and recreational, occupational, and travel histories, microscopic with the use of the first generation or typical antipsychotics and laboratory tests, and drug-induced or neurological in managing delusional infestations, especially pimozide, disease-associated dysesthesias (Table 1). Ectoparasitic in- Trabert reported nearly 70% improvement in patients with fections, such as scabies and animal mite infestations, may pharmacotherapy.7,12 occur in large seasonal clusters, such as in Pittsburg, Kansas, Today, the best management strategies for patients with in August 2004, when 300 residents sought immediate medi- delusional infestations include careful and empathetic work-

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Table 2: Second Generation Antipsychotics Recommended for Delusional Infestations: Comparison of Dosing Schedules and Adverse Effects Medications: generic names Olanzapine Risperidone Ziprasidone Medications: trade names Zyprexa® Risperdal® Geodon® Daily dosing schedule 5 mg po q day hs 2 mg po q day hs Advance over 2 days from 20 mg bid to 40 mg tid (120 mg/day) Weight gain +++ ++ 0/+ Hyperglycemia + 0 0 Dyslipidemias + 0 0 Sedation ++ ++ + Hypotension + + 0 Anticholinergic effects +++ + +

+++: High effect; ++: Moderate effect; +: Minimal effect; 0: No effect ups for evidence of parasitosis, psychological counseling, in the management of the disorder by increasing rCBF in and the use of the newer neuroleptic medications, especially specific brain regions.14 In addition, the neuroimaging study the second-generation or atypical antipsychotic medications, demonstrated an association between reduced rCBF and including olanzapine, risperidone, and ziprasidone.1,2,16-19 the dysesthesias of delusional infestation and the reversal Unlike pimozide and all other first-generation antipsychot- of dysesthesias with the restoration of rCBF, suggesting an ics, the second-generation antipsychotics carry less risk of ischemic mechanism for the disorder.14 precipitating cardiac arrhythmias, especially prolonged QT Although some reports have suggested that cases of intervals and torsades de pointes, extra-pyramidal syndromes, delusional infestation are increasing today, especially in arid and tardive dyskinesias.1,12-14 and tropical regions where arthropod-borne infectious dis- Several reports have now confirmed that relatively eases are hyperendemic, most studies have now confirmed a small daily doses of these atypical antipsychotics or neuro- relatively stable incidence rate over time and similar disease leptics are dramatically effective in reducing the delusions demographics worldwide.15 The management strategies for of infestation.1,13,14 Some of the atypicals are associated delusional infestations have, however, changed significantly with sedation, weight gain, and hyperglycemia, especially over time with second-generation, atypical antipsychotics olanzapine; but all have significantly lower potentials for offering safer adverse effect profiles and better prognoses causing cardiac arrhythmias, extrapyramidal syndromes, than earlier therapies with first-generation, typical antipsy- and tardive dyskinesias than the first generation antipsychotics. The most effective current management strategies chotics.1,13,14 Table 2 compares the adverse effects of the for delusional infestations include empathetic history-taking second-generation antipsychotics recommended for the and active listening to the patient; careful exclusion of true management of delusional infestations and their dosing parasitoses, such as mite infestations and cercarial derma- schedules. titis, and neurodegenerative or cerebrovascular disorders; In 2006, Narumoto and co-investigators reported a case and a therapeutic regimen that includes a second-generation that has now provided significant scientific support for a neuroleptic agent. physiochemical mechanism of dopaminergic and serotoner- gic neurotransmitter dysfunction in delusional infestation REFERENCES and for the continued use of second-generation antipsychotics in treating the disorder.14 In their case, a patient devel- 1. Meehan WJ, Badreshia S, Mackley CL. Successful treatment of oped delusional infestation following an acute, ischemic delusions of parasitosis with olanzapine. Arch Dermatol 2006; 142: stroke in the right temporoparietal region and was treated 352-355. with risperidone with rapid, dramatic improvement.14 2. Donabedian H. Delusions of parasitosis. Clin Infect Dis 2007; 45: 131-134. A pre-treatment single-photon emission computerized 3. Wilson JW, Miller HE. Delusion of parasitosis. Arch Dermatol tomography (SPECT) scan showed a global decrease in re- Syphiol 1946; 54: 39-56. gional cerebral blood flow (rCBF), but a post-treatment scan 4. Freudenmann RW, Lepping P. Delusional infestation. Clin showed marked increase in rCBF in the region of the brain Microbiol Rev 2009; 22: 690-732. infarct and in the basal ganglia bilaterally.14 This report was 5. Bourgeois ML, Duhamel P, Verdoux H. Delusional parasitosis: the first objective confirmation using sensitive neuroimaging folie à deux and attempted murder of a family physician. Br J techniques of the utility of second-generation antipsychotics Psychaitr 1992; 161: 709-711.

158 J La State Med Soc VOL 166 July/August 2014 6. Pearson ML, Selby JV, Katz KA, et al. Clinical, epidemiologic, 14. Narumoto J, Ueda H, Tsuchida H, et al. Regional cerebral blood histopathologic and molecular features of an unexplained flow changes in a patient with delusional parasitosis before and dermatopathy. Plos One 2012; 7: e29908. Doi: 10: 1371/journal. after successful treatment with risperidone: a case report. Prog pone.0029908. Published January 25, 2012. Neuropsychopharmacol Biol Psychiatr 2006; 30: 737-740. 7. Trabert W. 100 years of delusional parasitosis. Psychopathol 1995; 15. Sabry AH, Fouad MA, Morsy AT. Entomophobia, acarophobia, 28: 238-246. parasitic dermatophobia or delusional parasitosis. J Egypt Soc 8. Reilly TM, Batchlor DH. The presentation and treatment of Parasitol. 2012; 42: 417-430. delusional parasitosis: a dermatological perspective. Intl Clin Psychopharmacol 1986; 1: 340-353. 9. US Centers for Disease Control and Prevention. Outbreak of pruritic rashes associated with mites—Kansas, 2004. Morb Mort Dr. Diaz is Professor of Public Health and Preventive Medicine and Week Rep 2005; 54: 952-955. Head, Program in Environmental and Occupational Health Sciences, 10. Fleury V, Wayte J, Kiley M. Topiramate-induced delusional Schools of Public Health and Medicine, Louisiana State University Health Sciences Center in New Orleans. Prior to publication of this parasitosis. J Clin Neurosci 2008; 15: 597-599. article, Dr. Nesbitt Jr. passed away. He was Professor and Chair of 11. Bhatia MS, Jhanjee A, Srivastava S. Delusional infestation: a clinical the Department of Dermatology, School of Medicine, LSUHSC-New profile. Asian J Psychiatr 2013; 6: 124-127. Orleans. 12. Reilly TM, Jopling WH, Beard AW. Successful treatment with pimozide of delusional parasitosis. Br J Dermatol 1978; 98: 457-459. 13. Gowda BSN, Heebar S, Sathyanarayana MT. Delusional parasitosis responding to risperidone. Indian J Psychiatr 2002; 44: 382-383.

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Surgical Management of Middle Cerebral Artery Aneurysms

Anil Nanda, MD; Sudheer Ambekar, MD; Mayur Sharma, MD

Objectives: Treatment of middle cerebral artery (MCA) aneurysms remains controversial because of their morphological characteristics. The aim of our study was to analyze the morbidity, mortality, and outcome of patients who underwent clipping of MCA aneurysms and compare with that of endovascular therapy.

Patients and Methods: Patient and aneurysm characteristics and treatment outcomes of patients treated by the senior author from 1992 through 2012 were analyzed. Various factors associated with good outcome were analyzed.

Results: One hundred twenty-five patients with 132 aneurysms were included in the study. Seven patients had bilateral MCA bifurcation aneurysms, and 11 were giant aneurysms. Ninety-two point four percent aneurysms were located at MCA bifurcation, others being at pre- or post-bifurcation segments of M1. Intra- operative rupture was encountered in 4.8%. The overall perioperative morbidity and mortality was 8% and 0.8%, respectively. At a mean follow-up of 19.3 months, 83.8% patients had good outcome (mRS 0 and 1). The angiographic obliteration rate at one-year follow-up was 98%. Good preoperative Hunt and Hess grade and unruptured aneurysm were significantly associated with good outcome, whereas presence of hematoma was associated with poor outcome following surgery (P<0.05).

Conclusions: The results of clipping of MCA aneurysms are superior to that of published endovascular therapy. Surgical clipping remains the standard of care for MCA aneurysms with good clinical and angiographic outcome.

INTRODUCTION PATIENTS AND METHODS

Since the International Subarachnoid Aneurysm Trial The study was approved by the Institutional Review (ISAT),1 there has been a dramatic shift in the treatment Board. This was a retrospective study of all patients with paradigm of intracranial aneurysms towards coiling. With MCA aneurysms who underwent surgical clipping between the rapid advances in coil technology, increasing proportion 1992 and August 2012. Patients with traumatic and mycotic of aneurysms are being coiled each year compared to the aneurysms were excluded from the study. The demographic previous year. Although the middle cerebral artery (MCA) profile, clinical presentation, and aneurysm rupture status of can be easily catheterized, MCA aneurysms pose a unique all the patients was obtained from a prospectively collected challenge to endovascular therapy due to their unfavorable database. Patients were classified clinically according to the morphology. Factors that make MCA aneurysms unsuitable Hunt and Hess score at admission.5 Aneurysm size, loca- for endovascular therapy include location of the aneurysm tion, and other angiographic characteristics were obtained at MCA trifurcation, incorporation of one of the branches from the digital subtraction angiograms and computed by the aneurysm, low dome-to-neck ratio, and parent vessel tomographic angiograms (CTA). Aneurysms were sorted incorporation. into three groups depending on the size: (1) 0 to 10 mm, There has been discussion as to which modality of (2) 11 to 24 mm, and (3) greater than or equal to 25 mm. treatment is better for treatment of MCA aneurysms.2-4 All patients underwent surgery via the pterional approach. Some studies have found an inferior outcome following Patients who were diagnosed to have bilateral MCA endovascular treatment, whereas in others, the outcome aneurysms underwent surgery for the ruptured aneurysm is the same as surgical clipping. We report the experience first followed by surgery for the other MCA aneurysm in of the senior author (AN) with surgical clipping of MCA another sitting. Intraoperative aneurysm occlusion was aneurysms and compare the outcome with the outcomes assessed by visual examination in all cases, intraoperative following endovascular treatment as published in literature. angiography in a few cases, and with near infrared indo- cyanine green videoangiography (ICGA) during the latter

160 J La State Med Soc VOL 166 July/August 2014 Table 1: Clinical Characteristics of Patients Patient Characteristics Total patients 125 Mean age (yrs) + 2SD (range) 52.4 + 12.4 (15-91) Male:Female n (%) 40 (32):85 (68) Smoking n (%) 60 (48) Hypertension n (%) 66 (52.8) Diabetes n (%) 23 (18.4) Seizures n (%) 9 (7.2) Hydrocephalus n (%) 22 (17.6) Subarachnoid hemorrhage n (%) 81 (64.8) Hunt and Hess grade n (%) 0 10 (12.3) 1 20 (24.7) 2 25 (30.9) 3 12 (14.8) 4 13 (16.0) 5 1 (1.2) Bilateral aneurysms (mirror) n (%) 7 (5.6) Multiple aneurysms n (%) 28 (22.4%) Aneurysm characteristics Total aneurysms 132 Left:Right n (%) 71 (60.1):47 (39.9) Ruptured n (%) 81 (61.4) Unruptured n (%) 51 (38.6) Size n (%) < 10 mm 75 (56.8) 11-24 mm 44 (34.1) > 25 mm 11 (8.3) Location n (%) Pre-bifurcation M1 6 (4.5) Bifurcation/Trifurcation 122 (92.5) Post-bifurcation M1 4 (3.0) part of the series. Postoperative angiography was obtained of the clinical, radiological, operative, and follow-up details whenever the patient developed a new neurological deficit were not available were excluded from the study. or when vasospasm was suspected. Outcome was obtained from follow-up charts and clinic notes. Patient outcome was STATISTICAL ANALYSIS assessed using the modified Rankin scale (mRS).6 Patients with mRS scores 0 and 1 were grouped as having good Statistical analysis was performed using the SPSS outcome, and those with mRS scores 2 through 6 were software. Categorical variables were analyzed using the considered as having a bad outcome. Patients in whom all chi-square test, and continuous variables were compared

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Table 2: Complications and Outcome Following Surgical Clipping Complications n (~%) Clinical vasospasm 21 (16.8) Speech deficit 3 (2.4) Hemiparesis 4 (3.2) Hydrocephalus 14 (11.2) Ventriculoperitoneal shunting 5 (4) Menintitis 1 (0.8) Deep vein thrombosis 2 (1.6) Death 1 (0.8) Outcome n (%) No. of patients (%) 99 (79.2) Mean duration of follow-up (range) 19.3 months (1 month - 15 years) No. of patients with at least 1 year follow-up 52 (55.3) No. of patients with 1 year angiographic follow-up 45 (45.4%) Outcome mRS score n (~%) 0 55 (55.0) 1 28 (28.0) 2 11 (11.0) 3 2 (2.0) 4 2 (2.0) 5 1 (2.0) Angiographic obliteration at 1 year 44 (97.7) using the t-test when appropriate. Univariate analyses were intracerebral hematoma. conducted. Differences with a probability value of less than 0.05 were considered statistically significant. RADIOLOGICAL CHARACTERISTICS

RESULTS About half (56.8%) of the aneurysms were less than 10 mm in size. A majority (92%) of the aneurysms were Between 1992 and 2012, a total of 150 patients with 157 located at MCA bifurcation/trifurcation. All of the giant MCA aneurysms were operated on by the senior author aneurysms were located at the MCA bifurcation except for (AN). Complete clinical, radiological, and operative data one, which was located in the pre-bifurcation segment of was available for 125 patients with 132 aneurysms, and these the MCA. About one-fifth (22.4%) of patients had multiple were included in the study. aneurysms. These included anterior communicating artery aneurysm in 13 patients, contralateral MCA aneurysm in PATIENT CHARACTERISTICS seven patients, posterior communicating artery aneurysm in five patients, internal carotid artery bifurcation aneurysms The demographic, clinical, and aneurysm characteristics in three patients, and basilar bifurcation aneurysm in one of patients are listed in Table 1. There was one patient aged patient. Preoperative hydrocephalus was managed with less than 18 years, and 38 patients (30.4%) more than 60 external ventricular drainage. years of age. About two-thirds of the patients were females. Seven patients had bilateral MCA aneurysms. More than SURGERY half (60.1%) of the aneurysms were located on the left side. There was no association between the side of aneurysm All patients underwent surgery via the pterional ap- and rupture status. Eighteen (18%) patients presented with proach. Intraoperative rupture was encountered in six

162 J La State Med Soc VOL 166 July/August 2014 (4.8%) patients. Temporary clip was used in 55 (44%) patients either during the dissection or just before final clipping of the aneurysm. For giant aneurysms, multiple clips were used to reconstruct the parent vessel and its branches and maintain their patency. No patient required parent artery ligation with a revascularization procedure. Vessel patency was assessed using intraoperative angiography in three patients and using ICGA during the latter part of the series in 92 (73.6%) patients. Postoperative angiography was performed in 100 (75%) patients and correlated well with ICGA in all cases. In two patients, a small residual neck (<5%) was visualized on postoperative angiography. These patients were followed-up, and there was no increase in the residual neck size in subsequent angiograms.

COMPLICATIONS

Complications and outcome of patients are listed in Table 2. Clinical vasospasm was managed with triple H therapy and intra-arterial nimodipine infusion whenever deemed necessary. Speech and motor deficits improved completely in all patients, except in one patient who had persistent dysphasia at 12 months follow- up. Only five (4%) patients required ventriculoperitoneal shunting for permanent CSF diversion. Postoperative meningitis was successfully treated with intravenous Figure 1: Shows preoperative anteroposterior (a), lateral (b), postoperative lateral (c), and (d) images of a patient with right MCA bifurcation aneurysm. The small antibiotics. One patient with Hunt and perforator arising from the neck of the aneurysm is seen filling in the postoperative Hess grade 5 died in the postoperative angiogram and is indicated by blue arrow. period due to multiple cerebral infarcts. had a worse outcome when compared to the patients with- OUTCOME out hematoma in the initial CT scan (P<0.001). There was no significant difference in outcome between patients with Follow-up modified Rankin scores (mRS) were avail- history of smoking, hypertension or diabetes mellitus, and able for 79.2% (52 patients); 55.3% had at least one-year those without these risk factors (Table 1). History of seizure, follow-up (mean duration 34 months). Angiographic follow- side (left or right), location (pre-bifurcation, bifurcation, or up was available for 45.4% patients. post bifurcation), intraoperative rupture, and use of tempo- At last follow-up, 83.8% patients had good outcome rary clip during surgery did not have a significant difference (mRS 0 and 1), and 16.2% had an unfavorable outcome (mRS on the final outcome at follow-up. Patients with bilateral 2 to 6). Of the 45 patients in whom at least one-year angio- MCA aneurysms and multiple intracranial aneurysms did graphic follow-up was available, 97.7% showed complete not have a significantly different outcome compared to those obliteration of the aneurysm. Patients who were in a good with single aneurysm. clinical grade (Hunt and Hess 0 to 2) preoperatively had good outcome at follow-up, and the difference was signifi- CASE ILLUSTRATIONS cant (P<0.001). Patients with unruptured aneurysms had a better outcome at follow-up when compared to patients Case 1 with ruptured aneurysms, although the difference was not A 59-year-old lady was referred by a physician for significant (P=0.017). Patients with intracerebral hematoma management of a right MCA bifurcation aneurysm that was

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Case 2 53-year-old man presented with complaints of severe headache of sudden onset. On examination, he had no neurologic deficits except for mild dysphasia. CT scan revealed a hyperdense lesion in the left anterior temporal lobe adjacent to the sylvian fissure. There was no subarachnoid hemorrhage. DSA diagnosed a right MCA bifurcation aneurysm. The aneurysm measured 7.5x8.5 mm and neck measured 6 mm in width. Both the superior and inferior divisions of MCA were arising from the base of the aneurysm. He underwent left pterional craniotomy. At surgery, the MCA was seen to end in the aneurysm, which had a wide neck. Both the branches of MCA were seen to arise from the neck of the aneurysm. The aneurysm was dissected from its arachnoid adhesions, and MCA bifurcation was reconstructed using a 9 mm curved clip placed across the neck of the aneurysm sparing the origin of branches. The clip was placed parallel to the origin of branches rather than perpendicular to their origin to prevent kinking of the branches. Postoperatively, the patient improved well without any deficits. His dysphasia improved completely. Postoperative angiogram showed complete obliteration of the aneurysm (Figure 3 and 4).

DISCUSSION

The International Subarachnoid Aneurysm Trial (ISAT) concluded that in patients with ruptured intracranial aneurysms, endovascular coiling is more likely to result in Figure 2: Shows the pictorial representation of the method functionally independent status at one year when compared of aneurysm clipping. The clips have spared the origin of the with surgical clipping. However, the risk of rebleeding is perforator artery. definitely higher after coiling than clipping.1 In a subsequent subgroup analysis of patients aged 65 and above, the authors detected when she was being evaluated for possible stroke concluded that in good grade patients with anterior circula- due to transient right facial droop. On examination, she was tion aneurysms, endovascular therapy should be favored alert, oriented, and had no neurologic deficits. CT scan did over clipping, except in patients with MCA aneurysms not show any hemorrhage. Digital subtraction angiography (where clipping resulted in significantly better outcome at demonstrated a bilobed aneurysm measuring 9x7 mm with one year than coiling).7 a 4 mm wide neck located along the pre-bifurcation M1 seg- Traditionally, surgical clipping has been the standard of ment of M1. On close examination and on 3D reconstruction, care for MCA aneurysms. Endovascular therapy, although a small perforator was noted to arise from the neck of the initially considered to be a suboptimal option due to the aneurysm. At surgery, the aneurysm showed areas of ath- unfavorable morphology of these aneurysms, has evolved erosclerosis and two blebs on the dome suggestive of silent rapidly over the last few years. bleeds in the past. The perforator was seen to arise from the A recent study reported good outcome (GOS 5) in 70.5% neck of the aneurysm on the medial side. The aneurysm and favorable outcome (GOS 4 and 5) in 80 % of the patients.8 was dissected from the surrounding parenchyma to which Regli et al. first reported the results of endovascular it was attached, and the perforator located medial to the treatment of MCA aneurysms in 1999.9 In their series of 34 aneurysm was dissected. A 7 mm curved clip was applied unruptured MCA aneurysms, only 6% (n=2) were success- across the neck of the aneurysm not incorporating the ori- fully coiled with the GDC system. In 32%, the attempt at gin of the perforator artery. Then the aneurysm dome was coiling failed, and in 62%, there were anatomical contra- gently coagulated to shrink the aneurysm. Since the neck indications to coiling. The authors concluded that the two was atherosclerotic, a second clip was applied to reinforce major morphologic features that would predicate that an the first clip. Postoperative angiography showed complete MCA aneurysm was unsuitable for endovascular therapy obliteration of the aneurysm and good filling of the distal were a dome/neck ratio of 1.5 or less and an arterial branch vasculature. The perforator vessel was seen filling well in originating from the aneurysm neck. Although coil technol- the angiogram. At two-years follow-up, the patient is doing ogy has rapidly progressed since that first report by Regli well and has returned to work (Figure 1 and 2). et al., these angioanatomical features still have a role in determining the success of endovascular therapy. In another

164 J La State Med Soc VOL 166 July/August 2014 Figure 3: Shows the preoperative (a), (b), and (c) and postoperative (d) and (e) images of the patient with a wide neck right MCA bifurcation aneurysm with both the branches originating from the neck of the aneurysm. The aneurysm has been completely occluded and both of the branches are seen filling well in the postoperative angiogram.

series of stent-assisted coil embolization of unruptured MCA aneurysms, the authors reported that about 30% of MCA aneurysms referred for potential endovascular treatment were found to be unsuitable because of obscuration of the aneurysm neck on 3D images by MCA branches or by more proximal vessels (M1and ICA). Another contraindi- cation to coiling was the location of the aneurysm at MCA trifurcation instead of at MCA bifurcation.10 However, with the recent introduction of stent-assisted coiling techniques, flow-diverting stents, and the pCONus (Phenox GmbH, Bochum, Germany), there is a high possibility to overcome these anatomical difficulties which preclude endovascular therapy.11 In our series, the intraoperative rupture (IOR) rate was 4.8%. In patients with unruptured aneurysms, IOR was encountered in only one patient (2.2%). In none of these patients was IOR associated with an adverse treatment outcome (P>0.05). The overall treatment-related perioperative morbidity and mortality rates were 8% and 0.8%, respectively. The morbidity associated with surgical clipping of unruptured MCA aneurysms has been variously reported as being between 0.6% and 13.6%.9,12-20 In a systematic review of endovascular therapy for MCA aneurysms, the intraprocedural rupture rate in unruptured aneurysms has been reported as being 1.7% and 4.8% for ruptured aneurysms. Morbidity due to intraprocedural rupture and thromboenbolic complications was 0% and 4.2%, respectively in unruptured aneurysms and 1.2% and Figure 4: Shows the technique of clipping of the aneurysm, 2.4% for ruptured aneurysms. The overall morbidity and sparing the origin of both branches.

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mortality rates were 5.1% and 6% for ruptured and unrup- thromboembolic complications, lower rate of aneurysm tured aneurysms, respectively.21 These results indicate that obliteration, and a higher recanalization rate, recent develop- although periprocedural morbidity and mortality due to ments in endovascular therapy have improved the results.28 intraprocedural rupture during endovascular coiling is low, Management of complex MCA aneurysms with combined the overall morbidity and mortality is high due to the high microneurosurgical and endovascular techniques provides risk of thromboembolic complications. the best results.29 In our opinion, although microsurgical In our series, the immediate angiographic obliteration clipping carries better outcome following treatment of rate was 98% (n=98) and at one year was 97.7% (n=44 out MCA aneurysms, a combined team approach is required to of 45 patients). Brinjikji et al. reported an overall occlusion achieve optimal results, and the treatment modality should rate of 82.4% following endovascular therapy at immediate be individualized keeping in mind the various patient postoperative angiography. In his series, in 12.7% patients, and aneurysm factors. We suggest the following instances the aneurysm had been incompletely occluded and in 4.8%, where surgical clipping with or without revascularization the therapy had failed.21 At follow-up, 9.3% aneurysms in a patient with newly diagnosed MCA aneurysm may be had minor recurrence, and 9.5% aneurysms had significant considered as against endovascular therapy: recanalization requiring treatment. In other series’ of stent- 1. giant aneurysm (>25mm) assisted coiling, complete aneurysm occlusion rates were 2. incorporation of one of the branches or the parent 60.9% and 67%, and recanalization rates were 17% and 13%, vessel respectively.10,22 Additionally, in one study, the recanaliza- 3. aneurysm located at MCA trifurcation tion rate in MCA bifurcation aneurysms was 75% (mean 4. origin of a branch from the aneurysm follow-up duration 26.4 months).23 5. aneurysm of the M3 and M4 segment In the ISAT study, rebleeding occurred in 2.6% of pa- 6. associated hematoma causing significant mass tients who underwent coiling or attempted coiling and in effect 1% of those who underwent surgery or attempted surgery; this difference was found to be significant. The majority of CONCLUSIONS patients in both groups rebleed in the first month after treatment. However, this difference did not affect the outcome at Surgical clipping remains the standard of care for one year, and the endovascular group had a better outcome MCA aneurysms. Current data suggests that the aneurysm than the surgery group.24 When long-term follow-up was occlusion rate is lower; procedure-related morbidity and considered, there was a higher risk of recurrent bleeding recanalization rates are higher with endovascular therapy from a coiled aneurysm compared with a clipped aneurysm. for these aneurysms. Appropriate selection of patients and However, the risk of death at five years was significantly a team approach should be employed for optimal manage- lower in coiled group than it was in the clipped group.25 In ment of these aneurysms. the CARAT (Cerebral Aneurysm Rupture After Treatment), the annual rate of retreatment was 13.3% in the coiling group REFERENCES and 2.6% in the clipping group and the difference was significant (P<0.0001). In the second year, 4.5% patients in the 1. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold coiling group underwent retreatment, whereas no patient JA, et al. International subarachnoid aneurysm trial (ISAT) of in the clipping group underwent retreatment.26 It remains neurosurgical clipping versus endovascular coiling in 2143 to be determined whether the clinical outcome, obliteration patients with ruptured intracranial aneurysms: a randomised rate, rebleeding rate, and recanalization rate of MCA aneu- comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005 Sep rysms treated with endovascular therapy are maintained in 3-9;366(9488):809-17. long-term follow-up. Guresir et al. reported an obliteration 2. Regli L, Dehdashti AR, Uske A, de Tribolet N. Endovascular coiling rate of 98% in surgically clipped aneurysms vis-a-vis 68% compared with surgical clipping for the treatment of unruptured for coiled aneurysms in the time period between three and middle cerebral artery aneurysms: an update. Acta Neurochirurgica five years after treatment. They also noted that aneurysm Supplement. 2002;82:41-6. size > 15 mm was associated with aneurysm remnants after 3. Doerfler A, Wanke I, Goericke SL, Wiedemayer H, Engelhorn T, surgical treatment and “broad neck” and “unruptured sta- Gizewski ER, et al. Endovascular treatment of middle cerebral tus” were related to aneurysm remnants after endovascular artery aneurysms with electrolytically detachable coils. AJNR American Journal of Neuroradiology. 2006 Mar;27(3):513-20. treatment.27 In our series, we had 0% rebleed rate and 1.9% 4. Quadros RS, Gallas S, Noudel R, Rousseaux P, Pierot L. (n=1) recurrence rate at one-year follow-up. This patient Endovascular treatment of middle cerebral artery aneurysms as had a small residual neck on the postoperative angiogram first option: a single center experience of 92 aneurysms. AJNR and was followed-up. Angiogram repeated after one year American Journal of Neuroradiology. 2007 Sep;28(8):1567-72. revealed mild increase in the residual neck. The patient, 5. Hunt WE, Hess RM. Surgical risk as related to time of intervention however, opted for conservative management. At last in the repair of intracranial aneurysms. Journal of Neurosurgery. follow-up, 83.8% patients had a good outcome. 1968 Jan;28(1):14-20. Although the endovascular therapy for MCA aneu- 6. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. rysms is fraught with a higher risk of procedure-related Interobserver agreement for the assessment of handicap in stroke

166 J La State Med Soc VOL 166 July/August 2014 patients. Stroke. 1988 May;19(5):604-7. C5a and antibody in the release of heparan sulfate from endothelial 7. Ryttlefors M, Enblad P, Kerr RS, Molyneux AJ. International cells. European Journal of Immunology. 1991 Nov;21(11):2887-90. subarachnoid aneurysm trial of neurosurgical clipping versus 24. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton endovascular coiling: subgroup analysis of 278 elderly patients. J, et al. International Subarachnoid Aneurysm Trial (ISAT) of Stroke. 2008 Oct;39(10):2720-6. neurosurgical clipping versus endovascular coiling in 2143 8. Mortimer AM, Bradley MD, Mews P, Molyneux AJ, Renowden patients with ruptured intracranial aneurysms: a randomised SA. Endovascular Treatment of 300 Consecutive Middle Cerebral trial. Lancet. 2002 Oct 26;360(9342):1267-74. Artery Aneurysms: Clinical and Radiologic Outcomes. AJNR 25. Molyneux AJ, Kerr RS, Birks J, Ramzi N, Yarnold J, Sneade M, American Journal of Neuroradiology. 2013 Nov 14. et al. Risk of recurrent subarachnoid haemorrhage, death, or 9. Regli L, Uske A, de Tribolet N. Endovascular coil placement dependence and standardised mortality ratios after clipping compared with surgical clipping for the treatment of unruptured or coiling of an intracranial aneurysm in the International middle cerebral artery aneurysms: a consecutive series. Journal of Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurosurgery. 1999 Jun;90(6):1025-30. Neurology. 2009 May;8(5):427-33. 10. Fields JD, Brambrink L, Dogan A, Helseth EK, Liu KC, Lee DS, et 26. Investigators* TC. Rates of Delayed Rebleeding From Intracranial al. Stent assisted coil embolization of unruptured middle cerebral Aneurysms Are Low After Surgical and Endovascular Treatment. artery aneurysms. Journal of Neurointerventional Surgery. 2011 Dec Stroke. 2006 June 1, 2006;37(6):1437-42. 14. 27. Guresir E, Schuss P, Berkefeld J, Vatter H, Seifert V. Treatment 11. Mpotsaris A, Henkes H, Weber W. Waffle Y technique: pCONus results for complex middle cerebral artery aneurysms. A for tandem bifurcation aneurysms of the middle cerebral artery. prospective single-center series. Acta Neurochirurgica. 2011 Journal of Neurointerventional Surgery. 2013 Dec 20. Jun;153(6):1247-52. 12. Flamm ES, Grigorian AA, Marcovici A. Multifactorial analysis 28. Pierot L, Spelle L, Vitry F, investigators A. Immediate anatomic of surgical outcome in patients with unruptured middle cerebral results after the endovascular treatment of unruptured intracranial artery aneurysms. Annals of Surgery. 2000 Oct;232(4):570-5. aneurysms: analysis of the ATENA series. AJNR American Journal 13. Morgan MK, Mahattanakul W, Davidson A, Reid J. Outcome of Neuroradiology. 2010 Jan;31(1):140-4. for middle cerebral artery aneurysm surgery. Neurosurgery. 2010 29. Shi ZS, Ziegler J, Duckwiler GR, Jahan R, Frazee J, Ausman JI, et Sep;67(3):755-61; discussion 61. al. Management of giant middle cerebral artery aneurysms with 14. Moroi J, Hadeishi H, Suzuki A, Yasui N. Morbidity and mortality incorporated branches: partial endovascular coiling or combined from surgical treatment of unruptured cerebral aneurysms at extracranial-intracranial bypass--a team approach. Neurosurgery. Research Institute for Brain and Blood Vessels-Akita. Neurosurgery. 2009 Dec;65(6 Suppl):121-9; discussion 9-31. 2005 Feb;56(2):224-31; discussion -31. 15. Rinne J, Hernesniemi J, Niskanen M, Vapalahti M. Analysis of 561 patients with 690 middle cerebral artery aneurysms: anatomic and clinical features as correlated to management outcome. Drs. Nanda, Ambekar, and Sharma are with the Department of Neurosurgery. 1996 Jan;38(1):2-11. Neurosurgery, Louisiana State University Health Sciences Center in 16. Deruty R, Pelissou-Guyotat I, Mottolese C, Amat D. Management Shreveport, Louisiana. of unruptured cerebral aneurysms. Neurological Research. 1996 Feb;18(1):39-44. 17. Nanda A, Vannemreddy P. Surgical management of unruptured aneurysms: prognostic indicators. Surgical Neurology. 2002 Jul;58(1):13-9; discussion 9-20. 18. Niskanen M, Koivisto T, Rinne J, Ronkainen A, Pirskanen S, Saari T, et al. Complications and postoperative care in patients undergoing treatment for unruptured intracranial aneurysms. Journal of Neurosurgical Anesthesiology. 2005 Apr;17(2):100-5. 19. Nussbaum ES, Madison MT, Myers ME, Goddard J. Microsurgical treatment of unruptured intracranial aneurysms. A consecutive surgical experience consisting of 450 aneurysms treated in the endovascular era. Surgical Neurology. 2007 May;67(5):457-64; discussion 64-6. 20. Aghakhani N, Vaz G, David P, Parker F, Goffette P, Ozan A, et al. Surgical management of unruptured intracranial aneurysms that are inappropriate for endovascular treatment: experience based on two academic centers. Neurosurgery. 2008 Jun;62(6):1227-34; discussion 34-5. 21. Brinjikji W, Lanzino G, Cloft HJ, Rabinstein A, Kallmes DF. Endovascular treatment of middle cerebral artery aneurysms: a systematic review and single-center series. Neurosurgery. 2011 Feb;68(2):397-402; discussion 22. Zhou Y, Yang PF, Fang YB, Xu Y, Hong B, Zhao WY, et al. Endovascular treatment for saccular aneurysms of the proximal (M1) segment of the middle cerebral artery. Acta Neurochirurgica. 2012 Oct;154(10):1835-43. 23. Platt JL, Dalmasso AP, Lindman BJ, Ihrcke NS, Bach FH. The role of

J La State Med Soc VOL 166 July/August 2014 167 Journal of the Louisiana State Medical Society

Firearm-Related Mortality, Louisiana 1999-2010

Susanne Straif-Bourgeois, PhD, MPH; Raoult Ratard, MD, MS, MPH&TM

This report is a purely descriptive study of firearm-related deaths occurring in Louisiana from 1999 to 2010. Mortality data were collected from death certificates from this 12-year period to describe firearm fatalities by year, race, gender, age group, and manner of death (accident, homicide, suicide). Louisiana data were also compared to national data. Race, sex, and age were important factors influencing mortality rates and the death manner. Rates were higher in males than in females and higher in African-Americans than in Whites. The highest rates were observed for homicides among African-American males. The ratio of Louisiana age/race-adjusted firearm mortality rates over the US rates were 1.8. Both Louisiana and the US mortality rates remained fairly constant over the 12-year period. Parish level data showed a wide variation in firearm mortality rates with some urban and some rural parishes having the highest rates. Data obtained from death certificates have limitations due to the limited number of variables available.

INTRODUCTION divided in three subgroups according to the type of firearm: Handgun (H); rifle, shotgun, and larger firearm discharge Firearm-related deaths are a significant public health (L); and other or unspecified firearm (O). Data on the type problem. They are the second leading cause of injury deaths of firearm (“handgun” or “rifle, shotgun, and larger firearm after deaths due to motor vehicle accidents in the United discharge” were not analyzed since most were categorized States (US). The Center for Disease Control and Prevention as “other or unspecified firearm”). (CDC) estimates that about 33,000 Americans die each year The age groups selected were increments of five-year from firearms. Younger age groups are affected dispropor- age groups, except for the first group (ages less than nine tionately.1 One of the goals of “Healthy People 2010,” an years old), and in all, there were 17 age groups. In order to initiative from the Department of Health and Human Ser- make the description of the manners of deaths (accident, vices to improve the health of Americans, is to reduce the homicide, and suicide) more simple, five age groups were current firearm annual mortality rate from 10.3 per 100,000 used for that section. to 4.9 per 100,000. The goal of this study is to describe the The trend analysis comparing Louisiana, the United basic epidemiologic features of firearm deaths in Louisiana, States, and the parish level rates included all races. Since understand the pattern by age, sex, and race, evaluate the the large majority of cases were among Whites (W) and trend over a 12-year period, compare the situation of Loui- African-Americans (AA), any detailed analysis by race was siana and that of the United States as a whole, and provide limited to these two race groups. a basis to future studies. The data were extracted to a database and tabulated using SQL queries. Average age-group-specific mortality rates POPULATION AND METHODS (per 100,000) were calculated for the entire 12-year period weighted for the population of each age group in each year. Mortality data were collected from Louisiana death To depict the trends of mortality rates over the 12-year span certificates for the 12-year period from 1999 to 2010. The between Louisiana and the United States, an age-adjusted International Classification of Diseases (ICD) 10 Codes listed mortality rate was calculated (US 2000 standard population, in Table 1 were used for data extraction. One of these codes all races, both sexes). had to be present among the first eight causes of death to be The basic statistical tests were performed using Win- included in this study. All of the firearm deaths were listed PEpi downloaded in 2013. as the first cause of death except for 18 of the 9,722 deaths included. For further analysis, the causes of death were • For comparison of each race, sex, and age group grouped in three categories (with the descriptive “Manner stratum, a crude rate ratio and an Upton x2 were of death” used on the death certificate) shown on Table 1: used, and for all strata a Mantel-Haenszel x2 esti- Accident, Suicide, and Homicide. Each manner of death was

168 J La State Med Soc VOL 166 July/August 2014 Table 1: Classification of Causes of Death by Type Code Cause of Death Death Manner W32 Handgun discharge Accident W33 Rifle, shotgun and larger firearm discharge Accident W34 Discharge from other and unspecified firearms Accident X72 Intentional self-harm by handgun discharge Suicide X73 Intentional self-harm by rifle, shotgun, and larger firearm discharge Suicide X74 Intentional self-harm by other and unspecified firearm discharge Suicide X93 Assault by handgun discharge Homicide X94 Assault by rifle, shotgun, and larger firearm discharge Homicide X95 Assault by other and unspecified firearm discharge Homicide Y350 Legal intervention involving firearm discharge Homicide Y364 War operations involving firearm discharge and other forms of Homicide

Table 2: Annual Mortality Rates per 100,000 Persons by Age Group, Race, and Sex for Louisiana, 1999-2010 Males Females Age AAM WM AA/W Upton p-Value AAF WF AA/W Upton p-Value Group Chi Chi 0-9 1.8 0.9 2.0 5.3 0.020 0.7 0.5 1.50 0.9 0.350 10-14 4.2 2.4 1.8 5.4 0.020 1.2 0.9 1.27 0.3 0.580 15-20 69.2 16.8 4.1 124.7 0.000 9.0 3.3 2.69 23.3 0.000 20-24 153.6 31.6 4.9 850.7 0.000 13.3 5.2 2.55 35.7 0.000 25-29 155.0 30.3 5.1 814.9 0.000 13.4 7.2 1.85 16.2 0.000 30-34 95.9 29.2 3.3 334.2 0.000 9.2 6.5 1.43 4.4 0.030 35-39 99.7 24.6 4.0 401.4 0.000 7.9 8.3 0.95 0.1 0.770 40-44 39.4 24.1 1.6 34.5 0.000 6.0 7.9 0.76 2.2 0.134 45-49 35.8 29.5 1.2 4.7 0.020 4.2 7.1 0.59 5.8 0.010 50-54 29.4 27.5 1.1 0.4 0.510 2.9 7.0 0.41 10.1 0.002 55-59 25.8 31.5 0.8 2.3 0.120 2.8 7.2 0.39 8.4 0.004 60-64 16.2 26.4 0.6 9.1 0.003 2.7 5.6 0.48 3.8 0.050 65-69 17.3 26.0 0.7 4.4 0.030 2.8 4.5 0.63 1.3 0.250 70-74 19.8 30.0 0.7 4.5 0.040 1.3 3.8 0.36 1.3 0.070 75-79 17.2 64.4 0.3 32.8 0.000 2.9 3.5 0.83 3.1 0.710 80-84 17.9 55.6 0.3 14.6 0.000 1.7 3.9 0.44 2.1 0.260 85+ 17.5 59.4 0.3 13.8 0.000 1.6 2.1 0.80 1.3 0.770 Total 52.0 23.3 2.2 1.36 0.000 5.4 5.0 1.08 0.93 0.330

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mator of the ratio was used, • For the trend analysis, a Cochran- Armitage trend was calculated.

RESULTS

Number and rates of deaths by race, sex, and age groups During the 12-year period, there were a total of 9,722 firearm-related deaths. There were large discrepancies by race, sex, and age group. Whites (W) and African-Americans (AA) represented the large majority of deaths (9,632 deaths out of a total of 9,722 deaths, i.e 99% of all cases). There were only 91 other deaths, including 52 Asian males, 16 Asian females, 10 American/Indian males, 3 American/Indian females, and 9 Figure 1: Annual firearm death rate by age group, sex, and race in Louisiana, 1999-2010. males and 1 female of unspecified race. Key: AAM=African-American Male; WM=White Male; AAF=African-American Female; Mortality rates are presented WF= White Female in Table 2 and Figure 1. There were major differences by age group, race, and sex. Overall, the annual mortality rates per 100,000 were 52.0 for AA males, 23.3 for W males, 5.4 for AA females, and 5.1 for W females. The comparison between AA females and W females shows a crude rate ratio of 1.08 (Upton x2 =0.938, p=0.33). A comparison for each age group shows that rates are significantly higher among AA females up to age 34, then show no significant difference from 35 to 44 and, from age 45 onward, rates are higher among white females (overall stratified Mantel-Haenszel estimator of the ratio 1.11, MHx2=3.42, p=0.06). There are important differences between rates observed in AA males (overall rate 52.0) and W males (23.3). The crude rate ratio is 2.22, (Upton x2 =1,368; p<0.0001). Figure 2: Age-adjusted* firearm death rate (per 100,000 population) United States (US) A pattern similar as that observed and Louisiana (LA), 1999-2010. between females is observed among the two male groups, but with a *US 2000 Standard Population, all races, both sexes wider difference. Up to age 44, the rates among AA males are two to five times higher than for W; then from age 45 to 54, the rates are practically equal between AA and W; finally above age 55 the W males

170 J La State Med Soc VOL 166 July/August 2014 have higher rates than AA (overall stratified Mantel-Haenszel estimator of the ratio 2.09, MHx2=1,111.9, p=0.000).

Trends over the 12-year period The average number of deaths per year was 810, with a range from 599 to 915 (Fig- ure 2). The average age-adjusted rate is 18.6 per 100,000 in Louisiana versus 10.2 for the United States, a ratio of 1.8 with a narrow range of 1.7 to 1.9. While the age-adjusted mortality rate for the United States is fairly constant at 10.3 per 100,000, the trend for the Louisiana population is very slightly increasing over this 12-year period (y=0.1016x + 17.901 (Cochrane-Armitage test for linear trend: x2 = 0.00 [DF: 1] P = 0.985). Trends by sex and race are presented in Figure 3: Age-adjusted* firearm death rate (per 100,000 population) by race and Figure 3. There was no significant increase sex. over time that could be detected in any of these groups. The Cochrane-Armitage test Key: AAM=African-American Male; WM=White Male; AAF=African-American for linear trends are for African-American Female; WF= White Female males x2=0.48, p=0.49; for African-Amer- ican females x2=0.06, p=0.81; for White *US 2000 Standard Population, all races, both sexes males x2=0.14, p=0.71; and for White females x2=0.0, p=0.98.

Distribution of manners of death by race, sex, and age group There were 5,176 deaths by homicide, 4,112 by suicide, and 416 by accident. There were also 44 deaths due to “legal intervention involving firearm discharge,” and there were no deaths due to “war operations involving firearm discharge and other forms.” Rates per 100,000 population are presented in Table 3. Over the 12-year span, there were differences in mortality rates among accidental (0.8/100,000), suicidal (8.0), and homicidal (18.9) deaths. The rate ratio suicide/ accident =9.84 (Upton x2=3008, p<0.0001), homicide/accident = 12.2 (Upton x2=3981, p<0.0001), and homicide/suicide = 1.24 (Upton x2=108, p<0.0001). Accidental mortality rates were low in male children <15 years old at 0.7 for AAM Figure 4: Mortality rates for accidental firearm deaths by race, sex, and age group and for WM (rate ratio = 1.1, Upton x2=0.08, in Louisiana, 1999-2010. p=0.77) and even lower in female children at 0.2 for AAF and 0.1 for WF (rate ratio = Key: AAM=African-American Male; WM=White Male; AAF=African-American 1.4, Upton x2=0.24, p=0.62). But the rate Female; WF= White Female ratio between M and F was 4.8 (rate ratio = 4.8, Upton x2=19.9, p<0.0001). The rates remained low for females throughout the age group. For males, the rates increased in the older age groups to stay around 2.0 with

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Table 3: Mortality Rates Per 100,000 Persons by Race, Sex, and Age Group and Manner of Deaths, Louisiana, 1999-2010 Accidents Homicide Suicide

AAM WM AAF WF All AAM WM AAF WF All AAM WM AAF WF All

0-14 0.7 0.7 0.2 0.1 0.4 1.8 0.4 0.7 0.4 0.8 0.2 0.4 0.0 0.1 0.2

15-19 2.5 2.2 0.2 0.3 1.4 65.9 4.0 7.0 1.1 17.6 3.7 14.5 0.5 1.9 5.8

20-39 2.4 1.6 0.3 0.3 1.1 117.8 7.7 10.3 2.7 22.9 12.5 20.4 1.0 4.0 10.2

40-74 0.9 1.4 0.1 0.3 0.8 21.7 4.3 3.2 1.6 5.4 8.0 22.6 0.6 4.9 10.8

75+ 2.8 1.6 0.0 0.1 0.8 5.5 0.9 1.9 1.3 1.5 9.6 29.3 0.0 2.0 12.4

Total 1.5 1.4 0.2 0.3 0.8 45.3 4.3 4.9 1.6 10.0 6.4 17.7 0.5 3.3 8.0 minor variations (see Figure 4). For ages above 15 years, the rate ratio AAM/WM =1.17 (Upton x2=1.17, p=0.19). Homicide rates are presented in Figures 5A and 5B. The extremely high rates among the AAM 20-39 age group mortality rate at 117.8 dwarfed all other rates. To better display the differences between other rates, Table 5B displays them with a logarithmic scale on the y axis. The rate ratio between AAF (4.9) and WF (1.6) were 3.0 (Upton x2=226, p<0.0001). For males, the rate ratio between AAM (45.3) and WM (4.3) was obviously very significant (rate ratio 10.6, Upton x2=5,218, p<0.0001). Suicide rates per 100,000 among children <15 years old were very low (less than 0.5). For all females, rates Figure 5A: Mortality rates for homicidal firearm deaths by race, sex, and age group in increased slowly to reach their highest Louisiana, 1999-2010. in the 40 to 74 age group and then de- Key: AAM=African-American Male; WM=White Male; AAF=African-American creased. Suicide rates were much higher Female; WF= White Female among WF than among AAF (rate ratio 6.4, Upton x2=194, p<0.0001). For AAM 100,000. Other parishes with rates higher than 16/100,000 they remained low, with a high at 12.5 in the 20-39 age were either large urban parishes (Caddo 8.9, East Baton group. For WM, the peak was reached in the 75+ age group Rouge 18.2, Jefferson 16.7) or small rural parishes (East at 29.3. Suicide rates were also much higher among WM Carroll 24.9, Washington 19.4, Evangeline 19.0, St. Helena than among AAM (rate ratio 2.8, Upton x2=501, p<0.0001). 18.0, Madison17.1, Claiborne 16.6). There were only 44 deaths in the category “Legal intervention involving firearm discharge.” Only one WM in the DISCUSSION age group 15 to 19 years, 12 AAM and 17 WM in the age group 20-39, 6AAM and 8 WM in the age group 40-74, and The data have shown that race, sex, age, and whether none among females. deaths were due to accident, suicide, or homicide were important variables when describing mortality rates by Parish level data firearms in Louisiana. Because this descriptive study was Parish firearm mortality rates reflect the influence of the done from death certificates only, no other risk factors were important variables already identified: composition of the available for exploring the specific reasons for these distribu- population by race, sex, and age group and other variables tion patterns. The literature shows that another risk factor (poverty, crime levels…) that could not be identified from for firearm-related homicide is living in a poor urban area. the limited data included in the death certificates. Getting involved in gang-related urban violence partially Parish mean annual mortality rates from firearms explains the high mortality rates among juveniles and young ranged from 6.9 to 38.8/100,000. The distribution of parish adult males.3-5 Availability of unsecured guns in the home mean annual rates are displayed in Figure 7. Orleans Parish is also a risk factor to be considered. had the highest annual firearm related death rate at 38.8 per Large discrepancies were also observed among Loui-

172 J La State Med Soc VOL 166 July/August 2014 siana parishes. There seems to be two patterns for high firearm mortality rates. The first pattern includes urban areas with a concentration of poor living conditions such as in Orleans, East Baton Rouge, and Caddo parishes. Orleans Parish firearm-related death rate is the highest in Louisiana, more than twice as high as in East Baton Rouge and Caddo Parishes. According to census data, more than 25% of Orleans Parish residents live below the poverty level compared to 18.4% in Louisiana as a whole.6 The second pattern includes rural areas which have been much less studied than urban areas. Firearm mortality rates observed in Louisiana are consistently higher than those observed in the United States, even Figure 5B: Mortality rates for homicidal firearm deaths by race, sex, and age group in after adjusting for race, sex, and age Louisiana, 1999-2010, logarithmic scale. distribution. Key: AAM=African-American Male; WM=White Male; AAF=African-American Mortality data are easily acces- Female; WF= White Female sible and very useful for the purpose of describing the magnitude of a public health problem in specified populations and trends over time. However, firearm-related mortality data have some serious limitations. Data on homicides might be underreported since at time of filling out the death certificate, the criminal investigation often is still ongoing. Data on suicide death might be underreported because of stigma of this manner of death.7 Another limitation is that mortality data only describe the tip of the iceberg. Data based on emergency department visits estimate that about two-thirds of firearm-related injuries are non-fatal and makeup the majority of firearm violence.8 The likelihood of dying from a gunshot wound also depends on the intent of the person using the weapon; case fatality rates for firearm injuries range from 20% for homicides and to 80% for suicides.2 Figure 6: Mortality rates for suicidal firearm deaths by race, sex, and age group in Louisiana, 1999-2010. REFERENCES

Key: AAM=African-American Male; WM=White Male; AAF=African-American 1. Center for Disease Control and Female; WF= White Female Prevention WISQARS database. Available at: http://www.cdc.gov/ncipc/wisqars. Accessed April 2013. 2. Firearm injury in the U.S. (2009). Firearm & Injury Center at Penn. Available at: http://www.uphs.upenn.edu/ficap. Last accessed April, 2013. 3. Bjerregaard, B; Lizotte A. Gun Ownership and Gang Membership. Journal of Criminal Law and Criminology. 1995;86:37–58.

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Figure 7: Distribution of firearm mortality rates per 100,000 by parish in Louisiana, 1999-2010.

4. Wright, J; Sheley, J; Smith MD. Kids, Guns, and Killing Fields. Society. 1993;30. 5. Dahlberg, L; Ikeda R ; Kresnow M. Guns in the Home and Risk of Violent Death in the Home: Findings from a National Study. Am. J. Epidemiol. 2004;160:929-936 6. Census data for Orleans Parish. Available at http://quickfacts. census.gov/qfd/states/22/22071.html. Accessed April 2013. 7. Straif-Bourgeois, S: Suicide Mortality Rates in Louisiana, 1999 – 2010. J Louisiana State Medical Society. 2012;164:274-282. 8. CDC (2001). Surveillance for Fatal and Nonfatal Firearm-Related Injuries – Unites States, 1993 – 1998. MMWR Surveillance Summaries 50 no SS-2.

Dr. Straif-Bourgeois is with the School of Public Health at Louisiana State University Health Sciences Center in New Orleans. Dr. Ratard is with the Infectious Disease Epidemiology Section, Office of Public Health, Louisiana Department of Health and Hospitals.

174 J La State Med Soc VOL 166 July/August 2014 Protecting the Private Practice of Medicine: We Need More Data

Sabrina L. Noah

When we last checked in with Dr. Joshua Lowentritt those patients with chronic ambulatory conditions who are of New Orleans and his Accountable Care Organization high utilizers of healthcare services. Each practice will be (ACO), Louisiana Physicians ACO, they were just turn- able to identify patterns of behavior and areas for improve- ing on the proverbial lights. Since our first editorial piece, ment. It is in the best interest of the patient and the ACO “Protecting the Private Practice of Medicine, Louisiana’s to come up with strategies to improve the quality of care First Physician-Owned Accountable Care Organization,” and health outcomes for all patients. Lowentritt pointed Lowentritt and his 35 independent physician partners have out that, with the complex patients, “much of the decision- been busy laying the foundation of their new organization. making had been left to non-physicians” when it came to An ACO, as you might remember, is a physician-managed care coordination. This model provides each physician with health organization comprised of physicians, nurses, and “incentive to change the way they provide care, to make care coor¬dinators who share the responsibility of providing a difference for the patient, and ultimately help keep our quality, financially responsible, coordinated care. medical safety net solvent,” he added. Some of the first items needed to As we mentioned previously, the cornerstone of mak- get the ACO running included uni- ing the model a success is the link between the quality of versally agreed upon treatment plans care provided and the economic incentive to save the entire and protocols for all of the clinics to system money. In an ACO, a high quality of care leads to follow. These policies and procedures lower utilization, and a lower level of utilization increases were drafted by consensus with input the financial reward for the ACO and physician owners. But from each physician, allowing each the lynchpin is that the physicians are directly involved or practitioner to share his or her opinions responsible for that higher quality of care. Therefore, the and experiences. Lowentritt stressed more they put into the system, the more they get out. And that an important goal of the first few furthermore, Lowentritt strongly believes that this system months was to “allow each medical “creates an incentive for physicians to keep engaged” in not Dr. Joshua practice complete management over just the short-term success of lower utilization but long-term Lowentritt their operation, while building in positive health outcomes of each patient. standardized quality and assurance The first few months of the Louisiana Physicians ACO measurements” that would help create has shown that the ACO model can create a better, more uniformity within the ACO. As we discussed in our first sustainable workplace for physicians. Lowentritt reported editorial, the cornerstone of an ACO is the independent that his ACO’s 35 physicians “feel engaged and interested.” practitioner. When it came to laying the foundation of how For the first time in a long time, a physician has complete this ACO would operate on a day-to-day basis, no decision control over all aspects of a patient’s treatment. Further, he was made without the utmost consideration for each phy- reports increased satisfaction because physicians are able to sician to “work collaboratively within the ACO but retain “monitor and review their referral patterns and the patient’s their independence,” emphasized Lowentritt. ultimate health outcome” to see what is or is not working. The most crucial step in the first few months was the The ability to unilaterally access all claims data is incredibly delivery of the Centers for Medicare & Medicaid (CMS) significant in the modern practice of medicine; Lowentritt data set on the 5,600 patients attributed to the ACO. This compared it to no longer practicing medicine in the dark. It’s data contains the patients’ medical records, cost data, and most telling that when asked how the first six months have a resource utilization score assigned by CMS. According to gone, he replied, “I’m having fun!” If the first few months Lowentritt this data “is the key to the ACO’s success.” The are representative of the path Louisiana Physicians ACO is next few months will be busy as the ACO physicians focus on, the future of managed care could be looking up. on extracting and evaluating the data to better understand their patients and their individual needs. Not only does this data help “set a baseline for the ACO, it helps determine the areas that are opportunities for improvement,” he added. The next step will be to use that data to better manage

J La State Med Soc VOL 166 July/August 2014 175 Journal of the Louisiana State Medical Society ECG of the Month

Out-of-Hospital Cardiac Arrest

Stephanie C. El Hajj, MD; Curley J. Bordelon, MD; D. Luke Glancy, MD

A muscular-appearing 50-year-old man was found down in his home by family members. Paramedics documented pulseless electrical activity and began cardiopulmonary resuscitation that included placement of an endotracheal tube. The resuscitation was continued in the hospital emergency department (ED), and after 20 minutes, an arterial pulse returned. An electrocardiogram (ECG) was obtained (Figure 1). Meanwhile, a past history established that the patient was a personal trainer who seemed fit and healthy until 10 days earlier, when he came to the ED because he had begun to lose his balance and fall frequently. Computed tomography (CT) at that time revealed lytic lesions in the fifth lumbar vertebra and extensive retroperitoneal lymphadenopathy involving the aortic, iliac, and obturator chains and the perirectal region. Arrangements had then been made for outpatient workup of a presumed malignancy.

Figure 1: Electrocardiogram recorded in the emergency department. See text for explication.

What is your diagnosis?

Explication is on p. 177

176 J La State Med Soc VOL 166 July/August 2014 ECG of the Month Table 1: Some risk factors for pulmonary embolism Presentation is on p 176. Prior venous thromboembolism DIAGNOSIS: Atrial fibrillation with a rapid ventricular Hypercoaguability Acute trauma response (150 beats/minute) and right bundle branch block. Hip or knee replacement Other major operation The list of causes of systemic arterial hypotension is Paralysis long and in this patient, should take into account his prior Hospitalization good health, the absence of legal or illegal drugs, the recent Other prolonged immobilization discovery of what appears to be a widespread malignancy, Malignancy the profound nature of the hypotension, and the changes on Autoimmune disease ECG. Although the first manifestation of coronary arterial Venous endothelial injury disease can be a large myocardial infarct with profound Indwelling venous catheter or pacemaker lead hypotension, there is nothing in this ECG to indicate a large Heart failure acute infarct. Pericardial metastases can produce atrial fibril- Atrial fibrillation lation, cardiac tamponade, and profound hypotension; but Myocardial infarction no pericardial effusion was noted on CT 10 days earlier, and Estrogenic medications the ECG does not suggest pericarditis. Malignancy is a major Pregnancy risk factor for pulmonary emboli (Table 1),1-7 and pulse- Cigarette smoking less electrical activity, atrial fibrillation, and right bundle Obesity branch block are among the ECG changes seen in patients Advanced age with pulmonary embolism (Table 2). Although pulmonary emboli may not affect the ECG, the number and severity of As is often the case, the echocardiogram provided the abnormalities listed in Table 2 roughly correlate with crucial information: right ventricular pressure overload the degree of right ventricular dysfunction, which in turn and a severely dilated and hypokinetic right ventricle with is related to the extent of the pulmonary arterial obstruc- preserved right ventricular apical contraction, i.e., McCon- 15 tion.1,7-14 Sinus tachycardia, non-specific ST-segment change, nell’s sign, characteristic of extensive pulmonary emboli. and anterior T-wave inversion are the changes found most The left ventricle was hyperdynamic and underfilled, frequently in patients with hemodynamically significant consistent with obstructive shock. CT revealed multiple pulmonary emboli.1,2,8 bilateral pulmonary emboli as the cause of the obstructive

Table 2: Electrocardiographic abnormalities in pulmonary embolism Rhythm Sinus tachycardia Atrial flutter, fibrillation, or premature complexes Right ventricular (RV) premature complexes Ventricular fibrillation Pulseless electrical activity Sinus bradycardia or asystole (rarely) P waves Rightward axis (>75o) Tall (>2.5 mm) in leads II, III, or a VF QRS complex Right axis deviation or rightward axis shift Clockwise rotation RV conduction delay or R bundle branch block Right ventricular hypertrophy Inferior, anterior, and/or RV pseudoinfarction 1 S1Q3T3 pattern of McGinn and White Left axis deviation (rarely) ST segment Elevation inferiorly and/or anteriorly Depression T wave Inversion inferiorly Inversion anteriorly QT prolongation

Modified from references 8, 14

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Figure 2: Computed tomographic angiogram of the chest performed soon after admission shows multiple bilateral pulmonary arterial filling defects consistent with extensive pulmonary arterial embolization.

shock (Figure 2). ECG on admission in patients with acute major pulmonary The patient was declared brain dead the day after embolism. Eur Respir J 2005; 25:843-848. admission. At the request of the family, support was with- 10. Panos RJ, Barish RA, Whye DW Jr, et al. The electrocardiographic drawn, and the patient expired soon thereafter. Autopsy manifestations of pulmonary embolism. J Emerg Med 1988; 6:301- 307. revealed diffuse intra-abdominal malignant lymphoma. 11. Ferrari E, Imbert A, Chevalier T, et al. The ECG in pulmonary embolism. Chest 1997;111:537-543. REFERENCES 12. Ullman E, Brady W, Perron A, et al. Electrocardiographic manifestations of pulmonary embolism. Am J Emerg Med 1. McGinn S, White PD. Acute cor pulmonale resulting from 2001;19:514-519. pulmonary embolism: its clinical recognition. JAMA 1935;104:1473- 13. Chan CT, Vilke GM, Pollack M, et al. Electrocardiographic 1480. manifestations: pulmonary embolism. J Emerg Med 2001;21:263- 2. Stein PD, Saltzman HA, Weg JG. Clinical characteristics of patients 270. with acute pulmonary embolism. Am J Cardiol 1991; 68:1723-1724. 14. Glancy DL, Mikdadi GM. Syncope in a 67-year-old man. BUMC 3. Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of Proceedings 2005;18:74-75. risk factors for deep vein thrombosis and pulmonary embolism: 15. McConnell MV, Solomon SD, Ryan ME, et al. Regional right a population-based study. Arch Intern Med 2002;162:1245-1248. ventricular dysfunction detected by echocardiography in acute 4. Darze ES Latado AL, Guimaraes AG, et al. Incidence and clinical pulmonary embolism. Am J Cardiol 1996;78:469-473. predictors of pulmonary embolism in severe heart failure patients admitted to a coronary care unit. Chest 2005;128:2576-2580. 5. Zöller B, Li X, Sundquist J, et al. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up Drs. El Hajj and Bordelon are Residents in the Louisiana State study from Sweden. Lancet 2012;379:244-249. University Internal Medicine Program in Baton Rouge. Dr. Glancy is 6. Goldhaber SZ, Grodstein F, Stampfer MJ, et al. A prospective a Professor of Medicine at the LSU Health Sciences Center in New Orleans. study of risk factors for pulmonary embolism in women. JAMA 1997;277:642-645. 7. Kucher N, Goldhaber SZ. Recent advances in the diagnosis and treatment of pulmonary thromboembolism. ACC Current Journal Review; Nov/Dec 2003:28-32. 8. Brugada P, Gorgels AP, Wellens HJJ. The electrocardiogram in pulmonary embolism. In Wellens HJJ, Kulbertus HE, eds. What’s New in Electrocardiography. The Hague: Martinus Nijhoff;1981:366-380. 9. Geibel A, Zehender M, Kasper W, et al. Prognostic value of the

178 J La State Med Soc VOL 166 July/August 2014 Radiology Case of the Month 55-Year-Old Female With Shortness of Breath and Cough

Arielle Bauer; David Manning, MD; Harold Neitzschman, MD, FACR, FACNM, FAAP

A 55-year-old African-American woman presents with progressive shortness of breath, non-productive cough, and muscle aches for two weeks. Her medical history is non-contributory. She is a current smoker with a 20-year history of smoking one pack per day. Vital signs and oxygen saturation are normal. Physical exam reveals crackles over the right middle lobe of her lung. The remainder of her physical exam is unremarkable. Blood tests demonstrate a mild leukocytosis.

Figure 2a and 2b: Axial computed tomography (above) and coronal reconstruction (bottom) demonstrate innumerous cysts Figure 1: Posteroanterior chest radiograph demonstrates of varying sizes with few interspersed scattered nodules. There diffuse reticulononodular changes and subtle cysts with relative is relative sparing of the lung bases and subpleural spaces. sparing of the lung bases.

J La State Med Soc VOL 166 July/August 2014 179 Journal of the Louisiana State Medical Society

DISCUSSION function tests can show an obstructive, restrictive, or mixed pattern. Vital capacity is often low, and residual volume is Pulmonary Langerhans Cell Histiocytosis (PLCH) is a often normal or increased, leading to a total lung capacity rare lung disease caused by the accumulation of inflamma- that is relatively normal.8 tory cells in small airways of the lung, leading to nodular In most adult patients, LCH affects only the lungs.3 granulomatous changes of the lung parenchyma, which However, the most likely extrapulmonary findings in PLCH over time, progress to reticular and cystic changes. There are cystic bone lesions, diabetes insipidus (DI), and skin le- are no data regarding the overall prevalence of PLCH in the sions.4 Patients should be carefully examined for these other adult population. However, two series of patients under- signs with a skeletal survey and physical exam if diagnosed going lung biopsy for diffuse interstitial disease reported with PLCH. PLCH in 3%-5% of all diffuse lung disease biopsies, in PLCH is not typically a strictly nodular or cystic disease comparison with sarcoidosis, which was found in 12.5% of but a spectrum of varying degrees of granulomatous nodular the same patients.1,2 It has been hypothesized that PLCH is changes, which predominate earlier in the disease process likely underdiagnosed because it can be asymptomatic and and cystic changes which predominate later in the disease sometimes undergoes spontaneous remission.3 process.3,6,9,10 Brauner proposed that the initial nodules The incidence of PLCH peaks in young adults between eventually cavitate, leading to thick-walled cysts, which ages 20-40.4 Gender distribution of PLCH has recently been then mature to thin-walled and ultimately confluent cysts.9,10 shown to be equal. As the rates of smoking between men Imaging is fundamental for diagnosis of PLCH, as and women have evened out over the past few decades, so symptoms are non-specific. Early nodular PLCH is charac- has the incidence of the disease.3,5 terized by radiography, computed tomography (CT), and PLCH is strongly associated with smoking tobacco high-resolution CT as bilateral mid- to upper-lung zone cigarettes. More than 90% of adult patients are smokers.6,7 distribution of pulmonary nodules with relative sparing of It has been suggested that cigarette smoke may irritate the the lung bases, especially the costophrenic sulci, and normal small airways, leading to injury and inflammation.7 to increased lung volumes. The nodules are typically irregu- Langerhans cells are a subgroup of antigen-presenting larly marginated, 1 to 10 mm in size, and can range from dendritic cells found in the skin and in the epithelium of the a few scattered nodules to innumerous and/or confluent tracheobronchial tree. Their normal function is to survey nodules. A chest radiograph is the initial imaging modality antigens that are deposited in the airway during inhala- of choice; however, high-resolution CT (HRCT) is markedly tion. Activation of Langerhans cells leads to a cascade of more sensitive and specific for PLCH.3,6,9 signaling, leading to an adaptive immune response. PCLH The differential diagnosis for nodular PLCH includes is characterized by peribronchiolar proliferation of Langer- sarcoidosis, silicosis, metastasis, and hematogenous infec- hans cells, forming stellate nodules that cavitate and form tious processes such as military tuberculosis. HRCT is cysts. The advanced disease is characterized by scarring of utilized to narrow the diagnosis by distinguishing the cen- airways and pulmonary vascular remodeling. trilobular distribution of PLCH nodules from the periphym- The etiology of PLCH is poorly understood. It has been phatic distribution of sarcoidosis, silicosis, and lymphangitic proposed that PLCH is an immune response to an unknown carcinomatosis.6,9 antigen, leading to T-cell activation. The unknown antigen Cystic lesions of PLCH can also be difficult to distin- likely is related to cigarette smoking. However, there are also guish from bullous emphysema, lymphangioleiomyoma- host factors involved, as only a small percentage of cigarette tosis (LAM), bronchiectasis, and honeycombing associated smokers develop PLCH.8 Theories that have been proposed with end stage fibrotic lung diseases. However, an emphy- include a viral origin, neoplastic proliferation, and immune sematous bulla is typically a focus of parenchymal destruc- system dysregulation.8 tion lacking a cyst wall. LAM occurs almost exclusively in PLCH has also been shown to be associated with lym- females and has a diffuse bilateral distribution and more phoma and is more likely to be diagnosed in a patient pre- uniform appearing cysts. Cystic bronchiectasis has a com- viously treated with chemotherapy and radiation therapy, municating branching pattern. Honeycombing tends to be usually for Hodgkin’s disease.3 peripheral and basilar in distribution with associated ground Many patients with PLCH are asymptomatic, leading to glass opacity and parenchymal architectural distortion. diagnosis based on chest radiograph for other indications. HRCT can often be utilized to reach an accurate diagnosis Symptomatic patients typically present with a nonproduc- in 84% of cases and can preclude the need for an invasive tive cough, dyspnea, an abnormal chest radiograph, or lung biopsy.6,9 recurrent spontaneous pneumothorax.3 Diagnosis of PLCH Pneumothorax can occur as a complication of PLCH is difficult based on these nonspecific symptoms. A minor- and may be the initial presenting clinical and imaging ity of patients may also experience fever, weight loss, and finding. Lymphadenopathy, air-space consolidation, and malaise.4 a solitary pulmonary nodule are rare imaging findings of Laboratory findings tend to be within normal limits PLCH.9 Advanced disease can be associated with pulmonary in PLCH patients, with the exception of a possibly moder- hypertension.3 ately elevated erythrocyte sedimentation rate.8 Pulmonary First-line treatment for PLCH is immediate cessation

180 J La State Med Soc VOL 166 July/August 2014 of smoking. Symptoms will stabilize in the majority of Cell Histiocytosis.” Radiographics. 2004 May-Jun;24(3):821-41 patients with no need for further treatment.8 Cessation of 9. Abbott GF, Rosado-de-Christenson ML, Franks TJ, Frazier AA, smoking can also reduce incidence of associated malig- Galvin JR. From the Archives of AIRP: Pulmonary Langerhans nancies. Corticosteroid therapy is another option that has Cell Histiocytosis. Radiographics 2004; 24:821-841. 3 10. Brauner MW, Grenier P, Moueli MM, Mompoint D, Lenoir S. demonstrated beneficial effects in stabilization. However, Pulmonary histiocytosis X: evaluation with high-resolution CT. no randomized trials have been conducted to compare the Radiology 1989; 172:225-258. efficacy of corticosteroid treatment with that of smoking cessation alone. Severe PLCH has been treated with chemotherapeutic agents (cladribine, cyclophosphamide, and methotrexate) without significant effect.7 Pleurodesis may be Ms. Bauer is a Fourth-Year Medical Student at Tulane University School of Medicine in New Orleans, Louisiana. Dr. Manning is a PGY-5 required in patients with recurrent pneumothoraces. Lung Radiology Resident at Tulane University Health Sciences Center in transplantation should also be considered for patients with New Orleans, Louisiana. Dr. Neitzschman is a Professor of Radiology rapidly deteriorating lung function or disease refractory to and the Chairman of the Department of Radiology at Tulane University medical treatment. Health Sciences Center in New Orleans, Louisiana. Patients with PLCH generally have a good prognosis.8 However, it has been shown that patients have a decreased average survival rate compared to the general population and have a poorer health-related quality of life than would be expected.6,7 Spontaneous regression has been reported in up to 25% of patients and stabilization in up to 50% of patients. The remaining 25% of patients follow a variably deteriorating course culminating in diffuse cystic change and lung destruction, sometimes complicated by pulmonary hypertension or respiratory insufficiency leading to death.2 Relapse may occur, even with lung transplantation, especially if the patient continues to smoke. Long-term follow-up of PLCH patients is necessary because of the risk of relapse, even years after disease resolution. Adult patients with PLCH are at an increased risk for developing malignant neoplasm of the lung, as well as lymphoma as mentioned earlier.3 However, this may be due to the high prevalence of cigarette smoking. Patients should be monitored for these complications.

REFERENCES

1. Gaensler EA, Carrington CB: Open biopsy for chronic diffuse infiltrative lung disease: clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg 1980, 30(5):411-426. 2. Thomeer M, Demedts M, Vandeurzen K. Registration of interstitial lung diseases by 20 centers of respiratory medicine in Flanders. Acta Clin Belg 2001;56:163-722002;166:1483-90. 3. Tazi A, Soler P, Hance AJ. “Adult Pulmonary Langerhans’ cell histiocytosis.” Thorax. 2000;55:405-416 4. Vassallo R, Ryu JH, Schroeder DR, Decker PA, Limper AH: Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. Semin Respir Crit Care Med. 2002 Apr;23(2):93-101 5. Varkki S, Tergestina M, Bhonsle VS, Moses PD, Mathai J, Korula S. “Isolated Pulmonary Langerhans Cell Histiocytosis” Indian J Pediatr. 2012 Sep 23. [Epub ahead of print] 6. Juvet SC, Hwang D, Downey GP. “Rare lung diseases III: Pulmonary Langerhans’ cell histiocytosis.” Can Respir J. 2010 May/ June; 17(3): 55-62 7. Suri HS, Yi ES, Nowakowski GS, Vassallo R. “Pulmonary Langerhans Cell Histiocytosis.” Orphanet Journal of Rare Diseases. 2012; 7(16): 1-13 8. Abbot GF, Rosado-de-Christenson ML, Franks TJ, Frazier AA, Galvin JR. “From the Archives of the AFIP: Pulmonary Langerhans

J La State Med Soc VOL 166 July/August 2014 181 Journal of the Louisiana State Medical Society Clinical Case of the Month

A 44-Year-Old HIV-Infected Man With Right- Shoulder Swelling

Carl Mickman, MS; Carrie Caruthers, MD; Jaclyn Spiegel, MD; Ron Schiro, BS; Joanne Maffei, MD; Charles V. Sanders, MD; Fred A. Lopez, MD

Immunocompromised patients are susceptible to various joint infections with less-common pathogens, such as mycobacterium. Physicians should have a low threshold to investigate the cause of an arthropathy further. An aspiration of the effusion is usually warranted to identify the possible pathogen and target treatment. We report an unusual presentation of a human immunodeficiency virus-infected patient with a chronic effusion arthropathy of his right shoulder due to Mycobacterium kansasii. We review the risk factors, transmission, clinical manifestations, and management of Mycobacterium kansasii.

CASE PRESENTATION were no associated skin lesions. He had nearly full active range of motion, and his strength was only mildly decreased A 44-year-old man with a past medical history of hu- compared to the contralateral side. The patient developed man immunodeficiency virus (HIV) and hepatitis C infec- minimal discomfort with medial humeral rotation; however, tions presented for a therapeutic paracentesis secondary to he had no point tenderness or pain with use of rotator-cuff acute liver failure. His past medical history also included muscles. non-adherence to combination antiretroviral therapy, a his- An X-ray revealed degenerative changes of the humeral tory of Pneumocystis jirovecii pneumonia, and a resection of head, including subchondral cysts and narrowing of the a squamous cell cancer of the tongue. At this presentation, joint space. Swelling caused displacement of the deltoid the patient was also evaluated for a longstanding effusion muscle laterally. Magnetic resonance imaging (MRI), with arthropathy of the right shoulder. He had first noticed swell- and without gadolinium contrast, revealed a large simple ing in the area two years earlier and denied any trauma, subacromial-subdeltoid bursa fluid collection with no associated pain, or limitation of his daily activities. Three septations or irregularity of the wall (see Figure C). The weeks prior to presentation, his CD4 count was 40/mm3 fluid collection involved the majority of the entire under- with a CD4 percentage of 8.3% and a viral load of 49,504 surface of the deltoid muscle. It measured approximately copies/mL. His tuberculous interferon-gamma release as- 11 cm anteroposteriorly, 8 cm craniocaudally, and 2 cm say test was negative, he denied any respiratory symptoms, in thickness. There was no communication between the and his chest X-ray was within normal limits. He admitted subacromial-subdeltoid bursa and the glenohumeral joint to prior intravenous drug use, and his last use was more space. Extensive diffuse synovial thickening with pannus than one year prior to presentation. He had been monoga- formation and periarticular erosions was present in the mous for the past two years with one partner who was also glenohumeral joint. HIV-infected. At the time of presentation, the patient had The patient underwent a diagnostic arthrocentesis of the recently been prescribed a new regimen of combination bursa. Approximately 10 ml of a thick, reddish, myxoid fluid antiretroviral therapy; however, he had been non-adherent with fatty material were aspirated. Drainage was limited in due to medication side effects. quantity by the viscosity of the fluid. A Gram stain noted On examination, the patient’s right shoulder mani- moderate white blood cells (WBC) and no organisms. No fested a marked effusion anterior to the deltoid muscle crystals were noted, and the cytology for malignant cells was that extended to the subdeltoid region (see Figures A, B). negative. Smears for fungal and mycobacterial organisms The area was non-tender, non-erythematous, and cool to were also negative (including acid-fast bacilli smears), and the touch; and a transillumination test was positive. There cultures for aerobic and anaerobic organisms were negative

182 J La State Med Soc VOL 166 July/August 2014 after five days. The patient was discharged home with symptomatic treatment for his ascites. He was restarted on combination antiretroviral therapy and scheduled for close follow-up with his infectious diseases primary care provider. Two weeks after discharge, cultures of the shoulder aspirate grew Mycobacte- rium kansasii (see Figures D, E). The speciation of the mycobacteria was first determined by high-performance liquid chromatography, which gave the isolate a similarity index of 0.887 for Mycobacterium kansasii and 0.573 for Mycobacterium szulgai (see Figure F). The isolate was later confirmed as My- cobacterium kansasii with a DNA probe for RNA target (GEN-PROBE). Blood cultures were consistently negative for acid-fast bacilli, indicating that his infection was likely not disseminated. Due to marked serum transami- Figure A: Gross anterior image of chest and bilateral shoulders. The degree of anterior nase elevations, thought to be hepatic and lateral swelling of the right shoulder can be appreciated in comparison to the disease, the patient was not able to patient’s left shoulder. receive treatment for his mycobacterial infection. His combination antiretroviral therapy was halted as well. The patient expired approximately three months later due to progressively worsening liver failure.

INTRODUCTION

Mycobacterium kansasii is an atypical, slow-growing mycobacterium that causes pulmonary infections in the immunocompromised host. It is the second-most common opportunistic atypical mycobacterial pathogen after Mycobacterium Avium Complex (MAC).3 M. kansasii is commonly differentiated by its characteristic yellow pigmentation. It has been isolated almost exclusively from municipal water sources, and the majority of reported cases have presented in the southern United States.1 M. kansasii is not considered a public-health threat, as there is no evidence of person-to- person transmission. The primary Figure B: Anterolateral view of the patient’s right shoulder, status post-removal of fluid method of colonization is thought to sample from bursa. be pulmonary. Pulmonary-disease presentation is similar to that of Mycobacterium tuberculosis, though symptoms are typically milder.2 Pulmonary M. kansasii occurs in both

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TRANSMISSION

Mycobacterial articular infections typically occur through one of two methods: direct inoculation or disseminated infection. Joint infection with M. kansasii via direct inoculation has been documented in both immunocompromised and immunocompetent patients.3 Patients usually present with monoarticular disease and a history of trauma, though recent steroid injection is also a significant risk factor.6 Patients rarely present with systemic symptoms such as fever or malaise and usually complain of only localized pain and swelling. Disseminated infection leading to joint colonization with M. kansasii has almost exclusively been documented in immunocompromised patients, and case reports reveal presentations of both monoarticular and polyarticular disease. Patients can present with systemic symptoms, though subacute presentation with only mild articular complaints is more common.3 Pulmo- nary infections have been reported to lead to disseminated infections in 35% of those infected with HIV.4 Joint colonization in the presence of disseminated disease is well documented; however, no study has looked at the likelihood of dis- Figure C: Magnetic resonance imaging of right shoulder with contrast semination leading to articular manifestations. agent shows large subacromial subdeltoid fluid collection with extensive synovial thickening and periarticular erosions in the glenohumeral joint, DIAGNOSIS consistent with hypertrophic HIV arthoropathy. No communication between subacromial subdeltoid bursa and glenohumeral joint space is observed. Healthcare providers should consider mycobacterial infection when evaluating immunocompromised patients who present with subacute immunocompetent and immunocompromised patients, but joint pathology. Aspirates of the infected area it is much more common in immunocompromised hosts, should be sent for histopathologic analysis and cultured for including HIV-infected patients.3-4 Louisiana, in particular, aerobic, anaerobic, fungal, and mycobacterial organisms. has a high incidence of both HIV and M. kansasii and has A histopathologic analysis should be performed using the recorded more co-infections than any other state.4 fluorochrome technique for optimal sensitivity. Smear analysis is often negative; however, a negative smear does 3 RISK FACTORS not rule out infection.

HIV-infected patients, particularly those with CD4 CLINICAL MANIFESTATIONS counts below 100/mm3, represent the largest percentage of those with articular mycobacterial infections.3 Individuals Articular manifestations of M. kansasii infections, and receiving immunosuppressive therapy for inflammatory particularly infections of the bursae, are extremely rare. In diseases that affect the joints are also at high risk, such as 1999, only 50 cases of Mycobacterium kansasii septic arthritis 3 those with rheumatoid arthritis, psoriatic arthritis, dermato- were described, and another review in 2012 discussed four 7 myositis, lupus, gout, or those receiving intrarticular steroid cases of M. kansasii bursitis. Of the four cases reported, one injections.3 Previous articular pathologies are thought to presented with monoarticular disease while the three others 7,8 promote the colonization of injured tissue and predispose presented with polyarticular disease. affected individuals to hematogenous spread.3 Researchers M. kansasii is seldom reported to infect via direct in- have also described cases of acute-onset articular manifes- oculation while organisms such as Mycobacterium fortuitum, tations secondary to immune reconstitution inflammatory Mycobacterium chelonae, and Mycobacterium marinum are syndrome (IRIS).5 well-known causes of localized trauma-associated infections.9 The most common bursal infections associated with these organisms are the olecranon and prepatellar bursae, as

184 J La State Med Soc VOL 166 July/August 2014 alone is often inadequate, and needle or surgical drainage is recommended. Pulmonary infections with rifampin-susceptible M. kansasii isolates have been shown to respond well to a prolonged regimen of isoniazid (300 mg/d), rifampin (600 mg/d), ethambutol (15 mg/kg/d), and pyridoxine (50 mg/d) for at least 12 to 18 months.13 As in HIV-associated MAC infections, the duration of therapy should also be dictated by the immune status of the patient. Clinical recovery should be monitored closely as resistance to rifampin can lead to failure of treatment and resistance to other drugs.13 If failure of the initial regimen does occur, a new three-drug regimen based on susceptibilities should include clarithromycin or azithromycin, moxifloxacin, ethambutol, sulfamethoxazole, or streptomycin.13 For patients who are co-infected with HIV, additional information must be considered. Combination antiretroviral therapy and the Figure D: A thin-pour agar plate (Hardy Diagnostics) with a Myobacterium agents used for the treatment of M. kansasii kansasii sample grown from a broth culture of the aspirate of myxoid- have associated side effects and may also inter- appearing fluid drawn from right subacromial-subdeltoid bursa. act with each other when used concomitantly. Heterogeneously yellow hue is indicative of a photochromogen. Importantly, rifabutin is known to interact less Identification of organism as Mycobacterium kansasii was confirmed by DNA with combination antiretroviral therapy than probe of RNA target (GEN-PROBE). rifampin.14 The interplay of preexisting comorbidities must also be taken into account. Since 10 they are superficial and most frequently exposed to trauma. isoniazid is a known hepatotoxic drug, liver enzymes should This presentation is in contrast to that of M. tuberculosis, be closely monitored, and patients must be educated to which, due to its propensity for hematogenous spread, does strictly avoid alcohol. 10 not show preference for particular bursae. One patient, Since the majority of HIV patients with disseminated described by Barham and Hargreaves, presented with M. kansasii infections present with very low CD4 counts, the monoarticular M. kansasii bursitis contracted through local possibility of IRIS must be considered as well. Currently, 8 trauma and direct inoculation. no guidelines exist recommending when to discontinue In contrast, three cases of polyarticular M. kansasii combination antiretroviral therapy, and clinical judgment bursitis described by Mathew et al. were thought to result must be used in these situations. Steroids should be used to from hematogenous spread. Interestingly, all three patients treat any inflammatory symptoms that appear. Combination were immunocompromised secondary to immunosuppres- antiretroviral therapy should only be discontinued in the sive therapies. The only patient described with M. kansasii presence of life-threatening inflammatory conditions that subacromial bursitis was predisposed to infection second- do not respond to steroids.15 ary to articular manifestations of dermatomyositis. The patient initially presented with cutaneous nodules on his DISCUSSION OF CASE forearms that later spread to the subacromial bursa, a result 7 of hematogenous dissemination. M. tuberculosis is the only Our patient’s case is significant for multiple reasons. other mycobacteria that has been demonstrated to infect this First, his presentation was more indolent than the cases particular bursa, though neither of the two cases described described in the available literature. His lack of pain or 11 were in HIV-infected patients. All of these infections oc- inhibition of his daily activities contrasts with the other 7, 11 curred in the absence of trauma. cases, in which patients directly sought medical attention for their joint complaints. In addition, the patient’s physical MANAGEMENT exam showed no signs of acute inflammation such as pain, warmth, or erythema – all of which were present in the Guidelines for the treatment of M. kansasii joint infec- other cases of M. kansasii joint infections, even those with tions currently do not exist due to the uncommon nature deficient immune status.3 Immunocompromised patients of this condition, and guidelines regarding disseminated are susceptible to less-common pathogens and often pres- nontuberculous mycobacterial infections are similar to those ent with unusual symptoms and findings. It is imperative for pulmonary infections. Clinical experience has shown that that physicians have a low threshold to further investigate with other infectious causes of bursitis, antibiotic treatment the cause of an arthropathy, whether it be monoarticular or

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Figure E: Mycobacterium kansasii with TB Carbolfuchsin KF stain (Becton-Dickinson) from 7H11 plate that was inoculated with an aspirate from the right subacromial-subdeltoid bursa, viewed at 1,000x with oil- immersion lens.

Figure F: High-performance liquid chromatography (MIDI, Inc.) results identified a similarity index for Mycobacterium kansasii (0.887) and Mycobacterium szulgai (0.573).

186 J La State Med Soc VOL 166 July/August 2014 polyarticular. It is often essential to sample fluid from the 2007;175:367-416. joint space or bursa in order to identify any pathogen and 14. Spradling P, Drociuk D, McLaughlin S, et al. Drug-drug tailor treatment. interactions in inmates treated for human immunodeficiency Another noteworthy aspect of our case is the pres- virus and Mycobacterium tuberculosis infection or disease: An institutional tuberculosis outbreak. Clin Infect Dis 2002 Nov ence of articular pathology, including subchondral cysts, 1;35(9):1106-12. diffuse synovial thickening with pannus formation, and 15. Puthanakit T, Oberdorfer P, Ukarapol N, et al. Immune periarticular erosions. The pathology could be explained reconstitution syndrome from nontuberculous mycobacterial as a primary bone or joint infection that later spread to the infection after initiation of antiretroviral therapy in children with bursa or repetitive mechanical friction between bone and HIV infection. Pediatr Infect Dis 2006 Jul;25(7):645-8. skin leading to chronic bursitis.12 A differential diagnosis of these changes could include common joint pathology, such as rheumatoid or psoriatic arthritis or, more rarely, HIV Mr. Mickman is a Medical Student at the Louisiana State University arthropathy; however, an indolent infectious process should School of Medicine in New Orleans. Dr. Caruthers is a Chief also be included. The mechanism of infection in our patient Resident in the Department of Medicine at the LSU Health Sciences remains unclear as he had no evidence of lung pathology, Center in New Orleans. Dr. Spiegel is a Resident in the Department no other manifestations of disseminated M. kansasii, and no of Medicine at the LSUHSC-New Orleans. Mr. Schiro is a Medical Laboratory Technician in the Microbiology Department at the Interim history of trauma to the area. LSU Hospital in New Orleans. Dr. Maffei is an Associate Professor of Our patient’s case presentation and diagnosis stress Clinical Medicine in the Department of Medicine, Section of Infectious the importance of further investigating unusual presenta- Diseases/HIV, at the LSUHSC-New Orleans and the Medical Director of tions of uncommon infections in the immunocompromised the Infection Control Department at the Interim LSU Hospital in New patient population. Orleans. Dr. Sanders is the Chairman of the Department of Medicine, the Edgar Hull Professor of Medicine, and a Professor of Microbiology, Immunology, and Parasitology at the LSUHSC-New Orleans. Dr. Lopez CITATIONS is the Vice Chair of Education in the Department of Medicine, the Richard Vial Professor of Medicine, and Assistant Dean of Student 1. Bailey RK, Wyles S, Dingley M, Hesse F, Kent GW. The isolation Affairs in the School of Medicine at the LSUHSC-New Orleans. of high catalase Mycobacterium kansasii from tap water. Clin Am Rev Respir Dis 1970;101:430-1. 2. Mazor Y, Sprecher H, Braun E. Mycobacteria kansasii disseminated disease. Israel Med Assoc J 2010;12:121-2. 3. Bernard L, Vincent V, Lortholary O, et al. Mycobacterium kansasii septic arthritis: French retrospective study of 5 years and review. Clin Infect Dis 1999 Dec;26(6):1455-60. 4. Witzig RS, Fazal BA, Mera RM, et al. Clinical manifestations and implications of coinfection with Mycobacterium kansasii and human immunodeficiency virus type 1. Clin Infect Dis 1995;21:77-85. 5. Ito M, Komatsu Y, Ushiki A, et al. An AIDS patient with immune reconstitution inflammatory syndrome due to pulmonary Mycobacterium kansasii infection during antiretroviral therapy. J Infect Chemother 2009 Oct;15(5):331-4. 6. Leader M, Revell P, Clarke G. Synovial infection with Mycobacterium kansasii. Ann Rheum Dis 1984;43:80–2. 7. Mathew SD, Tully CC, Borra H, et al. Septic subacromial bursitis caused by Mycobacterium kansasii in an immunocompromised host. Mil Med 2012 May;177(5):617-20. 8. Barham GS, Hargreaves DG. Mycobacterium kansasii olecranon bursitis. J Med Microbiol 2006;55:1745-6. 9. Woods G, Washington J. Mycobacteria other than Mycobacterium tuberculosis: Review of microbiologic and clinical aspects. Rev Infect Dis 1987;9:275-94. 10. Wolinsky E. Nontuberculous mycobacteria and associated diseases. Am Rev Respir Dis 1979;119:107-59. 11. Kenin A. Tuberculosis of the subdeltoid bursa. Bull Hosp Jt Dis 1950;11:128-33. 12. Norden C, Gillespie W, Nade S. Mycobacterial infections of the musculoskeletal system. In: Norden C, Gillespie W, Nade S (editors). Infections in bones and joints. Boston: Blackwell Scientific, 1994:211-30. 13. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med

J La State Med Soc VOL 166 July/August 2014 187 Journal of the Louisiana State Medical Society Pathology Image of the Month

Black Esophagus Detected at Autopsy in a Patient With Abdominal Pain and Bloody Diarrhea

Christin Tsao, MD; Louise Thomas; Robin R. McGoey, MD

A 73-year-old African-American male was transported to the emergency department due to what emergency personnel described as “coffee ground emesis.” He was pronounced dead shortly after arrival. An unlimited autopsy examination was conducted under authorization of the coroner’s office. Medical record review revealed that the decedent had been discharged from the hospital just one day prior to his death following a three-day admission for abdominal pain, bloody diarrhea, and a 22-lb unintentional weight loss. Medical history documented hypertension, chronic obstructive lung disease, and a 57-pack-year smoking history. Alcohol abuse was also endorsed, but cessation of use was reported six months prior. During that admit, he was treated for volume-depletion, a urinary tract infection, and suspected infective colitis with antibiotics. Symptoms had resolved on hospital day three, and the patient was discharged home with a two-week course of ciprofloxacin and metronidazole and a follow-up colonoscopy appointment in one month.

At the time of autopsy, the decedent was described as cachectic. Figure 1a shows the decedent’s esophagus, opened longitudinally. Figure 1b shows the corresponding histology from the esophagus. Other findings documented at autopsy included ischemic bowel disease in the descending colon with patchy superimposed pseudomembranous colitis, emphysematous change, papillary renal cell carcinoma of the right kidney, microscopic prostatic adenocarcinoma, hepatic fibrosis, and intact hepatic hemangiomata.

188 J La State Med Soc VOL 166 July/August 2014 Figure 1: (A) (Left) Esophagus opened longitudinally to reveal a deeply stained distal esophageal mucosa with an abrupt transition at the gastroesophageal junction. (B) (Above) Histology from blackened esophagus showing full thickness epithelial necrosis, overlying nonspecific black pigment, inflammatory infiltrate, and multiple small caliber thromboemboli (hematoxylin-eosin, original magnification 40x).

What is the cause of death in this case?

DIAGNOSIS: Acute esophageal necrosis, ischemic and with an average age of 67 years.1,4 pseudomembranous colitis The gross pathology of AEN is pathognomonic characterized by circumferential black discoloration of the DISCUSSION esophageal mucosa, primarily in the distal segment (97%) but occasionally with proximal extension to involve the Acute esophageal necrosis (AEN) is a rare disorder upper one-third.1 Notable is the sharp contrast and abrupt with an unclear etiology that is also known as “black transition with normal appearing gastric epithelium at the esophagus.”1,2 A relatively newly described diagnosis, AEN gastroesophageal junction.1,4 Gross features are so remark- was first reported by Goldenberg et al. in 1990.1,3 Affected able that diagnosis is frequently made by esophagogas- patients most often present with upper gastrointestinal troduodenoscopy (EGD) without the requisite need for bleeding, including hematemesis. Other symptoms may in- biopsy.1,2 Histology, however, is also typical and includes clude nausea and vomiting, dysphagia, fever, lightheaded- necrosis of the mucosa and submucosa without any remain- ness, and syncope. AEN occurs more often in patients with ing recognizable viable squamous epithelium. Necrosis into multiple co-morbidities, particularly those with diabetes the muscularis layers and full thickness into the adventitia mellitus, malignancies, hypertension, alcohol abuse, coro- have also been described. Additional findings include a nary artery disease, chronic obstructive pulmonary disease heavy leukocytic infiltrate, deranged muscle fibers, and (COPD), renal insufficiency, immunosuppression, sepsis, vascular thrombi.1,2,4,5 Altenberger et al. also describe a black broad spectrum antibiotic use, and aortic dissection.1,2,4,5 nonspecific granular pigment that stains positively with AEN is a rare disorder. Two large autopsy studies have periodic acid Schiff (PAS) and negatively for iron.5 found zero cases in 1,000 consecutive autopsies and a 0.2% The etiology of AEN is unclear but is thought to be frequency in 3,000 total autopsies.1,6,7 Two retrospective multi-factorial and result from a combination of ischemia, endoscopic studies have estimated the incidence at 0.01% backflow reflux of acidic gastric contents, and impaired local and 0.28%. 1,8-10 Men are affected four times more commonly defense barriers.1,2,4 Several studies have supported a role than women. The disease has been documented in all age for ischemia in the pathogenesis of AEN, particularly since groups, but the peak incidence occurs in the sixth decade the distal esophageal segment is relatively hypovascular compared to the more proximal segments.1,2,4,5 The histo-

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logical appearance of AEN also bears similarities to that clearly had a substantial contribution to his fatal outcome. which is seen in ischemic colitis, offering added support for the hypothesis that the two diseases may share common ACKNOWLEDGEMENTS mechanistic etiologies.2 Other diagnoses that need to be entertained upon The authors would like to gratefully acknowledge the identifying a black esophagus include infectious agents support of the Orleans Parish Coroner’s Office: Dr. Jeffrey and toxic ingestions. Infectious esophagitis is more likely Rouse and Chief Investigator John Gagliano for providing when microscopy reveals inclusion bodies, microorganism the case material for this report. colonies, and multinucleated giant cells. Caustic ingestions do not display the typical gross pattern of AEN such that REFERENCES there is distal segment involvement with relative sparing of the proximal esophagus and sharp delineation from the 1. Gurvits GE. Black esophagus: Acute esophageal necrosis gastric mucosa.1,2,4,5 syndrome. World J Gastroenterol. 2010 Jul 14; 16(26):3219–25. The mortality rate for AEN is reportedly as high as 2. Mishkin, D, Gelrud D. “Acute Esophageal Necrosis.” UpToDate. 32% and is thought primarily to be due to patients’ existing Ed. Shilpa Grover. N.p., 20 Jan. 2014. Web. 01 July 2014. co-morbidities.1,4 Uncomplicated AEN in a patient without 3. Goldenberg SP, Wain SL, Marignani P. Acute necrotizing esophagitis. Gastroenterology. 1990 Feb;98(2):493–6. co-morbidities follows a far more indolent clinical course 4. Gurvits GE, Shapsis A, Lau N, et al. Acute esophageal necrosis: and is potentially reversible with a far lower mortality rate a rare syndrome. J Gastroenterol. 2007 Jan; 42(1):29–38. 1 at approximately 6%. The goal for treatment in AEN mainly 5. Altenburger DL, Wagner AS, Li S, et al. A case of black esophagus targets treating the patient’s underlying conditions but with histopathologic description and characterization. Arch Pathol also includes parenteral nutrition, proton pump inhibitors, Lab Med. 2011;135(6):797–798. H2 blockers, and sucralfate. Healing and resolution of the 6. Postlethwait RW, Musser AW. Changes in the esophagus in 1,000 esophageal mucosa have been observed over a varied time autopsy specimens. J Thorac Cardiovasc Surg. 1974; 68:953–956. course, ranging from one week to one month following 7. Etienne JP, Roge J, Delavierre P, et al. Esophageal necrosis of vascular origin. Sem Hop. 1969;45:1599–1606. diagnosis. Perforation of the esophagus is the most serious 8. Lacy BE, Toor A, Bensen SP, et al. Acute esophageal necrosis: primary complication in AEN, reported to occur in 7% of report of two cases and a review of the literature. Gastrointest cases; but stricture and stenosis are also described in another Endosc. 1999;49:527–532. 10% of cases.1,4 9. Moretó M, Ojembarrena E, Zaballa M, et al. Idiopathic acute In conclusion, acute esophageal necrosis or AEN is a esophageal necrosis: not necessarily a terminal event. Endoscopy. rare condition with a high mortality rate that occurs most 1993;25:534–538. often in patients with multiple co-morbidities. The charac- 10. Augusto F, Fernandes V, Cremers MI, et al. Acute necrotizing teristic black stained esophageal mucosa, circumferentially esophagitis: a large retrospective case series. Endoscopy. favoring the distal segment, is easily seen on endoscopic 2004;36:411–415. visualization. The discoloration abruptly terminates at the gastroesophageal junction but may extend proximally into the mid and even proximal one-third. Histology of From the Department of Pathology at Louisiana State University the involved segment shows no viable squamous mucosa, School of Medicine in New Orleans. Dr. Tsao is a third-year Pathology prominent necrosis, or overlying black granular pigment Resident; Ms. Thomas is a fourth-year Medical Student at the University of Queensland in Brisbane, Australia; and Dr. McGoey is and small caliber thromboemboli. The etiology is unclear an Associate Professor of Pathology and Residency Program Director. but is hypothesized to be a combination of ischemia, reflux of gastric acids, and impaired barrier defenses. The high mortality rate and poor prognosis are due in large part to the patient’s co-morbidities, and treatment is aimed at treating the coexistent conditions and maintaining hemodynamic stability in the patient. The case illustrated here demonstrates the classic clinical presentation and typical gross and microscopic pathology of AEN. Even though retrospective historical review offers the possibility that the decedent’s complaints upon his prior admission may have suggested AEN, a remark- ably high index of suspicion, and EGD would have been required in order to have diagnosed this exceedingly rare and underappreciated pathologic entity. Still further, this patient’s multiple significant comorbidities, which included two primary incidental carcinomas, chronic lung disease and prior alcohol abuse as well as the more recent evolution of an ischemic bowel and overlying pseudomembranous colitis

190 J La State Med Soc VOL 166 July/August 2014 Editor Volume 166, Number 5 • September/October 2014 Established 1844 D. LUKE GLANCY, MD

Associate Editor L.W. JOHNSON, MD

BOARD OF TRUSTEES Chair, GEOFFREY W. GARRETT, MD Vice Chair, K. BARTON FARRIS, MD Secretary/Treasurer, RICHARD PADDOCK, MD ANTHONY P. BLALOCK, MD D. LUKE GLANCY, MD LESTER W. JOHNSON, MD FRED A. LOPEZ, MD Featured Articles EDITORIAL BOARD MURTUZA J. ALI, MD RONALD AMEDEE, MD James H. Diaz, MD, MPH&TM, DrPH, FACPM 186 Recognition and Management of Rodent-Borne Infectious Disease SAMUEL ANDREWS, II, MD Outbreaks After Heavy Rainfall and Flooding BOB BATSON, MD EDWIN BECKMAN, MD Christian Fauria-Robinson, MD 193 Dysplastic Cerebellar Gangliocytoma GERALD S. BERENSON, MD Rebecca Meyers, MD Lhermitte-Duclos Disease C. LYNN BESCH, MD Sarah Castillo-Jorge, MD Imaging and Magnetic Resonance Spectroscopy JOHN BOLTON, MD Jeremy Nguyen, MD MICHELLE BOURQUE, JD Enrique Palacios, MD, FACR JAMES N. BRAWNER, III, MD BRETT CASCIO, MD Kamesh Sivagnanam, MD 197 Spontaneous Rectus Sheath Hematoma: Two Variant Cases QUYEN CHU, MD Vatsal Ladia, MD WILLIAM PATRICK COLEMAN III, MD Vedang Bhavsar, MD GUSTAVO A. COLON, MD Jeffery Summers, MD RICHARD COULON, MD Timir Paul, MD, PhD LOUIS CUCINOTTA, MD VINCENT A. CULOTTA, JR., MD Camille Robichaux 200 Bisphosphonate-Related Osteonecrosis of the Jaw JOSEPH DALOVISIO, MD Menchu Ong, MD NINA DHURANDHAR, MD Diana Veillon, MD JAMES DIAZ, MD, MPH & TM, Dr. PH Stavan Patel, DDS, MD JOHN ENGLAND, MD James Cotelingam, MD JULIO FIGUEROA, MD ELIZABETH FONTHAM, MPH, Dr. PH Hosein Shokouh-Amiri, MD, FACS, FICS 203 Aberrant Left Main Bile Duct Draining Directly Into the Cystic EDWARD FOULKS, MD Mohammad Kazem Fallahzadeh, MD Duct or Gallbladder: An Unreported Anatomical Variation and HENRY G. HANLEY, MD Sophia T. Abdehou, MD Cause of Bile Duct Injury During Laparoscopic ELIAS B. HANNA, MD Miles Sugar, MD Cholecystectomy LYNN H. HARRISON, JR., MD Gazi B. Zibari, MD, FACS ROBERT HEWITT, MD MICHAEL HILL, MD Gazi B. Zibari, MD, FACS 207 Portal-Endocrine and Gastric-Exocrine Drainage Technique of LARRY HOLLIER, MD Mohammad Kazem Fallahzadeh, MD Pancreas Transplantation Provides an Easy Access for Evaluation of JOHN HUNT, MD Alireza Hamidian Jahromi, MD Pancreatic Allograft Dysfunction: Six-Year Experience at a Single BERNARD JAFFE, MD Joseph Zakhary, MD Center NEERAJ JAIN, MD David Dies, MD TRENTON L. JAMES, II, MD Greg Wellman, MD STEPHEN KANTROW, MD Neeraj Singh, MD KEVIN KRANE, MD Hosein Shokouh-Amiri, MD, FACS MAUREEN LICHTVELD, MD, MPH FRED A. LOPEZ, MD Adam Hauch, MD, MBA 213 Atypical Mycobacterial Infections of Peritoneal Dialysis Catheter Exit F. BROBSON LUTZ, JR., MD Bridget Ory, MD Sites - A Louisiana Issue DAVID MARTIN, MD Anil Paramesh, MD, FACS JORGE A. MARTINEZ, MD, JD ELIZABETH MCBURNEY, MD Sabrina L. Noah 217 Protecting the Private Practice of Medicine: Direct Primary Care - ELLEN MCLEAN, MD Louisiana Poised to Lead NORMAN E. MCSWAIN, JR., MD REINHOLD MUNKER, MD DAVID MUSHATT, MD JOSEPH NADELL, MD HAROLD R. NEITZSCHMAN, MD STEVE NELSON, MD Departments

NORA OATES, MD D. Luke Glancy, MD 219 ECG OF THE MONTH DONALD PALMISANO, MD, JD, FACS Timothy D. McShurley, MD ECG in a 49-Year-Old Man With Chest Pain PATRICK W. PEAVY, MD ROBERTO QUINTAL, MD Christian Mabry, MD 221 RADIOLOGY OF THE MONTH RAOULT RATARD, MD, MS, MPH & TM Gretchen Yandle, MD Abnormally Dilated Arteries in an Asymptomatic Male ROBERT RICHARDS, MD Jen Erbil, MD DONALD RICHARDSON, MD Kyle Happel, MD, FCCP FRANK A. RIDDICK, JR., MD Harold R. Neitzschman, MD WILLIAM C. ROBERTS, MD DONNA RYAN, MD Daniel Englert, MD 224 CLINICAL CASE OF THE MONTH JERRY ST. PIERRE, MD Paula Seal, MD A 22-Year-Old Man With AIDS Presenting With Shortness of Breath CHARLES SANDERS, MD Chris Parsons, MD and an Oral Lesion OLIVER SARTOR, MD Adrienne Arbour, MD CHARLES SCHER, MD Evans Roberts III, MD RICHARD SPECTOR, MD Fred A. Lopez, MD JACK P. STRONG, MD PRAMILLA N. SUBRAMANIAM, MD Joel France, DO 231 PATHOLOGY IMAGE OF THE MONTH KEITH VAN METER, MD Robin R. McGoey, MD Death in a Young Adult With Sickle Cell Disease DIANA VEILLON, MD HECTOR VENTURA, MD CHRIS WINTERS, MD GAZI B. ZIBARI, MD Journal of the Louisiana State Medical Society

Recognition and Management of Rodent-Borne Infectious Disease Outbreaks After Heavy Rainfall and Flooding

James H. Diaz, MD, MPH&TM, DrPH, FACPM

Climatic events, especially heavy rains and flooding following periods of relative drought, have precipitated both arthropod-borne and rodent-borne infectious disease outbreaks. Heavy rainfall encourages excessive wild grass seed production that supports increased outdoor rodent populations, and flooding forces rodents from their burrows near water sources into the built environment and closer to humans. The objectives of this review are to alert clinicians to the climatic conditions common to hurricane-prone regions, such as Louisiana, that can precipitate outbreaks of the two rodent-borne diseases most often associated with periods of heavy rainfall and flooding, leptospirosis (LS) and hantavirus pulmonary syndrome (HPS). It will also describe the epidemiology, presenting clinical manifestations and outcomes of these rodent-borne infectious diseases, and recommend both prophylactic therapies and effective control and prevention strategies for rodent-borne infectious disease outbreaks. Healthcare providers should maintain high levels of suspicion for LS in patients developing febrile illnesses after contaminated freshwater exposures during flooding or recreational events, and for HPS in patients with febrile illnesses that progress rapidly to respiratory failure following rodent exposures in enclosed spaces. Public health educational strategies should encourage limiting human contact with all wild and peridomestic rats and mice, avoiding all contact with rodent excreta, safely disposing of all rodent excreta, and modifying the built environment to deter rodents from colonizing households and workplaces.

Climatic events, especially heavy rains and flooding to examine the latest scientific articles on rodent-borne infec- following periods of relative drought, have precipitated tious disease outbreaks in the US in order to describe the both arthropod-borne and rodent-borne infectious disease epidemiology and presenting clinical manifestations and outbreaks. Heavy rainfall encourages excessive wild grass outcomes of leptospirosis (LS) and hantavirus pulmonary seed production that supports increased outdoor rodent syndrome (HPS) outbreaks. They were also used to recom- populations; and flooding forces rodents from their bur- mend both prophylactic therapies and control and preven- rows near water sources, such as bayous, canals, rivers, and tion strategies for these disease outbreaks. The keywords sewers, into the built environment and closer to humans. included hantavirus, New World hantaviruses, American Unanticipated regional outbreaks of leptospirosis (LS) and hantaviruses, Sin nombre virus, Bayou virus, Black Creek hantavirus pulmonary syndrome (HPS) have occurred fol- Canal virus, hantavirus pulmonary syndrome; Leptospira lowing heavy rainfall and flooding in the United States (US). interrogans, leptospirosis, Weil’s disease; infectious disease As a result, the objectives of this review are to alert clini- outbreaks, climatic factors, and rodent-borne. cians to the climatic conditions common to hurricane-prone regions, such as Louisiana, that can precipitate outbreaks RESULTS of LS and HPS; describe the epidemiology and presenting clinical manifestations and outcomes of these rodent-borne Leptospirosis Outbreak 1: Leptospirosis Outbreak infectious diseases; and recommend both prophylactic Among Athletes Participating in Triathlons - therapies and effective control and prevention strategies Wisconsin and Illinois, 1998. for rodent-borne infectious disease outbreaks. (Adapted from MMWR, July 24, 1998)1 Once considered an occupational disease of abattoir METHODS and sewer workers, LS outbreaks are now being increasingly reported among flood survivors, white water rafters, Internet search engines were queried with the keywords adventure travelers, soldiers, and triathlon participants.1-4

186 J La State Med Soc VOL 166 September/October 2014 Figure 1: Photomicrograph of a positive leptospiral microscopic agglutination test (MAT) with live antigen using darkfield microscopy. Source: US Centers for Disease Control and Prevention.

The largest US outbreak occurred during a combination 31-November 2, 2004, a 56-year-old genetics professor of two international triathlon events with more than 1,500 waded throughout his flooded laboratory in sandals and registered participants that featured 1.5 mile lake swims developed blisters on his feet. On November 10, 2004, he held in consecutive months in Illinois and Wisconsin dur- developed fever, chills, nausea, and vomiting. Although ing the summer of 1998.1 Of 639 single or combined event his fever subsided over the next four days, he developed participants interviewed by telephone, 74 had illnesses tremor, poor balance, and visual scotomata. He presented consistent with the case definition of LS that included fever to a local emergency department and was hospitalized for with or without chills, headache, myalgia, abdominal pain, empiric treatment of probable LS with oral doxycycline. eye pain, red eyes, or diarrhea during the month-long period Later, both an ELISA IgM dipstick test and a convalescent encompassing the two events for an attack rate of 12%. The serum microscopic agglutination test (MAT) were positive median age of probable cases was 36 years; 80% were males, for Leptospira IgM antibodies (Figure 1). On suspicion of a and 54 of 74 case-patients sought medical attention (73%), leptospirosis outbreak, the university and state health de- of whom 21 (39%) were hospitalized. Among hospitalized partment established an immediate Internet-based febrile patients, two patients manifested jaundice and acute renal disease surveillance system among all persons on campus failure requiring hemodialysis (Weil’s disease), and two during the flooding. Persons reporting febrile illnesses after underwent exploratory laparotomies for acute abdomens. contact with floodwaters were offered free ELISA testing for Acute-phase serum samples from several triathletes were leptospirosis. A total of 271 persons responded to the Inter- positive for LS by enzyme-linked immunosorbent assay net survey, with 90 (33%) reporting febrile illnesses within (ELISA) IgM dipstick tests. As a result of the outbreak, 30 days of floodwater contacts. Forty-eight respondents public health authorities temporarily closed the lake in met the case definitions for suspected LS; and all 48 were which triathletes participated to swimming, water-skiing, tested for LS by ELISA IgM dipsticks, in addition to another and personal watercraft use for further testing. 32 floodwater-contact victims requesting testing. Of the 80 floodwater-exposed persons tested, only one additional Leptospirosis Outbreak 2: Leptospirosis After Flooding case of leptospirosis was detected in a 27-year-old gradu- of a University Campus - Hawaii, 2004 ate student (Case 2) who assisted the index-case professor (Adapted from MMWR, February 10, 2006)4 (Case 1) in his lab over the period October 31-November 4 On October 31, 2004, heavy rains in the Honolulu area and lacerated his foot during flood clean-up. The graduate caused a stream adjacent to the University of Hawaii to student reported fever, chills, headache, nausea, vomiting, overflow its banks and flood the campus with six or more and diarrhea within 10 days of his first floodwater contact inches of standing water. Although the university was but recovered without treatment within a week. Authorities evacuated and the campus was closed temporarily, clean-up concluded that both patients were at risk for LS by wading by faculty, students, staff, contractors, and National Guard in contaminated floodwaters in sandals with open wounds troops began immediately. During the period of October on their feet.

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Table 1: Summary of the laboratory-confirmed cases of hantavirus pulmonary syndrome cases, United States, 1993-2013.10 US hantavirus species Rodent reservoirs: Number of US cases States of occurrence Common name (Latin name) (unknown for 28 cases) Sin nombre (Spanish for Deer mouse (Peromyscus 658 Every US state except “without a name”) maniculatus) MI, OH, NH, CT, MA, RI, NJ, DL, ML, MO, AR, KY, TN, LA, MS, AL, GA, FL, SC Bayou Marsh rice rat (Oryzomys palustris) 5 TX, LA Monongahela Deer mouse (Peromyscus 4 PA, WV maniculatus) New York White-footed mouse (Peromyscus 2 NY leucopus) Black Creek Canal Hispid cotton rat (Sigmodon 1 FL hispidus)

Hantavirus Outbreak: Hantavirus Pulmonary myscus maniculatus, in states west of the Mississippi River.6 Syndrome - California, 2012 All 624 HPS cases in the US during the period 1993-2004 (Adapted from MMWR, November 23, 2012)5 are depicted by cumulative case counts for each state in On August 16, 2012, after a mild winter and a rainy Figure 2.6 Although the deer mouse ranges throughout the spring and summer, the California Department of Pub- western US, it is not indigenous to the southeastern US or lic Health in conjunction with the CDC announced two to the Atlantic seaboard states.6 The few cases of HPS de- serologically-confirmed cases of hantavirus pulmonary scribed in these areas (n=12) were caused by other species syndrome (HPS) in two California residents who had stayed of hantaviruses, each having different, preferred rodent overnight in cabins in Yosemite National Park. Follow- reservoirs (Table 1).6 Bayou virus with a rodent reservoir ing this outbreak, the National Park Service contacted all in the marsh rice rat, Oryzomys palustris, was responsible 260,000 overnight visitors to Yosemite during the period, for the second largest number of HPS cases in the US after June 1-September 17, 2012; provided information on the Sin nombre virus; four in Texas and one in Louisiana in 1995 transmission and presenting clinical manifestations of HPS; (Figure 3).7-11 In 1996, Khan and co-investigators reported and requested immediate health status responses. This a fatal case of HPS associated with renal insufficiency in surveillance detected two cases of HPS in non-residents of a 33-year-old Florida man caused by a newly identified California who had returned to their home states of Penn- hantavirus, the Black Creek Canal (BCC) virus (Figure 4).8 sylvania and West Virginia after their summer vacations to A rodent reservoir in the indigenous cotton rat, Sigmodon Yosemite. By October 30, 2012, 10 cases of HPS with three hispidus, was suspected and established initially by a 13% deaths were confirmed among overnight visitors to the park seroprevalence of antihantaviral IgG antibodies in trapped during the period, June 1, 2012 to August 28, 2012; nine of cotton rats; it was later confirmed by the detection of BCC whom spent at least one night in the same park village of 91 virus RNA in seropositive rats by reverse transcriptase- cabins. Since HPS was first described in California in 1994, polymerase chain reaction (RT-PCR) assay.8,12,13 Ravkov and there had been 58 cases of HPS in the state; only two of those co-investigators emphasized that the combination of the were visitors to Yosemite. Environmental investigation of genetically diverse genome of the Black Creek Canal virus, the cabins in the park village detected evidence of deer the high seroprevalence of subclinical chronic infection in mouse infestation between the exterior and interior walls cotton rats, and the vast distribution range of the cotton rat of all 91 cabins. In addition, several regional area deer mice in the Americas compared to the limited ranges of the deer (Peromyscus maniculatus) were seropositive for Sin nombre mouse and the rice rat could pose a significant public health virus, the causative agent of HPS throughout the western threat throughout the Americas (Figure 4).14 US. The park’s cabin village was closed indefinitely. The Infected mice copiously shed hantavirus in urine, feces, case fatality rate (CFR) for HPS in the Yosemite outbreak and saliva into the environment, with virions remaining was 33%, which was consistent with the current national viable and infective for up to 15 days.15 All outdoor rodent CFR for HPS of 36%.5 populations are extremely sensitive to climatic conditions and will seek shelter, food, and water whenever forced Hantaviruses in the US: 1993-Present into the built environment by heavy precipitation and Over the past 20 years, 624 cases of HPS have been floodwaters.16 Engelthaler and co-investigators studied described, with most cases (n=612, 98%) caused by the Sin the environmental patterns associated with the initial HPS nombre virus and its rodent reservoir in deer mice, Pero- outbreak in the Four Corners region in 1993.16 The investiga-

188 J La State Med Soc VOL 166 September/October 2014 Figure 2: Hantavirus pulmonary syndrome cases by state of exposure, United States, 1993-2013. A total of 624 cases occurred in 34 states. The state of exposure was unknown for another 28 cases. Source: Knust B., Rollin PE. Twenty-year surveillance for human hantavirus infections, United States. Emerg Infect Dis 2013; 19: 1934-1937.

tors concluded the dramatic increase in high-desert rainfall and the rat-bite fever bacterium, Streptobacillus moniliformis. associated with the 1992-1993 El Niño weather pattern Although plague is often considered a rodent-borne dis- contributed to the risks of Sin nombre virus exposure in the ease, rodents are only the animal reservoirs of the plague region and that annual precipitation predictions would be bacterium and not the vectors of Yersinia pestis, which is of value in designing disease prevention campaigns.16 transmitted by the bites of plague-infected rat fleas. While most other rodent-borne infectious diseases are sporadic DISCUSSION and rare in occurrence, regional cluster outbreaks of leptospirosis and hantavirus pulmonary syndrome (HPS) have Like arthropods, rodents serve as animal reservoir been associated with periods of heavy rainfall and flooding hosts and vectors for several pathogens - including bacte- throughout the US. ria, viruses, and protozoa - and are usually immune to any Leptospirosis (LS) is now the most commonly reported pathogenic effects. The rodent-borne infectious diseases of zoonotic disease worldwide.17 Unanticipated regional greatest medical importance include leptospirosis, hanta- outbreaks of leptospirosis (LS) following heavy rainfall virus, monkeypox, lymphocytic choriomeningitis virus, and flooding events have occurred in the US, such as after extensive Mississippi River flooding in Iowa in 1993.18 Between 100-200 cases of LS are reported every year in the US, with most cases reported from Hawaii, where the incidence is increasing during the rainy seasons and on Kauai, the wettest island.17 Leptospirosis is endemic in Louisiana with reservoirs in rodents and insectivores.18 Ichinose and colleagues reported one of the earliest clusters of six fatal cases of LS-caused Weil’s disease with hepatorenal failure in Louisiana in 1963.18 Leptospires are motile spirochetes of the family Leptospiraceae, with nearly 300 serotypes divided into human pathogenic strains and saprophytic strains.2 The larger group of pathogenic leptospires comprises the Leptospira interrogans sensu lato complex with more than 200 serotypes.2 Although many wild and domestic mammals serve as reservoir hosts for leptospires in their kidneys; rodents, primarily rats and mice, are the most common reservoirs world- Figure 3: Range of the marsh rice rat (Oryzomys palustris), reservoir of wide.2 Asymptomatically infected rodents excrete Bayou virus, United States. Source: US Centers for Disease Control and leptospires in their urine that proliferate in freshwa- Prevention. Hantavirus pulmonary syndrome - United States: Updated ter, mud, moist soil, and wet vegetation and remain recommendations for risk reduction. Morb Mort Week Rep 2002; 51: viable and infectious for months.7 As heavy rains and 1-12.

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leptospirosis or Weil’s disease.2 Weil’s disease is characterized by jaundice, thrombocytopenia, acute renal failure, respiratory distress, and cardiac arrhythmias.2 Weil’s disease occurred in two patients in the triathlon outbreak and has a 5%-10% case fatality rate, with males experiencing more severe illnesses and more fatalities than females.1 The differential diagnosis of LS is broad and includes most febrile infectious diseases, including HPS, and relies on a careful exposure history and clinical suspicion supported by serologic testing. Dipstick screening tests using ELISA to detect serum IgM antibodies to leptospires are quick and easy to perform but do not cover all serotypes of pathogenic L. interrogans. The microscopic agglutination test (MAT) is the most reliable test for LS but is more time-consuming and only offered by reference laboratories, such as the CDC (Figure 1).1,2 Since IgM antibodies cannot be detected until five to seven days into the illness, acute serologic tests may be negative initially and positive later in the illness and during convalescence. Cultures of leptospires from blood or urine are time-consuming and of limited value in clinical management. Antibiotic therapy with oral doxycycline, ampicillin, amoxicillin, erythromycin, or azithromycin is recommended for mild cases; with intravenous therapy with ceftriaxone or penicillin G recommended for severe cases.1,2 Chemoprophylaxis with doxycycline, 200 mg/week, has an efficacy rate of 95% and should be considered for soldiers on tropical training maneuvers and for triathletes participating in competitive swimming or paddling events 1,3 Figure 4: Range of the cotton rat (Sigmodon hispidus), in LS-endemic, tropical areas. reservoir of Black Creek Canal virus in North America. Source: Although vaccines are under development for LS, none US Centers for Disease Control and Prevention. Cotton are universally available today; and the best preventive Rat Habitat in North America. Available at http://cdc.gov/ strategies for LS include drinking boiled or bottled water hantavirus/rodents/cotton-rat.html. and minimizing exposure to rodent-urine contaminated environments by wearing waterproof boots and clothing. flooding saturate soil and surface vegetation, leptospires All cuts and abrasions should be covered with waterproof percolate into ground and surface waters, contaminating dressings. Triathletes participating in distance swimming large inland freshwater systems, including lakes and rivers.3 events, kayakers, and whitewater rafters should wear goggles to prevent transconjunctival transmission and avoid Human LS infections are transmitted most commonly 1,3 by direct or indirect contact of mucous membranes, includ- submersion in and ingestion of river water. All healthcare ing conjunctivae, or abraded or broken skin with urine from providers should maintain high levels of suspicion for LS infected rodents or contaminated surface waters.1-4 Less after flooding events and freshwater immersions, and public common modes of transmission include rodent bites, inges- health officers should immediately promote heightened tion of rodent-urine contaminated water or food, inhalation awareness of leptospirosis outbreaks among all flood- of infectious aerosols of rodent excreta, congenital trans- affected populations. mission, and transmission following breast-feeding, blood Like the leptospires, the hantaviruses (family Bunyaviri- transfusions, and organ transplants.1,2 Person-to-person dae, genus Hantavirus) are rodent- and insectivore-borne transmission is possible but rarely described. pathogens with a worldwide distribution except in Antarc- After an incubation period of 1 to 30 days (mean 7-14 tica. However, unlike leptospirosis, hantavirus infections are days), LS displays a wide spectrum of clinical manifestations never mild or asymptomatic, and all result in severe illnesses ranging from a mildly symptomatic, almost subclinical, ranging from hemorrhagic fevers to hemorrhagic fevers with renal or cardiopulmonary failure with high case fatality infection as in most cases; to a constellation of abrupt fever, 6, 20-22 headache, myalgias, nausea, vomiting, and an occasional rates (36%-76%). Among the Old World hantaviruses maculopapular rash that resolves in a week (as in Case 2 (Hantaan, Dobrava, Seoul, and Puumala viruses), Hantaan of the University of Hawaii outbreak); to a biphasic illness virus was first described as the cause of hemorrhagic fever renal syndrome (HFRS) in US soldiers returning from the that starts with fever, myalgias, and conjunctival suffusion 6 in the first week, and in 5%-10% of cases progresses to icteric Korean War in the early 1950s. All of the Old World hantaviruses target the kidneys and can cause HFRS.6

190 J La State Med Soc VOL 166 September/October 2014 Among the New World hantaviruses (Sin nombre virus, frigerated foods, including pet foods in thick plastic, glass, Andes, Bayou, Black Creek Canal, New York, and Monon- or metal containers with tight-fitting lids; limiting contact gahela), Sin nombre virus (SNV) was first described in 1993 with all wild and peridomestic rats and mice; avoiding all as the cause of a cluster outbreak of severe pneumonia with contact with rodent excreta; safely disposing of all rodent respiratory failure or hantavirus pulmonary syndrome excreta; and modifying the built environment to deter (HPS) in 24 young patients - 18 of whom died (CFR = 76%) rodents from frequenting and colonizing households and - in the Four Corners region of the southwestern US, where workplaces.24 Only spring-loaded traps that kill rodents the borders of Arizona, Colorado, New Mexico, and Utah should be deployed, as live and sticky traps do not kill meet.20 All of the New World hantaviruses target the heart rodents which can bite humans during disposal, transmit- and lungs and can cause HPS.6 Only Andes virus, which is ting hantaviruses and creating open wounds for potential endemic in South America, is capable of human-to-human leptospirosis transmission.24 While struggling to get free of transmission.6 Although the US hantaviruses cause HPS non-lethal traps, rodents chronically infected with lepto- and not HFRS like the Old World hantaviruses, both of the spires or hantavivuses may urinate and/or emit infectious Southeastern hantaviruses, Bayou virus, and Black Creek aerosols contaminating enclosed spaces.24 All areas inhab- Canal virus may cause HPS associated with clinical find- ited by rodents should be cleaned with mops wetted with ings similar to Eurasian strain-caused HFRS, including dilute bleach solutions rather than swept or vacuumed, severe myositis, renal insufficiency with elevated creatinine which could create infectious aerosols. Interested readers are and blood urea nitrogen (BUN) levels, and intra-alveolar referred to the MMWR Recommendations and Reports Series, hemorrhage.8,9 No. 9, 2002, for a listing of all CDC-recommended strategies Humans become infected by inhalation of aerosolized to limit household exposures to rodents, to rodent-proof virions from rodent excreta, or, less commonly, by rodent households and workplaces, to select the best disinfecting bites (1 of 10 cases in the Yosemite HPS outbreak), often solutions to clean-up rodent excreta and nesting materials, during sweeping and clean-up of rodent habitats within and to safely dispose of dead rodents and their nests.24 closed spaces.5 Following an incubation period of 9-33 days (median=14-17 days), patients with HPS develop a prodro- CONCLUSIONS mal febrile syndrome with chills, headache, myalgias, and vomiting followed within three to seven days by a cardio- Healthcare providers should maintain high levels of pulmonary phase with cough, dyspnea, pulmonary edema, suspicion for leptospirosis in patients developing febrile and respiratory failure requiring mechanical ventilation.6 illnesses after contaminated freshwater exposures dur- Associated hematological findings include hemoconcentra- ing flooding events or freshwater recreational events; tion, thrombocytopenia, and left-shifted granulocytosis.15 and public health officers should immediately promote An early, pathognomonic immunological response in HPS heightened awareness of leptospirosis outbreaks among is the appearance of circulating immunoblasts, which herald all flood-affected populations. Clinicians should consider a the end of the prodromal phase and the onset of the cardio- diagnosis of hantavirus pulmonary syndrome in all persons respiratory phase.23 Hypoalbuminemia and elevated hepatic with febrile illnesses that progress rapidly to respiratory enzymes may occur in severe cases.15 insufficiency following rodent exposures in enclosed spaces. Since all available serologic tests for the diagnosis of Public health educational strategies should encourage lim- HPS are broadly cross-reactive with all of the New World iting human contact with all wild and peridomestic rats hantaviruses, specific hantavirus identification requires and mice, avoiding all contact with rodent excreta, safely polymerase chain reaction (PCR) with sequencing with acute disposing of all rodent excreta, and modifying the built specimens collected early in the illness and shipped to refer- environment to deter rodents from colonizing households ence laboratories frozen to preserve RNA for analysis.21 Since and workplaces. The causative agents for leptospirosis and there is no vaccine or specific antiviral therapy - including HPS are widely distributed in the US and will continue to ribavirin - for HPS, only early diagnosis and intensive sup- cause sporadic outbreaks of potentially fatal illnesses, often portive care, potentially including extracorporeal membrane precipitated by cyclical climatic conditions associated with oxygenation (ECMO) and nitric oxide (NO) administration, heavy rainfall and flooding. will reduce the high CFRs from HPS.15 Clinicians should always consider a diagnosis of HPS in persons with febrile REFERENCES illnesses that progress rapidly to respiratory insufficiency following rodent exposures in enclosed spaces. 1. Outbreak of acute febrile illness among athletes participating in Eradicating all rodent reservoir hosts for both pathogen- triathlons—Wisconsin and Illinois, 1998. Morb Mort Week Rep ic leptospires and hantaviruses is both impractical, because 1998; 47: 585-588. of the widespread distribution of rodents, and undesirable, 2. Pavli A, Maltezou HC. Travel-acquired leptospirosis. J Travel because of the importance of rodents as insectivores and Med 2008; 15: 447-453. 24 3. Outbreak of leptospirosis among white-water rafters—Costa Rica, prey for larger predators in the ecosystem. The best and 1996. Morb Mort Week Rep 1997; 46: 577-579. most effective strategies for the control and prevention of 4. Brief Report: Leptospirosis after flooding of a university campus— rodent-borne infectious diseases include storing all unre-

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Hawaii, 2004. Morb Mort Week Rep 2006; 55: 125-127. 5. Hantavirus pulmonary syndrome in visitors to a National Park— Yosemite Valley, California, 2012. Morb Mort Week Rep 2012; 61: 952. 6. Knust B, Rollin PE. Twenty-year surveillance for human hantavirus infections, United States. Emerg Infect Dis 2013; 19: 1934-1937. 7. Morzunov SP, Feldman H, Spiropoulou CF, et al. A newly recognized virus associated with a fatal case of hantavirus pulmonary syndrome in Louisiana. J Virol 1995; 69: 1980-1983. 8. Khan AS, Spiropoulou CF, Morzunov SP, et al. Fatal illness associated with a new hantavirus in Louisiana. J Med Virol 1995; 46: 281-286. 9. Helle B, Goade D, Torrez-Martinez N, et al. Hantavirus pulmonary syndrome, renal insufficiency, and myositis associated with infection by Bayou hantavirus. Clin Infect Dis 1996; 23: 495-500. 10. Ksiazek TG, Nichol ST, Mills JN, et al. Isolation, genetic diversity, and geographic distribution of Bayou virus (Bunyaviridae: hantavirus). Am J Trop Med Hyg 1997; 57: 445-448. 11. Torrez-Martinez N, Bharadwaj M, Goade D, et al. Bayou virus- associated hantavirus pulmonary syndrome in Eastern Texas: identification of the rice rat, Oryzomys palustris, as reservoir host. Emerg Infect Dis 1998; 4: 105-111. 12. Khan AS, Gaviria M. Rollin PE, et al. Hantavirus pulmonary syndrome in Florida: association with the newly identified Black Creek Canal virus. Am J Med 1996; 100: 46-48. 13. Rollin PE, Ksiazek TG, Elliott LH, et al. Isolation of black creek canal virus, a new hantavirus from Sigmodon hispidus in Florida. J Med Virol 1995; 46: 35-39. 14. Rackov EV, Rollin PE, Ksiazek TG, Peters CJ, Nichol ST. Genetic and serologic analysis of Black Creek Canal virus and its association with human disease and Sigmodon hispidus infection. Virology 1995; 210: 482-489. 15. Rhee DK, Clark RP, Blair RJ, Katz JT, Loscalzo J. Clinical Problem Solving—Breathtaking journey. N Engl J Med 2012; 367: 452-457. 16. Engelthaler DM, Mosley DG, Cheek JE, et al. Climatic and environmental patterns associated with hantavirus pulmonary syndrome, Four Corners region, United States. Emerg Infect Dis 1999; 5: 87-94. 17. Katz AR, Buchholz AE, Hinson K, Park SY, Effler PV. Leptospirosis in Hawaii, USA, 199-2008. Emerg Infect Dis 2011; 17: 221-226. 18. Fuortes L, Nettelman M. Leptospirosis: a consequence of the Iowa flood. Iowa Med 1994; 84: 449-450. 19. Ichinose H, Estrada H, Roth EE. Observation on Weil’s disease with a report of six recent deaths in Louisiana. Bull Tulane Univ Med Fac 1963; 22: 81-90. 20. Outbreak of acute illness—Southwestern United States, 1993. Morb Mort Week Rep 1993; 42: 421-424. 21. Two cases of hantavirus pulmonary syndrome—Randolph County, West Virginia, July 2004. Morb Mort Week Rep 2004; 53: 1086-1089. 22. Hantavirus pulmonary syndrome in five pediatric patients—four states, 2009. Morb Mort Week Rep 2009; 58: 1409-1412. 23. Graziano KL, Tempest B. Hantavirus pulmonary syndrome: a zebra worth knowing. Am Fam Physician 2002; 66: 1015-1020. 24. Hantavirus pulmonary syndrome—United States: Updated recommendations for risk reduction. Morb Mort Week Rep Recommendation and Reports Series # 9 2002; 51: 1-12.

Dr. Diaz is Professor of Public Health and Preventive Medicine and Head of the Program in Environmental and Occupational Health Sciences, Schools of Public Health and Medicine, Louisiana State University Health Sciences Center in New Orleans.

192 J La State Med Soc VOL 166 September/October 2014 Dysplastic Cerebellar Gangliocytoma Lhermitte-Duclos Disease Imaging and Magnetic Resonance Spectroscopy

Christian Fauria-Robinson, MD; Rebecca Meyers, MD; Sarah Castillo-Jorge, MD; Jeremy Nguyen, MD; and Enrique Palacios, MD, FACR

Lhermitte-Duclos disease (LDD) is a rare, benign, slow-growing, unilateral mass of the cerebellar cortex. Our case is that of a 71-year-old male with a superior cerebellar lesion consistent with LDD on imaging and Magnetic Resonance Spectroscopy (MRS). It has been reported that MRS can be a valuable diagnostic addition, as it allows for a non-invasive diagnosis and analysis to distinguish a benign lesion, such as an intraparenchymal lesion, and in our case, from a true neoplastic lesion.

INTRODUCTION hypertension, and cardiac arrhythmia. He did not report any relevant family history. On neurologic exam, reflexes Lhermitte-Duclos disease (LDD), also known as dys- were normal at 2+, except for 1+ Achilles tendon reflexes plastic cerebellar gangliocytoma, is a rare, benign, slow- bilaterally. Finger-to-nose testing was normal using both growing, unilateral mass of the cerebellar cortex. Although upper extremities. Heel-to-shin testing revealed slight ataxia this lesion was first described in 1920, debate continues as on the right but was found to be normal on the left. Gait to whether LDD represents a hamartoma, malformation, or testing was remarkable with mild right leg circumduction a neoplasm.1,2 The LDD tumor is composed of hypertrophic during ambulation. Otherwise, the patient had no signs of granular cells, but the degree of differentiation of these CNS lesions, such as cranial nerve palsy, aphasia, or any granular cells is variable.2,3 Although most cases of LDD are other focal neurologic deficits. sporadic, it is closely associated with the autosomal-dom- Upon presentation, the patient underwent computed to- inant Cowden Syndrome (multiple-hamartoma-neoplasm mographic (CT) evaluation for possible intracranial trauma syndrome), with adult onset of LDD considered as a phenol versus cerebrovascular accident. His initial CT scan was variant of Cowden Syndrome11 and with mutations of the performed without contrast and revealed a hypodensity in PTEN gene.4 Typically, patients with LDD can present in the right cerebellar hemisphere measuring 3.2 x 2.9 cm with the third or fourth decade with clinical signs of cerebellar a striated pattern abutting the tentorium with small linear dysfunction, increased intracranial pressure, cranial nerve areas of hyperattenuation that were considered to reflect palsies, and obstructive hydrocephalus caused by the mass traumatic hemorrhages or calcifications. lesion.2 Patients presenting with LDD may have other as- A subsequent magnetic resonance (MR) evaluation sociated signs, including polydactyly, hemangiomas, and was performed with and without contrast to clarify the skull defects.2 In addition, patients may present with signs findings on CT. MR (Figure 1) demonstrated a heteroge- of Cowden Syndrome: trichilemmomas, papillomatous neously hyperintense lesion on DWI without restriction papules, acral keratoses, lipomas, neuromas, hemangio- in the superior portion of the right cerebellar hemisphere mas, scrotal tongue, macrocephaly, breast adenomas and measuring 4.6 x 2.7 x 2.2 cm. The lesion demonstrated het- fibrocystic breast disease, thyroid adenomas, and uterine erogeneous, somewhat striated pattern of T2 hyperintensity leiomyomas.5 and T1 hypointensity, with mixed signal intensity on FLAIR sequences. Gross hyperintensity and punctate hypointensity CASE REPORT were seen on gradient echo, representing calcification. The lesion caused mass effect, with effacement of the superior A 71-year-old man presented to Tulane Medical Center fourth ventricle. Based on the MR findings, the differential with a history of unsteady gait for two weeks and a fall included Lhermitte-Duclos, low-grade glioma, epidermoid on the previous day, during which he hit his head. His tumor, and hypovascular meningioma. medical history was positive only for diabetes mellitus, A correlative proton MR Spectroscopy (1H MRS) exam

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Figure 1: MR images. Axial FLAIR (a), axial T2W (b), and coronal T2 (c) demonstrate a mass in the superior cerebellar hemisphere on the right with characteristic striations. DWI (d) and ADC (e) reveal no evidence of diffusion restriction. Sagittal T1W post- administration of Gd-DTPA (f) revealed the striating mass with no significant enhancement. was performed on the abnormal area in the right superior lesions, allowing non-invasive assessment of the meta- cerebellar hemisphere using both short and long echo times bolic characteristics of abnormal tissue. Proton magnetic (TE) of 144 and 35 ms, respectively (Figure 2).6 The lesion resonance spectroscopy (1H MRS) is useful in analyzing the was compared with normal comparable tissue in the left central nervous system (CNS), due to the high hydrogen hemisphere.7 Within the lesion, there was maintenance of concentration in brain tissue.9 In MR spectroscopy, varying N-acetyl-aspartate (NAA), choline (Cho) and myo-inositol amounts of metabolite are displayed as peaks on a spectral (MI), as well as maintenance of the creatine/choline ratio graph. The greater the area under the curve, the larger the (Cr/Cho). Abnormal elevated lactate was demonstrated amount of metabolite is present in the sample.10 In order with both TE times and was most likely due to increased to obtain this spectrum, free induction decay (FID) signal glucose metabolism.8 is acquired following the application of radio frequency (RF) pulse. The FID signal is analyzed and converted to a DISCUSSION spectrum of unique resonance frequencies corresponding to different metabolites.10,11 These unique resonance frequen- MRS can be a valuable tool in the analysis of intracranial cies are determined by the chemical shifts of the protons

194 J La State Med Soc VOL 166 September/October 2014 Figure 2: Single-voxel spectroscopy utilizing point- resolved spectroscopy (PRESS) on May 21, 2013. The voxel is placed at the lesion in the right cerebellar hemisphere (a). The spectra showed: lactate peak as doublet at approximately 1.3 ppm above the baseline for TE of 35 msec (b) and the lactate peak become inverted at TE of 144 msec (c). Note that NAA, Cr, and Choline peaks retain normal relation.

present in each compound. Using this method, MRS reveals layer, and inner portions of the dysplastic molecular layer.3 the relative concentrations of several key products of brain In our patient, the LDD lesion, NAA, Cho, MI, and the metabolism, such as N-acetyl aspartate (NAA), choline Cr/Cho ratio were all found to be normal. Presence of lactate (Cho), creatine (Cr), myo-inositol (MI), and lactate, among was definitively confirmed, which manifested as a doublet others.6 Comparing metabolites to the normal tissue on the at approximately 1.3 parts per million (ppm). The lactate contralateral side provides characterization of the lesion, doublet had been consistently shown to undergo inversion in addition to analysis of intermetabolite ratios within the from short to long TEs. The maintenance of NAA specific lesion. for brain tissue represented normal neuronal and axonal In Lhermitte-Duclos disease, lesions can be diagnosed viability and essentially ruled out a neoplasm, as well as the by their typical superficial striations on MR imaging; how- remaining normal markers, including the creatinine/choline ever, there are only a few reports of MRS findings for these ration, suggested near-normal tissue. Lactate, however, is lesions.11 The characteristically enlarged folia is a result of not normally present in the brain parenchyma.10,12 The in- a thickened internal granular layer secondary to replace- creased lactate most likely represented increased glycolysis ment by hypertrophic ganglion cells, increased myelina- in the lesion. These findings supported the proliferation tion of the adjacent molecular layer, and diminishment or of normal brain tissue as one would find in a dysplastic complete absence of purkinje cells and astroglial/ganglion gangliocytoma of the cerebellum, Lhermitte-Duclos disease. cells at the interface of the granular and molecular layers.4,11 In our patient, the initial MR of the brain, performed Hence, the superficial striations with T1 hypointensity and with and without contrast, identified an incidental cerebellar T2 hyperintensity correspond to the thinned white matter lesion. MR spectroscopy was an additional valuable tool to with filling cerebral spinal fluid (CSF), widened granular cell increase the diagnostic sensitivity and specificity of the MR

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to differentiate a benign from a malignant process that made a biopsy or surgical procedure unnecessary. In our case, MRS provided a unique assessment and metabolic signature in this unusual benign dysplastic cerebellar gangliocytoma, LDD.11,12 In light of the findings of a benign cerebellar lesion, no intervention was warranted and the patient continued to be asymptomatic six months later.

REFERENCES

1. Klisch J, Juengling F, Spreer J, Koch D, Thiel T, Buchert M, Arnold S, Feuerhake F, Schumacher M. Lhermitte-Duclos disease: assessment with MR imaging, positron emission tomography, single-photon emission CT, and MR spectroscopy. AJNR Am J Neuroradiol 2001; 22:824–830. 2. Nowak DA, Trost HA. Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma): a malformation, hamartoma or neoplasm? Acta Neurol Scand 2002; 105:137–145 3. Barkovich A, Millen, Dobyns W. A developmental and genetic classification for midbrain-hindbrain malformations. Brain. 2009; 132(12): 3199–3230. 4. Zhou XP, Marsh D, Morrison C, Chaudhury A, Maxwell M, Reifenberger G, Eng C. Germline Inactivation of PTEN and Dysregulation of the Phosphoinositol-3-Kinase/Akt Pathway Cause Human Lhermitte-Duclos Disease in Adults. Am J Hum Genet. 2003; 73(5): 1191–1198. 5. Gammon A, Jasperson K, Kohlmann W, Burt RW. Hamartomatous polyposis syndromes. Best Pract Res Clin Gastroenterol. 2009; 23(2):219-31 6. Majós C, Julià-Sapé M, Alonso J, Serrallonga M, Aguilera C, Acebes JJ, Arús C, Gili J. Brain tumor classification by proton MR spectroscopy: comparison of diagnostic accuracy at short and long TE. AJNR Am J Neuroradiol. 2004; 25(10): 1696-704. 7. Möller-Hartmann W, Herminghaus S, Krings T, Marquardt G, Lanfermann H, Pilatus U, Zanella FE. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology. 2002; 44(5): 371-81. 8. Thomas B, Krishnamoorthy T, Radhakrishnan VV, Kesavadas C: Advanced MR Imaging in Lhermitte-Duclos disease: moving closer to pathology and pathophysiology. (Diagnostic Neuroradiology) Neuroradiology (2007) 49:733-738. 9. Singh AK, Wang A-M, Sanders W. Magnetic resonance spectroscopy of the brain. Applied Radiology. 2002; 31(12): 58-65. 10. Wirt M, Petermann G. Magnetic resonance spectroscopy: A basic guide to data acquisition and interpretation. Applied Radiology. 2003; 32(4): 25-30. 11. Nagaraja S, Powell T, Griffiths PD, Wilkinson ID. MR imaging and spectroscopy in Lhermitte-Duclos disease. Neuroradiology. 2004; 46(5): 355-8. 12. Wu CH, Chai JW, Lee CH, Chen WH, Lee T, Chen CC. Assessment with magnetic resonance imaging and spectroscopy in Lhermitte- Duclos disease. J Chin Med Assoc. 2006 Jul;69(7):338-42.

Drs. Fauria-Robinson, Castillo-Jorge, Nguyen and Palacios are from the Department of Radiology at the Tulane University School of Medicine in New Orleans. Dr. Meyers is a resident in the department of Pediatrics at UCLA in Los Angeles, California.

196 J La State Med Soc VOL 166 September/October 2014 Spontaneous Rectus Sheath Hematoma: Two Variant Cases

Kamesh Sivagnanam, MD; Vatsal Ladia, MD; Vedang Bhavsar, MD; Jeffery Summers, MD; Timir Paul, MD, PhD

We present two variant cases of spontaneous rectus sheath hematoma (SRSH). A 71-year-old woman presented with ST elevation myocardial infarction and was found to have multivessel coronary artery disease. She was treated with aspirin, clopidogrel, eptifibatide, and heparin. Heparin was continued while preoperative workup for coronary artery bypass grafting was done. She developed a large 20x10 cm actively bleeding SRSH while on heparin. It was surgically evacuated. The second case represents an atypical cause of SRSH. A 64-year-old woman with Wegener’s Granulomatosis presented with anemia and abdominal pain. Abdomi- nal CT showed a large 22 cm SRSH without active bleeding that was treated conservatively. Both patients did well on follow-up. The incidence of SRSH is likely to increase in the coming years with the increasing use of antithrombotic agents for many disease processes. Clinicians should be aware of typical and atypical presentations of SRSH and its variant management options.

INTRODUCTION to 35 seconds). Eptifibatide was stopped after 18 hours, and heparin was continued. Her platelet count at this time was Spontaneous rectus sheath hematoma (SRSH) is an mildly reduced (lowest count of 120/mm3). On day four of uncommon cause of abdominal pain, with an estimated her hospital stay, she developed severe left upper quadrant incidence of 1 in 10,000 emergency visits.1 Approximately abdominal pain associated with a palpable mass. An ultra- 73%-100% cases of SRSH are associated with anticoagula- sound of the abdomen showed fluid collection in this area tion2 and are rarely associated with vasculitis.3,4 that measured 8.7 cm x 5.6 cm. A CT scan confirmed the presence of a rectus sheath hematoma with extravasation of CASE 1 contrast, suggesting active bleeding (Figure 1). There was a significant increase in the size of the hematoma measuring A 71-year-old female presented with chest pain radiat- 20 cm x 10 cm by CT scan, which was performed within two ing to her left arm. She had a history of myocardial infarc- hours of the ultrasound. Her hemoglobin dropped from 11.1 tion and drug-eluting stent placement to the right coronary g/dl to 8.1 g/dl during this time (normal hemoglobin for artery and left anterior descending artery (LAD). Other women - 12.1-15.1 g/dL). Heparin was stopped, and she was medical problems included hypertension and tobacco use. transfused with two units of packed red blood cells (PRBC). Her medications included metoprolol, ranolazine, simvas- The rectus sheath hematoma was surgically evacuated and tatin, aspirin, and clopidogrel. Her vitals were stable, and approximately 500 cc of non-clotted old blood was removed. physical examination was unremarkable. An EKG showed After suturing the incision site, a wound vac was placed ST segment elevation in anterior leads. Troponins were inferiorly in the left upper quadrant draining the rectus mildly elevated at 0.03 ng/ml (normal – <0.02 ng/ml). sheath. She recovered well and was hemodynamically stable She was given full dose of aspirin and a loading dose of with no further evidence of subsequent bleeding over the clopidogrel. An emergent left heart catheterization showed next seven days. Her wound vac was then removed, and she in-stent thrombosis of the LAD stent and multivessel coro- underwent CABG. She recovered well postoperatively. Since nary artery disease. She underwent balloon angioplasty the patient had the hematoma removed and had no further to the LAD with good angiographic results. Intravenous evidence of an active bleed and was hemodynamically bivalirudin (bolus and infusion) was used as anticoagulation stable, she was discharged on aspirin 81 mg and clopidogrel during the procedure. It was felt that she would have bet- 75 mg every day. ter outcome from coronary artery bypass grafting (CABG) compared with multivessel percutaneous intervention. Post- CASE 2 catheterization, she was started on eptifibatide and heparin drips. Her aPTT ranged between 24-80 seconds (normal – 25 A 64-year-old woman was referred to the ER by her

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Figure 1: Transverse and sagittal views showing the presence of a large (20 cm x 10 cm) spontaneous rectus sheath hematoma.

Figure 2: Transverse and sagittal views showing the presence of a large (22 cm x 2 cm) spontaneous rectus sheath hematoma.

primary care physician with hemoglobin of 5.8 g/dl (normal bin improved with transfusion to 10 g/dl. Her symptoms 12.1-15.1 g/dL) and abdominal discomfort. The abdominal improved, and she was hemodynamically stable. She was pain was present over three weeks and localized to the discharged with close follow-up in seven days at outpatient left lower quadrant. She also complained of worsening clinic. At follow-up, her hemoglobin remained stable; her fatigue over two weeks. She denied any history of trauma bruising and abdominal pain had improved. or bleeding disorders. Additionally, she had a recent upper respiratory infection with non-productive cough. She had a DISCUSSION renal biopsy confirming Wegener’s Granulomatosis and was taking prednisone 25 mg daily and mycophenolate 1 gram The most common risk factor for the development of twice daily. Wegener’s was originally diagnosed when she SRSH is anticoagulation and over anticoagulation increases presented with rapidly progressive renal failure two months the risk substantially.5 Triggering factors, such as cough, are earlier. She was not on dialysis. She also had hypertension, usually present in up to 70% of the patients with SRSH.6 dyslipidemia, depression, and gastroesophageal reflux The first patient was anticoagulated for five days with disease. She was taking citalopram, famotidine, labetalol, intravenous heparin. Her aPTT was in the therapeutic range. and pravastatin. Her vital signs were stable on admission. She was given aspirin and a loading dose of clopidogrel, On examination, there was visible bruising and associated the effect of which lasts for five to seven days. Although she tenderness over the left lower quadrant. Her hemoglobin was treated initially with bivalirudin and eptifibatide, those was 5.3 mg/dl. She was started on intravenous fluid and are less likely to have triggered the hematoma formation as was transfused with four units of PRBC. CT of the abdomen they have a short half-life. Moreover, she had a mild drop showed a large rectus sheath hematoma measuring 22 cm in platelets (lowest count of 120/mm3) possibly related to in the cranio-caudal dimension (Figure 2). Her hemoglo- heparin infusion in the absence of heparin-induced throm-

198 J La State Med Soc VOL 166 September/October 2014 bocytopenia. The SRSH was therefore possibly attributable pain in the setting of anticoagulation. On the other hand, to mild thrombocytopenia, inhibited platelets from aspirin, although vasculitis-related SRSH is uncommon, diagnosis and clopidogrel and continued anticoagulation with hepa- is facilitated by high clinical suspicion and imaging of the rin. The use of multiple anti-thrombotic agents substantially abdomen by CT scan. Clinicians should be aware of typical increases the risk of bleeding complications when compared and atypical presentations of SRSH and its variant manage- to a single agent. ment options. Vasculitis as a cause of SRSH is relatively uncommon. To our knowledge, only one case of SRSH was described REFERENCES with PR3-ANCA-(Proteinase-3-Antineutrophil Cytoplasmic Antibody) associated vasculitis.4 PR3 is the most common 1. Bear G, Robles M, Cernuda B et al. [Spontaneous Hematoma of antigen target for ANCA in Wegeners Granulomatosis. the Sheath of the Rectus Abdominis Muscle: a Challenge for the Other vasculitides that have been associated with SRSH Diagnosis]. Emergencias 2000; 4:269–71. Spanish include mixed cryoglobulinemia in hepatitis C infection.3 2. Dag A, Ozcan T, Turkmenoglu O et al. Spontaneous Rectus Sheath Hematoma in Patients on Anticoagulation Therapy. Ulus Travma Our second patient was not on anticoagulation. Al- Acil Cerrahi Derg 2011; 3:210-4 though her platelet counts were normal, it was postulated 3. Moschella CM, Palmieri I, Bartolucci P et al. Spontaneous rectus that she probably had mildly dysfunctional platelets be- sheath hematoma in HCV mixed cryoglobulinemia requiring cause of her renal failure. The presence of vasculitis and emergency treatment. G Chir 2002; 8-9:331-3 concomitant coughing were risk factors that probably led 4. Sakaguchi Y, Niihata K, Yasuda K et al. [Autopsy case of PR3- to the SRSH. ANCA-associated vasculitis complicated with rectus muscle As in both cases described above, SRSH usually presents hematoma]. Nihon Jinzo Gakkai Shi 2009; 5:550-6. Japanese as abdominal pain and swelling. Both ultrasound and ab- 5. Fujikawa T, Kawato M, Tanaka A. Spontaneous rectus sheath dominal CT can be used for the diagnosis of SRSH, with CT haematoma caused by warfarin-induced over anticoagulation. BMJ Case Rep. Advance online publication. doi: 10.1136/ being the gold standard for the diagnosis with a sensitivity bcr.07.2011.4533 7 and specificity of 100%. 6. Salemis NS. Spontaneous rectus sheath hematoma presenting Most SRSH can be managed conservatively with dis- as acute surgical abdomen: an important differential in elderly continuation of anticoagulation, volume resuscitation, blood coagulopathic patients. Geriatr Gerontol Int. 2009; 2:200-2 transfusion, and observation.8 With conservative measures, 7. Gallego A Aguayo JL, Flores B et al. Ultrasonography and small and uncomplicated SRSH usually resolves spontane- computed tomography reduce unnecessary surgery in abdominal ously.9 Even in the setting of a large hematoma, conservative rectus sheath haematoma. Br J Surg 1997;84:1295–7 management is still an option, as long as there is no evidence 8. Berna JD, Zuazu I, Madrigal M et al. Conservative treatment of large rectus sheath hematoma in patients undergoing of active bleeding and the resultant anemia is corrected. anticoagulant therapy. Abdom Imaging 2000; 3:230–234 Active bleeding and hemodynamic compromise are 9. Titone C, Lipsius M, Krakauer JS. Spontaneous Hematoma of indications for aggressive intervention. Open surgery with the Rectus Abdominis Muscle: Critical Review of 50 Cases with evacuation of the hematoma is often not recommended, as Emphasis on Early Diagnosis and Treatment. Surgery 1972;72:568- there is a theoretical propensity for more bleeding secondary 72 to the reduced tamponade effect from the removal of the 10. Donaldson J, Knowles CH, Clark SK et al. Rectus sheath hematoma.10 In spite of CT-confirmed contrast extravasa- haematoma associated with low molecular weight heparin: a case tion, the first patient did not have recurrent bleeding with series. Ann R Coll Surg Engl 2007; 3:309–312 the placement of a wound vac, which provides the exact op- 11. Smithson A, Ruiz J, Perello R et al. Diagnostic and management of spontaneous rectus sheath hematoma. Eur J Intern Med 2013; posite effect of tamponade, establishing a negative pressure Advance online publication. doi: 10.1016/j.ejim.2013.02.016 around the vessels. Our patient had a wound vac without 12. Hildreth DH. Anticoagulation therapy and rectus sheath any detrimental hemodynamic effects, which questioned hematoma. Am J Surg 1972;124: 80–6 the theoretical need for tamponade. Mortality from SRSH ranges between 4% and 25%. The more severe the hemodynamic effects, larger the hematoma, Drs. Sivagnanam and Ladia are Residents in the Department of and less aggressive the management of severe SRSH, the Internal Medicine at East Tennessee State University in Johnson City, 11,12 more the mortality. Tennessee. Dr. Bhavsar is a Fellow in the Department of Cardiology, Dr. Summers is a Professor in the Department of Internal Medicine, and CONCLUSION Dr. Paul is Assistant Professor and Director of Cardiac Rehabilitation and Prevention at East Tennessee State University. Peri-procedural anticoagulation with multiple anti- platelet agents and anticoagulants during cardiac catheterization is a risk factor for SRSH. With more diseases being treated with antithrombotic agents and presence of multiple new and old agents in the market, SRSH may occur more commonly than before. SRSH should be in the differential diagnosis of elderly patients who present with abdominal

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Bisphosphonate-Related Osteonecrosis of the Jaw

Camille Robichaux; Menchu Ong, MD; Diana Veillon, MD; Stavan Patel, DDS, MD; James Cotelingam, MD

Although there has been a growing body of literature about bisphosphonates since 1969, it was not until 2003 that treatment with this medication was associated with osteonecrosis of the jaw. Presented herein is such a case.

CASE REPORT of infection, plus at least one severe complication, such as pathologic fracture or extra-oral fistula.1 A 57-year-old female with history of diabetes mellitus Bisphosphonates were first recognized as therapeutic and breast cancer with osteoporosis was treated with IV agents in 1969, but it was not until 2003, when BRONJ was bisphosphonates for five years. She has a history of recurrent described.2,3 BRONJ occurs in 1 in 10,000 patients who painful infections of the posterior right mandible. Infections receive BP therapy.4,5 However, a number of factors predis- intermittently resolved with antibiotic therapy and antimi- pose to this condition. These include the type of BP used crobial mouthwash but continued to recur. Based on the (amino vs. non-aminobisphosphonates), length of therapy, clinical and radiological findings (Figure 1), a diagnosis of concomitant therapy with steroids, radiotherapy, chemo- bisphosphonate related osteonecrosis of the jaw (BRONJ) therapy, dental procedures, and co-morbidities including was made and sequestrectomy performed. diabetes mellitus, coagulation disorders, hypercalcemia, Histologic examination of the removed tissue showed and obesity.6-8 osteonecrosis with chronic inflammatory changes in the Although the exact mechanism is uncertain, a number periosteum, confirming the diagnosis of BRONJ. (Figure 2) of factors seem to play a role in the pathogenesis of BRONJ. Bisphosphonates act by suppressing bone turnover by inhi- DISCUSSION bition of osteoclastic and osteoblastic activity and chelation of divalent cations, such as calcium. Cases of BRONJ in the Bisphosphonates are used for treatment of hypercalce- maxilla are well reported in the literature, but the mandible mia and excessive bone resorption, including osteoporosis, is particularly predisposed to BRONJ due to its vascular- postmenopausal status, metastatic carcinoma, multiple ity, affinity for trauma, local infection, and high turnover myeloma, Paget’s disease, and inheritable skeletal disor- estimated at up to 20 times that of the normal iliac crest.9 ders, such as osteogenesis imperfecta. In 2003, Marx first Unaffected areas of the jaw in patients with BRONJ have identified osteonecrosis of the jaw associated with biphos- prominent trabecular structures and smaller and fewer Ha- phonate therapy. Subsequently, the American Association versian Canals.10 Aminobisphosphonates (alendronate and of Oral and Maxillofacial Surgeons (AAOMS)1 named three pamidronate) also have an antiangiogenic effect,3,4 which, criteria for the diagnosis: current or previous treatment of while preventing metastatic disease to the bone, may play the patient with a bisphosphonate (BP), exposed necrotic a role in the pathogenesis. In short, the combination of de- bone in the maxillofacial region that has persisted more creased bone turnover, decreased angiogenesis, prominent than eight weeks, and absence of radiation therapy to the bacterial flora, and frequent mechanical activity lead to a jaw. BRONJ is subdivided into four main stages. Stage 0 is predisposition to BRONJ. diagnosed in patients with no clinical evidence of necrotic A number of therapeutic options are available to treat bone who complain of pain and altered neurosensory func- BRONJ. Per the 2009 update to the AAOMS guidelines, the tion. Loosening of teeth in the absence of chronic periodontal goals of treatment for patients with BRONJ are preservation disease may also be present. Stage 1 denotes a patient with of quality of life while supporting the ongoing treatment. exposed necrotic bone lacking signs of infection. Stage 2 This includes controlling pain and secondary infection, indicates exposed necrotic bone with pain and clinical signs while preventing extension of the current lesion and/or of infection. Stage 3 is reserved for those patients with signs development of new lesions.11 Prevention is key since the

200 J La State Med Soc VOL 166 September/October 2014 Figure 1: Orthopantogram (cone beam computed tomography) of a partially edentulous maxilla and mandible. Right posterior edentulous body and proximal ramus of the mandible showing 3x2 cm non-viable bony sequestrum surrounded by necrotic tissue. The lesion is noted to extend from the oral cavity superiorly and to the inferior alveolar canal inferiorly. The inferior alveolar canal is a linear hypodensity traveling through the ramus and body of the mandible.

Figure 2: A. Acellular necrotic bone (sequestrum) from edentulous part of mandible. Note lack of viable marrow elements, rimming osteoblasts, osteoclasts, bony remodeling, or metastatic carcinoma (hematoxylin-eosin, original magnification x 40). B. Absence of osteocytes in lacunar spaces (hematoxylin-eosin, original magnification x 40). C. Chronic inflammation of periosteal soft tissue. Note reactive (polyclonal) increase in CD138 positive plasma cells (CD138 immunohistochemical stain, original magnification x 40). condition is seldom curable. Before commencement of BP reduction in the diameter of the initial lesion.13 It should be therapy, patients should undergo a clinical and radiographic noted, however, that with the minimally invasive protocol dental examination. Any necessary dental procedures described, many patients remained with exposed bone, should be completed before onset of BP therapy. On detec- despite reduction in size. Surgical treatment is reserved for tion of BRONJ, BP therapy should be discontinued and the Stage 3 or higher as aggressive surgery may result in larger jaw stabilized to reduce symptoms.4,12 areas of exposed bone and worsening BRONJ. Hyperbaric Treatment for Stage 1 and 2 BRONJ is typically medical. oxygen (HBO) is effective when used in conjunction with A recent prospective clinical trial by Moretti et al. used anti- other therapies and may neutralize the antiangiogenic ef- biotic therapy (Augmentin/Flagyl or Ciprofloxacin/Flagyl) fects of aminobisphosphonates. While hyperbaric oxygen for the acute phase of infection, in addition to antiseptic oral therapy is not indicated as the primary method of treatment rinses, (Chlorhexidine digluconate 0.12% and essential oils) for BRONJ, a recent randomized controlled trial by Frie- and achieved control of pain with statistically significant berger et al. showed a decreased mean time to improvement

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in HBO-treated patients, a faster decrease in pain score, and Radiol Endod 2011; 112: 777-782. no decrease in quality of life scores when compared to the 14. Freiberger JJ, Padilla-Burgos R, McGraw T, et al. What is the Role control group.14 Low-level laser therapy may be used to of Hyperbaric Oxygen in the Management of Biphosphonate- remove dead tissue and improve the reparative process.4 Related Osteonecrosis of the Jaw: A Randomized Controlled Trail of Hyperbaric Oxygen as an Adjunct to Surgery and antibiotics. A thorough microscopic examination of surgically re- J Oral Maxillofac Surg 2012; 70:1573-1583. moved tissue is necessary to confirm the diagnosis. Patients 15. Poulias E, Melakopoulos I, Tosios K. Metastatic breast carcinoma are often placed on BPs for metastatic disease, which, when in the mandible presenting as a periodontal abscess: a case report. affecting the mouth, can present with symptoms similar to Journal of Medical Case Reports 2011; 5:265. BRONJ. Therefore, metastatic disease should be considered in the differential diagnosis,15 and the latter excluded on debrided bone and soft tissue. There were no signs of Dr. Robichaux is a Medical Student, Dr. Ong is Assistant Clinical metastatic disease on microscopic examination of bone tis- Professor of Pathology, Dr. Veillon is a Clinical Professor of Pathology, sue from our patient. Hence, the diagnosis was confirmed Dr. Patel is House Officer, and Dr. Cotelingam is Professor of Pathology as BRONJ. A point of interest in this case is its overlapping at Louisiana State University Health Sciences Center in Shreveport. AAOMS criteria, including absence of ulceration and concomitant infection, as observed in the biopsy

REFERENCES

1. American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of Jaws. J Oral Maxillofac Surg 2007; 65:369-376. 2. Russell RG. Biphosphonates: The first 40 years. Bone 2011; 49(1):2- 19. 3. Marx RE. Pamidronate (Aredia) and Zoledronate (Zometa) induced avascular necrosis of the jaws. A growing epidemic. J Oral Maxillofac Surg 2003; 61:115-118. 4. Petcu et al. Bisphosphonate-related osteonecrosis of jaw: an antiangiogenic side-effect? Diagnostic Pathology 2012; 7:78 5. Wehrhan F, Stockmann P, Nkenke E, et al. Differential impairment of vascularization and angiogenesis in biphosphonate-associated osteonecrosis of the jaw-related mucoperiosteal tissue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011; 112(2):216-221. 6. Vescovi P, Merigo E, Meleti M, et al. Bisphosphonate-related osteonecrosis of the jaws: a concise review of the literature and a report of a single-centre experience with 151 patients. Journal of Oral Pathology and Medicine 2012; 41:214-221. 7. Favus MJ. Diabetes and the risk of osteonecrosis of the jaw. J Clin Endocrinol Metab 2007; 92:817-818. 8. Woo SB, Hellstein JW, Kalmen JR. Systematic Review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144:753-761. 9. Han ZH, Palnitkar S, Rao DS et al. Effects of ethnicity and age of menopause on the remodeling and turnover of the iliac bone: implications of mechanisms of bone loss. J Bone Miner Res 1997; 12:498-508. 10. Favia G, Pilolli GP, Maiorano E. Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaw: An analysis of 31 cases with confocal laser scanning microscopy. Bone 2009; 45:406-413 11. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrota B. American Association of Oral and Maxillofacial Surgeons Position Paper on Biphosphonate –related Osteonecrosis of the Jaws-2009 Update. J Oral Maxillofac Surg 2009; 67:2-12, Suppl. 12. Edwards BJ, Gounder M, McKoy JM et al. Pharmacovigilance and reporting oversight in US-FDA fast tract process: Bisphosphonates and osteonecrosis of the jaw. Lancet Oncol 2008; 9:1166-1172. 13. Moretti F, Pellicioni GA, Montebugnoli L, Marchetti C. A prospective clinical trial for assessing the efficacy of a minimally invasive protocol in patients with biphosphonate –associated osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral

202 J La State Med Soc VOL 166 September/October 2014 Aberrant Left Main Bile Duct Draining Directly Into the Cystic Duct or Gallbladder: An Unreported Anatomical Variation and Cause of Bile Duct Injury During Laparoscopic Cholecystectomy

Hosein Shokouh-Amiri, MD, FACS, FICS; Mohammad Kazem Fallahzadeh, MD; Sophia T. Abdehou, MD; Miles Sugar, MD; Gazi B. Zibari, MD, FACS

Despite recent advances, iatrogenic bile duct injury remains one of the most common complications of laparoscopic cholecystectomy. Aberrant biliary tract anatomy is one of the major risk factors for iatrogenic bile duct injury. In this case report, for the first time, we report a case of aberrant left main bile duct draining directly into the cystic duct or gallbladder that presented with bile duct injury after laparoscopic cholecystectomy. We hope that the diagnostic and management approach used in this case will help physicians to identify and manage their patients should they face such a rare anatomy.

INTRODUCTION through the Jackson-Pratt (J-P) drain. Therefore, she was taken back to the operating room the same day, but once Despite improvements in laparoscopic technology and again, no identifiable source of bile leak was found. Hence, enhanced expertise in performing laparoscopic procedures, a T-tube was inserted and intraoperative cholangiogram iatrogenic bile duct injury (IBDI) remains one of the most was obtained, which was initially interpreted as normal common complications of laparoscopic cholecystectomy ductal anatomy with no evidence of leak (Figure 1-A). The (LC).1-3 Aberrant biliary tract anatomy is one of the major abdomen was closed; however, the patient continued to risk factors for IBDI during LC.2,3 We report a case of an have a bile leak postoperatively. With the suspicion of a bile aberrant anatomy of the biliary ductal system that resulted duct anomaly, even though there was a T-tube in place, an in a bile leak during LC at a local hospital. While the sur- endoscopic retrograde cholangiopancreatography (ERCP) geon observed the bile leak, he was not able to identify the was performed that was interpreted at the local hospital as source of the bile leak by conventional diagnostic workup normal without any radiologic evidence of extravasation and referred the patient to our center due to continued bile (Figure1-B). Sphincterotomy was performed, and a biliary leak. By implementing a novel approach, we were able to stent was placed to address any possible unidentified bile identify that the bile leak was due to the unavoidable injury duct damage. The patient was observed for a few weeks with of an aberrant bile duct that, to our knowledge, has not been a J-P drain in place to control biliary fistula. At this time, reported previously in the literature published in English. the patient was transferred to our hepatopancreatobiliary center seven weeks after the initial LC. With the high index CASE REPORT of suspicion for the presence of an aberrant biliary anatomy and since all other relevant studies such as T-tube cholan- A 71-year-old Caucasian woman underwent LC due giogram and ERCP have already proven to be non-helpful, a to gallstone pancreatitis. The procedure was converted to cholangiogram through J-P drain was performed. This chol- open due to bile leak in the surgical field and the inability angiogram finally resolved the diagnostic conundrum and to find the source of the leak. A duct of Luschka was identi- illustrated a completely transected left main hepatic duct fied and ligated. A drain was placed, and the abdomen was without any communication to the remaining part of the bili- closed. Postoperatively, she continued to have a bile leak ary system (Figure 1-C). A hepatobiliary iminodiacetic acid

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Figure 1: Panel 1a: Intraoperative T-tube cholangiogram showing apparently normal bile duct anatomy without any leak while the patient continued to have copious bile leak. Right anterior hepatic duct (white arrowhead) was mistaken as right main hepatic duct. Right posterior hepatic duct (black arrowhead) was mistaken as left main hepatic duct. Black arrow shows common bile duct and white arrow with black outline shows cystic duct stump. Panel 1b: Postoperative ERCP findings showing again no leak and similar anatomical findings as during surgery (patient continues to have copious bile leak). Panel 1c: Cholangiogram 50 days after surgery via J-P drain showing the exact location of leak from a transected left main hepatic duct (white arrow) without any relation to rest of biliary system.

Figure 2: Panel 2a: Injection directly into left biliary system during final operation showing the opacification of transected left main hepatic duct (white arrow). Panel 2b: Injection via T-tube during final operation showing the right anterior hepatic duct (white arrowhead), the right posterior hepatic duct (black arrowhead), and the left main hepatic duct (white arrow) simultaneously in one image.

(HIDA) scan was not considered for this patient, since it was T-tube in order to reconstruct the whole bile duct anatomy already known that the patient had bile leak, and a HIDA in one picture (Figure 2-B). After ascertaining the detailed scan is not accurate enough to show the exact anatomical anatomy, a Roux-en-Y selective left hepaticojejunostomy site of the leak. The patient was taken back to the operating was performed. The patient did well postoperatively, and room. After identifying the retracted left hepatic duct that the bile leak was resolved. Subsequently, both the T-tube was the source of bile leak, a confirmatory sequential chol- and J-P drain were removed a few days after the surgery. angiogram via transected left hepatic duct (Figure 2-A) and The patient is doing well 43 months after the surgery. through the T-tube was performed. The contrast was kept in the transected duct while injecting the contrast via the

204 J La State Med Soc VOL 166 September/October 2014 DISCUSSION ography during cholecystectomy may reduce the chance of IBDI,6 in a recent population-based data study by Sheffield LC has become the operation of choice for a variety of et al.,7 which retrospectively evaluated 92,932 patients with gallbladder disorders, most commonly symptomatic cho- cholecystectomy, intraoperative cholangiography was not lelithiasis.1-3 Although LC has an acceptable safety profile, found to be effective in the prevention of IBDI. it could result in major complications with high rates of There is a growing body of evidence demonstrating morbidity and mortality.2,5 One of the most common major the importance of early referral of IBDI patients to tertiary complications of LC is IBDI.2,5 Aberrant biliary tract anatomy care centers, which provide a multidisciplinary approach to is one of the major risk factors for IBDI during LC.2,3 Misiden- treat IBDIs.5,8 Besides being helpful in diagnosis, endoscopic tification of the aberrant bile ducts as the cystic duct is the and percutaneous radiological techniques can be used for cause of 70%-80% of all IBDIs during LC.2 Therefore, proper primary treatment of IBDIs.2 Surgical management of IBDIs identification of biliary anatomy before clipping, ligating, or is usually reserved for the cases that do not respond to or dividing the structures during LC is of utmost importance.2 are not suitable candidates for radiological or endoscopic Although direct drainage of aberrant right bile ducts into the techniques.2,5 A transected bile duct draining a segment cystic duct has been previously reported,4 to our knowledge, or a smaller part of the liver can be safely ligated before it our case is the first report of direct drainage of an aberrant becomes colonized with bacteria and fungi. Subsequently, left main bile duct into the cystic duct or gallbladder. the draining segment of the liver will be atrophied without Only 25%-32% of IBDIs are recognized during LC.5 Most any significant sequelae. However, if the transected bile IBDIs are diagnosed after LC.2,5 Radiological investigations duct is colonized, ligation of the duct is contraindicated for evaluation of IBDIS include HIDA scan, ERCP, percuta- because it could lead to segmental cholangitis with the need neous transhepatic cholangiography (PTC), and magnetic for prolonged antibiotic therapy, significant morbidity, and resonance cholagniopancreatography (MRCP).2 PTC is help- even resection of the affected segment of the liver. In our ful in evaluating the biliary tract anatomy proximal to the case, since the left main hepatic duct was transected for an site of injury.2 ERCP can demonstrate the injured bile ducts extended period of time and was most probably colonized, and be used to stent the injuries of major hepatic ducts if the we decided to do selective left Roux-en-Y hepaticojejunos- common bile duct is not completely transected or ligated.2,5 tomy. Roux-en-Y hepatico/choledoco jejunostomy is the MRCP can be useful for preoperative evaluation of IBDI in most widely used surgical operation for reconstruction of patients requiring surgical reconstruction by providing an IBDIs.1,2,5 Roux-en-Y hepaticojejunostomy has been reported excellent delineation of biliary anatomy.2,5 However, MRCP to have favorable success rates with good short- and long- can miss small biliary leaks.5 In this case, T-tube cholangi- term outcomes if done at specialized hepatobiliary surgery ography and ERCP did not initially diagnose the aberrant centers. In a study by Schmidt et al.,9 successful long-term left main hepatic duct that was cut during LC. Looking results were achieved in 50 (93%) out of 54 patients with retrospectively at this case, it could be observed that the left major bile duct injuries who underwent roux-en-Y hepa- biliary system is actually missing in T-tube cholangiography tiocojejunostomy. However, biliary reconstruction in the and ERCP images (Figures 1A and 1B). Also, the branches presence of peritonitis, combined vascular and bile duct of the biliary system, which were mistakenly interpreted injuries, and injury at or above the level of the biliary bifur- as left biliary system, are, in reality, the branches of the cation were among the major predictors of poor outcome right posterior biliary system. Furthermore, the fact that after roux-en-Y hepatiocojejunostomy. Liver resection has no leak from the biliary system during ERCP and T-tube been rarely used in the management of patients who have cholangiogram was observed made this scenario even more combined IBDI and major vascular injury.10,11 Liver trans- complicated. These findings should have raised the possi- plantation has been used for treatment of a small number bility of an existing aberrant biliary ductal system draining of patients who develop acute or chronic liver failure due directly into either the cystic duct or the gallbladder. The to the catastrophic complication of IBDI, such as hepatic final diagnosis in our case resulted from a high index of necrosis in the presence of concomitant portal vein and/ suspicion and a cholangiography via J-P drain. Usually, or hepatic artery damage or secondary biliary cirrhosis as a false tract forms around the J-P drain and the site of the a consequence of inappropriate management of transected transected bile duct that facilitates cholangiogram through bile duct with too lengthy stent placement or inadequate the J-P drain. We suggest that our approach should be used treatment of stenotic hepaticojejunostomy.8 for cases of IBDI in whom ERCP, T-tube cholangiography, or We are reporting an extremely rare anatomical varia- PTC do not show the location of bile duct injury. It should tion of biliary system for the first time. We hope that the be mentioned that the transection of this type of bile duct diagnostic and management approach used in this case will anomaly is unavoidable during either open or LC. There- help other physicians to identify and manage their patients fore, time and accuracy of diagnosis plays a major role in should they face such a rare anatomy. the management of transection of this type of complication. There is controversy about the role of routine cholangi- REFERENCES ography during cholecystectomy in the prevention of IBDI. Although some studies suggest that intraoperative cholangi- 1. Sicklick JK, Camp MS, Lillemoe KD, et al. Surgical management of

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bile duct injuries sustained during laparoscopic cholecystectomy: perioperative results in 200 patients. Ann Surg 2005;241:786-92; discussion 93-5. 2. Jablonska B, Lampe P. Iatrogenic bile duct injuries: etiology, diagnosis and management. World J Gastroenterol 2009;15:4097-104. 3. Strasberg SM. Avoidance of biliary injury during laparoscopic cholecystectomy. J Hepatobiliary Pancreat Surg 2002;9:543-7. 4. Mortele KJ, Ros PR. Anatomic variants of the biliary tree: MR cholangiographic findings and clinical applications. AJR Am J Roentgenol 2001;177:389-94. 5. Lau WY, Lai EC, Lau SH. Management of bile duct injury after laparoscopic cholecystectomy: a review. ANZ J Surg 2010;80:75-81. 6. Flum DR, Dellinger EP, Cheadle A, et al. Intraoperative cholangiography and risk of common bile duct injury during cholecystectomy. JAMA 2003;289:1639-44. 7. Sheffield KM, Riall TS, Han Y, et al. Association between cholecystectomy with vs without intraoperative cholangiography and risk of common duct injury. JAMA 2013;310:812-20. 8. Parrilla P, Robles R, Varo E, et al. Liver transplantation for bile duct injury after open and laparoscopic cholecystectomy. The British journal of surgery 2014;101:63-8. 9. Schmidt SC, Langrehr JM, Hintze RE, et al. Long-term results and risk factors influencing outcome of major bile duct injuries following cholecystectomy. The British journal of surgery 2005;92:76- 82. 10. Schmidt SC, Langrehr JM, Raakow R, et al. Right hepatic lobectomy for recurrent cholangitis after combined bile duct and right hepatic artery injury during laparoscopic cholecystectomy: a report of two cases. Langenbeck’s archives of surgery / Deutsche Gesellschaft fur Chirurgie 2002;387:183-7. 11. Truant S, Boleslawski E, Zerbib P, et al. Liver resection in management of post-cholecystectomy biliary injury: a case series. Hepato-gastroenterology 2012;59:2403-6.

Drs. Shokouh-Amiri, Fallahzadeh, Abdehou, Sugar, and Zibari are with the John C. McDonald Regional Transplant and Hepatopancreatobiliary Surgery Center, Willis-Knighton Health System in Shreveport.

206 J La State Med Soc VOL 166 September/October 2014 Portal-Endocrine and Gastric-Exocrine Drainage Technique of Pancreas Transplantation Provides an Easy Access for Evaluation of Pancreatic Allograft Dysfunction: Six-Year Experience at a Single Center

Gazi B. Zibari, MD, FACS; Mohammad Kazem Fallahzadeh, MD; Alireza Hamidian Jahromi, MD; Joseph Zakhary, MD; David Dies, MD; Greg Wellman, MD; Neeraj Singh, MD; Hosein Shokouh-Amiri, MD, FACS

Background: The aim of this study is to report our six-year experience with portal-endocrine and gastric- exocrine drainage technique of pancreatic transplantation, which was first developed and implemented at our center in 2007.

Methods: In this study, the outcomes of all patients at our center who had pancreas transplantation with portal-endocrine and gastric-exocrine drainage technique were evaluated.

Results: From October 2007 to November 2013, 38 patients had pancreas transplantation with this technique - 31 simultaneous kidney pancreas and seven pancreas alone. Median duration of follow-up was 3.8 years. One-, three-, and five-year patient and graft survival rates were 94%, 87%, 70% and 83%, 65%, 49%, respectively. For pancreas allograft dysfunction evaluation, 51 upper endoscopies were performed in 14 patients; donor duodenal biopsies were successfully obtained in 45 (88%). We detected nine episodes of acute rejection (eight patients) and seven episodes of cytomegalovirus (CMV) duodenitis (six patients). No patient developed any complication due to upper endoscopy.

Conclusions: Portal-endocrine and gastric-exocrine drainage technique of pancreas transplantation provides lifelong easy access to the transplanted duodenum for evaluation of pancreatic allograft dysfunction.

INTRODUCTION about 15%-20% of these patients have to undergo bladder to enteric conversion. These complications are not observed in Several techniques of pancreas transplantation have the enteric drainage technique of pancreas transplantation;1,5 been tried in the past four decades, each with a different however, the main disadvantage of enteric drainage tech- approach to manage exocrine and endocrine drainages of nique is lack of a noninvasive access for detection of pancreas the pancreas, including bladder vs. enteric drainage with or allograft rejection. In order to address this issue, our team, without Roux-en-Y for exocrine drainage and systemic vs. who had previously developed portal enteric technique of portal for endocrine drainage.1-4 The advantage of bladder pancreas transplantation in 19923 and revised it by placing drainage is detection of pancreatic rejection by measuring a temporary venting jejunostomy in 2000,9 for the first time the urinary levels of the pancreatic enzymes.1,5 However, due introduced the portal-endocrine and gastric-exocrine tech- to profuse urinary loss of pancreatic exocrine secretions, this nique of pancreas transplantation in 2007.4 The feasibility technique could result in metabolic complications such as and optimal three-year outcomes of the portal-endocrine volume depletion and metabolic acidosis, as well as urologic and gastric-exocrine technique of pancreas transplantation complications such as recurrent urinary tract infection and have already been reported by our team.4 The aim of this hemorrhagic cystitis.1,5-8 To manage these complications, study was to evaluate the six-year outcomes of this technique

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with donor’s common, internal, and external iliac artery (y-graft) to either directly-to-right common iliac artery or to an already placed arterial conduit from right common iliac artery to facilitate this anastomosis (Figure 1). At this time, the allograft is reperfused, hemostasis is achieved, and allograft splenectomy is performed by endovascular stapler. The end of duodeno-jejunal segment of allograft is then anastomosed either end-to-side or side-to-side in an antecolic fashion to the anterior aspect of the greater curvature of the stomach (Figure 1). In the case of simultaneous kidney pancreas (SKP) transplantation, the kidney can be transplanted either before or after pancreas transplantation. Because the kidney table benchwork is much faster than the pancreas; we transplant the kidney first, while the pancreas allograft is prepared. Transplanting the kidney first also decreases the pressure on the pancreas allograft during implantation of the kidney. Per our center’s protocol, all pancreas transplant recipients received anti-thymocyte globulin (1mg/ kg/day for four to five days) for induction therapy. Tacrolimus, mycophenolate mofetil, and steroids were used for maintenance immunosuppression. All patients also received prophylactic therapy for Pneumocystis jiroveci, cytomegalovirus (CMV), and fungi for three months after transplantation. Upper endoscopy was performed for every patient Figure 1: Schematic drawing of the portal-endocrine and gastric-exocrine with possible pancreatic dysfunction to study the technique of pancreatic transplantation. transplanted duodenum (Figure 2). Pancreatic dysfunction was defined as elevated serum levels of of pancreas transplantation. pancreatic enzymes or signs of possible pancreatic rejection, such as unexplained fever or abdominal pain. Episodes of METHODS rejection or CMV duodenitis were confirmed by biopsy from the transplanted duodenum obtained during upper endos- This study was approved by the institutional review copy (Figure 3). Pancreas transplant failure was defined as board of our center and was done in accordance with Dec- c-peptide levels <0.8 ng/mL, pancreatectomy, or death. laration of Helsinki and Good Clinical Practice guidelines. Pancreas allograft rejection was treated by anti-thymo- All patients who had pancreas transplantation with the cyte globulin, pulse steroid therapy, and increasing the dose technique of portal-endocrine and gastric-exocrine drainage of maintenance immunosuppressive medications. CMV at our center from October 2007 to November 2013 were duodenitis was treated by valganciclovir and decreasing included in this retrospective study. Demographics, clini- the dose of maintenance immunosuppression. cal characteristics, and the post-transplant course of these patients were analyzed. RESULTS All transplant recipient candidates were informed on this new technique of pancreas transplantation and signed From October 2007 to November 2013, 40 pancreas the consent form to undergo transplantation with this transplants were done at our center. Among them, 38 pa- technique. We have already described the portal-endocrine tients (mean age = 40.8±9.1 years; male = 19 [50%]; Cauca- and gastric-exocrine drainage technique of pancreas trans- sian = 25 [66%]) underwent pancreas transplantation with 4 plantation in detail. In brief, after evaluating the recipi- the portal-endocrine and gastric-exocrine technique; 31 were ent’s superior mesenteric vein (SMV) to make sure that it is SKP and seven were pancreas transplant alone (PTA). Only patent and adequate in size, the allograft, which has been two patients (5%) were transplanted with other techniques; procured in a standard fashion with only a 4-5 inch extra one recipient had inadequate SMV and was transplanted duodenojejunal segment, is implanted. First, anastomosis with systemic enteric technique. In the other case, the small is fashioned with an end-to-side portal to SMV anasto- bowel was procured for transplantation; therefore, the do- mosis to be subsequently followed by anastomosis of the nor’s duodenum would not reach to stomach. This case was reconstructed arterial supply of pancreas, which was done transplanted with portal enteric technique. In 38 enrolled

208 J La State Med Soc VOL 166 September/October 2014 Figure 2: Upper endoscopy of transplanted duodenum in one of the patients with pancreatic dysfunction. Panel A: Site of gastroduodenal anastomosis. Panel B: Transplanted duodenum. patients, median duration of follow-up was 3.8 years (range: DISCUSSION one month to six years). One-, three-, and five-year patient survival rates were 94%, 87%, and 70% for all patients; 92%, Our results show that portal-endocrine and gastric- 88%, and 67% for SKP patients; and 100%, 83%, and 83% for exocrine technique of pancreatic transplantation provides PTA patients. As demonstrated in Figure 4, one-, three-, and easy access to transplanted duodenum through upper five-year graft survival rates were 83%, 65%, and 49% for all endoscopy. As a result, this technique could lead to timely patients; 89%, 79%, and 58% for SKP patients; and 57%, 14%, evaluation and management of different causes of pancreatic and 14% for all patients. Seven patients died during follow- dysfunction, such as pancreas allograft rejection and CMV up (five due to cardiovascular causes [all SKP], one due to infection, while eliminating the risk of major complications donor duodenal perforation [SKP], and one due to unknown secondary to a more invasive diagnostic procedure. cause [PTA]); all of these patients had functioning graft at The pancreas graft survival in PTA patients is typically the time of death. Another SKP patient also presented with inferior to the graft survival in SKP patients.10-12 Lack of a donor duodenal perforation but had emergency operative proper marker for detection of pancreas allograft rejection repair of perforation and recovered well postoperatively. is one of the main contributing factors to the lower graft Of the 31 living patients, four (two SKP and two PTA) had survival in PTA patients.10 Due to the high capacity of pancreas failure due to rejection; three of these rejections the pancreas for maintaining glucose hemostasis, a large (two SKP, one PTA) were due to the non-compliance of the proportion of islet cells should be destroyed before labora- patients. Three more cases (all PTA) had vascular throm- tory markers of insulin production, such as blood glucose, bosis of the transplanted pancreas within eight days post- HbA1C, or C-peptide levels, become abnormal.13,14 Rise of transplantation. These three patients were later diagnosed serum enzymes like amylase is neither sensitive nor specific to have antithrombin-3 deficiency, protein S deficiency, and for detection of rejection and could happen due to several high levels of lupus anticoagulant antibodies, respectively. factors other than pancreas allograft rejection.13,14 In SKP Mean levels of serum c-peptide, Hb-A1C, and eGFR in the patients, a rise in serum creatinine levels may indicate si- patients with functioning grafts at their last follow-up visit multaneous kidney and pancreas rejection and is generally were 3.64 ng/ml, 5.7 and 61 ml/min/m2, respectively. considered a more sensitive marker for detection of pancreas For the evaluation of the pancreas allograft dysfunction, allograft rejection as compared with serum amylase levels.13 51 upper endoscopies were performed in 14 patients; donor However, even in SKP patients, isolated pancreas allograft duodenal biopsies were successfully obtained on 45 occa- rejection could occur in the absence of kidney rejection in sions (88%). Nine episodes of acute rejection (eight patients), 30% to 75% of times.13,15 Although percutaneous pancreatic and seven episodes of CMV duodenitis (six patients) were biopsy remains the gold standard for diagnosis of pancreatic detected by upper endoscopy of the transplanted duodenum rejection, its failure rate is high and also could lead to seri- and were treated accordingly. Moreover, two patients were ous complications, such as bowel perforation, hemorrhage, found to have peptic ulcer at the site of the duodenogastric or pancreatic leak.16 Therefore, development of a pancreas anastomosis. No patient developed any complication due transplant technique that could provide an easy access for to the upper endoscopy. detection of rejection is of utmost importance.

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pancreas transplantation that provides an easy access for endoscopy of the transplanted duodenum.18,19 However, the major concern about this technique is the troublesome repair of the native duodenum or the duodenoduodenal anastomosis in case of the need for allograft pancreatectomy or duodenoduodenal anastomosis leak, respectively.1 Our results show that the portal- endocrine and gastric-exocrine technique of pancreatic transplantation, by providing an easy access to donor duodenum through upper endoscopy, could potentially solve the issue of evaluation of pancreas allograft dysfunction. By evaluating the donor duodenum as a surrogate marker for the transplanted pancreas, our technique could facilitate early detection and differentiation of acute pancreas Figure 3: Panel A: Photomicrograph image of a biopsy from normal transplanted allograft rejection and CMV infec- duodenum. Note the normal villous architecture and lack of significant inflammatory tion. Moreover, through upper en- changes. Hematoxylin and Eosin stain, 100x original magnification. Panel B: doscopy of the donor duodenum, Photomicrograph image of a biopsy from a patient with acute rejection. The biopsy endoscopic ultrasound-facilitated demonstrated areas of neutrophilic inflammation (thin arrows), erosive change, and biopsy of transplanted pancreas numerous apoptotic bodies (thick arrows). Hematoxylin and Eosin stain, 400x original could be potentially achieved. magnification. Panel C: Photomicrograph image of a biopsy from a patient with The site of anastomosis of enteric Cytomegalovirus duodenitis involving the transplanted duodenum. Arrow denoted cells drainage is also prone to develop- with viral cytopathic effect. Hematoxylin and Eosin stain, 400x original magnification. Panel ment of ulcers and bleeding.1 Our D: Photomicrograph image of a biopsy from a patient with Cytomegalovirus duodenitis technique also provides an easy involving the transplanted duodenum. Arrow denoted cell with positive reaction with CMV access to the site of enteric drainage immunohistochemical stain. CMV immunohistochemical stain, 400x original magnification. anastomosis for early detection and In the bladder exocrine drainage technique of pancreas management of ulcer or bleeding. transplantation, measurement of urinary amylase levels Furthermore, in contrast to the duodenoduodenostomy could provide an easy assay for detection of rejection.1,5 technique, in our method, if the pancreas allograft needs However, this technique results in profuse urinary loss to be removed, the site of the gastric anastomosis can be of pancreatic exocrine secretions, which could result in repaired without any difficulty or long-term consequence. The duodenum and pancreas have the same embryo- metabolic acidosis, hypovolemia, and urinary complication, 20 such as hemorrhagic cystitis.1,5-8 These complications require logic origin and MHC background. Previous animal and clinical studies have shown that duodenal and pancreatic bladder to enteric drainage conversion in 15%-25% of pa- 20-23 tients. The enteric exocrine drainage technique of pancreas allograft biopsies are closely correlated. These studies transplantation results in physiologic drainage of pancreatic have also shown that duodenal biopsies are very useful in guiding clinical management of the patients when pancreas exocrine secretions and prevents complications of bladder 16,20 drainage technique.1,5 However, the main disadvantage of allograft biopsy was not available. However, despite this technique is lack of an easy access for evaluation of these preliminary data in favor of correlation of duodenal pancreatic rejection. In order to solve this problem, our team and pancreatic allograft results, large clinical studies are still introduced a Roux-en-y venting jejunostomy technique that needed to conclusively confirm this correlation. provides an easy percutaneous access to the transplanted The portal-endocrine and gastric-exocrine drainage duodenum.9 The disadvantages of this technique, however, technique of pancreas transplantation, by facilitating the are the decreased quality of life of patients due to having a proper diagnosis and management of pancreas allograft re- jejunostomy and its resultant complication and the need to jection and CMV infection, probably has improved the graft close the jejunostomy 9-12 months after transplantation.9,17 and patient survival rates of our patients. However, our total Duodenoduodenostomy is another interesting technique of five-year pancreas allograft survival results are not better than the national average (49% vs. 66%, respectively).10 In

210 J La State Med Soc VOL 166 September/October 2014 our study, 75% of our patients who lost their organ due to rejection were non-compliant. Moreover, 71% of deaths in our study were due to cardiovascular causes. Therefore, other factors like noncompliance and death due to comorbid disorders were among the main contributing factors to our inferior results as compared with the national average. The SKP and PTA patients in our center were transplanted by the same surgeons and both had good quality donors. Conse- quently, one of the major contributing factors to the lower graft survival in PTA versus SKP patients was development of pancreatic vascular thrombosis in three PTA patients. Post-transplantation studies showed that all these three patients had hypercoagulable disorders. Moreover, due to the absence of uremia-induced platelet dysfunction in PTA patients, they are more predisposed to develop Figure 4: Allograft survival in simultaneous kidney pancreas (SKP), pancreas pancreatic vascular thrombosis as compared transplant alone (PTA), and all patients. with SKP patients. Additionally, underlying hypercoagulable disorders are more likely to the technique of transplantation. Therefore, portal-endocrine be diagnosed in SKP patients before transplantation because and gastric-exocrine technique of pancreatic transplantation these patients will most probably present with repeated vas- appears not to be associated with higher risk of any major cular access thrombosis before transplantation. Therefore, complication. after these three cases of pancreatic vascular thrombosis, The limitations of this study are its retrospective design, all PTA candidates at our center undergo evaluation for lack of control group, and small sample size. Since October hypercoagulable disorders before transplantation. 2007, all pancreas transplants at our center were performed Choosing the optimal type of venous drainage remains using the portal-endocrine and gastric-exocrine drainage 1,24 one of the controversial issues in pancreas transplantation. technique of pancreas transplantation, except for two cases. In the systemic venous drainage technique, the portal vein is Because of the changes in the guidelines for management of 24 connected to the recipient’s iliac vein or inferior vena cava. pancreas transplantation over time, the patients who had In the portal venous drainage technique, the technique that pancreas transplantation at our center with a different tech- was used in this study, the end of donor portal vein is anas- nique before October 2007 were not considered as optimal tomosed to the side of recipient’s superior mesenteric vein, controls for comparison with patients who had pancreas resulting in direct delivery of the pancreas allograft venous transplantation with portal-endocrine and gastric-exocrine 3,24 outflow to the liver. The portal technique is more physi- drainage technique, thereafter. However, the best study ologic and results in less hyperinsulinemia because nearly design to compare the advantages and disadvantages of half of the insulin produced by the pancreas is metabolized different techniques of pancreas transplantation would be 24,25 by the liver before entering the systemic circulation. It a randomized controlled trial with large sample size. has been suggested that hyperinsulinemia could have a Our study shows that portal-endocrine and gastric- potential adverse effect on the lipid profile and accelerate exocrine technique of pancreatic transplantation provides 26,27 atherosclerosis. Moreover, initial studies suggested that an easy access to the transplanted duodenum for evaluation the portal technique could provide immunologic advan- of pancreatic dysfunction. This technique should be com- 28-30 tages and result in less acute rejection and graft loss. In pared with other techniques of pancreas transplantation in contrast, a recent long-term study has shown that these two randomized controlled trials. techniques of venous drainage have similar graft and patient 24 survival rates and cardiovascular outcomes. REFERENCES In our study, two patients developed donor duodenal perforation, and two developed peptic ulcer at the site 1. Boggi U, Amorese G, Marchetti P. Surgical techniques for pancreas of the duodenogastric anastomosis. However, these are transplantation. Curr Opin Organ Transplant 2010;15:102-11. known complications of enteric techniques of pancreas 2. Stratta RJ. Surgical nuances in pancreas transplantation. Transplant transplantation, and their incidence is not higher with our Proc 2005;37:1291-3. technique. Moreover, as mentioned before, pancreatic vas- 3. Shokouh-Amiri MH, Gaber AO, Gaber LW, et al. Pancreas cular thrombosis in three patients was due to undetected transplantation with portal venous drainage and enteric exocrine underlying hypercoagulable disorders and probably not to diversion: a new technique. Transplant Proc 1992;24:776-7.

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4. Shokouh-Amiri H, Zakhary JM, Zibari GB. A novel technique and correlation of duodenal and pancreas biopsy tissue in of portal-endocrine and gastric-exocrine drainage in pancreatic pancreaticoduodenal transplants with emphasis on therapeutic transplantation. J Am Coll Surg 2011;212:730-8; discussion 8-9. use. Transplantation proceedings 1995;27:1327-8. 5. Sutherland DE, Gruessner RW, Gruessner AC. Pancreas 24. Bazerbachi F, Selzner M, Marquez MA, et al. Portal venous versus transplantation for treatment of diabetes mellitus. World J Surg systemic venous drainage of pancreas grafts: impact on long-term 2001;25:487-96. results. Am J Transplant 2012;12:226-32. 6. White SA, Shaw JA, Sutherland DE. Pancreas transplantation. 25. Gaber AO, Shokouh-Amiri MH, Hathaway DK, et al. Results of Lancet 2009;373:1808-17. pancreas transplantation with portal venous and enteric drainage. 7. Sollinger HW, Messing EM, Eckhoff DE, et al. Urological Ann Surg 1995;221:613-22; discussion 22-4. complications in 210 consecutive simultaneous pancreas-kidney 26. Stout RW. Insulin and atheroma. 20-yr perspective. Diabetes Care transplants with bladder drainage. Ann Surg 1993;218:561-8; 1990;13:631-54. discussion 8-70. 27. Hughes TA, Gaber AO, Amiri HS, et al. Kidney-pancreas 8. Sollinger HW, Odorico JS, Knechtle SJ, et al. Experience with 500 transplantation. The effect of portal versus systemic venous simultaneous pancreas-kidney transplants. Ann Surg 1998;228:284- drainage of the pancreas on the lipoprotein composition. 96. Transplantation 1995;60:1406-12. 9. Zibari GB, Aultman DF, Abreo KD, et al. Roux-en-Y venting 28. Nymann T, Hathaway DK, Shokouh-Amiri MH, et al. Patterns of jejunostomy in pancreatic transplantation: a novel approach to acute rejection in portal-enteric versus systemic-bladder pancreas- monitor rejection and prevent anastomotic leak. Clin Transplant kidney transplantation. Clin Transplant 1998;12:175-83. 2000;14:380-5. 29. Philosophe B, Farney AC, Schweitzer EJ, et al. Superiority of 10. Kandaswamy R, Stock PG, Skeans MA, et al. OPTN/SRTR 2011 portal venous drainage over systemic venous drainage in pancreas Annual Data Report: pancreas. Am J Transplant 2013;13 Suppl transplantation: a retrospective study. Ann Surg 2001;234:689-96. 1:47-72. 30. Nymann T, Hathaway DK, Shokouh-Amiri MH, et al. Incidence 11. Gruessner AC, Sutherland DE, Gruessner RW. Pancreas of kidney and pancreas rejection following portal-enteric versus transplantation in the United States: a review. Curr Opin Organ systemic-bladder pancreas-kidney transplantation. Transplant Transplant 2010;15:93-101. Proc 1997;29:640-1. 12. Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant 2012;17:100-5. 13. Troxell ML, Koslin DB, Norman D, et al. Pancreas allograft Drs. Zibari, Fallahzadeh, Dies, Wellman, Singh, and Shokouh-Amiri rejection: analysis of concurrent renal allograft biopsies and are with the John C. McDonald Regional Transplant Center, Willis- posttherapy follow-up biopsies. Transplantation 2010;90:75-84. Knighton Health System in Shreveport. Dr. Singh is also with the Department of Medicine at Louisiana State University Health Sciences 14. Papadimitriou JC, Drachenberg CB, Wiland A, et al. Histologic Center in Shreveport. Drs. Hamidian-Jahromi and Zakhary are with grading of acute allograft rejection in pancreas needle biopsy: the Department of Surgery at LSUHSC-Shreveport. correlation to serum enzymes, glycemia, and response to immunosuppressive treatment. Transplantation 1998;66:1741-5. 15. Gruessner RW, Nakhleh R, Tzardis P, et al. Differences in rejection grading after simultaneous pancreas and kidney transplantation in pigs. Transplantation 1993;56:1357-64. 16. Laftavi MR, Gruessner AC, Bland BJ, et al. Diagnosis of pancreas rejection: cystoscopic transduodenal versus percutaneous computed tomography scan-guided biopsy. Transplantation 1998;65:528-32. 17. Zibari GB, Boykin KN, Sawaya DE, et al. Pancreatic transplantation and subsequent graft surveillance by pancreatic portal-enteric anastomosis and temporary venting jejunostomy. Ann Surg 2001;233:639-44. 18. De Roover A, Detry O, Coimbra C, et al. Exocrine pancreas graft drainage in recipient duodenum through side-to-side duodenoduodenostomy. Transpl Int 2008;21:707. 19. Hummel R, Langer M, Wolters HH, et al. Exocrine drainage into the duodenum: a novel technique for pancreas transplantation. Transpl Int 2008;21:178-81. 20. Mark W, Hechenleitner P, Dietze O, et al. Duodenal histology for monitoring treatment of acute rejection in pancreaticoduodenal allografts in rats. Transplantation 2002;73:198-203. 21. Nakhleh RE, Sutherland DE, Tzardis P, et al. Correlation of rejection of the duodenum with rejection of the pancreas in a pig model of pancreaticoduodenal transplantation. Transplantation 1993;56:1353-6. 22. Nakhleh RE, Benedetti E, Gruessner A, et al. Cystoscopic biopsies in pancreaticoduodenal transplantation. Are duodenal biopsies indicative of pancreas dysfunction? Transplantation 1995;60:541-6. 23. Nakhleh RE, Sutherland DE, Benedetti E, et al. Diagnostic utility

212 J La State Med Soc VOL 166 September/October 2014 Atypical Mycobacterial Infections of Peritoneal Dialysis Catheter Exit Sites - A Louisiana Issue

Adam Hauch, MD, MBA; Bridget Ory, MD; Anil Paramesh, MD, FACS

Exit-site infections involving peritoneal dialysis catheters are a cumbersome issue that can be difficult to manage. Such infections are usually due to gram-positive organisms and are often treated successfully with oral and/or topical antibiotics. Infections associated with Mycobacterium sp. are much more rare and difficult to treat. We report our experience with four cases of exit-site infections with Mycobacterium sp. in the New Orleans area, along with a review of risk factors and current literature.

BACKGROUND approximately four to six weeks, at which time a new PD catheter could be placed. At the time of catheter removal, Infectious complications of long-term Peritoneal Dialy- initial cultures demonstrated no organism growth; however, sis (PD) most often include peritonitis and exit-site infections final culture results almost three weeks later grew Myco- (ESI) of the catheter. In fact, up to 31% of individuals will bacterium abscessus. After consultation with our infectious experience an ESI within the first year of PD.1 ESI are most disease staff, the patient was placed on azithromycin 250 commonly due to gram-positive bacteria, occasionally to mg PO qday and moxifloxacin 400 mg PO qday. gram-negative organisms, and less commonly to fungi and After five weeks of treatment with the combined regi- mycobacteria.2,3 men, the exit site demonstrated marked improvement and Mycobacterial infections, such as Mycobacterium tuber- the patient did very well clinically. Moxifloxacin was dis- culosis or nontuberculous (atypical) mycobacterial (NTM) continued, and the patient was maintained on azithromycin species, often present as indolent infections refractory to for a full four-month course for extrapulmonary localized treatment with antibiotics. These mycobacterial infections infection due to M. abscessus. Following completion of her are infrequent, and there have been few documented case antibiotic treatment, the patient underwent successful reports in the literature to date. Interestingly, several of these laparoscopic placement of a new PD catheter, which is still reports come from remote cases occurring throughout the functioning without issues. Louisiana area, some of these more than two decades ago.3,4 Given the sporadic nature of these infections and the CASE 2 limited data on their management, as well as the seemingly relative frequency with which they occur in this area, it The second case was a 67-year-old Caucasian male with seems prudent that we report the management and out- ESRD secondary to hypertension who had a laparoscopic PD comes of four cases of NTM PD catheter infections at our catheter placed in February 2013. In May 2013, the patient institution in New Orleans. developed purulent drainage from the catheter exit site without other signs of systemic infection. Peritoneal fluid CASE 1 cultures were negative. Cultures of the exit-site were performed, and in an The first patient, a 70-year-old Caucasian woman with attempt to salvage the catheter, the distal portion of the a history of hypertension and diabetes, had a PD cath- catheter with the subcutaneous cuff was excised, leaving eter placed in January of 2010. She presented in July 2010 the intraperitoneal segment intact. There were no signs of with complaints of intermittent purulent drainage from infection noted in the subcutaneous tissue where the cath- the catheter exit site for several weeks. The catheter was eter was divided. The residual stump of the catheter was functional, and the patient denied systemic symptoms of attached to an extension catheter and routed subcutaneously illness. Cultures from the peritoneal fluid and the exit site to an alternate exit-site, remote from the infected area in a were negative. fashion similar to the one first describe by Cheung et al.5 This However, because of its appearance, the decision was allowed continuation of PD without interruption. made to remove the PD catheter. Hemodialysis was initi- Two weeks later, the final exit-site culture results from ated through the patients existing arteriovenous fistula for two different samples grew Mycobacterium fortuitum. In ad-

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dition, we noticed evidence of infection developing at the CASE 4 new exit site. The patient was started on a six-week course of ceftazidime 2 gm IV q48hr after dialysis, amikacin 7.5 mg/ The final case was a 60-year-old female who had origi- kg IV following dialysis, and ciprofloxacin 250 mg PO bid. nally undergone laparoscopic peritoneal dialysis catheter We decided to remove the catheter at this point. placement at our center in October 2013 and had been The patient returned to the operating room for PD dialyzing through this catheter without issues until Febru- catheter removal and creation of an arteriovenous fistula. ary 2014. It was at this time that the dialysis center noticed The patient has since completed his course of antibiotics but seropurulent drainage at the exit site and obtained cultures. has elected to stay on hemodialysis. The patient denied any other symptoms of illness and was prophylactically started on ciprofloxacin and Augmentin CASE 3 by her dialysis center. The patient was referred to our center for further man- We performed a laparoscopic PD catheter placement in agement after culture results returned positive for AFB and April 2013 on a 62-year-old Caucasian male with end-stage subsequently, Mycobacterium fortuitum. Initial management renal disease secondary to diabetes and hypertension. He consisted of cefoxitin 2 gm IV, as well as amikacin 7.5mg/ had been on hemodialysis for two years before expressing kg IV following dialysis, with the plan to treat the patient a desire to switch to PD. In August 2013, the patient began for three to four weeks and then attempt a catheter salvage experiencing seropurulent drainage at the catheter exit site procedure (as described in Case 2, above). Unfortunately, without other signs of infection. The dialysis center per- after two weeks of antibiotic treatment, the patient’s cath- formed cultures of this fluid, and the patient was empirically eter began to malfunction, likely due to omental adhesions. treated with topical gentamicin. Three weeks later, cultures Instead of trying to revise the catheter, she elected to have turned positive for Mycobacterium abscessus chelonae (group her peritoneal dialysis catheter removed. She will be con- name that encompasses both M. abscessus and M. chelonae), tinued on her antibiotic regimen for a full six-week course. and the patient was referred to our hospital for treatment. Following consultation with the infectious disease DISCUSSION team and the review of culture sensitivities, the patient was started on clarithromycin 250 mg PO bid and amikacin 7.5 The diagnosis and treatment of peritoneal dialysis ESI mg/kg IV following hemodialysis, and the catheter was can be challenging. Diagnosis requires distinguishing nor- removed. During removal, indication of subcutaneous in- mal tissue reaction around the catheter from infection. The fection was evidenced as a gelatinous purulent collection presence of a small amount of exudate or crust formation along the catheter (Figure 1). may occur in non-infected tissue; however, if infection does The patient completed a six-week course of antibiot- develop, the amount of exudate often increases.2 ics, and his wound healed completely. He has undergone Positive cultures from skin flora colonization also com- repeat placement of PD catheter and is undergoing dialysis plicate the diagnosis. Most ESI are due to common bacterial successfully. pathogens, including gram-positive bacteria and occasionally, gram-negative organisms; and the majority of these bacterial ESI can be treated successfully with topical and oral antibiotics without removal of the catheter or interruption of peritoneal dialysis.2,6 Conditions that make therapy more difficult include cuff and/or tunnel infections or infections due to resistant or virulent organisms, such as Pseudomonas sp., Candida, or Myco- bacterium sp. In these cases, catheter removal is imperative, as there is a high failure rate with antibiotics alone; and untreated infections can progress from exit-site infections to tunnel infections and subsequently, to possible peritonitis. M. fortuitum, M. abscessus, and M. chelonei are subcategorized as rapidly growing mycobacteria (RGM). Figure 1 They may grow on culture media within seven days versus two to

214 J La State Med Soc VOL 166 September/October 2014 three weeks for other nontuberculous mycobacteria (NTM).7 within a 20-month period at an institution in Hong Kong, Of the NTM, these three are the most common causes of it was noticed that all patients had used topical gentamicin community-acquired and nosocomial skin and soft tissue ointment for ESI treatment or prophylaxis. Furthermore, in infections.3 The overall incidence, however, is difficult to one patient, following removal of the gentamicin ointment, ascertain secondary to limited reporting and the sporadic the infection cleared on its own. They postulated that growth nature of NTM infections. According to a report by the of these organisms might be enhanced further in areas where Centers for Disease Control and Prevention from the states there is an overall warmer climate and increased humidity, Public Health Laboratory System (PHLIS) database, skin and such as theirs. More recent reports have also implicated gen- soft tissue infections comprised only 2% of all NTM isolated.7 tamicin as a potential risk factor for mycobacterial ESI due In an epidemiologic study, it was found that within to its selective pressure on other microorganisms.19 In our the United States, clusters of RGM infections appear to series, none of the patients were treated with prophylactic occur more frequently in southern coastal regions.7 These gentamicin, although one was started on it upon concern organisms are present in a range of environments, includ- of a presumed bacterial ESI. ing a mixture of soils in the Northern and Southern United States, tap water, municipal water supplies, and moist ar- CONCLUSION eas in hospitals.3,8,9 Other mycobacterial species associated with PD and having been reported as causes of peritonitis Atypical mycobacterial infections of PD catheter exit- include M. gordonae, M. Kansasii, M. avium-intracellulare, sites are rare, yet the few cases described in the literature and M. gastri.3,10-12 occurred in warm and humid climates, such as Louisiana. Treatment of skin and soft tissue infections with RGM We report here our experience with a cluster of cases at an usually require a combination of antibiotics and surgical institution in New Orleans. Further thorough epidemiologic debridement, and removal of foreign bodies is essential studies are needed to identify the incidence of ESI and to recovery.7 Combination of two or more antibiotics is geographic variation. They are often difficult to recognize recommended to minimize development of resistance, and and treatment may require catheter removal and long-term antibiotic choice should be guided by in vitro susceptibili- therapy with dual antibiotic regimens. Successful reinitiation ties. Macrolides, fluoroquinolones, carbapenems, and ami- of PD is possible after treatment, as we have demonstrated. noglycosides are most commonly used. Treatment should Catheter salvage has been reported but should be attempted last 6 to 10 weeks.7 In more serious infections, therapy should under the umbrella of appropriate antibiotic coverage. include parenteral amikacin or cefoxitin for approximately In 2011, the Centers for Medicare and Medicaid (CMS) four weeks following removal of the indwelling catheter, introduced a new bundling system for payment of dialysis and overall therapy should be continued for three to six services.20 This encourages the use of home dialysis thera- months.4,13,14 pies, especially PD. In this setting of increased PD utilization, Published reports regarding the management of myco- clinicians should be alert for atypical infections such as these. bacterial infections in the peritoneal dialysis patient population are scarce. Most reports describe case series focusing REFERENCES on patients with peritonitis,3,9,15-18 and only a few describe the management of catheter exit-site infections.3,4,13 Interest- 1. Vas SI. Peritonitis, in Nolph KD (ed). Peritoneal dialysis (ed 3). ingly, two of these series are from the state of Louisiana.3,4 Dordrecht, The Netherlands. Kluwer Academic Publishers. 1989: Although the majority of ESI with Mycobacterium sp. 261-288. will require catheter removal, successful treatment of a M. 2. Twardowski ZJ. Peritoneal catheter exit-site and tunnel infections, fortuitum ESI without catheter loss has been documented.3 in Nissenson AR, Fine RN. Dialysis therapy (ed 3). Philadelphia, PA. Hanley & Belfus, Inc. 2002: 239-244. In their report, White et al. treated one of their patients 3. White R, Abreo K, Flanagan R, et al. Nontuberculous mycobacterial with oral ofloxacin 400 mg bid for six weeks, followed by infections in continuous ambulatory peritoneal dialysis patients. an additional two weeks of oral ofloxacin 200 mg bid. The Am J Kidney Dis. 1993; 22(4):581-587. patient was maintained on PD during the treatment period, 4. Kleinpeter M, Krane K. Treatment of mycobacterial exit-site and the infection resolved without further intervention. In infections in patients on continuous ambulatory peritoneal our series, an attempt at catheter salvage surgery was made dialysis. Adv Perit Dial. 2001; 17:172-175. for one patient with an ESI from M. fortuitum. However, 5. Cheung AH, Wheeler MS, Limm WM, Wong LL, Fan FL, Wong we did not have final cultures showing NTM prior to the LM. A salvage technique for continuous ambulatory peritoneal dialysis catheters with exit-site infections. Am J Surg. 1995; surgery (these returned two weeks after surgery), and the 170(1):60-61. patient subsequently developed infection at the new exit-site 6. Gokal R, Alexander S, Ash SR, et al. Peritoneal catheters and exit- as well, despite the initiation of appropriate antibiotics. It is site practices toward optimum peritoneal access: 1998 update. Perit possible that had the patient been on appropriate antibiotics Dial Int. 1998; 18:11–33. at the time of the salvage surgery, the catheter might have 7. Griffith DE, Aksamit T, Brown-Elliott BA. An official ATS/IDSA been saved. statement: diagnosis, treatment, and prevention of nontuberculous Interestingly, in the case series by Tse et al.,13 that de- mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175(4):367- scribes a cluster of five cases of atypical mycobacterium ESI 416.

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8. Falkinham JO, 3rd. Epidemiology of infection by nontuberculous mycobacteria. Clin Microbiol Rev. 1996; 9(2):177-215. 9. Pulliam JP, Vernon DD, Alexander SR, Harstein AI, Golper TA. Nontuberculous mycobacterial peritonitis associated with continuous ambulatory peritoneal dialysis. Am J Kidney Dis. 1983; 2:610-614. 10. Harro C, Braden GL, Morris AB, Lipkowitz GS, Madden RL. Failure to cure Mycobacterium gordonae peritonitis associated with continuous ambulatory peritoneal dialysis. Clin Infect Dis. 1997; 24(5):955–957. 11. Perlino CA. Mycobacterium avium complex: An unusual cause of peritonitis in patients undergoing continuous ambulatory peritoneal dialysis. Clin Infect Dis. 1993; 17(6):1083-1084. 12. Linton IM, Leahy SI, Thomas GW. Mycobacterium gastri peritonitis in a patient undergoing continuous ambulatory peritoneal dialysis. Aust NZ J Med. 1986; 16:224-225. 13. Tse KC, Lui SL, Cheng VCC, Yip TPS, Lo WK. A cluster of rapidly growing mycobacterial peritoneal dialysis catheter exit-site infections. Am J Kidney Dis. 2007; 50(1):E1-E5. 14. Gilbert DN, Moellering RC, Sande MA. The Sanford guide to antimicrobial therapy (ed. 30). Hyde Park, VT. Antimicrobial Therapy, Inc. 2000: 81–82. 15. Hakim A, Hisam N, Reuman PD. Environmental mycobacterial peritonitis complicating peritoneal dialysis: Three cases and review. Clin Infect Dis. 1993; 16:426-431. 16. Tan D, Fein P, Jordan A, Avram M. Successful treatment of tuberculous peritonitis while maintaining patient on CAPD. Adv Perit Dial. 1991; 7:102-104. 17. Harro C, Braden GL, Morris AB, Lipkowitz GS, Madden RL. Failure to cure Mycobacterium gordonae peritonitis associated with continuous ambulatory peritoneal dialysis. Clin Infect Dis. 1997; 24(5):955–957. 18. Merlin TL, Tzamaloukas AH. Mycobacterium chelonae peritonitis associated with continuous ambulatory peritoneal dialysis. Am J Clin Pathol. 1989; 91(6):717–720. 19. Lo MW, Mak SK, Wong YY, et al. Atypical mycobacterial exit- site infection and peritonitis in peritoneal dialysis patients on prophylactic exit-site gentamicin cream. Perit Dial Int. 2013; 33(3): 267-272. 20. Blagg CR. Dialysis composite rate bundling: potential effects on the utilization of home hemodialysis, daily and nocturnal hemodialysis, and peritoneal dialysis. Semin Dial. 2011; 24(6):674- 677.

Dr. Hauch is a General Surgery Resident; Dr. Ory is an Assistant Professor of Medicine in the Division of Infectious Diseases; and Dr. Paramesh is an Associate Professor of Surgery, Urology, and Pediatrics at Tulane University School of Medicine.

216 J La State Med Soc VOL 166 September/October 2014 Protecting the Private Practice of Medicine: Direct Primary Care - Louisiana Poised to Lead

Sabrina L. Noah

This is the fourth and final 2014 installment in our series that Examiners (LSBME). reports on emerging trends and new practice models in medicine. 2. A group of MDs or ODs, licensed to practice medicine by the LSBME. As we discussed in our April editorial, “Direct Primary 3. An entity that sponsors, employs, or is affiliated Care: Kicking Insurance Out of the Exam Room,” the new with a group of physicians. That entity must be primary care practice model known as direct primary care wholly owned by physicians or a 501(c)3 nonprofit. (DPC) is posed to force an evolution of the healthcare sys- That entity is not prohibited from being affiliated tem in Louisiana. DPC practices offer a membership-based with other providers who do not provide direct approach to routine and preventive care, whereby patients primary care practice. However, the group must pay a low monthly fee, typically $49 to $100, to their physi- provide direct medical care services and not any cian for all of their everyday health needs. DPC practices research, technological, operational, or administra- do not take insurance; therefore, there is no need for billing tive support. approval, deductibles, or co-payments. With lower overhead A DPC is defined by its operating practices, including: and dramatically less paperwork, providers have the time 1. Entering into a direct agreement with patients. to deliver high-quality care instead of managing insurance 2. Collecting a direct fee from patients. The practice claims. charges a direct fee on a periodic basis, agreed As of our April article, the Louisiana State Medical So- upon and stated in the direct agreement, which ciety had introduced legislation, Senate Bill 516 authored by represents the total amount due for all primary Senator Sherri Buffington and Representative Stuart Bishop, care services. to make it possible to operate a direct primary care practice 3. Does not accept payment for healthcare services in Louisiana. Prior to this law being enacted on August 1, provided to patients from any insurance entity. 2014, direct primary care practices would be subject to laws 4. Does not provide any procedures or supplies for that regulate insurance companies because of their prepay hospitalization, surgery, dialysis, high-level radiol- model. After near unanimous support in both the house and ogy, MSI, rehabilitation services, procedures requir- senate, SB 516, now Act 867, cleared the regulatory path, ing anesthesia, or similar advanced procedures. allowing DPC practices to begin operating in Louisiana. 5. A DPC can accept payment of the direct fees, di- In order to further educate our members about this rectly or indirectly, by third parties. An employer important legislation, we have drafted a detailed summary can pay the fees associated with a DPC for their of the legislation in hopes of expanding this practice model employees but cannot enter into a direct agreement statewide. with the employer. 6. DPC direct agreements may not be sold to a group ACT 867: DEFINITION AND FUNCTION OF A or “entered with a group of subscribers.” It may DIRECT PRIMARY CARE (DPC) PRACTICE only exist between the practice and the individual patient or family of direct patients. A direct primary care (DPC) practice is defined as one 7. A DPC can accept payments from the Louisiana that charges a fee to a patient to provide routine healthcare Medical Assistance Program if approved by the services, including screening, assessment, diagnosis and Centers for Medicare & Medicaid Services. treatment for the purpose of promotion of health, and detec- A DPC is required to: tion and management of disease or injury. 1. Maintain appropriate accounts and payment his- A DPC can be operated by: tory. 1. A sole proprietor MD or OD, licensed to practice 2. Allow patients to pay their monthly fees ahead of medicine by the Louisiana State Board of Medical time, but they must be held in trust, and any un-

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earned direct fees must be refunded to the patient agreement does not provide comprehensive health following termination of the relationship. insurance coverage. It provides only the healthcare 3. Notify patients 60 days prior to changing the direct services specifically described.” fee and may only increase the fee once a year. 2. The agreement must also include a disclosure A DPC practice is prohibited from: statement distributed to all patients, which in- 1. Submitting a claim for payment to any insurance forms the patient of his or her financial rights and entity, directly or through a subcontractor, for responsibilities. services covered by the direct primary care fee 3. Language must encourage patients to maintain and agreement. insurance for services not provided by the prac- 2. From being identified by any insurance entity for tice and states that the DPC practice will not bill purpose of network adequacy, or being available insurance for services covered under the direct by an enrollee under a health insurer issuers ben- agreement. efit plan. 4. A statement must also include contact information 3. Prohibited from paying for healthcare services for the LSBME. covered by a direct agreement rendered to patients In the 18 states direct primary care has already been by providers other than the providers in the direct implemented, physicians report increased satisfaction and practice or their employees. a renewed commitment to providing the kind of care that A DPC practice or provider may enter into a participat- initially inspired them to dedicate their lives to medicine. In ing provider contract with an insurance entity other than short, direct primary care facilities enable physicians to do for payment of claims of services provided. That practice or what they were trained to do, treat patients. We believe in physician will be subject to all provisions of the participating the near future, DPC practices will transform the physician provider contact, including but not limited to: and patient medical environment in Louisiana, and we are 1. Making referrals to other participating providers. proud to have been part of the process. 2. Admit the carriers’ members to participating hospitals and healthcare facilities. 3. Prescribe prescription drugs. 4. Implement other customary provisions of the contract not dealing with reimbursement of services. A DPC practice may pay for charges associated with: 1. Routine lab and imaging services. 2. Dispensing prescribed prescription drugs at no additional costs in line with all laws and regulations. 3. Charge for any vaccinations or medical supplies not specifically included in the DPC agreement, as long as the patient is made aware of additional charge ahead of time. A DPC practice must maintain an equal opportunity patient panel: 1. A DPC cannot discontinue or deny services based on the patient’s health status. 2. A DPC can decline a patient if they are at maximum capacity or unable to provide the appropriate level of care. A DPC practice can discontinue care to patient but is required to give notice and opportunity for the patient to find another provider, if the patient: 1. Fails to pay their fee. 2. Commits an act that constitutes fraud against the practice. 3. Repeatedly fails to comply with the recommended treatment plan. 4. Is abusive or puts the practice staff or patients in emotional or physical danger. If the practice discontinues to operate as DPC practice. The law requires the following regarding the direct agreement between the DPC practice and the patient: 1. A disclaimer must be included which states, “This

218 J La State Med Soc VOL 166 September/October 2014 ECG of the Month

ECG in a 49-Year-Old Man With Chest Pain

D. Luke Glancy, MD; Timothy D. McShurley, MD

Figure 1: ECG recorded on the patient’s arrival at another hospital. See text for explication.

What is your diagnosis?

Explication is on p. 220

J La State Med Soc VOL 166 September/October 2014 219 Journal of the Louisiana State Medical Society

ECG of the Month lead aVR. Chest 2002;122:134-139. Presentation is on p 219.

DIAGNOSIS: Sinus rhythm (rate, 97 beats/min); two Dr. Glancy is a Professor of Medicine and Dr. McShurley is a Fellow episodes of AV dissociation with an accelerated idioventricular of Cardiovascular Diseases at the Louisiana State University Health rhythm (rate, 103 beats/min) dissociated from sinus rhythm; the Sciences Center in New Orleans. two rhythms produce numerous fusion QRS complexes; acute inferoposterior myocardial infaraction; left atrial enlargement.

The first QRS is sinus-initiated. The second through the eighth QRS complexes are fusion complexes that progressively look more like accelerated idioventricular complexes and less like sinus-initiated complexes. The ninth QRS is a ventricular premature complex, and the next three complexes are sinus-initiated. The last five QRSs are fusions, again looking progressively more like accelerated idioventricular complexes and less like sinus-initiated complexes. Q waves with ST-segment elevation in the inferior leads and tall R waves with ST-segment depression in the anterior precordial leads indicate acute inferoposterior myocardial infarction. Accelerated idioventricular rhythm is common with acute myocardial infarction, and, in contrast to ventricular tachycardia, does not worsen prognosis.1 P-wave duration >0.12 s in the inferior leads suggests left atrial enlargement. In acute inferior myocardial infarctioin, the culprit lesion is in the right coronary artery four times as often as it is in the left circumflex coronary artery.2-4 In this patient, however, four findings suggest that the left circumflex coronary artery is the culprit: ST elevation in lead I, ST elevation lead

II > lead III, ST depression V1 and V2, and ST depression >1 mm (0.1 mV) in lead aVR.4 The patient was initially seen at another hospital where the ECG was performed, and the peak CK level was 1,764 U/L (reference < 230) with an MB fraction of 626 ng/ml (reference < 4.0). His coronary arte- riograms at our institution four days later showed 70% narrowing of the left anterior descending coronary artery in its midportion, 80% narrowing of the mid-left circumflex, and 80-90% narrowing of the mid-right. Both the left circumflex and the right coronary arterial lesions were stented.

REFERENCES

1. O’Keefe JH Jr, Hammill SC, Freed MS, et al. The Complete Guide to ECGs. A Comprehensive Study Guide to Improve ECG Interpretation Skills, 2nd edition. Royal Oak, Michigan: Physicians’ Press;2002:491. 2. Birnbaum Y, Wagner GS, Barbash GI, et al. Correlation of angiographic findings and right (V1 to V3) versus left (V4 to V6) precordial ST-segment depression in inferior wall acute myocardial infarction. Am J Cardiol 1999;83:143-148. 3. Correale E, Battista R, Martone A, et al. Electrocardiographic patterns in acute inferior myocardial infarction with and without right ventricle involvement: classification, diagnostic and prognostic value, masking effect. Clin Cardiol 1999;22:37-44. 4. Nair R, Glancy DL. ECG discrimination between right and left circumflex coronary arterial occlusion in patients with acute inferior myocardial infarction. Value of old criteria and use of

220 J La State Med Soc VOL 166 September/October 2014 Radiology Case of the Month Abnormally Dilated Arteries in an Asymptomatic Male

Christian Mabry, MD; Gretchen Yandle, MD; Jen Erbil, MD; Kyle Happel, MD, FCCP; Harold R. Neitzschman, MD

A 61-year-old male with a past medical history of chronic, uncontrolled hypertension received a non-contrasted computed tomogram (CT) of the chest and abdomen to investigate for possible Conn syndrome. This noncontrast study showed some areas of nodularity around the vertebral bodies bilaterally and extending into the posterior mediastinal region. A CT of the chest with intravenous contrast, and 3D reconstruction were then obtained.

Figure 1: (left) Axial CT image after nonionic intravenous contrast.

Figure 2: (right) Sagittal CT image after nonionic intravenous contrast.

Figure 3: (left) Coronal CT image after nonionic intravenous contrast.

Figure 4: (right) 3D reconstruction of the heart and its vessels.

What is your diagnosis?

Elucidation is on p. 222

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Radiology Case of the Month with little difference in the diastolic pressures.8 In addition Presentation is on p. 221 to this, renal hypoperfusion will increase renin secretion, resulting in volume expansion and further hypertension.9 RADIOLOGIC DIAGNOSIS: Aortic coarctation. There is Other more specific clinical findings include a delayed narrowing in the region of the aortic isthmus (arrows, Figures 2 femoral compared to brachial pulse or greatly diminished and 4). The extent of collateral arterial dilation (arrows, Figures 1 blood pressure in the lower extremities.10 and 3) suggests this to be a hemodynamically significant finding. With the advancements in imaging techniques in recent years, radiologic assessments have become the predominant INTERPRETATION OF IMAGES tool with which to diagnose an aortic coarctation. A chest radiograph can aid in the diagnosis, as the engorged collat- The noted abnormalities on the CT scan are shown to eral vessels will show notching of posterior ribs.8 This vessel represent dilated vessels (arrows in Figure 3). The ascending erosion is most commonly seen in the third to eighth ribs.8 aorta measures 4.3 cm x 4.3 cm in size but narrows to 1.5 cm Echocardiography is also used as a noninvasive technique (arrows in Figures 1, 2, and 4). Just beyond the narrowing to better visualize suspected coarctation. With the addition it measures 2.1 cm x 2.1 cm. The previously noted para- of Doppler, transthoracic echocardiography can allow for vertebral soft tissue densities represent dilated intercostal full identification of the severity of the disease, as well as any arteries. There are collaterals seen in the upper posterior associated cardiac defects.11,12 The gold standard, however, mediastinum in the paraspinal region, and one of the col- for diagnosing aortic coarctation using imaging is with either lateral vessels is posterior to the esophagus. Additional magnetic resonance imaging (MRI) or computed tomogra- internal mammary artery collaterals are seen. phy (CT). As with our patient, these modalities allow for clear visualization of the severity of the coarctation, as well DISCUSSION as any collateral vessels that have developed. From our experience, a CT with intravenous contrast should always Coarctation of the aorta (coarctation) is most com- be performed if this abnormality is suspected. monly a congenital abnormality that involves stenosis of Treatment of this anomaly depends largely on age at the proximal descending thoracic aorta.1 The majority of presentation, severity of illness, and degree of collaterals these abnormalities are congenitally acquired; however, surrounding the area. Neonates and infants generally get there have been case reports of severe atherosclerosis, um- surgical correction of the anatomy while adult treatment bilical artery catheterization, or surgical aortotomy causing includes the option of percutaneous stenting.4 Although the stenosis.2 This process was first described in 1760 and less than 1% of patients have surgical complications, these accounts for about 7% of all congenital heart diseases.1 It oc- complications can be devastating and include nerve paraly- curs twice as frequently in men and should always be ruled sis, spinal cord ischemia, or bowel infarction.4,13 Currently, out if other conditions like bicuspid aortic valve, Turner there is not enough evidence to recommend stenting versus syndrome, Shone syndrome, ventricular septal defect, or surgical correction as the optimal treatment for coarcta- aneurysms of the circle of Willis are present because of the tion in adults.4 Stenting appears to have better short-term high association of these defects with coarctation.2 Up to improvement, while the long-term affects have not been 40% of patients with bicuspid aortic valve will also have studied well enough to make a recommendation.4 Moni- coarctation of the aorta.3 Diagnosis of the disease is critical, toring of the patient, regardless of intervention, is similar.4 as the mortality rate is high in poorly managed patients. For At least one MRI or CT of the head should be performed at unoperated cases, the average survival is approximately 35 or near diagnosis to exclude intracranial aneurysm forma- years with a 75% mortality by age 46.4 tion.4 In addition to this, all aortic coarctation patients need The pathologic changes that lead to this disease are close monitoring and follow-up by a cardiologist at yearly rooted in the wall of the aorta. These changes become so intervals.4 These visits should include evaluation of blood severe that the lumen of the vessel narrows, resulting in poor pressure in all extremities, as well as aggressive treatment perfusion of systemic organs. The pathophysiologic changes if hypertension is found.4 Imaging (MRI or CT) of the chest in the congenital cases involve medial thickening and hy- should be performed at five-year intervals with the purpose perplasia of the intima.5 The etiology of this thickening is of catching progression of the disease before a catastrophic believed to result from fetal aortic arch underdevelopement event occurs.4 and constricted ductal tissue.6,7 If antegrade intrauterine blood flow is reduced and ductal tissue extends into the tho- REFERENCES racic aorta, then the fetal aortic arch will not develop fully, and this excess tissue will cause constriction just distal to the 1. Shih MC, Tholpady A, Kramer CM, et al. Surgical and endovascular aortic valve.6,7 For clinicians, the end result is a few tell-tale repair of aortic coarctation: normal findings and appearance of physical examination findings. The major manifestation is a complications on CT angiography and MR angiography. Am J Roentgenol. 2006;187:W302-12. difference in systolic blood pressure between the upper and 2. Starc TJ, Abramson SJ, Bierman FZ, et al. Acquired coarctation of lower extremities (usually upper extremity hypertension) the aorta. Pediatr Cardiol. 1992;13:33-6.

222 J La State Med Soc VOL 166 September/October 2014 3. Nihoyannopoulos P, Karas S, Sapsford RN, et al. Accuracy of two-dimensional echocardiography in the diagnosis of aortic arch obstruction. J Am Coll Cardiol. 1987;10:1072. 4. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2008;118:714. 5. Jimenez M, Daret D, Choussat A, et al. Immunohistological and ultrastructural analysis of the intimal thickening in coarctation of human aorta. Cardiovasc Res. 1999;41:737-45. 6. Rudolph AM, Heymann MA, Spitznas U. Hemodynamic considerations in the development of narrowing of the aorta. Am J Cardiol. 1972;30:514. 7. Wielenga G, Dankmeijer J. Coarctation of the aorta. J Pathol Bacteriol. 1968;95:265. 8. Bricker ME, Hillis LD, Lange RA. Congenital heart disease in adults. First of two parts. N Engl J Med. 2000;342:256. 9. Alpert BS, Bain HH, Balfe JW, et al. Role of the renin-angiotensin- aldosterone system in hypertensive children with coarctation of the aorta. Am J Cardiol. 1979;43:828. 10. Wyszynski, Diego, and Adolfo Correa-Villaseñor. Congenital Heart Defects: From Origin to Treatment. Oxford University Press, 2010. 11. Teien DE, Wendel H, Bjornebrink J, Ekelund L. Evaluation of anatomical obstruction by Doppler echocardiography and magnetic resonance imaging in patients with coarctation of the aorta. Br Heart J. 1993;69:352. 12. Greenburg SB, Balsara RK, Faerber EN. Coarctation of the aorta: diagnostic imaging after corrective surgery. J Thorac Imaging. 1995;10:36. 13. Saalouke MG, Perry LW, Breckbill DL, et al. Cerebrovascular abnormalities in postoperative coarctation of the aorta. Four cases demonstrating left subclavian steal on aortography. Am J Cardiol. 1978;42:97.

Dr. Mabry is a second-year Internal Medicine resident at LSU Health Sciences Center in New Orleans. Dr. Yandle is a first-year Pulmonary/ Critical Care Fellow in the Section of Pulmonary/Critical Care at LSUHSC-New Orleans. Dr. Erbil is a third-year Internal Medicine resident at LSUHSC-New Orleans. Dr. Happel is an Associate Professor of Medicine in the Section of Pulmonary/Critical Care at LSUHSC. Dr. Neitzschman is Professor of Radiology and Chairman of the Department of Radiology at Tulane University Health Sciences Center in New Orleans.

J La State Med Soc VOL 166 September/October 2014 223 Journal of the Louisiana State Medical Society Clinical Case of the Month

A 22-Year-Old Man With AIDS Presenting With Shortness of Breath and an Oral Lesion

Daniel Englert, MD; Paula Seal, MD; Chris Parsons, MD; Adrienne Arbour, MD; Evans Roberts III, MD; Fred A. Lopez, MD

Since the development of combination antiretroviral therapy (cART), the incidence and mortality associated with Kaposi sarcoma (KS) have been reduced, although not eliminated. Clinical presentations of KS range from simple skin involvement to disseminated disease, including involvement of the oral cavity and viscera, which portends a more ominous prognosis. Multiple case reports and data from clinical trials indicate that administration of systemic corticosteroids may aggravate KS. We present a case of disseminated KS following administration of prednisone for presumed immune reconstitution inflammatory syndrome (IRIS) associated with fungal pneumonia in an HIV-infected individual. The discussion that follows outlines the pathophysiology and clinical presentations associated with KS and existing data for the role of corticosteroids in promoting KS progression.

CASE PRESENTATION and cough persisted, and he presented to another hospital approximately three weeks prior to admission, where he A 32-year-old man with a past medical history of HIV/ was noted to be hypoxic with multilobar infiltrates on chest AIDS and remote tobacco abuse presented to our facility radiography that were more extensive than those seen dur- with a chief complaint of shortness of breath and persis- ing his prior hospitalization. He received a diagnosis of tent cough, which began three months prior to admission. multilobar community-acquired pneumonia and was started He initially tried over-the-counter cough suppressants, on levofloxacin. Bronchoscopy with bronchoalveolar lavage which provided little relief. Over the next four weeks, he (BAL) revealed no endobronchial lesions, a negative evalu- had progressive fatigue, decreased appetite, night sweats, ation for PJP, negative Gram stain and bacterial cultures, shortness of breath, dry cough, and oral thrush with chest negative AFB cultures, and negative KOH stain. He was pain on swallowing. Approximately two months prior to discharged on levofloxacin, high-dose fluconazole, and a admission, he presented with the above symptoms and was prednisone taper for presumed pneumonia in the context of noted to be afebrile with normal values for pulse oximetry an immune reconstitution inflammatory syndrome (IRIS). at rest. His CD4+ T-cell count was 8 cells/mm3 (228-2,290 Fungal cultures from the BAL subsequently grew a few cells/mm3). A chest radiograph revealed mild bilateral, colonies of Paecilomyces species, and serum cryptococcal centrally located interstitial infiltrates, and blood cultures antigen was negative. were negative. Based on the duration of his illness, his lack One week prior to admission, he was again seen in of prophylaxis for Pneumocystis jirovecii pneumonia (PJP), the HIV outpatient clinic, where he was noted to have a and the appearance of his chest radiograph, he was treated violaceous, fungating lesion on the hard palate (Figure presumptively for both PJP and candida esophagitis. 1). On further questioning, the patient stated that a much Approximately one-and-a-half months prior to admis- smaller form of this lesion had been present for the past three sion, the patient was seen in the HIV outpatient clinic for months, although masked by severe overlying thrush. In hospital follow-up visit. He had not received cART for the addition, he had worsening shortness of breath and cough previous two years. cART therapy was initiated, along with now productive of copious brown sputum. Repeat CD4+ prophylactic trimethoprim-sulfamethoxazole, azithromycin, T-cell count was 31 cells/mm3 at this time. Outpatient and oral fluconazole treatment for diffuse oral candidiasis. computed tomography (CT) of the chest revealed diffuse Following this outpatient clinic visit, his shortness of breath lung parenchymal opacities, with areas of nodularity and

224 J La State Med Soc VOL 166 September/October 2014 Figure 1: Violaceous, fungating, infiltrative lesion on the hard Figure 2: Initial CT of the chest showing diffuse nodular palate. opacities and consolidation.

Figure 3: (H&E 200x) High-power image of the biopsied hard-palate lesion showing proliferation of atypical spindle cells within soft tissue. There are two cleft-like spaces with mildly enlarged endothelial cells in a background of extravasated red blood cells and chronic inflammation.

consolidation (Figure 2). Due to these findings and the lack smaller lesion on the maxillary gingival mucosa. Lung exam of improvement, he was sent to the emergency department revealed diffuse crackles and rhonchi in all lung zones, with (ED). decreased breath sounds at the bases. He had no skin lesions In the ED, he was visibly short of breath but without and no significant lymphadenopathy. The remainder of the thrush or odynophagia. Review of systems was significant physical exam was unremarkable. Initial laboratory assess- for decreased appetite, fatigue, night sweats, and cough ment revealed a total protein of 5.9 g/dL (6.0-8.0 g/dL), productive of a large amount of thick, brown sputum. He an albumin of 2.7 g/dL (3.4-5.0 g/dL), a mild normocytic was afebrile, with a normal blood pressure and pulse. Oxy- anemia, and mild hypokalemia. His white blood cell count gen saturation on room air by pulse oximetry was 83%. The was 9,200/µL (4,500-11,000/µL) with a normal differential. oropharyngeal examination was significant for the lesion on The patient was admitted to the hospital with a di- the hard palate previously noted, as well as a similar but agnosis of multilobar fungal pneumonia and suspicion

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for oropharyngeal Kaposi sarcoma (KS). The infectious disease consultants recommended use of liposomal amphotericin for the treatment of Paecilomyces infection, as well as a biopsy of the hard palate lesion. Oral prednisone was continued due to concerns for ongoing IRIS. The biopsy revealed proliferation of atypical spindle cells forming fascicles, bundles, and cleft-like structures lined by mildly atypical endothelial cells. Red cells were noted between the spindle cells and vascular lumina (Figure 3). Immuno- histochemical stains for human herpesvirus-8 (HHV-8), CD31, CD34, and Factor VII were strongly positive, supporting the diagnosis of KS (Figure 4). Oncology was consulted and recommended bronchoscopy and colonoscopy for staging. Bronchoscopy revealed several new, violaceous, submucosal endobronchial lesions suggestive of KS. The lesions were not biopsied due to concern Figure 4: (HHV-8 immunostain 100x) Low-power image of atypical spindle for bleeding. Gram stain performed on BAL fluid cells in fascicles showing strong nuclear immunostaining for HHV-8. revealed a few yeast colonies which did not grow in culture. Routine cultures for bacteria and acid-fast bacilli were negative. Colonoscopy revealed a rectal lesion suggestive of KS, further confirming the disseminated nature of the illness in this patient. Because of the concern for his concomitant fungal pneumonia, chemotherapy was held until his pneumonia had improved. After an 18-day hospital stay, he was discharged home. Steroids were tapered off, liposomal amphotericin was discontinued, and voriconazole was initiated with a minimum of six additional months of antifungal therapy planned. At the time of hospital discharge, his productive cough had ceased, and he was no longer requiring supplemental oxygen. On outpatient follow-up, he continued to improve. Repeat CT scan of the chest eight weeks following discharge showed improvement in the basilar consolidations and decreased size of several of the nodular lesions (Figure 5).

KS EPIDEMIOLOGY

Prior to 1981, the estimated annual incidence of KS in the United States was between 0.02 and 0.06 cases per 100,000.1,2 In June 1981, numerous case reports of KS began to surface in large metropolitan areas of New York and California.2-4 In contrast to previous cases, these Figure 5: Follow-up CT of the chest showing improvement in the basilar patients were typically young men (39 years old consolidations and decreased size of several of the nodular lesions. on average) who were homosexual or bisexual.2 In addition, these tumors behaved more aggres- sively. These cases led to the establishment of the Task Force on KS and Opportunistic Infec-

226 J La State Med Soc VOL 166 September/October 2014 tions, which eventually led to the discovery of AIDS in on cART.27 However, the exact mechanism is unknown. 1982. While the causative agent of AIDS was determined in Some HIV-positive patients with undetectable viremia and 1984, it was not until a decade later that the viral etiology normal CD4+ T-cell counts also develop KS,28 implicating of KS, the Kaposi sarcoma-associated herpesvirus (KSHV; mechanisms other than immunodeficiency in KS progres- or HHV-8), was identified.5 sion, including chronic inflammation associated with HIV Four subtypes of KS have been described, including or other co-existant opportunistic infections.23,24 classic, endemic, iatrogenic, and AIDS-related KS. Current Clinical observations strongly suggest that corticoste- estimates of the prevalence of KS among AIDS patients roids not only increase the risk of KS, but can also exacer- vary. A study in 1989 showed that the prevalence among bate existing KS.21,27,29-31 Dexamethasone has been shown homosexual men with AIDS was 21% and only 1% in AIDS to stimulate proliferation of cultured KS cells in vitro.32 KS patients who had contracted the virus by way of blood cells possess an unusually high concentration of cortico- transfusion.6 The cumulative incidence in HIV patients has steroid receptors, which can be further upregulated with since fallen from 14.3% in 1980-1989 to 1.8% in 1996-2006, corticosteroid treatment in a positive feedback mechanism.32 mostly due to the emergence of cART.7 Inflammatory cytokines also synergize with corticosteroids to induce proliferation of KS cells.26,32 RISK FACTORS AND TRANSMISSION OF HHV-8 Recognition of these associations is important due to the frequent use of systemic corticosteroids in HIV-infected Several epidemiologic studies indicate that sexual con- patients for illnesses such as PJP and cryptococcal meningi- tact is the most common mode of transmission for HHV-8.6,8 tis. Before initiating steroids in these patients, it is important Higher circulating viral loads have been associated with to perform a thorough examination of the skin and oral homosexual activity, increasing number of sexual partners, cavity to identify suspicious lesions. We would advocate commercial sex work, and attendance at STD clinics.8-11 that if suspicious lesions are present, corticosteroids should Viral DNA has been detected in the semen and prostatic generally be held until the diagnosis has been ruled out by fluid of HIV-positive men, but higher viral loads in saliva biopsy. Sexual history is also important, as men who have relative to anal and genital tissue/fluid samples support sex with men have a much higher risk of acquiring HHV-8 saliva exposure as the most likely mode of transmission.12,13 and subsequently, KS relative to other risk groups.6,33 The Salivary transmission is further supported by observation association of steroid treatment with KS appears to have of horizontal transmission of HHV-8 among children and been demonstrated in our patient, who developed clinically relatives in endemic regions.14,15 Recipients of blood transfu- evident disease of the oral cavity and progressive pulmo- sions and solid organ transplants are also at greater risk of nary distress after receiving prednisone for IRIS. Further, HHV-8 acquisition if the donor is seropositive for HHV-8.16,17 our patient improved after the discontinuation of steroids, Although all patients with KS are infected with HHV- although it is unclear to what degree this was due to anti- 8, only about 0.03% of men and 0.02% of women infected fungal therapy and cART. with the virus will develop KS annually.18 Immunosup- pression, either inherited, acquired, or iatrogenic, is a well- CLINICAL FEATURES AND DIAGNOSIS documented risk factor for the development of KS. Male gender, lower total lymphocyte count, lower CD4+ T cells, In contrast to other subtypes of KS, AIDS-related KS is and a history of systemic and topical corticosteroid use have generally more fulminant, with a higher incidence of wide- all been associated with development of KS.19-21 spread disease. Typical lesions are purple, red, or brown, highly-vascular papules, although many morphological PATHOPHYSIOLOGY OF KS AND variants exist. The most common sites of clinically appar- CORTICOSTEROIDS ent disease include the extremities, face, oral mucosa, and genitalia, although virtually any tissue in the body can be af- HHV-8 is grouped in the human gamma-herpesvirus fected.34 The presentation is variable, including mild disease family, which also includes Epstein-Barr virus. Members limited to the skin and more severe disease involving the of this family cause tumors in both humans and animals lymph nodes and viscera. Although cutaneous disease pre- by induction of uncontrolled cellular proliferation.22 Target cedes dissemination in most cases, disseminated or visceral cells for infection include endothelial cells, epithelial cells, disease may be present in the absence of skin involvement.34 macrophages, and B lymphocytes. A host of factors have Prior to the emergence of cART, most patients who devel- been shown to activate latent virus, including inflamma- oped KS would eventually develop disseminated disease, tory cytokines, immunosuppression, and tissue hypoxia.23-25 most often of the oral cavity, GI tract, and respiratory tract, Inflammatory cytokines, including IL-6, induce proliferation which is associated with a high mortality rate. The most of KS cells in vitro through the gp130 protein pathway,26 important clinical mimic is bacillary angiomatosis (BA), and increased inflammation associated with immune re- which can present as multiple, red, vascular skin lesions constitution inflammatory syndrome (IRIS) may explain and also involve visceral organs.34,35 Although uncommon, the induction or KS tumors in patients recently started BA has a higher prevalence among HIV-infected individuals than the normal population.36

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Histopathologic assessment is needed for diagnostic of KS in high-risk patients.46 Local therapy with intralesional confirmation of KS. The typical stages include the macular, vinblastine, radiation, and other topical agents is typically patch, and nodular stages, each with different degrees of used for cosmesis or reduction in symptoms associated with angiogenesis, inflammation, and proliferation.37 Immunohis- bulky lesions but does not prevent progression of disease tochemical staining using monoclonal antibodies targeting in other tissues. the HHV-8 latent nuclear antigen-1 (LNA-1) is considered the gold standard for diagnosis of KS, as it has a very high PAECILOMYCES sensitivity and specificity.38 Staining with D2-40, CD31, and CD34 are used as adjunct stains, although the specificity for Paecilomyces is a filamentous fungus common in the these markers is lower. environment, inhabiting the soil, decaying plants, and food products. Although often viewed as a contaminant, it has STAGING AND TREATMENT been known to cause a variety of diseases in humans and animals, including pneumonia in immunocompromised AIDS-related KS patients are stratified into risk catego- hosts. While there are only a handful of case reports, the ries based on three parameters: Extent of tumor (T), Immune most commonly reported species linked to respiratory status (I), and Severity of systemic illness (S). Patients are infections are P. variotii and P. lilacinus. Respiratory tract given a zero or one in each category. This staging system infection with P. lilacinus is usually characterized by pleural was developed by the AIDS Clinical Trial Group (ACTG) effusions and pulmonary abscess, while P. variotii can pres- of the National Institute of Health in 1989 and revised in ent with hilar lymphadenopathy, cavitary lesions, confluent 1997.39,40 This staging should only be used for AIDS-related patchy opacities, and pulmonary nodules. It is important KS, and there is currently no universally accepted staging to differentiate species as they display different resistance system for the other subtypes. patterns to antifungal therapy, with reports of poor suscep- cART is recommended for all patients with AIDS-relat- tibility to amphotericin B, itraconazole, and echinocandins ed KS. In the mid-1990s, the incidence and overall survival for P. variotii.47 It is unclear if Paecilomyces played a role in with KS dramatically changed with the introduction of our patient’s disease process. However, his clinical and cART. A French cohort study of HIV patients showed that radiographic improvement with antifungal therapy leads the incidence fell from 32 per 1,000 person-years in 1993 to us to believe his respiratory symptoms were at least partly 3 per 1,000 person-years in 1999.41 A similar study in 2011 due to fungal pneumonia. showed that the cumulative incidence of Kaposi sarcoma was 14.3% from 1980 to 1989, 6.7% from 1990 to 1995, and CONCLUSION 1.8% from 1996 to 2006.7 Similarly, patients with KS showed significantly higher survival rates in the cART era as com- KS was one of the most feared complications in the early pared to the pre-cART era.42 AIDS epidemic. A once rare disease exploded onto the scene The improvement in prognosis may in part be explained in the early 1980s and was quite morbid and potentially by overall immune reconstitution, rather than regression of fatal to those afflicted. Advances in cART in the mid-1990s tumor. A small number of patients (6%-14%) may develop have been essential to reducing the prevalence, morbidity, worsening of their disease after the initiation of cART, and mortality associated with this disease. The discovery of which is thought to be due to the IRIS.43,44 Most patients HHV-8 as the cause for KS in 1994 was critical to understand- who develop IRIS-induced KS flares are able to tolerate ing its pathophysiology. Although the exact mechanism of continuation of cART.43 transmission has yet to be proven, studies suggest sexual Systemic chemotherapy is usually reserved for patients transmission, possibly by exposure to saliva, as the most with more extensive or rapidly progressive disease. The likely vector. Inflammation and immunosuppression in the 2008 British HIV Association guidelines for HIV-associated setting of HHV-8 infection have been shown to cause KS malignancies recommend that the decision to use systemic proliferation leading to tumor formation. Corticosteroids chemotherapy should be based on a number of parameters, can induce KS tumorigenesis and exacerbate pre-existing le- including prognostic index, initial response to cART, patient sions, often leading to disseminated disease. Consequently, performance status, and end organ function.45 Furthermore, steroids should be avoided if there is reasonable suspicion disseminated tumors (widespread skin involvement, exten- for the presence of KS. Clinical presentations range from sive oral involvement, tumor-associated edema or ulcer- focal skin involvement to extensive involvement of visceral ation, visceral involvement) and those with IRIS-induced KS organs. More fulminant presentations are more common flares should be considered for chemotherapy.45 Liposomal in HIV-infected patients, particularly those who are not on anthracyclines (doxorubicin, daunorubicin) and taxanes (pa- cART. While a clinical diagnosis can be made by observing clitaxel) are the mainstays of treatment.45 Despite the use of classic lesions, definitive diagnosis is made by histology cART and standard chemotherapy, Stage III disease (T1I1S1) and immunohistochemical staining to identify HHV-8 latent portends a particularly poor prognosis, with a median sur- nuclear antigen-1. Staging is based on the extent of tumor vival of only 15 months.40 Ganciclovir has demonstrated burden, immune status, performance status, and coexisting activity against HHV-8 and may be useful in the prevention

228 J La State Med Soc VOL 166 September/October 2014 systemic illness. Antiretroviral therapy continues to be a 19. Touloumi G, Hatzakis A, Potouridou I, et al. The role of mainstay of treatment, along with systemic chemotherapy immunosuppression and immune-activation in classic Kaposi’s for patients with more severe disease. However, patients sarcoma. Int J Cancer. 1999;82(6):817. with advanced stage disease have a poor prognosis, even 20. Goedert JJ, Vitale F, Lauria C, et al. Classical Kaposi’s Sarcoma Working Group. Risk factors for classical Kaposi’s sarcoma. J Natl with cART and chemotherapy. Cancer Inst. 2002;94(22):1712. 21. Trattner A, Hodak E, David M, Sandback M. The appearance REFERENCES of Kaposi sarcoma during corticosteroid therapy. Cancer. 1993;72(5):1779. 1. Biggar Rj, Horm J., Fraumeni Jf, Green Mh, Goedert JJ. Incidence 22. Antman K, Chang, Y. Kaposi’s Sarcoma. 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Ann Intern Med. 1989;110(11):937- seroprevalence and correlates in prostitutes in Mombasa, Kenya. 940 J Infect Dis. 2003;187(3):359. 31. Bursics A, Morvay K, Abraham, K, et al. HHV-8 positive, HIV 11. Eltom MA, Mbulaiteye SM, Dada AJ, et al. Transmission of human negative disseminated Kaposi’s sarcoma complicating steroid herpesvirus 8 by sexual activity among adults in Lagos, Nigeria. dependent ulcerative colitis: a successfully treated case. Gut AIDS. 2002;16(18):2473. 2005;54:1049-1050 12. Boshoff C, Weiss RA. Epidemiology and Pathogenesis of KSHV. 32. Guo WX, Antakly T. AIDS-related Kaposi’s sarcoma: evidence for Philos Trans R Soc Lond B Biol Sci. Apr 29, 2001; 356(1408): 517–534. direct stimulatory effect of glucocorticoid on cell proliferation. Am 13. Pauk J, Huang ML, Brodie SJ, et al. Mucosal shedding of human J Pathol. Mar 1995; 146(3): 727-734. herpesvirus 8 in men. N Engl J Med. 2000;343(19):1369. 33. Giuliani M, Cordiali-Fei P, Castilletti C, et al. Incidence of 14. Butler LM, Were WA, Balinandi S, Downing R, Dollard S, Neilands Human Herpesvirus 8 (HHV-8) infection among HIV-uninfected TB, Gupta S, Rutherford GW, Mermin J. Human herpesvirus 8 individuals at high risk for sexually transmitted infections. BMC infection in children and adults in a population-based study in Infectious Diseases 2007, 7:143 rural Uganda. Infect Dis. 2011;203(5):625. 34. Groopman JE. AIDS-related Kaposi sarcoma: Clinical 15. Borges JD, Souza VA, Giambartolomei C, et al. Transmission of manifestations and diagnosis. In: UpToDate, Ross ME (Ed), human herpesvirus type 8 infection within families in american UpToDate, Waltham, MA. (Accessed on May 29th, 2014) indigenous populations from the Brazilian Amazon. J Infect Dis. 35. Cotell SL, Noskin GA. Bacillary angiomatosis. Clinical and 2012 Jun;205(12):1869-76. Epub 2012 May 3. histologic features, diagnosis, and treatment. Arch Intern Med 16. Hladik W, Dollard SC, Mermin J, et al. Transmission of human 1994; 154:524. herpesvirus 8 by blood transfusion. N Engl J Med. 2006;355(13):1331. 36. Mohle-Boetani JC, Koehler JE, Berger TG, et al. Bacillary 17. Regamey N, Tamm M, Wernli M, et al. Transmission of human angiomatosis and bacillary peliosis in patients infected with herpesvirus 8 infection from renal-transplant donors to recipients. human immunodeficiency virus: clinical characteristics in a case- N Engl J Med. 1998;339(19):1358. control study. Clin Infect Dis. 1996;22(5):794. 18. Vitale F, Briffa DV, Whitby D, et al. Kaposi’s sarcoma herpes 37. Grayson W, Pantanowitz L. Histological variants of cutaneous virus and Kaposi’s sarcoma in the elderly populations of 3 Kaposi sarcoma. Diagnostic Pathology 2008, 3:31 Mediterranean islands. Int J Cancer. 2001;91(4):588. 38. Cheuk W, Wong KO, Wong CS, et al. Immunostaining for human

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herpesvirus 8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its mimickers. Am J Clin Pathol. 2004;121:335–342. 39. Krown SE, Metroka C, Wernz JC. Kaposi’s Sarcoma in the Acquired Immune Deficiency Syndrome: A Proposal for Uniform Evaluation, Response, and Staging Criteria. J Clin Oncol. 1989;7(9):1201. 40. Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol. 1997 Sep;15(9):3085-92. 41. Grabar S, Abraham B, Mahamat A, et al. Differential impact of combination antiretroviral therapy in preventing Kaposi’s sarcoma with and without visceral involvement. J Clin Oncol. 2006 Jul 20;24(21):3408-14. 42. Gallafent JH, Buskin SE, De Turk PB, Aboulafia DM. Profile of patients with Kaposi’s sarcoma in the era of highly active antiretroviral therapy. J Clin Oncol. 2005 Feb 20;23(6):1253-60. 43. Bower M, Nelson M, Young AM, et al. Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol. 2005;23(22):5224. 44. Letang E, Lewis JJ, Bower M, et al. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AIDS. 2013 Jun;27(10):1603-13. 45. Bower M, Collins S, Cottrill C, et al. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Medicine (2008), 9, 336–388. 46. Kedes DH, Ganem D. Sensitivity of Kaposi’s sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy. J Clin Invest. 1997 May 1;99(9):2082. 47. Steiner B, Aquino VR, Paz AA, et al. Paecilomyces variotii as an emergent pathogenic agent of pneumonia. Case Reports in Infectious Diseases. ID 273848, 3 pp, 2013. doi:10.1155/2013/273848

Dr. Englert is Chief Resident of the Louisiana State University Health Sciences Center Internal Medicine Residency Program. Dr. Seal is Assistant Professor of Medicine at LSUHSC-NO in the section of Infectious Diseases. Dr. Parsons is Associate Professor of Medicine and Microbiology and Director of the HIV Cancer Care Program at LSUHSC – NO. Dr. Arbour is former Chief Resident of LSUHSC-NO Internal Medicine Residency Program. Dr. Roberts III is a Resident in the Tulane University Pathology and Laboratory Medicine Program. Dr. Lopez is a Professor and Vice Chair in the LSUHSC-NO Department of Medicine.

230 J La State Med Soc VOL 166 September/October 2014 Pathology Image of the Month

Death in a Young Adult With Sickle Cell Disease

Joel France, DO; Robin R. McGoey, MD

A 27-year-old African-American female with known sickle cell disease was admitted for sickle cell crisis and presumed sepsis. The patient’s past medical history was complicated by multiple sickle cell-related complications, including seizures and multiple prior blood transfusions. Her hospital course included Staphylococcus epidermidis bacteremia, for which broad spectrum antibiotics were prescribed. On hospital day nine, the patient was found unresponsive and declared dead after unsuccessful efforts at resuscitation. An unlimited autopsy examination was conducted under authorization of the coroner. Findings included numerous pathologic features ascribed to sickle cell disease, including systemic siderosis and splenic atrophy [weight 10gm (140±78)], fibrosis, and Gamna Gandy nodules. Additional autopsy findings included cardiomegaly with a heart weight of 450gm (312±78), right atrial and right ventricular chamber dilatation, and hepatomegaly with a liver weight of 2650gm (1475±362). The image below demonstrates microscopic examination of the lung parenchyma.

Figure 1: Histologic section from lung parenchyma demonstrating a small caliber pulmonary artery with an intraluminal plexus of capillary-like channels separated by proliferating intimal cells and resulting in luminal stenosis and superimposed thrombotic material (40x, Hematoxylin and Eosin stain).

What is the name of this hallmark arterial lesion? What clinical disorder does it represent?

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ANSWER: plexiform arterial lesion (Grade IV) indicative of Sickle cell disease (SCD) is an autosomal recessive in- pulmonary hypertension herited genetic disorder caused by a single point mutation in the gene for the B-globin chain of hemoglobin that results Pulmonary hypertension (PH) is a complex clinical in chronic, severe hemolytic anemia.5 It is one of the most diagnosis that has a variety of causes and encompasses common heritable hematologic diseases, with more than multiple subtypes that, over the course of time, have been 200 million worldwide mutation carriers and nearly 1 in sub-classified, defined, and then reclassified again. Previ- 600 African-Americans homozygous for the SCD mutation.5 ously subdivided into two main categories, the revised While the median age of survival in SCD has risen to roughly consensus schema now details five clinical groupings of 45 years of age, lung manifestations remain the leading cause 1 disorders that cause PH. An overview of these five clinical of both morbidity and mortality, despite the fact they remain groupings can be seen in Table 1. The microscopic features underdiagnosed by physicians.6 Pulmonary complications ascribed to PH can broadly be called plexogenic arteriopathy in SCD vary widely and include acute chest syndrome, 2 (PA). However, details regarding the spectrum of distinct restrictive lung disease, thromboembolism, and PH. SCD histopathologic features have also been subject to a variety as a cause of PH has gained only recent acceptance despite of grading systems that have undergone subsequent revi- being initially described in 1936 by Yater and Hansman.7 sions and subdivisions. The more widely accepted schema As a cause of PH, SCD is now recognized within the new for describing the histopathologic lesions of PA was detailed clinical classification scheme, falling clearly into Group 5: PH 3 by Katzenstein et al. and yields six graded lesions (Grade with unclear multifactorial mechanisms, subgroup 5.1: those I –VI), with each successive grade meant to reflect increasing due to hematologic disorders such as chronic hemolytic severity of the clinical disease. A modified grading system anemia.1 It is associated with impaired exertional tolerance, for histologic lesions can be seen in Table 2. The Grade V progressive heart failure, and a higher relative mortality lesion, otherwise known as the plexiform lesion, remains largely due to right heart failure, thromboembolism, or the pathologic hallmark of clinical PH, and a variety of cardiac arrhythmia.6,8,9 Right heart catheterization remains 4 hypotheses have been offered to explain its pathogenesis. the gold standard test for the diagnosis of PH, defined as a

Table 1: Current Clinical Classification Scheme for Pulmonary Hypertension (PH) [adapted from Simmoneau et al.]1 Clinical Group Number Major Category Subcategories Group 1 Pulmonary Arterial 1.1 Idiopathic, 1.2 Heritable [1.2.1 BMPR2, 1.2.2 ALK-1, Hypertension (PAH) ENG, SMAD9, CAV1, KCNK3, 1.2.3 Unknown Gene] 1.3 Drug- and Toxin-Induced, 1.4 Associated with [1.4.1 Connective tissue disease, 1.4.2 HIV, 1.4.3 Portal hypertension, 1.4.4 Congenital heart disease, 1.4.5 Schistosomiasis] 1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1” Persistent PH of newborn (PPHN) Group 2 PH Due to Left Heart Disease 2.1 LV Systolic dysfunction, 2.2 LV Diastolic dysfunction, 2.3 Valvular disease, 2.4 Congenital/Acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies Group 3 PH Due to Lung Disease 3.1 COPD, 3.2 ILD, 3.3 Mixed restrictive/obstructive pattern disease, 3.4 Sleep disordered breathing, 3.5 Alveolar hypoventilation disorders, 3.6 Chronic exposure to high altitude, 3.7 Developmental lung disease Group 4 Chronic Thromboembolic PH (CTEPH) Group 5 PH Due to Unclear 5.1 Hematologic disorders: chronic hemolytic anemia, Multifactorial Mechanisms MPO disorders, splenectomy; 5.2 Systemic disorders: sarcoidosis, histiocytosis, lymphangioleiomyomatosis; 5.3 GSD, gaucher, thyroid disorders; 5.4 Other: tumoral obstruction, fibrosing mediastinitis, CRF, segmental PH

BMPR2 = bone morphogenic protein receptor type II, ALK-1; ENG = endoglin, SMAD9; CAV1 = caveolin-1; HIV = human immunodeficiency virus; LV = left ventricle; COPD = chronic obstructive pulmonary disease; ILD = interstitial lung disease; MPO = myeloproliferative; GSD = glycogen storage disease; CRF = chronic renal failure.

232 J La State Med Soc VOL 166 September/October 2014 Table 2: Current Histopathologic Classification Scheme for Plexogenic Arteriopathy (PA) in Pulmonary Hypertension (PH) [adapted from Katzenstein et al.]3 Grade Predominat Pathogenic Histologic Features Process Grade I (early) Thickening of vascular medial Thickening and proliferation (hypertrophy and (increased muscularity) hyperplasia) of smooth muscle in the arterial media to >5%-7% of the diameter of the vessel Grade II-III Thickening of vascular intima Proliferation (hyperplasia) of arterial intima causing an attenuated lumen (Grade II) followed by deposition of collagen and/or elastin fibers (fibrosis) around the arterial lumen in a concentric (onion-ring) fashion (Grade III) Group IV Dilatation and degeneration Localized dilatation of the arterial branches arising from a thick-walled parent artery due to marked degeneration of the vascular media. When arterial branch dilatation affects a cluster of vessels, it is termed an angiomatoid lesion Grade V (hallmark Plexiform proliferation Plexus of capillary-like channels within a dilated arterial lesion) branch of the thick-walled parent artery that yields a glomoid appearance to the vessel + overlying thrombotic material Grade VI (rare) Vascular necrosis + Fibrinoid necrosis of smooth muscle in the vascular inflammation media + a necrotizing arteritis with either lymphocytes or neutrophils mean pulmonary arterial pressure (PAP) >25 mmHg. Using failure is needed. Further signs of right heart failure in the PAP pressures, the estimated prevalence of PH in SCD has current case include the right-sided cardiac dilatation, car- been reported to be approximately 10%.10 Autopsy studies diomegaly, and hepatomegaly. As previously mentioned, in patients with SCD, however, have yielded rather differ- autopsy studies depicting the morphologic changes seen ent information. In one study, changes of PH were found in SCD lungs have provided valuable insights into SCD as in 100% (20 of 20) of the autopsied individuals with SCD;11 a cause of PH. Further studies are warranted, as our un- while in another, more recent study conducted by Graham derstanding of the processes underlying PA continues to et al.,12 PH changes were found in only one-third of its 21 evolve and our efforts turn to therapies targeted at each of SCD decedents who underwent autopsy. The histopatho- the clinical subgroups or perhaps each of the histopathologic logic severity of vascular lesions associated with PH in SCD grades of lesions.13,14 has also been debated in the autopsy literature, with the hallmark Grade V plexiform lesion being recognized by one ACKNOWLEDGEMENTS series in 12 of 20 patients (60%)11 but in only 1 of 21 patients (0.05%) in the more recent study.12 The authors would like to gratefully acknowledge the Aside from SCD as a cause of PH, extensive research support of the Orleans Parish Coroner’s Office for providing and ample literature over the last 50 years have greatly the case material for this report. expanded the number of clinical disorders known to cause PH, including pulmonary capillary hemangiomatosis, REFERENCES veno-occlusive disease, interstitial lung disease, sarcoidosis, chronic obstructive lung disease, left heart dysfunction, and 1. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical individuals harboring a bone morphogenic protein receptor classification of pulmonary hypertension. J Am Coll Cardiol. type 2 (BMPR2) mutation. The vast majority and diversity 2013;62:D34-41. of these causes was considered in the development of the 2. Wagenvoort CA. Plexogenic arteriopathy. Thorax. 1994;49:S39-S45. newest consensus clinical subcategories of PH.1 3. Katzenstein ALA, Askin FB, Livolsi VA, et al. “Pulmonary Hypertension and Other Vascular Disorders.” Katzenstein The autopsy case depicted here of a young adult with and Askin’s Surgical Pathology of Non-neoplastic Lung Disease. SCD demonstrates the hallmark plexiform lesion (Grade IV) Philadelphia: W.B. Saunders, 1997. 434-57. Print. seen in plexogenic arteriopathy (PA) of PH. Greater aware- 4. Fishman AP. Changing concepts of the pulmonary plexiform ness is needed of the fact that lung manifestations of SCD lesion. Physiol Res. 2000;49:485-492. remain the main contributors to morbidity and mortality. 5. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. With the nonspecific clinical presentation of PH in SCD, a 2010;376:2018–2031. higher index of clinical suspicion for PA and right heart 6. Siddiqui AK, Ahmed S. Pulmonary manifestations of sickle cell disease. Postgrad Med J. 2003;79:384-390.

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7. Yater WM, Hansman GH. Sickle cell anemia: a new cause of cor pulmonale. Am J Med Sci. 1936;191:474-484. 8. Sutton LL, Castro O, Cross DJ, et al. Pulmonary hypertension in sickle cell disease. Am J Cardiol. 1994;74:626-628. 9. Aboubakr SE, Girgis RE, Swerdlow P. Pulmonary hypertension in sickle cell disease. Am J Respir Crit Care Med. 1999;160:A144. 10. Miller AC, Gladwin MT. Pulmonary Complications of Sickle Cell Disease. Am J Respir Crit Care Med. 2012;185(11):1154-1165. 11. Haque AK, Gokhale S, Rampy BA, et al. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol. 2002;33(10):1037-1043. 12. Graham JK, Mosunjac M, Hanzlick R, et al. Sickle cell lung disease and sudden death. A retrospective/prospective study of 21 autopsy cases and literature review. Am J Forensic Med Pathol. 2007;28:168-172. 13. Tuder RM, Archer SL, Dorfmuller P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25):D4-12. 14. Tuder RM, Stacher E, Robinson J, et al. Pathology of pulmonary hypertension. Clin Chest Med. 2013;34:639-650.

In the Department of Pathology at Louisiana State University School of Medicine in New Orleans, Dr. France is a second-year Pathology Resident and Dr. McGoey is an Associate Professor of Pathology and Residency Program Director.

234 J La State Med Soc VOL 166 September/October 2014 Editor Volume 166, Number 6 • November/December 2014 Established 1844 D. LUKE GLANCY, MD

Associate Editor L.W. JOHNSON, MD

EDITORIAL BOARD MURTUZA J. ALI, MD RONALD AMEDEE, MD Nadine Kaskas, BS 236 Toxic Erythema of Chemotherapy Following Leukemia Cutis SAMUEL ANDREWS, II, MD Catherine DiGiorgio, MD BOB BATSON, MD Bethaney Vincent, MD EDWIN BECKMAN, MD Suneeta Walia, MD GERALD S. BERENSON, MD Julie Mermilliod, MD C. LYNN BESCH, MD JOHN BOLTON, MD Terrell Caffery, MD 239 Delayed Detection of a Ventricular Septal Defect Following MICHELLE BOURQUE, JD Danny Robinson, MD Penetrating Trauma JAMES N. BRAWNER, III, MD Hollis O’Neal Jr., MD, MSc BRETT CASCIO, MD Azheem Kahn, MD QUYEN CHU, MD Scott Thurston, MD WILLIAM PATRICK COLEMAN III, MD Mandi Musso, PhD GUSTAVO A. COLON, MD RICHARD COULON, MD Ashley Weiss, DO, MPH 242 Psychopharmacological Treatment of Delirium: Does Earlier LOUIS CUCINOTTA, MD Michael S. Scheeringa, MD, MPH Treatment and Scheduled Dosing Improve Outcomes? VINCENT A. CULOTTA, JR., MD JOSEPH DALOVISIO, MD Alireza Hamidian Jahromi, MD, MRCS 248 A 36-Year-Old Male With a Painless Lower Extremity Skin Lesion NINA DHURANDHAR, MD Howard W. Wright, MD JAMES DIAZ, MD, MPH & TM, Dr. PH JOHN ENGLAND, MD Brijesh Patel, MD 251 Limited Circumferential Dissection of the Ascending Aorta Mimicking JULIO FIGUEROA, MD Liam Morris, MD an Acute Coronary Syndrome ELIZABETH FONTHAM, MPH, Dr. PH Nuri I. Akkus, MD EDWARD FOULKS, MD Alireza Hamidian Jahromi, MD HENRY G. HANLEY, MD Vyas Rao, MD, FACS ELIAS B. HANNA, MD LYNN H. HARRISON, JR., MD Siu-Hin Wan, MD 254 Inclusion Body Myositis Masquerading as Cardiac Dyspnea ROBERT HEWITT, MD Jackson J. Liang, DO MICHAEL HILL, MD Andrew C. Greenlund, MD, PhD LARRY HOLLIER, MD JOHN HUNT, MD Ikrita K. Klair, MD 258 Broken Lung BERNARD JAFFE, MD Jaime Palomino, MD NEERAJ JAIN, MD Fayez Kheir, MD TRENTON L. JAMES, II, MD Daniel A. Salerno, MD STEPHEN KANTROW, MD KEVIN KRANE, MD MAUREEN LICHTVELD, MD, MPH FRED A. LOPEZ, MD F. BROBSON LUTZ, JR., MD DAVID MARTIN, MD JORGE A. MARTINEZ, MD, JD ELIZABETH MCBURNEY, MD Departments ELLEN MCLEAN, MD NORMAN E. MCSWAIN, JR., MD D. Luke Glancy, MD 262 ECG OF THE MONTH REINHOLD MUNKER, MD Neeraj Jain, MD ECG in a 44-Year-Old Man With Chest Pain DAVID MUSHATT, MD JOSEPH NADELL, MD Juan S. Gomez, MD 264 RADIOLOGY OF THE MONTH HAROLD R. NEITZSCHMAN, MD Enrique Palacios, MD An Uncommon Chest Wall Mass in Renal Disease STEVE NELSON, MD Jeremy B. Nguyen, MD NORA OATES, MD Harold R. Neitzschman, MD DONALD PALMISANO, MD, JD, FACS PATRICK W. PEAVY, MD Vaughan Washco, DO 268 CLINICAL CASE OF THE MONTH ROBERTO QUINTAL, MD Ross McCarron, MD A 63-Year-Old Woman With Rash and Proximal Muscle Weakness RAOULT RATARD, MD, MS, MPH & TM Lee S. Engel, MD, PhD ROBERT RICHARDS, MD Sanjay Kamboj, MD DONALD RICHARDSON, MD Fred A. Lopez, MD WILLIAM C. ROBERTS, MD DONNA RYAN, MD Ellen E. Connor, MD, PhD 272 PATHOLOGY IMAGE OF THE MONTH JERRY ST. PIERRE, MD Ally Darga Autopsy Findings in an Adult with Down Syndrome CHARLES SANDERS, MD Robin R. McGoey, MD OLIVER SARTOR, MD CHARLES SCHER, MD RICHARD SPECTOR, MD JACK P. STRONG, MD PRAMILLA N. SUBRAMANIAM, MD KEITH VAN METER, MD DIANA VEILLON, MD HECTOR VENTURA, MD CHRIS WINTERS, MD GAZI B. ZIBARI, MD Journal of the Louisiana State Medical Society

Toxic Erythema of Chemotherapy Following Leukemia Cutis

Nadine Kaskas, BS; Catherine DiGiorgio, MD; Bethaney Vincent, MD; Suneeta Walia, MD; Julie Mermilliod, MD

A 56-year-old Caucasian male newly diagnosed with acute myelogenous leukemia (AML) M3 presented with a six-week history of multiple painful erythematous nodules scattered on his trunk and extremities, previously treated as abscesses with incision and drainage plus oral trimethoprim-sulfamethoxazole without improvement. A punch biopsy was performed, and the histopathology and immunostaining profile were compatible with leukemia cutis secondary to AML. Induction chemotherapy for AML with cytarabine, etoposide, and mitoxantrone was initiated. Dermatology was reconsulted two weeks later for evaluation and treatment of a new eruption on both dorsal hands and wrists that began three days after starting induction chemotherapy. On physical exam, there were well-demarcated erythematous patches and plaques with mild induration on the hands, extending onto the distal forearms and sparing the dorsal metacarpalphalangeal joints and ventral wrists. Biopsy findings were consistent with toxic erythema of chemotherapy, likely secondary to cytarabine.

CASE PRESENTATION histopathology and staining profile were compatible with leukemia cutis secondary to AML. Induction chemotherapy A 56-year-old Caucasian male newly diagnosed with for AML with cytarabine, etoposide, and mitoxantrone was acute myelogenous leukemia (AML) M3 presented with initiated. Dermatology was reconsulted two weeks later a six-week history of multiple painful erythematous nod- for evaluation and treatment of a new eruption on both ules scattered on his trunk and extremities, previously dorsal hands and wrists that began three days after starting treated as abscesses with incision and drainage plus oral induction chemotherapy. Discontinued medications at the trimethoprim-sulfamethoxazole without improvement. time included senna-docusate; recently added medications In addition to AML M3, the patient’s past medical history included acyclovir, potassium phosphate, promethazine, included schizophrenia and anxiety. He had no past surgery vancomycin, and piperacillin-tazobactam. The patient re- history and denied the use of alcohol, tobacco, and illicit ported the eruption began on his left hand as a red, scaly drugs. Inpatient medications at the time of consultation spot that progressed to include his wrists circumferentially included acetaminophen, allopurinol, ciprofloxacin, diphen- and then his dorsal hands and fingers (Figure 2a). Though hydramine, fluconazole, fluoxetine, haloperidol, olanzapine, he reported occasional pruritus, he stated the eruption was piperacillin-tazobactam, senna-docusate, and ondansetron. not bothersome. At the time of the initial consult to dermatology, On physical exam, there were well-demarcated ery- physical exam revealed several scattered, non-tender, firm thematous patches and plaques with mild induration and erythematous superficial and subcutaneous nodules. A scattered subcutaneous nodules on both dorsal wrists and 4 mm punch biopsy was performed on a nodule on the hands, extending onto the distal forearms. The palms and abdomen. Histopathology showed sheets of large, atypical soles were spared. The skin on the dorsal metacarpalphalan- mononuclear cells with slightly eccentric basophilic nuclei, geal, proximal interphalangeal, and distal interphalangeal single nucleoli, and scant cytoplasm. Numerous mitotic joints was also spared (Figure 2b). A 4 mm punch biopsy figures were identified. The tumor also focally assumed was performed of a nodule on the left dorsal hand. His- a leukemic infiltrative pattern (Figure 1). Immunohisto- topathology showed epidermal pseudo-epitheliomatous chemistry revealed the dermal atypical lymphoproliferative hyperplasia and dysmaturation with scattered dyskeratotic infiltrate stained strongly and diffusely positive for CD43, keratinocytes (Figure 3a). Prominent dilated, telangiectatic CD45, myeloperoxidase, and C117. The tumor stained blood vessels were noted within the superficial dermis with largely positive for CD68. Rare positive CD15 cells were an associated lymphohistiocytic inflammatory infiltrate. noted in the infiltrate. CD56 and CD34 were negative. The Extensive syringo-metaplasia was noted within the mid to

236 J La State Med Soc VOL 166 November/December 2014 deep dermis (Figure 3b). Despite the atypical sparing of palms and soles, the biopsy findings supported a diagnosis of toxic erythema of chemotherapy, likely secondary to cytarabine. The patient was instructed to apply triamcinolone ointment 0.1% twice daily to affected areas.

DISCUSSION

Leukemia cutis is the extramedullary infiltration of malignant hematopoietic cells in the epidermis, dermis, or subcutis.1 This neoplastic leukocytic infiltrate is associated with acute monocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.1 The clinical presentation can include macules, papules, plaques, nodules, and ulcers, Figure 1: Focal leukemic infiltrative pattern with large, atypical mononuclear cells with which can be localized or dissemi- slightly eccentric basophilic nuclei, single nucleoli, scant cytoplasm. (Hematoxylin-eosin nated.2 Following the establishment stain, 20x) of a diagnosis with the gold standard of a tissue biopsy, curative treatment is aimed at elimination of the systemic leukemia through a combination of chemotherapy and radiotherapy.1 Chemotherapeutic agents can cause a broad range of overlapping cutaneous reactions characterized by areas of painful erythema, collectively referred to as toxic erythema of chemotherapy (TEC).3 TEC includes Burg- dorf’s Reaction, erythrodysesthesia, acral erythema, toxic acral erythema, Figure 2: (a) Circumferential erythematous plaques on wrists with sparing of palms. eccrine squamous syringometaplasia, (b) Erythematous, scaly plaque on left dorsal hand and forearm with sparing of epidermal dysmaturation, epidermal metacarpalphalangeal, proximal interphalangeal, and distal interphalangeal joints. dystrophy, hand-foot syndrome, palmar-plantar erythema, palmar- plantar dysesthesia, and neutrophilic eccrine hidradenitis.3 TEC occurs from 24 hours to 10 months following the use of chemotherapeutic agents such as cytarabine, anthracyclines, 5-fluorouracil, capecitabine, and taxanes.4,5 Clinically, patients present with erythematous and occasionally edematous plaques, typically affecting the palms and the soles, that may be associated with pain, burning, and Figure 3: (a) Pseudoepitheliomatous hyperplasia of epidermis. (b) Extensive syringo- tenderness.2-4,8 While several cases in metaplasia in mid to deep dermis. the literature describe involvement in intertriginous areas such as the axillae and groin, as well as other sites such as the elbows and knees, the majority of these documented manifestations

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are in conjunction with palmar and plantar involvement.3,8,9 Ms. Kaskas is with the Louisiana State University Health School The sparing of the palms and soles in our patient was a of Medicine in Shreveport. Drs. DiGiorgio, Vincent, Walia, and 3,9 Mermilliod are with the Department of Dermatology at the Louisiana relatively unique presentation. Histopathologic correla- State University Health Sciences Center in New Orleans and the tion with clinical findings is indicated for a diagnosis of Ochsner Clinic Foundation, Department of Dermatology in New TEC, particularly in cases with an uncharacteristic clinical Orleans. presentation.1 There is no current consensus regarding the pathogenesis of TEC, but the most popular etiologic theory, which claims excretion of chemotherapeutic agents via eccrine sweat, causes direct toxic damage to the cells of the straight portion of the eccrine duct, acrosyringuim, and epidermis.5-7 This proposal is supported by the propensity of the syndrome to occur in acral areas with a high concentration of eccrine glands, such as the palms, soles, and intertriginious areas.5 Furthermore, studies have found localized eccrine squamous syringometaplasia at the site of doxorubicin extravasation.8,10 TEC follows a self-limited course, which resolves upon discontinuation of the inciting agent.4 Dose reduction or increasing the time between cycles of chemotherapy is recommended to decrease the risk of recurrence.6 Other treatment options include topical corticosteroids and an- algesics, local hypothermia, systemic corticosteroids, and pyridoxine supplementation.3,6 Desquamation and post- inflammatory hyperpigmentation frequently accompany resolution of TEC.4

REFERENCES

1. Bakst RL, Tallman MS, Douer D, Yahalom J. How I treat extramedullary acute myeloid leukemia. Blood. 2011;118(14):3785- 93. 2. Kang YS, Kim HS, Park HJ, et al. Clinical characteristics of 75 patients with leukemia cutis. J Korean Med Sci. 2013;28(4):614-9. 3. Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008;59(3):524-9 4. Repass TS, Wetter DA, Camilleri MJ. Toxic erythema of chemotherapy. Am J Hematol. 2012;87(9):923. 5. Lipworth AD, Robert C, Zhu AX. Hand-foot syndrome (hand- foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology. 2009;77(5):257-71. 6. Huang V, Anadkat M. Dermatologic manifestations of cytotoxic therapy. Dermatol Ther. 2011;24(4):401-10. 7. Spicknall KE, Mutasim DF. Localized toxic erythema of chemotherapy during treatment with paclitaxel. Int J Dermatol. 2013. 8. Serrano T, Saez A, Moreno A. Eccrine squamous syringometaplasia. A prospective clinicopathologic study. J Cutan Pathol. 1993;20(1):61- 65. 9. Ziemer M, Goetze S, Kaatz M, Elsner P. Chemotherapy-induced toxic erythema under treatment with pegylated liposomal doxorubicin: No restriction to palms and soles. J Am Acad Dermatol. 2008;58(2 Suppl):S44-6. 10. Jacobi U, Waibler E, Schulze P, et al. Release of doxorubicin in sweat: first step to induce the palmar-plantar erythrodysesthesia syndrome? Ann Oncol. 2005;16(7):1210-1.

238 J La State Med Soc VOL 166 November/December 2014 Delayed Detection of a Ventricular Septal Defect Following Penetrating Trauma

Terrell Caffery, MD; Danny Robinson, MD; Hollis O’Neal Jr., MD, MSc; Azheem Kahn, MD; Scott Thurston, MD; Mandi Musso, PhD

This is a case report of a 27-year-old male who sustained a stab wound to the chest with a resulting penetrating cardiac injury and subsequent emergency thoracotomy. The patient survived his injury and on post-op day two, a holosystolic murmur was noted during physical exam, but he remained hemodynamically stable and intubated. A transthoracic echocardiogram revealed the presence of a ventricular septal defect (VSD), with Doppler flow revealing shunting from the left ventricular cavity into the right ventricular cavity. Ultimately, the clinicians decided upon a trial of extubation with a plan for delayed closure of the VSD. Upon extubation, the patient became hypoxemic with evidence of pulmonary edema; thus, he was re-intubated. The defect was surgically repaired, and the patient had an uneventful recovery thereafter. The purpose of this case report is to present an example of delayed detection of a ventricular septal defect after a penetrating cardiac injury.

INTRODUCTION After Advanced Trauma Life Support protocol was initiated, tube thoracostomy was performed on the left Penetrating thoracic trauma is one of the most com- chest with some air return. At this time, the patient lost mon causes of major cardiac injury and is becoming more consciousness and became apneic. The emergency physician prevalent in the emergency setting, especially in areas where then performed an emergent thoracotomy, which revealed violent crimes occur frequently.1 A large majority of these cardiac tamponade due to a hemopericardium. This was patients (up to 94%) die before they reach the hospital.2 For emergently treated with opening of the pericardial sac and patients who survive long enough to make it to the hospital evacuation of the effusion. A two centimeter laceration to and receive an emergency thoracotomy, mortality rates are the myocardium was noted and was rapidly repaired with estimated to range between 81%-92%.3-5 Delayed sequelae of a skin stapler and five purse-string sutures. The patient cardiac injury include ventricular dilation, ventricular dys- was intubated immediately following the initial emergency function, septal hypokinesia, pericardial effusion,6 valve in- repair of the heart and went into ventricular fibrillation. Car- sufficiency, abnormal ST-T, conduction defects, myocardial diac massage was initiated, and the patient was defibrillated infarction, cardiomegaly, paradoxical septum, arrhythmia, with 200 Joules/biphasic. After defibrillation, normal sinus and ventricular septal defects (VSD).7 The purpose of the rhythm was noted on the monitor, with visual confirmation current case is to present a patient with delayed detection of organized cardiac activity. Pulses were palpable, and of a traumatic VSD who was stable while under positive transfusion of blood was initiated. pressure ventilation but quickly became unstable with the Cardiothoracic surgery was consulted and arrived physiological change to negative pressure ventilation. to take the patient to the operating room for exploration and definitive repair of the heart. Initial evaluation by the CASE REPORT surgical consultants revealed that the emergent closure was adequate with no further bleeding. Therefore, it was A 27-year-old male presented to the emergency de- determined that no further exploration was necessary at that partment after sustaining a single stab wound to the chest. time. The surgical site was irrigated and closed. Afterwards, Upon arrival, the patient had an unobtainable blood pres- the patient was admitted to the intensive care unit (ICU) sure, heart rate of 110 beats/minute, and respirations of 20 for management of hypothermia, hypovolemic shock, and breaths/minute. His initial Glascow Coma Score was 11, postoperative care. While in the ICU, it was found that the with eye opening to speech, verbal confusion, and with- patient had visual deficits but was recovering well from drawal from pain. A 2 cm vertical stab wound was noted the operation. Computed tomography of the head without to the left, upper chest wall at the fourth intercostal space. contrast revealed two areas within the left parietal and right Lung sounds revealed decreased breath sounds on the left. occipital lobes with low attenuation, likely representing Heart sounds were undetectable. The patient had no other areas of encephalomalacia. noted injuries.

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Figure 2: Transesophageal echocardiogram with color Doppler revealing the ventricular septal defect and left-to-right shunt. Note: LV=left ventricle; S = left-to-right shunt.

Figure 1: Transesophageal echocardiogram revealing a ventricular septal defect. Note: LV = left ventricle; RV = right ventricle; VSD = ventricular septal defect.

Physical exam of the patient in the ICU revealed a holo- inpatient rehabilitation facility. The patient was discharged systolic murmur. A bedside transthoracic echocardiogram three weeks later with residual blindness from anoxic brain revealed the presence of a VSD with left-to-right shunting injury sustained during his initial period of cardiac arrest. of blood, but the patient remained hemodynamically stable. Because of the VSD, there was concern that liberation from DISCUSSION positive pressure ventilation may result in cardiopulmonary compromise; however, noting that the patient remained There are no established criteria for detecting ventricu- hemodynamically stable and that most VSDs will close lar septal defects upon physical examination. In general, spontaneously, the decision was made to proceed with usual physicians are trained to look for signs of cardiac injury care and further evaluate the septal defect once the patient or dysfunction. Because all initial effort is directed toward was breathing spontaneously. The patient was weaned from keeping the patient with cardiac trauma alive in a hectic sedation and liberated from the mechanical ventilator per and noisy emergency department, hearing a VSD murmur the institutional Spontaneous Awakening and Breathing often first occurs days later. Diagnostic information can be Trial Protocols that were derived from previously reported gathered expeditiously through computed tomography and data.8 Immediately following extubation, the patient became echocardiography. ECG-gated CT offers improved spatial hypoxic while receiving oxygen at 5 liters/minute by na- and temporal resolution and can be helpful in detecting sal cannula. Oxygen saturation reached 89% with labored complications after cardiac injury.9 Transthoracic echocar- respirations, tachypnea, and tachycardia. The patient was diography can be performed in the emergency department reintubated with resumption of invasive positive-pressure and has demonstrated excellent reliability in patients who ventilation, and the treating clinicians chose to proceed with received penetrating cardiac injury treated with emergency urgent repair of the VSD. A preoperative transesophageal thoracotomy.10 However, echocardiography may fail to de- echocardiogram (TEE) revealed an unmeasured ventricular tect a VSD.11 Strong suspicion of VSDs is warranted in the septal defect (Figure 1) with left-to-right shunt (Figure 2). presence of penetrating cardiac injuries and a holosystolic Repair of the defect was performed on hospital day four. murmur. In such cases, VSDs should not be ruled out based A posteroperative TEE revealed no evidence of residual solely on a negative echocardiogram.12 Cardiac catheteriza- shunt following the repair. The remainder of the course tion may offer more accurate information about the presence was uncomplicated, and the patient was admitted to an and size of VSDs to facilitate decision-making regarding

240 J La State Med Soc VOL 166 November/December 2014 the need for intervention. It is also important to note that thoracotomy for penetrating cardiac injuries: A new perspective. there have been case reports in which the initial examina- Interactive Cardiovasc and Thorac Surg 2008;7:845-848. tion and transthoracic echocardiogram were normal, but 6. Abbott JA, Cousineau M, Cheitlin M, et al. Late sequelae delayed examinations revealed septal defects.9,13 Therefore, of penetrating cardiac wounds. J Thorac and Cariovasc Surg 1978;75:510-518. it is imperative that the patient receive an echocardiogram 7. Demetriades D, Charalambides C, Sareli, P, et al. Late sequelae 14 prior to discharge, as well as a follow-up echocardiogram of penetrating cardiac injuries. Br J Surg 1990;77:813-814. at the first post-op clinic visit to determine whether a VSD 8. Girard T, Kress, JP, Fuchs BD, et al. Efficacy and safety of a has developed or whether there were changes in the pre- paired sedation and ventilator weaning protocol for mechanically sentation of an existing VSD. ventilated patients in intensive care (Awakening and Breathing Treatment of VSDs varies depending on hemodynamic Controlled trial): a randomized controlled trial. Lancet stability of patients and size of the shunt ratio. Ventricular 2008;371:126-134. septal defects secondary to cardiac injury may not result 9. Jeon K, Lim, W-H, Kang, S-H, et al. Delayed diagnosis of traumatic ventricular septal defect in penetrating chest injury: Small in any physical symptoms or require corrective action. In evidence on echocardiography makes big difference. J Cardiovasc many instances, posttraumatic VSDs resolve spontane- Ultrasound 2010;18(1):28-30. 15,16 ously. It is recommended, if the patient does not exhibit 10. Skoularigis J, Essop MR, Sareli P. Usefulness of transesophageal symptoms, that invasive intervention be postponed in order echocardiography in the early diagnosis of penetrating stab to determine whether the VSD will close spontaneously.12,15 wounds to the heart. Am J Cardiol 1994;73:407-409. However, closure of VSDs is indicated in the presence of 11. Sugiyama G, Lau C, Tak, V, et al. Traumatic ventricular septal hemodynamic instability, pulmonary hypertension, or en- defect. Ann Thorac Surg 2011;91:108-110. larged left chambers. Traditionally, surgical interventions 12. Jones MB, Hunt JP, Glancy DL, et al. Ventricular septal defect from for VSD closure required sternotomy or thoracotomy. In a gunshot to the buttock. J La State Med Soc 2009;161:148-152. 13. Antoniades L, Petrou, P, Eftychiou C, et al. A penetrating heart 1988, the first transcatheter closure of a VSD was reported in injury resulting in ventricular septal defect. Hellenic J Cardiol 17 the literature. Today, physicians may employ an Amplatzer 2011;52:71-74. VSD occluder, a device designed specifically for closure of 14. Tang AL, Inaba K, Branco BC, et al. Postdischarge complications VSDs.18 In the present case, further investigation of the VSD after penetrating cardiac injury: A survivable injury with a high may have resulted in less invasive correction, using one of postdischarge complication rate. Arch Surg 2011;146(9):1061-1066. these methods. 15. Dehghani P, Ibrahim R, Collins N, et al. Post-traumatic ventricular septal defects: Review of the literature and a novel technique for percutaneous closure. J Invasive Cardiol 2009;21:483-487. SUMMARY 16. Glancy DL, Itscoitz SB, McIntosh CL, et al. Successful operative correction of intrapulmonary rupture of a post-traumatic left In the current case, a holosystolic murmur was noted ventricular aneurysm: documentation of complete spontaneous during the physical examination on the second day, and a closure of an associated ventricular septal defect. Am J Cardiol transthoracic echocardiogram revealed a VSD. Because the 1972;30:914-918. patient was hemodynamically stable while intubated and 17. Lock JE, Block PC, McKay RG., et al. Transcatheter closure of many VSDs close spontaneously, it was decided that an at- ventricular septal defects. Circulation 1988;782:361-368. tempt at extubation would be made. Once the patient was 18. Fraisse A, Piechaud J-F, Avierinos J-F, et al. Transcatheter closure extubated, the left to right shunt increased with the mani- of traumatic ventricular septal defect: An alternative to surgical repair? Ann Thorac Surg 2002;74:582-584. festations of heart failure, pulmonary overload, hypoxemia, and tachycardia. In retrospect, follow-up assessment of the holosystolic murmur using cardiac catheterization may have resulted in corrective surgery prior to extubation. Emergent repair of the VSD was required. As the current case illustrates, follow-up assessments are of paramount importance Dr. Caffery is an Assistant Professor in Louisiana State University for patients who have sustained penetrating cardiac injuries. Health Sciences Center’s School of Medicine and the Program Director of the LSUHSC’s Emergency Medicine Residency Program in Baton REFERENCES Rouge. Dr. Robinson recently completed his residency at LSUHSC’s Emergency Medicine Residency Program in Baton Rouge, and he is 1. Tintinalli JS. Tintinalli’s Emergency Medicine: A Comprehensive Study currently an Emergency Medicine Physician at St. Tammany Parish Hospital. Dr. O’Neal is an Assistant Professor of Clinical Medicine, Guide, Seventh Edition. New York: McGraw Hill; 2011. Pulmonary & Critical Care Medicine, LSUHSC - Baton Rouge. Drs. 2. Kang N, Hsee, L, Rizoli S, et al. Penetrating cardiac injury: Kahn and Thurston are Assistant Professors of Surgery in the CVT Overcoming the limits set by nature. Injury, Int J Care Injured Surgical Center at the LSUHSC in New Orleans. Dr. Musso is the 2009;40:919-927. Academic Research Director for LSUHSC’s Emergency Medicine 3. Asensio JA, Soto SN, Forno W, et al. Penetrating cardiac injuries: Residency Program in Baton Rouge. a complex challenge. Injury, Int. J. Care Injured 2001;32:533-543. 4. Rhee PM, Acosta, J, Bridgeman, A, et al. Survival after emergency department thoracotomy: Review of published data from the past 25 years. J Am Coll Surg 2000;190:288-298. 5. Molina E, Gaughan JP, Kulp H, et al. Outcomes after emergency

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Psychopharmacological Treatment of Delirium: Does Earlier Treatment and Scheduled Dosing Improve Outcomes?

Ashley Weiss, DO, MPH; Michael S. Scheeringa, MD, MPH

Purpose: The goals of this study were to examine how dosing strategies and timeliness of antipsychotic medication initiation would affect delirium duration. Methods: This is a retrospective paper and electronic record review of patients in an academic hospital who had been diagnosed with delirium. Forty-two patients met inclusion criteria. Quantitative and qualitative data on the course of delirium was gathered, as well as important demographic and medical variables. Results: There were no significant differences in duration of delirium between the scheduled and PRN groups using survival analysis, although the test was marginally significant (log rank test, p<0.06). Those who received treatment within 24 hours of recognition had significantly shorter durations of delirium compared to those who began treatment after 24 hours (log rank test, p<0.006). Conclusion: These data suggest that early psychopharmacological treatment of delirium can reduce duration. Future research needs to investigate prompt and scheduled medication dosing strategies for treatment of delirium symptoms.

INTRODUCTION following orthopedic surgery for hip fracture.6 Treatment strategies for delirium are still controversial. Delirium is a central nervous system manifestation of There is no approved treatment from the Federal Drug a systemic disease process that has crossed the blood brain Administration, and the optimal doses and regimen have barrier. Delirium occurs at rates ranging from 10%-30% of not been defined in clinical trials. There is evidence that all general hospital admissions, leads to longer hospital treatment of delirium with antipsychotic medications is ef- stays and higher mortality, and is associated with increased fective and may shorten time delirious and decrease hospital functional decline and morbidity, especially if unrecognized stays. Both typical antipsychotics (e.g., haloperidol) and and undertreated.1 Delirium risks are cumulative, and with newer atypical antipsychotics (aripiprazole, olanzapine, each day delirious, there is an increased risk of prolonged and risperidone) have shown preliminary effectiveness in hospitalization and 10% increased risk of death.2 Delirium is controlled7 and uncontrolled studies.8,9 In the only known independently associated with higher ICU costs ($22,346 vs placebo-controlled study, a randomized trial of 101 end $13,332, respectively) and hospital costs ($41,836 vs $27,106, stage cancer patients, there were no differences in duration respectively) compared to those without delirium.3 of delirium until death between haloperidol, ziprasidone, There has been increased attention to early recogni- and placebo.10 However, the severe, terminal status of this tion and treatment of this disorder. Evidence indicates that population makes generalization of the results problematic. prompt and scheduled medication treatment is most effec- In a review of the literature by Campbell et al.,11 the existing tive;4 however, evidence is scarce. Prompt treatment may be controlled studies compared pharmacologic intervention to important because delirium seems to result from a cascade of no pharmacologic intervention (as opposed to placebo) in interacting processes, beginning with a physical stress and/ the treatment of delirium in hospitalized adults. Antipsy- or trauma and leading to systemic inflammation, compro- chotic medications showed the greatest effectiveness and mised oxidative metabolism; and resulting in cellular dam- appeared to decrease the severity and duration.11 age and neurotransmitter disruptions. The cellular damage One study has examined scheduled antipsychotic has been thought to be the result of dopamine-induced cell dosing in the treatment of delirium. Maldonado and col- death,5 and in a recent study, protein markers of brain dam- leagues (2003) followed patients prospectively and found age were elevated in the blood and CSF of delirious patients that a protocol used by the psychosomatic medicine service

242 J La State Med Soc VOL 166 November/December 2014 (scheduled dosing of haloperidol at 4:00 AM, 11:00 AM, 4:00 time of onset was coded as 4:00 AM; for “afternoon,” time PM, and 10:00 PM) when compared with the standard ap- was coded as 12:00 PM; and for “evening,” time was coded proach (which mainly included sporadic and PRN dosing) as 8:00 PM. If no time of the day was described, then time led to shorter durations of delirium.4 of onset was coded as 12:00 PM. Only five cases had to be The first goal of this naturalistic chart review is to ex- coded with these conventions. amine the duration of delirium after initiation of scheduled doses of antipsychotic medication compared to PRN (as Date and time that doses of antipsychotic medications needed) dosing. The existing literature has devoted little were given attention to the issue of scheduled versus PRN dosing. A The electronic medical record contained the exact times second goal is to examine whether duration of delirium re- that doses of antipsychotic medications were given as en- solves more rapidly when medications (whether scheduled tered by nursing staff. We were also able to see if medications or PRN) are initiated sooner after diagnosis as opposed to were scheduled to be given but were held. later. If delirium resolves more rapidly with prompt initiation of treatment (i.e., before the delirium can worsen or Date and time that delirium resolved have secondary impacts on other physiological systems), Delirium was considered resolved when the consult- this would have direct and immediate implications for ing psychiatrist’s assessment reflected this in the progress clinical practice. notes. Specific times of resolution were present in the progress notes for 38 patients. For the other eight patients, PATIENTS AND METHODS the progress notes did not contain a specific time when delirium symptoms resolved, so the standard convention Patients for estimation of time that was described earlier was used. The setting was an academic-affiliated hospital in a If patients were discharged with delirium symptoms, their medium-size city in the southeastern United States. The discharge date and time were used to determine their dura- hospital is situated in the downtown area and provides tion of delirium. both general inpatient medical services as well as multiple specialized and tertiary referral services typical of an Duration of delirium symptoms after medication was academically-based institution. Investigators reviewed the started paper and electronic charts of all 86 patients admitted to the The time it took for delirium symptoms to resolve after hospital from January 2007 to January 2013 who received medication treatment was initiated was estimated as the diagnosis of delirium from the consult-liaison psychiatrist. number of hours from the first dose of antipsychotic medica- Inclusion criteria were a clinical diagnosis of delirium by tion until documentation that delirium symptoms resolved. the psychiatric consultant, 18 years of age and older, and a recommendation from the consultant to use an antipsychotic Timeliness of starting medication for treatment. Subjects were excluded if they had a history If patients received a dose of antipsychotic medication of a primary psychotic disorder, diagnosis of delirium tre- within the first 24 hours after delirium was first noted, then mens or substance-induced psychosis (if an illicit substance). they were coded as the Timely group. If they did not receive Eighty-six patient charts were reviewed, and 42 patients met a dose within the first 24 hours, then they were coded as criteria for inclusion in analyses. the Delayed group.

Procedure Type of delirium The study protocol was submitted and accepted Mental status exam findings from progress notes were through the Tulane University Institutional Review Board. used to classify the types of delirium at the time of diagnosis Data abstractors were not blinded to hypotheses. The data as hypoactive, hyperactive, and mixed, following methods abstractors were the first author and a research assistant. In used in previous studies.12 Besides the presence of fluc- this hospital setting, there was not an established protocol tuating level of consciousness, criteria for being coded as for treatment of delirium on any of the hospital services. “hypoactive” delirium included lethargy, sedation, and/ Data were systematically collected and entered onto a stan- or psychomotor retardation. To be coded as “hyperactive,” dardized Case Report Form (CRF) developed for this study. symptoms included agitation, aggression, and/or psychotic symptoms. If the patient had symptoms from both, they Measures were coded as “mixed.” Date and time for onset of initial recognition of delirium symptoms Data Analysis Progress notes indicated a specific time that the onset All of the statistical analysis was performed using SAS of delirium was noted. If the progress notes did not conversion 9.3 (Cary, NC). Assignment to Scheduled versus tain a specific time, then a standard convention was used PRN groups was determined empirically (see Results). for estimation. If the progress note noted “morning,” then

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antipsychotic medication to the resolution of delirium. The distribution of the durations of delirium symptoms after medications were started was right-skewed and non-normally distributed. Patients who were discharged with delirium were censored. Kaplan-Meier survival curves and log-rank tests were used to test differences in time to resolution between groups, with shorter times indicating better clinical outcome. Potential covariates were entered into the main models and tested with Cox proportional hazards regression models. Probability of Persistence of Delerium Probability of Persistence

RESULTS

Patients were divided empirically into two groups based on how they actually received antipsychotic medication (as opposed Figure 1: Kaplan-Meier survival estimates for duration of delirium symptoms in to how it was ordered). The Scheduled group Scheduled (N=31) vs. PRN (N=11) groups. received two or more doses of antipsychotic medication per 24 hours once treatment began; the PRN group received on average one or fewer doses during each 24-hour period (which included some 24-hour periods in which the patient did not receive any doses). This method was based on the duration of action and conventional recommendations of using antipsychotic medications. There were 42 patients with complete data to analyze; 31 received scheduled doses, and 11 received PRN doses. Sixteen patients were discharged with delirium symptoms that had not resolved and their durations of delirium ranged from 13 to 1,400.5 hours. The demographics of the Scheduled and

Probability of Persistence of Delerium Probability of Persistence PRN groups are shown in Table 1. The Sched- uled group included significantly more white patients (68% vs. 9%) and had more patients with delirium that resolved (74% vs. 27%) compared to the PRN group. The groups did not differ on age, sex, reason for psychiatry consultation, type of delirium, disposition Figure 2: Kaplan-Meier survival estimates for duration of delirium symptoms in status, or location of consultation. Timely (N=20) vs. Delayed (N=22) groups. Table 2 shows means and medians for durations of delirium after initiation of anti- Differences in demographic variables between the psychotic. The median duration of delirium Scheduled and PRN groups were compared with chi-square for the total sample was 129 hours (5 days and 9 hours). The tests for categorical variables and t-test for the continuous range was 13 to 1,400 hours, with 37% of the sample (n=15) age variable. Because some patients were discharged before showing delirium symptoms for more than one week. The resolution of their delirium, survival analysis was used, types of medication that patients received included halo- which can handle data when the endpoint of interest has peridol (n=22), olanzapine (n=10), risperidone (n=4), and not been reached. This method was used to test durations quetiapine (n=9). Fourteen percent of the sample showed of delirium between the Scheduled vs. PRN groups and hypoactive delirium, 67% showed hyperactive delirium, between the Timely vs. Delayed groups. The time to event and 19% presented with mixed delirium. variable was the number of hours from the first dose of

244 J La State Med Soc VOL 166 November/December 2014 Table 1: Characteristics of Patients With Delirium PRN Number PRN Percentage Scheduled Scheduled Total N Number Percentage Sex Male 8 73 25 81% 33 Female 3 27 6 9% 9 Race White 1 9 21 68 22 Black 10 91 6 19 16 Hispanic 0 0.0 1 4 1 Other 0 0.0 3 10 3 Reason for Consultation Altered Mental 6 55 16 52 22 Status Depression 1 9 1 3 2 Anxiety 0 0.0 4 13 4 Agitation 1 9 2 6 3 Confusion 0 0.0 4 13 4 Disorientation 3 27 4 13 7 Disposition Home 4 20.0 16 80.0 20 Skilled Nursing 1 25.0 3 75.0 4 Facility Inpatient Rehab 1 14.3 6 85.7 7 Home Health 3 75.0 1 25.0 4 Hospice 0 0.0 1 100.0 1 Other 2 40.0 3 60.0 5

Table 2: Means and medians of duration of delirium symptoms after first dose of antipsychotic medication (hours). Group n Median Mean SD Scheduled 31 130.1 194.0 253.8 PRN 11 88.6 244.3 308.6 Timely 20 86.4 101.7 86.9 Delayed 22 173.8 303.0 333.6

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Hypothesis 1: Scheduled dosing of antipsychotic delirium compared to the group that received PRN doses. medication vs. PRN dosing reduces delirium duration This is difficult to interpret in an uncontrolled, naturalistic The plot of the Kaplan-Meier survival estimates for chart review. Nevertheless, we interpret this as highly Scheduled vs. PRN groups is shown in Figure 1. The ex- suggestive evidence that scheduled doses not only make pected separation of curves occurred as the Scheduled group rational sense clinically but have growing preliminary showed a greater proportion of cases moving to resolution of empirical support. delirium. Formal testing between groups with the log-rank There were qualitative findings from this chart review test, however, showed that duration of delirium between that are of clinical interest. There was rarely a standardized groups was only marginally significant (chi-square 3.4, df=1, method used for screening, diagnosing, or treating delirium. p = .06). Table 2 shows the median duration of symptoms In addition, it was often the nurses who made initial docu- is shorter in the PRN group, but the greater proportion of mentation of mental status changes. Van der Boogard and patients with unresolved delirium in the PRN group resulted colleagues [2010] showed that when the confusion assess- in a longer mean duration. ment method-ICY (CAM-ICU) tool was implemented in the ICU, compliance and delirium knowledge improved Hypothesis 2: Timely initiation of antipsychotic in physicians and nurses, and results also indicated that medication reduces duration of delirium compared to more patients were treated with antipsychotic medication delayed initiation but with lower doses and for a shorter period of time.14 In Figure 2, clear separation of the Kaplan-Meier Given this evidence, as well as our findings, implementing survival estimates for duration of delirium in the Timely standardized tools to improve detection and management vs. Delayed groups is evident. The Timely group showed of delirium in this hospital setting would be a future direc- shorter durations of delirium compared to the Delayed tion of our research. group (log-rank test = 7.4, df=1, p < .05). As shown in Table In addition to the limitations already mentioned, the 2, patients who received their first dose of antipsychotic allocations of patients to Scheduled vs. PRN groups and medication within 24 hours of the onset of delirium had to Timely vs. Delayed groups were not controlled. Given significantly shorter durations of delirium symptoms (me- the known effectiveness of antipsychotic medications for dian 86.4 hours) compared to patients who received their delirium and the data on the prolonged course of untreated first dose of antipsychotic medication more than 24 hours delirium, it would be unethical to allocate subjects ran- after the onset of delirium (median 173.8 hours). domly to these types of groups. As imperfect as it was, this With age, sex, race (Black/African-American vs. White), uncontrolled, naturalistic investigation appeared to be the or type of delirium (mixed and hypo-delirium vs. hyper- only way to examine the relative impacts of these dosing delirium) entered as covariates in separate Cox proportional strategies. Also, delirium diagnosis was made from clinical hazards regression models, the effect of timely initiation of evaluation, without the use of standardized tools. However, antipsychotic medication was still significant (p <.05). descriptions of the cases in consultation and progress notes appeared consistent with delirium. DISCUSSION There were many confounding factors that we were unable to control for without a randomized design. An in- The most important finding was that initiation of herent difficulty in studying delirium is an inability to take antipsychotic medication within 24 hours of the recogni- into account etiologies of delirium, as the cause of delirium tion of delirium was associated with shorter durations of in many, if not most, cases of delirium is never known. delirium compared to delayed initiation of medication. However, there are few data to suggest that the course or While delayed treatment of delirium has previously been treatment response of delirium differs by etiology. Assessing addressed in the literature,13 empirical data on this issue has how specific delirium etiologies relate to treatment outcomes been limited. This finding has at least two important clinical would be an area of further research. implications. First, this suggests that prompt recognition of Despite these limitations, it is important to note that delirium, which would allow more prompt treatment, has data on effects of delayed treatment and on dosing regi- the potential to lead to improved clinical outcomes. Inpa- mens are scarce. This study provides preliminary empirical tients may be served well by implementation of standard- information that early recognition, and perhaps scheduled ized screening for delirium at early and regular intervals. dosing that is more biologically informed by the half-lives Second, these data suggest that clinicians consider delirium of antipsychotic medications, is important for outcomes. as being in need of more pressing and aggressive intervention, as earlier intervention may interrupt a cascade of toxic REFERENCES metabolic processes in the central nervous system that have been shown to predict cellular death.5 1. Briskman I, Dubinski R, Barak Y. Treating Delirium in a General Of additional importance, was our finding that there Hospital: A Descriptive Study of Prescribing Patterns and was a trend of marginal statistical significance for the group Outcomes. Int Psychogeriatr. 2010; 22: 328-331. 2. Pun BT, Ely EW. The Importance of Diagnosing and Managing that received scheduled doses to have shorter durations of ICU Delirium. Chest. 2007; 132: 624-636

246 J La State Med Soc VOL 166 November/December 2014 3. Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, Truman B, Bernard GR, Dittus RS, Ely EW. Costs Associated With Delirium in Mechanically Ventilated Patients. Crit Care Med. 2004; 32: 955-62. 4. Maldonado J.R., Dhami N. Recognition and management of delirium in the medical and surgical intensive care wards. J Psychosom Res. 2003; 150-155. 5. Maldonado JR. Pathoetiological Model of Delirium: A Comprehensive Understanding of the Neurobiology of Delirium and an Evidence-Based Approach to Prevention and Treatment. Crit Care Clin. 2008; 24: 789-856. 6. Van Munster BC, Korse CM, de Rooij SE, Bonfrer JM, Zwinderman AH, Korevaar JC. Markers of Cerebral Damage During Delirium in Elderly patients with Hip Fracture. BMC Neurol. 2009; 9:21. 7. Han CS, Kim YK. A Double-Blind Trial of Risperidone and Haloperidol for the Treatment of Delirium. Psychosomatics. 2004; 45: 297-301. 8. Boettger S, Friedlander M, Breitbart W, Passik S. Aripiprazole and Haloperidol in the Treatment of Delirium. Aust N Z J Psychiatry. 2011; 45: 477-482. 9. Elsayem A, Bush SH, Munsell MF, Curry E,3rd, Calderon BB, Paraskevopoulos T, et al. Subcutaneous Olanzapine for Hyperactive or Mixed Delirium in Patients With Advanced Cancer: A Preliminary Study. J Pain Symptom Manage. 2010; 40: 774-782. 10. Girard TD, Pandharipande PP, Carson SS, Schmidt GA, Wright PE, Canonico AE, et al. Feasibility, Efficacy, and Safety of Antipsychotics for Intensive Care Unit Delirium: The MIND Randomized, Placebo-Controlled Trial. Crit Care Med. 2010; 38: 428-437. 11. Campbell N, Boustani MA, Ayub A, Fox GC, Munger SL, Ott C, et al. Pharmacological Management of Delirium in Hospitalized Adults—A Systematic Evidence Review. J Gen Intern Med. 2009; 24: 848-853. 12. Smith HA, Fuchs DC, Pandharipande PP, Barr FE, Ely EW. Delirium: An Emerging Frontier in the Management of Critically Ill Children. Anesthesiol Clin. 2011; 29: 729-750. 13. Heymann A, Radtke F, Schiemann A, Lutz A, Macguill M, Wernecke KD, Spies C. Delayed Treatment of Delirium Increases Mortality Rate in Intensive Care Unit Patients. The Journal of International Medical Research. 2010; 38: 1584-1595. 14. van den Boogaard M, Pickkers P, van der Hoeven H, Roodbol G, van Achterberg T, Schoonhoven L . Implementation of a delirium assessment tool in the ICU can influence haloperidol use. Crit Care. 2009; 13:R131.

Dr. Weiss is Assistant Professor of Psychiatry in the Department of Psychiatry and Behavioral Health Sciences at Tulane University School of Medicine. Dr. Scheeringa holds the Remigio Gonzalez, MD Professorship of Child Psychiatry at Tulane University School of Medicine.

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A 36-Year-Old Male With a Painless Lower Extremity Skin Lesion

Alireza Hamidian Jahromi, MD, MRCS; Howard W. Wright, MD

CASE REPORT

A 36-year-old previously healthy African-American cough, sputum) 15 months before. The CXR findings did male truck driver presented with a 12-month history of a not change following a two-week course of antibiotics. The large (10 x 6 cm) painless, circular, expanding plaque on patient subsequently underwent a broncoscopy and bron- the posterolateral aspect of his left-lower thigh associated choalveolar lavage (BAL) during which the right-upper, with serous discharge and discomfort (Figure 1). Differ- middle, and lower lobe segmental orifices were visualized ent courses of topical and oral antibiotics did not resolve to be non-inflamed. A right middle lobe transbronchial lung the lesion. The patient did not have chills, fever, cough, biopsy (fluoroscopic guidance) did not show any abnormal- sputum, night sweat, or weight loss. Punch biopsy results ity, and the BAL was negative for malignancy and fungal from four different areas of the plaque were non-diagnostic cultures. The follow-up CXR did not show any change. The but showed chronic, nonspecific inflammation and fibrosis. patient underwent resection of the skin lesion which showed CT scan of the thigh revealed localized superficial irregular pseudoepitheliomatous hyperplasia (Figure 2), presence of nodular soft tissue thickening associated with mild under- the budding yeast with a double-contoured wall (Figures lying subcutaneous fat stranding. There was no involve- 3,4) and confirmed a diagnosis of a cutaneous blastomycosis. ment of thigh musculature/bones and no evidence of fluid Acid fast staining of the pathology specimen was negative. collections/abscess. HIV serology and TB skin test were Patient was started on Itraconazole orally. Repeat CXR negative. The patient had a history of incidental finding showed no active pulmonary disease. of right lung middle lobe infiltrate on a chest X-ray (CXR) without having clinical signs of pneumonia (chills, fever,

DISCUSSION

Blastomycosis is a fungal infection which is caused involvement generally begins as papules, postules, and by Blastomyces dermatitidis and is especially endemic in or subcutaneous nodules and will develop into verrucous areas of the United States with a moist climate, i.e. Loui- plaques or ulcers that may suppurate and spontaneously siana, Mississippi, Tennessee, Illinois, and Wisconsin.1 In drain, forming deep cutaneous ulcers.1 The differential Louisiana, the highest number of cases has been reported diagnoses for such lesions includes but are not limited to from Washington, Tangipahoa, Jefferson, and St Tammany pyoderma gangrenosum, squamous cell carcinoma, basal Parishes.2 Although pulmonary disease ranging from sub- cell carcinoma, keratoacanthoma, and other chronic cutane- clinical asymptomatic infection to acute respiratory distress ous infections, such as sporotrichosis, nocardiosis, atypical syndrome (less than 10% of cases) is the most common mycobacteriosis, tularemia, anthrax, or leishmaniasis.1,4 manifestation, involvement of bone, skin, genitourinary, Visualization of the yeasts on 10% KOH preparation, and central nervous system can be seen.1,3 Inhalation of Gomori’s stain, PAS stain, or Papanicolaou’s smear of tissue aerosolized conidial forms of the organism, hematogenous biopsy, tracheal aspirates, BAL fluid, and sputum specimens spread following organism transformation to a yeast after or tissue cytological analysis or fungal culture on Sabouraud pulmonary infection (thick cell wall in yeast form confers dextrose agar at room temperature are some basic methods resistance to phagocytosis), and direct skin infection follow- for diagnosis of the Blastomyces dermatitidis infections.1 The ing a traumatic inoculation event (exposure in moist wooded organism appears as single or budding spherical cells (8- areas during outdoor activities, animal bites and scratches) 15µm in diameter) with thick cell walls. Although micro- are possible means of infection. scopic visualization of broad-based budding yeast can be Diagnosis of skin lesions in the cutaneous blastomycosis diagnostic, fungal cultures of skin biopsies should always is challenging and requires a high index of suspicion. Skin be done, especially when microscopy is inconclusive.1 Anti-

248 J La State Med Soc VOL 166 November/December 2014 Figure 2: Histologic appearance of the skin lesion, HIE stain x 200

Figure 1: Gross appearance of skin lesion

Figure 3: Periodic-acid-Schiff Stain of the resected skin lesion, Figure 4: Pas stain at 1000 shows the double-contoured wall magnification x 400, shows budding yeast (see arrow) of the yeast

body detection by complement fixation, immuno-diffusion, erroneous diagnosis of squamous cell carcinoma or kerato- and enzyme immunoassay (EIA) has also been described, acanthoma.6 Oral antifungal agents, i.e. Itraconazole, have but the diagnostic yield of these methods are not high.5 In become the standard of care for cutaneous or pulmonary cases with cutaneous involvement, skin biopsy with histo- non-life threatening blastomycosis infections; the same is logical hematoxylin and eosin (H&E) and silver staining true with using Amphotericin-B for disseminated or life may reveal the organism, although the skin biopsy may not threatening diseases (ARDS) or in patients with immuno- be diagnostic (i.e. current case). The histological changes suppression. without the visualization of the organism may prompt an

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REFERENCES

1. Emer JJ, Spear JB. Primary cutaneous blastomycosis as a cause of acute respiratory distress syndrom: case report and literature review. J Clin Aesthet Dermatol 2009; 2(3):22-30. 2. Retrieved information from Louisiana office of public health data on 4/28/2014. http://new.dhh.louisiana.gov/assets/ oph/Center-PHCH/Center-CH/infectious-epi/Annuals/ LaIDAnnual_Blastomycosis.pdf 3. Meyer KC, McManus EJ, Maki DG. Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med 1993; 329(17):1231-6. 4. Pappas PG, Dismukes WE. Blastomycosis: Gilchrist’s disease revisited. Curr Clin Top Infect Dis. 2002; 22:61–77. 5. Klein BS, Vergeront JM, Kaufman L, et al. Serological tests for blastomycosis: assessments during a large point-source outbreak in Wisconsin. J Infect Dis 1987;155(2):262–268. 6. Bradsher RW, Martin MR, Wilkes TD, et al. Unusual presentations of blastomycosis: ten case summaries. Infect Med 1990;7:10–19.

Dr. Hamidian Jahromi is in the Department of Surgery at University Health Shreveport. Dr. Wright is in the Department of Pathology at University Health Conway in Monroe.

250 J La State Med Soc VOL 166 November/December 2014 Limited Circumferential Dissection of the Ascending Aorta Mimicking an Acute Coronary Syndrome

Brijesh Patel, MD; Liam Morris, MD; Nuri I. Akkus, MD; Alireza Hamidian Jahromi, MD; Vyas Rao, MD, FACS

CASE HISTORY A transthoracic echocardiogram (TTE) showed a normal left ventricular (LV) ejection fraction, LV hypertrophy, A 52-year-old hypertensive female transferred from moderate aortic regurgitation (AR) (Figure 3A), and normal an outside hospital to our unit for management of an acute LV wall motion. A transesophageal echocardiogram (TEE) coronary syndrome. She presented initially with sudden showed a type-A aortic dissection limited only to the ascend- onset severe chest pain radiating to the neck, right jaw, ing aorta, just distal to the structurally normal aortic valve, and right arm, associated with nausea and shortness of with the intimal flap prolapsing into the left ventricle (Figure breath. On examination, the blood pressure (BP) was 177/59 3B), causing moderate aortic regurgitation (Figure 3C). CT mmHg, and the pulse was 77 beats per minute. There was angiogram of the chest showed a linear filling defect limited a diastolic decrescendo murmur located over the lower left to the ascending aorta above the aortic valve annulus (Figure sternal border. Peripheral pulses were equally palpable 4). Surgery revealed a circular dissection of the ascending bilaterally. The remainder of the examination was unre- aorta disrupting the normal anatomical suspension of the markable. An electrocardiogram showed sinus rhythm, left aortic leaflets (Figure 5A). The dissection was surgically ventricular hypertrophy, and ST-T wave abnormalities in repaired with pledgeted horizontal mattress stitches, and the anterolateral leads (Figure 1). A chest radiograph (chest the native aortic valve was re-suspended (Figure 5B). The X-ray, CXR) showed a mildly prominent cardiac silhouette patient made a full recovery after surgery. with perihilar congestion (Figure 2). Troponin level on admission was 0.03 μg/l, which subsequently increased to DISCUSSION 0.14 μg/l (normal range <0.03 μg/l). Acute aortic dissection is a medical emergency in which having a high degree of clinical suspicion is of critical importance for prompt diagnosis and treatment. Herein, we described a novel case of a limited circumferential aortic type-A dissection mimicking an acute coronary syndrome. The patient did not have pain radiating to back, widened mediastinum on CXR, or significant BP difference in the upper extremities. Uncontrolled hypertension and history of smoking, coupled with TTE findings of normal LV wall motion and AR led to clinical suspicion of aortic dissection. Only a few cases of limited circumferential type-A dissection are reported in the Figure 1: Twelve lead electrocardiogram (ECG) showing sinus rhythm, left ventricular literature.1-4 TEE is a highly sensitive hypertrophy, and ST-T wave abnormalities in the anterolateral leads. and specific imaging modality used to diagnose aortic dissection. This type of

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Figure 2: Chest radiograph (posterior- anterior (PA) view) showing a mildly prominent cardiac silhouette with perhilar congestion.

Figure 3: (A) TTE (Parasternal Long Axis View) showing moderate aortic regurgitation. (B) TEE (Mid-esophogeal long axis view) showing a type-A aortic dissection with the intimal flap only limited to the ascending aorta just distal to the structurally normal aortic valve. (C) TEE (Mid-esophogeal long axis view) showing moderate aortic regurgitation.

Figure 4: CT angiogram of the chest showing a linear filling defect (arrow) limited to the ascending aorta just above the aortic valve.

252 J La State Med Soc VOL 166 November/December 2014 Figure 5: (A) Intraoperative photograph showing a circumferential ascending aortic dissection (indicated by the white arrow). (B) Intraoperative photograph showing repair of the aortic dissection with pledgeted horizontal mattress sutures (indicated by the white arrow) and resuspension of the native aortic valve. dissection may cause intimal intussusception. An antegrade prolapse into the aortic arch causes obstruction of the great supra aortic vessels,2 whereas a retrograde prolapse into the LV causes aortic regurgitation3 and obstruction of the coronary artery.4 Our case describes a retrograde prolapse into the LV with an accompanying AR. Thus, a type-A aortic dissection should be part of the differential diagnosis in a patient presenting with an acute coronary syndrome and newly diagnosed AR, even in the absence of typical signs and symptoms for the same.

ACKNOWLEDGEMENTS

The authors would like to thank Mr. John Cyrus who provided us editorial assistance.

REFERENCE

1. Hillemanns A, Möller-Hartmann W, Miche E, et al. Circular dissection of the ascending aorta with intimo – intimal invagination. CT diagnosis of a rare form of aortic dissection. Radiologe 1996;36(5):446-8. 2. Ishii H, Nakamura K, Yano M, et al. Circumferential dissection of the ascending aorta “intimo-intimal intussusception”. Ann Vasc Dis 2012;5(4):466-8. 3. Yang EH, Kwon MH, Mahajan A, et al. Circumferential type A aortic dissection and intimal intussusception of the aorta causing severe aortic regurgitation and obstruction of the left main coronary artery. Echocardiography 2013;30(3):E81-4. 4. Lajevardi SS, Sian K, Ward M, Marshman D. Circumferential intimal tear in type A aortic dissection with intimo-intimal intussusception into left ventricle and left main coronary artery occlusion. J Thorac Cardiovasc Surg 2012;144(2):e21-3.

Drs. Patel, Morris, and Akkus are with the Division of Cardiology at the Louisiana State University Health Sciences Center in Shreveport. Drs. Hamidian Jahromi and Rao are with the Department of Surgery at LSUHSC-Shreveport.

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Inclusion Body Myositis Masquerading as Cardiac Dyspnea

Siu-Hin Wan, MD; Jackson J. Liang, DO; Andrew C. Greenlund, MD, PhD

Dyspnea in the elderly can be due to a wide array of pathologies. We discuss a case of an elderly gentleman with an extensive cardiovascular history presenting with acute worsening of chronic dyspnea. Because of persistent respiratory distress unresponsive to standard therapy for congestive heart failure, chronotropic insufficiency, and pulmonary hypertension, further evaluation was undertaken which revealed that diaphragmatic weakness was the etiology of his respiratory failure. EMG and muscle biopsy confirmed the diagnosis of inclusion body myositis (IBM).

INTRODUCTION eterization was performed, which confirmed the presence of pulmonary hypertension. A trial of phosphodiesterase While respiratory failure is a frequent complication inhibitor therapy failed to improve his symptoms. Pulmo- from advanced and longstanding IBM, it is unusual for nary function tests demonstrated little change from previ- dyspnea to be a presenting symptom of the disease. The ous studies, with a vital capacity of 1.32 L (37% predicted), literature on IBM has commonly focused on neurological FEV1 0.88 L (32% predicted), FEV1/FVC 73.7%, and DLCO symptoms, such as proximal weakness, as the cardinal 8.0 mL CO/min/mmHg (36% predicted). His permanent presenting features of IBM. We present a case of dyspnea pacemaker, which had been placed 15 years prior for carotid due to IBM initially thought to be cardiogenic in nature. Our hypersensitivity and intermittent pacemaker dependency, case demonstrates the importance of performing a complete was interrogated and found to be functioning appropriately. history and physical examination in evaluation of dyspnea, Subsequent to the development of his dyspnea, a left and, to maintain a broad differential diagnosis, considering foot drop was noted. He was evaluated by a physiatrist who other less common causes when more frequent cardiovascu- believed the etiology to be either a peroneal neuropathy or lar and pulmonary etiologies have been excluded. S-1 radiculopathy. The patient believed the foot drop was improving and an electromyogram was deferred. General- CASE PRESENTATION ized gait impairment was attributed to deconditioning from decreased mobility due to exercise intolerance and exertional An 81-year-old gentleman was seen by his primary care dyspnea, and a walker was prescribed. provider over four months in early 2012 at Mayo Clinic in This patient then presented to the emergency depart- Rochester, Minnesota for persistent dyspnea on exertion. ment with acute progression of dyspnea that was signifi- His past medical history was notable for coronary artery cantly impacting completion of his daily activities. While disease, status post-coronary artery bypass grafting with the patient had a good cough reflex, he had a paradoxical multiple percutaneous interventions, a permanent pace- breathing pattern and substantial accessory muscle use, maker, congestive heart failure, restrictive lung disease, concerning for diaphragmatic dysfunction. Strength test- and obstructive sleep apnea. The dyspnea he complained ing demonstrated neck flexor weakness, as well as bilateral of was distinct from his previous episodes of angina, with deltoid and iliopsoas weakness. Distal muscle strength was his last percutaneous coronary intervention with a drug preserved. Toes were downgoing on Babinski’s examination. eluting stent having occurred approximately one year prior Laboratory investigation was significant for anemia to presentation. (hemoglobin 10.7 g/dL, normal 13.5-17.5) and a creatinine of Echocardiography demonstrated an ejection fraction of 1.5 mg/dL (normal 0.8-1.3). Initial troponin T was 0.24 ng/ 55% with a right ventricular systolic pressure of 55 mmHg. mL (normal <0.01) and remained unchanged after three and Decreased inspiratory collapse of his inferior vena cava was six hours. NT-pro-BNP was 1,900 pg/mL (normal <131), and noted. Trials of aggressive diuretic therapy failed to improve arterial blood gas showed a pH of 7.35, PCO2 of 54 mmHg, his dyspnea. Pulmonary embolism was ruled out with chest and PO2 of 85 mmHg. Creatine kinase was normal, and computed tomograpy angiography. Right-sided heart cath- aldolase was found to be 9.5 U/L (normal <7.7).

254 J La State Med Soc VOL 166 November/December 2014 Despite empiric treatment in the hospital with diuretics, antibiotics, and noninvasive positive-pressure ventilation, the patient’s dyspnea progressed. Based on his physical exam and the chest radiograph demonstrating bilateral elevation of the hemidiaphragms, Neurology was consulted to evaluate for a neuromuscular etiology of dyspnea. Electromyogram of the finger flexors, quadriceps, and right hemidiaphragm showed reduced recruitment of muscle fibers and small motor unit potentials. The electromyogram was an abnormal study and demonstrated electrophysiological evidence of a proximal and distal myopathy, as well as fibrillation potentials suggestive of myonecrosis, fiber splitting, and vacuolization consistent with inclusion body myositis. Muscle biopsy of the left vastus medialis muscle revealed rimmed vacuoles in muscle fibers with necrosis, regeneration, and congophilic Figure 1: Autoaggressive inflammatory exudate surrounding and invading muscle staining inclusions, consistent with a di- fibre (**) and vacuolated muscle fiber (*). Image courtesy of Dr. Andrew Engel. agnosis of inclusion body myositis (IBM) (Figures 1 and 2). Unfortunately, the patient developed worsening respiratory failure necessitating intubation and mechanical ventilation. In concordance with the patient’s wishes and advanced directives, ventilatory support was withdrawn.

DISCUSSION

Dyspnea is an extremely common complaint, particularly in the elderly. While the most common causes of dyspnea involve the respiratory and cardiovascular systems, it is essential to maintain a broad differential diagnosis, as there are a myriad of etiologies for dyspnea, spanning every organ system. Dyspnea reflects inadequate oxygen delivery to systemic organs, resulting in a sensation of breathing discomfort. Inadequate respiratory drive and oxygen Figure 2: Congophilic deposit in muscle fiber visualized with rhodamine intake, impaired gas exchange, shunt physi- fluorescence. Image courtesy of Dr. Andrew Engel. ology, reduced oxygen carrying capacity, inadequate pumping of the oxygen-rich blood, and poor oxygen exchange at periph- Radiographs of the chest demonstrated no evidence of eral tissues may all contribute to the sensation of dyspnea. pulmonary edema or infectious pneumonia. Transthoracic There are many neuromuscular conditions that may echocardiogram showed no wall motion abnormalities, and result in dyspnea. Guillain Barre Syndrome is a progressive left ventricular ejection fraction, as well as right ventricular inflammatory demyelinating polyneuropathy that often systolic pressure, was unchanged from six months prior. results in symmetric distal weakness and can progress to Ventilation perfusion scan of the lungs was performed, severe respiratory muscle weakness. Amyotrophic lateral which demonstrated low probability for chronic pulmonary sclerosis is a progressive, incurable neurodegenerative con- embolism. dition that causes combined upper- and lower-motor neuron

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patterns of weakness that inevitably lead to respiratory We present a case of IBM presenting primarily with failure and death. Myasthenia gravis is an autoimmune symptoms of dyspnea in an individual with impaired disorder of neuromuscular signal transmission, resulting cardiopulmonary reserve due to his underlying cardio- in fatigable weakness that commonly involves the ocular pulmonary comorbidities. In retrospect, even though the muscles and can also involve the respiratory muscles. patient’s major complaint was dyspnea, his foot drop and Inflammatory myopathies arise from immune-mediated gait impairment were subtle clues to an underlying neu- muscle injury and can progress from proximal muscle romuscular disorder. The restrictive respiratory pattern weakness to respiratory involvement. Differentiating these demonstrated on his pulmonary function tests also hinted at neuromuscular conditions requires a high clinical suspicion, a neuromuscular abnormality. While intrinsic lung diseases recognition of the pattern of weakness, and laboratory stud- such as interstitial lung disease may cause these findings on ies including electromyography and/or muscle biopsies. pulmonary function testing, extrinsic factors such as obesity Sporadic IBM is a devastating rheumatologic disease and neuromuscular disorders can also contribute to a restric- in the class of inflammatory myopathies. Prevalence varies tive pulmonary pattern. The patient expired approximately from 1 to 15 per million people and appears to be linked to two weeks after his diagnosis of inclusion body myositis. the HLA-DR3 autoimmune allele cluster.1 IBM is more com- This case highlights the importance of early diagnosis of mon among the elderly population, rarely occurring in those IBM, which would allow for the patient and family to discuss below age 50, and tends to afflict men more than women.2 treatment options and plan for end-of-life care. Unlike polymyositis and dermatomyositis, IBM tends to be associated with insidious onset of muscle weakness, most CONCLUSIONS notably involving the quadriceps, finger flexors, and ankle dorsiflexors.3 While most cases of IBM include weakness that Our patient’s presenting symptom was progressive is usually symmetric and in the proximal muscles, there is dyspnea that failed to respond to aggressive management an important subgroup of patients that have predominantly of multiple cardiac comorbidities. The diagnosis of IBM asymmetric or distal involvement at various locations, and was eventually made as respiratory failure progressed. IBM this proportion is greater than in polymyositis. Dysphagia is uncommonly presents as respiratory failure from diaphrag- also common. While respiratory muscle weakness leading to matic weakness. A high suspicion from a detailed history respiratory failure is a common cause of death among those and physical exam was required to make the correct diag- with IBM, it is considered extremely rare and unusual as a nosis in our patient after the more common cardiovascular presenting symptom of the disease.4 and pulmonary causes of dyspnea were ruled out. While a good clinical history is essential in detecting IBM, electrodiagnostic and pathologic confirmation is neces- ACKNOWLEDGEMENTS sary. Unlike polymyositis, laboratory studies are generally unremarkable in IBM, with muscle enzymes generally nor- We would like to acknowledge Dr. Andrew Engel, mal or only mildly elevated.5 Electromyography is revealing Professor of Neurology at the Mayo Clinic in Rochester, of a neurogenic and myopathic pattern, but it is generally for his contribution of the muscle biopsy pathology images. nonspecific among the inflammatory myopathies.6 The most definitive diagnostic test is a biopsy of an affected muscle. REFERENCES Pathologically unique to IBM are the presence of intramus- cular vacuoles and amyloid deposits.7 The pathophysiol- 1. Mastaglia FL. Sporadic inclusion body myositis: variability in ogy of IBM is believed to be related to the accumulation of prevalence and phenotype and influence of the MHC. Acta Myol injurious molecules and proteins in the muscle fibers.8 Cells 2009;28:66-71. thought to be associated with muscle fiber injury include 2. Wilson FC, Ytterberg SR, St Sauver JL, Reed AM. Epidemiology T-cells, dendritic-cells, and plasma-cells that infiltrate the of sporadic inclusion body myositis and polymyositis in Olmsted County, Minnesota. J Rheumatol 2008;35:445-7. fascicular myofibers.9 One possible antigen involved in the 3. Greenberg SA. Inclusion body myositis. Curr Opin Rheumatol immune response leading to muscle fiber damage is alphaB 2011;23:574-8. 10 crystallin. Furthermore, deposition of proteins such as 4. Voermans NC, Vaneker M, Hengstman GJ, et al. Primary beta-amyloid and phosphorylated microtubule-associated respiratory failure in inclusion body myositis. Neurology protein tau (MAPT) may contribute to muscle injury.11,12 2004;63:2191-2. IBM is unique among the inflammatory myopathies 5. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion because of its relative resistance to standard immuno- body myositis. Observations in 40 patients. Brain 1989;112 (Pt therapy (prednisone, methotrexate, and azathioprine), 3):727-47. with continued gradual deterioration of muscle strength. 6. Solorzano GE, Phillips LH, 2nd. Inclusion body myositis: diagnosis, pathogenesis, and treatment options. Rheum Dis Clin Physical and occupational therapy may play a role in pa- North Am 2011;37:173-83, v. tient rehabilitation and palliation. The most common cause 7. Engel WK, Askanas V. Inclusion-body myositis: clinical, of death among patients with IBM is respiratory infection, diagnostic, and pathologic aspects. Neurology 2006;66:S20-9. while direct respiratory failure from muscle weakness is 8. Dalakas MC. Pathophysiology of inflammatory and autoimmune also possible but rarer. myopathies. Presse Med 2011;40:e237-47.

256 J La State Med Soc VOL 166 November/December 2014 9. Greenberg SA. Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications. Neurology 2007;69:2008-19. 10. Banwell BL, Engel AG. AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology 2000;54:1033-41. 11. Fukuchi K, Pham D, Hart M, Li L, Lindsey JR. Amyloid-beta deposition in skeletal muscle of transgenic mice: possible model of inclusion body myopathy. Am J Pathol 1998;153:1687-93. 12. Salajegheh M, Pinkus JL, Nazareno R, Amato AA, Parker KC, Greenberg SA. Nature of “Tau” immunoreactivity in normal myonuclei and inclusion body myositis. Muscle Nerve 2009;40:520-8.

Drs. Wan, Liang, and Greenlund are with the Department of Internal Medicine in the Mayo Clinic in Rochester, Minnesota.

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Broken Lung

Ikrita K. Klair, MD; Jaime Palomino, MD; Fayez Kheir, MD; Daniel A. Salerno, MD

We report a case of severe acute respiratory distress syndrome (ARDS) complicated by a very large bronchopleural fistula (BPF) measuring 30 mm in length and evident on computed tomography (CT) chest scan. Such a large BPF is a very rare occurrence. Generally, a BPF of more than 6 mm in size is considered as large.1 Small BPFs can be easily missed on CT scan chest, but a persistent air-leak through an adequately placed chest tube should raise suspicion for a BPF.

INTRODUCTION

Bronchopleural fistula (BPF) is a communication between the pleural space and the bronchial tree.2 BPF is a life-threatening complication usually seen after pulmonary resection. The incidence varies from 4.5% to 20% after pneumonectomy and is only 0.5% after lobectomy.3 A large BPF occurring as a complication in patients with adult respiratory distress syndrome (ARDS) is rare. BPF occurring as a complication in patients with ARDS typically appears after one to two weeks of illness, and is associated with a poor prognosis.4

CASE PRESENTATION

A 37-year-old male presented with near-drowning. Past medical history was notable for congenital brain abnormalities and seizures. Upon emergency department (ED) arrival, his Glasgow coma scale (GCS) was found to be three, and he was intubated. Arterial blood gas (ABG), clinical findings, and chest X-ray (CXR) were consistent with ARDS. He was started on lung protective ventilation with low tidal volume (TV) strategy at 6 ml/kg predicted body weight. A few hours later, his oxygen saturations (O2 sats) dropped to 71% on FiO2 (fraction of inspired oxygen) of 100%. Mode of ventilation was changed to assisted pres- Figure A: Chest radiograph (antero-posterior view) showing sure control ventilation with inspiratory pressure of 18 cm large right-sided pneumothorax. of H2O and positive end expiratory pressure (PEEP) of 15 cm of H2O. But due to inadequate ventilation, he was then On hospital day two, due to worsening oxygenation switched back to assisted volume control ventilation with (PaO2/FiO2 68 on FiO2 100% and PEEP 20 cm of H2O) low TV and high PEEP of 20 cm of H2O, leading to improved and agitation (despite adequate sedation and analgesia), oxygenation. His plateau pressures were measured to be 31 he was started on cisatracurium (for 48 hours) in view of cm of H2O on these settings. evidence demonstrating mortality benefit with neuromus- Patient became hypotensive and a right internal jugular cular blocker when used early in patients with severe ARDS. (RIJ) central line was placed for vasopressor support. RIJ On hospital day three, a computed tomography (CT) placement was complicated by a large right-sided pneu- scan of the chest showed residual right-sided pneumo- mothorax (Figure A) requiring an emergent chest tube (12 thorax, subcutaneous emphysema, and extensive bilateral French) placement. He was subsequently admitted to the air-space disease consistent with ARDS. No lung lacera- intensive care unit (ICU). tion/BPF was noted. A large bore (28 French) chest tube

258 J La State Med Soc VOL 166 November/December 2014 varied between 31 and 38 cm of H2O. He maintained a normal arterial blood PH during most of his admission. On hospital day 11, the patient sud- denly became hypotensive and bradycardic requiring fluid boluses and vasopressor support with nor-epinephrine. Chest tube was noted to be functioning adequately. CXR did not reveal any acute changes. Soon thereafter, he went into asystole and CPR/ ACLS (cardio-pulmonary resuscitation/ advanced cardiac life support) was initiated immediately. Unfortunately, he died in cardiac arrest.

DISCUSSION

A BPF is a communication between the pleural space and the bronchial tree. Al- though rare, BPFs are associated with high morbidity and mortality. Postoperative complication of pulmonary resection is the most common cause, followed by necrotic lung complicating infection, chemotherapy Figure B: Computed tomography scan chest (axial reconstruction) showing 30 mm or radiotherapy (for lung cancer), and per- large bronchopleural fistula (arrow). sistent spontaneous pneumothorax. Less common risk factors include ARDS, chest was placed, and a 12 French chest tube (placed earlier) was trauma, invasive chest procedures (including central line removed. Repeat CXR showed improved reexpansion of placements), tuberculosis, and serious co-morbid illness(s).2 right lung. BPF in the setting of ARDS is most likely either a result On hospital day four, he came off of vasopressor sup- of chest trauma or ventilator-induced lung injury from port and was started on furosemide drip to keep negative rupture of overdistended alveolus. The ventilator strategy fluid balance in view of severe ARDS. Later that day, the of ARDS, directed to alveolar recruitment, conflicts the best patient developed respiratory distress with O2 sats of 71% management of BPF, which requires minimization of airway and respiratory rate of high 40s. He was once again started pressure to decrease the air leak.2,4,5 on cisatracurium, and his oxygenation improved marginally. The incidence of barotrauma in mechanically ventilated A large air-leak (more than previously noted during past patients with ARDS varies between 0% and 49%, and cor- three days) was noted from the chest tube. A cardiothoracic relates strongly with end-inspiratory pressure (Pplat), with surgery team was consulted for concern of development of a high incidence above 35 cm of H2O. With compliance, bronchopleural fistula. there is a high incidence below 30 ml/cm H2O. Clinical On hospital day five, a CT chest scan was repeated, studies maintaining Pplat lower than 35 cm of H2O found which revealed a large right-sided BPF (Figure B), explain- no apparent relationship between ventilatory parameters ing the persistent large air-leak. The BPF measured 30 mm and pneumothorax. Analysis of the literature suggests a in length, a very rare occurrence. The CT chest scan was correlation between patients receiving mechanical ventila- also significant for right-sided subcutaneous emphysema tion and Pplat levels exceeding 35 cm of H2O.6 and residual pneumothorax (Figure B). The location of BPF The clinical presentation is variable. It can rarely pres- was not suggestive of an iatrogenic etiology from RIJ central ent acutely as life-threatening tension pneumothorax. Other line placement. Also, absence of BPF on previous CT scan presentations include persistent air-leak in the setting of an from day three makes ARDS the most likely cause of the appropriately placed chest tube, fever, productive cough, development of BPF in this case. A cardiothoracic surgery and new or increasing air fluid levels seen on the chest team recommended conservative management in view of radiograph in the pleural space.2 patient’s critical illness. Suspicion of BPF is usually raised after persistent large On hospital day six, cisatracurium was discontinued air-leak noted from chest tube. Standard and thin-section after 48 hours. CTs are useful in the diagnosis and management of periph- Throughout his ICU stay, he required high FiO2 ranging eral BPFs.7 between 70%-100% most of the time. His ABG consistently A peripheral BPF can be localized with MDCT (multi- showed PaO2/FiO2 of <100. His end-inspiratory pressures detector row computed tomography) if there is a distinct

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channel between the lung or a peripheral bronchus and the In a study of nine patients with ARDS complicated by pleura.20 The underlying causes for BPFs can also be evalu- barotrauma-induced BEF, it was concluded that gas excreted ated with MDCT. Thin-section MDCT with axial and MPR via a chest tube in a patient with ARDS participated in gas (multiplanar reconstruction) images is important in the exchange and must be considered when calculating total detection of small, central BPFs. Standard CT images are at CO2 excreted via the leak. In this study, the mean total a disadvantage due to the plugging of the fistula with debris minute ventilation was 23.9 ± 7.5 L/min with 25% ± 17% of or secretions and the small size of the defect. Multidetector that gas escaping via the leak. Carbon dioxide was routinely CT scanners can solve these problems with their thin sec- present in the leaked gas, often in higher concentrations tions, faster scanning times, fewer respiration artifacts, and than in the expired gas, although the difference between higher image quality.8 the leaked and expired gas was not significant. The fraction Chest MDCT is an accurate, easy, and non-invasive of minute production of carbon dioxide excreted via the technique for diagnosing and monitoring BPFs and should leak correlated with the fraction of inspired gas excreted be the first diagnostic method of choice for patients who via the leak.11 are clinically suspected of having a BPF. Multidetector CT Endobronchial intervention includes either a sealant allows for the evaluation of the presence, size, and localiza- application or an endobronchial placement of a blocker, a tion of the fistula tract and also demonstrates the possible stent, or an occluding device. Successful closure of a BPF us- underlying causes of this rare occurrence.8 ing an occlusion device originally designed for transcatheter Other techniques used for the diagnosis of BPF include closure of an atrial septal defect has been recently done.12 bronchography, the instillation of methylene blue dye Surgical repair is considered to be the definitive treat- through the stump and its detection in the chest tube, small ment of BPF. In a study of 42 patients with postoperative metallic probes introduced through the working channel of BPF, surgical repair of BPF resulted in a success rate of 86% the bronchoscope, and changes in gas concentration in the and associated mortality of 9.5%.18 In another study of 13 pneumonectomy cavity after inhaling different concentra- patients with postoperative BPF, surgical repair was associ- 2,17 19 tions of oxygen and N2O. ated with one fatal recurrence at three months post-repair. Treatment options include conservative approach, Prognosis of BPF is poor in the setting of mechanical endobronchial intervention, or surgical repair. Small fistu- ventilation. BPF is an ominous complication of ventilator las (<5 mm) can be medically managed with conservative management in acute respiratory failure. In a single center strategies. Larger fistulas require surgical repair. In high study, 39 of the 1,700 patients receiving mechanical ventila- surgical risk patients, endoscopic/endobronchial options tion had BPFs lasting at least 24 hours. Overall mortality in can be pursued. these 39 patients was 67%. Mortality was higher when BPF Conservative management with chest tube(s) drainage developed late rather than early in the illness (94% vs 45%, and lung protective ventilation is sometimes chosen for respectively). Large air leaks also had significant mortality critically ill patients. The air flow through the BPF theoreti- compared to smaller leaks.13 cally delays the healing of the fistula site, and reducing flow through the fistula has been a major goal in management of CONCLUSION these patients. The BPF provides an area of low resistance to flow and acts as a conduit for the escape of a variable This case illustrates a rare but important presentation percentage of the delivered tidal volume during conven- of bronchopleural fistula in the setting of acute respiratory tional positive pressure mechanical ventilation. Strategies distress syndrome. Physicians should be aware of this entity to decrease fistula flow (reduce airway pressure) include and consider it in the differential diagnosis of a persistent application of lowest effective tidal volume, least number of air-leak in a technically adequate chest tube. mechanical breaths, lowest PEEP, and short inspiratory time. In our patient, this was complicated by poor oxygenation ACKNOWLEDGEMENTS secondary to ARDS requiring high PEEP.14 Other ventilatory strategies include differential lung The authors report that no potential conflicts of interest ventilation,18 selective intubation of the unaffected lung, exist with any companies/organizations whose products or and patient position. Positioning the patient such that BPF is services may be discussed in this article. dependent has been shown in one report to decrease fistula flow.16 Few case reports of successful use of high frequency REFERENCES oscillatory ventilation (HFOV) have been published.9,10 In a retrospective review of 39 patients with BPF sup- 1. Dutau H, Breen DP, Gomez C, Thomas PA, Vergnon JM. The ported by conventional ventilation, it was shown that even integrated place of tracheobronchial stents in the multidisciplinary in the face of significant fistula leaks, only two of the 39 management of large post-pneumonectomy fistulas: our patients developed severe respiratory acidosis (pH <7.30).15 experience using a novel customised conical self-expandable Literature suggests that the gas excreted via a chest tube metallic stent. Eur J Cardiothorac Surg. 2011 Feb;39(2):185-9. 2. Lois M, Noppen M. Bronchopleural fistulas: an overview of the participates in gas exchange prior to reaching the BPF and problem with special focus on endoscopic management. Chest. the chest tube. 2005 Dec;128(6):3955-65.

260 J La State Med Soc VOL 166 November/December 2014 3. Cerfolio RJ. The incidence, etiology, and prevention of Drs. Klair, Palomino, Kheir, and Salerno are with the Department of postresectional bronchopleural fistula. Semin Thorac Cardiovasc Pulmonary Diseases, Critical Care, and Environmental Medicine at the Surg. 2001 Jan;13(1):3-7. Tulane University School of Medicine in New Orleans. 4. Pierson DJ. Management of bronchopleural fistula in the adult respiratory distress syndrome. New Horiz. 1993 Nov;1(4):512-21. 5. Bombino M, Patroniti N, Foti G, Isgrò S, Grasselli G, Pesenti A. Bronchopleural fistulae and pulmonary ossification in posttraumatic acute respiratory distress syndrome: successful treatment with extracorporeal support. ASAIO J. 2011 Jul- Aug;57(4):336-40. doi: 10.1097/MAT.0b013e31821d8182. 6. Boussarsar M, Thierry G, Jaber S, Roudot-Thoraval F, Lemaire F, Brochard L. Relationship between ventilatory settings and barotrauma in the acute respiratory distress syndrome. Intensive Care Med. 2002 Apr;28(4):406-13. 7. Westcott JL, Volpe JP. Peripheral bronchopleural fistula: CT evaluation in 20 patients with pneumonia, empyema, or postoperative air leak. Radiology 1995;196:175-181. 8. Seo H, Kim TJ, Jin KN, Lee KW. Multi-detector row computed tomography evaluation of bronchopleural fistula: correlation with clinical, bronchoscopic, and surgical findings. J Comput Assist Tomogr. 2010;34:13–18 9. Ha DV, Johnson D. High frequency oscillatory ventilation in the management of a high output bronchopleural fistula: a case report. Can J Anaesth. 2004 Jan;51(1):78-83. 10. Campbell D, Steinmann M, Porayko L. Nitric oxide and high frequency jet ventilation in a patient with bilateral bronchopleural fistulae and ARDS. Can J Anaesth. 2000 Jan;47(1):53-7. 11. Bishop MJ, Benson MS, Pierson DJ. Carbon dioxide excretion via bronchopleural fistulas in adult respiratory distress syndrome. Chest. 1987 Mar;91(3):400-2. 12. Y ang L, Kong J, Tao W, Song Y, Huang T, He F, Zhang P, Cai X, Dou Y, Wang Z. Tuberculosis bronchopleural fistula treated with atrial septal defect occluder. Ann Thorac Surg. 2013 Jul;96(1):e9-e11. 13. Pierson DJ, Horton CA, Bates PW. Persistent bronchopleural fistula air leak during mechanical ventilation: a review of 39 cases. Chest 1986; 90:321–323. 14. Baumann MH, Sahn SA. Medical management and therapy of bronchopleural fistulas in the mechanically ventilated patient. Chest. 1990 Mar;97(3):721-8. 15. Pierson DJ, Horton CA, Bates PW. Persistent bronchopleural air leak during mechanical ventilation: a review of 39 cases. Chest 1986; 90:321-23. 16. Lau K. Ebstural management of bronchopleural fistula. Chest 1988; 94:1122. 17. Alifano M, Sepulveda S, Mulot A, et al. A new method for detection of postpneumonectomy broncho-pleural fistulas. Ann Thorac Surg 2003; 75:1662–1664 18. Carvalho P, Thompson WH, Riggs R, Carvalho C, Charan NB. Management of bronchopleural fistula with a variable-resistance valve and a single ventilator. Chest. 1997; 111:1452–1454. 19. John D. Puskas, Douglas J. Mathisen, Hermes C. Grillo, John C. Wain, Cameron D. Wright, Ashby C. Moncure. Treatment strategies for bronchopleural fistula. The Journal of Thoracic and Cardiovascular Surgery; volume 109, Issue 5, Pages 989–996, May 1995. 20. P. Misthos S. Kakaris E. Sepsas K. Athanassiadi I. Skottis. Surgical Management of Late Postpneumonectomy Bronchopleural Fistula: The Transsternal, Transpericardial Route. Respiration 2006;73:525–528.

J La State Med Soc VOL 166 November/December 2014 261 Journal of the Louisiana State Medical Society ECG of the Month

ECG in a 44-Year-Old Man With Chest Pain

D. Luke Glancy, MD; Neeraj Jain, MD

Figure

What is your diagnosis?

Explication is on p. 263

262 J La State Med Soc VOL 166 November/December 2014 ECG of the Month Presentation is on p 262.

DIAGNOSIS: Arm-lead reversal; normal sinus rhythm; right atrial enlargement and right ventricular enlargement suggesting an ostium secundum atrial septal defect; acute inferior myocardial infarction.

Negative P waves, QRS complexes, and T waves in lead I suggest arm lead reversal or situs inversus. Progres- sively larger QRS complexes in standard chest leads V1 to

V5 exclude situs inversus. When the arm leads are reversed, true lead I is inverted, producing the negative P, QRS, and T; lead II is actually true lead III; lead III is true lead II; lead aVR is true lead aVL; lead aVL is true lead aVR; and lead aVF and the precordial leads are unchanged. The presence of an incomplete right bundle branch

block pattern in true lead aVR and in lead V1, S waves in

leads V5 and V6, SV5 > 7 mm (where 10 mm = 1.0 mv), and 1,2 RV1 + SV5 > 10 mm suggest right ventricular enlargement.

The 2 mm P waves in lead V2 indicate right atrial enlargement,3 helping to confirm right ventricular enlargement and to suggest a fossa-ovalis type (ostium secundum) atrial septal defect. The atrial septal defect was confirmed by echocardiography. Correcting for arm-lead reversal, one can also recognize the changes of acute inferior myocardial infarction: large Q waves, ST-segment elevation, and T-wave inversion in the inferior leads with reciprocal tall R waves, ST-segment depression, and upright T waves in true leads I and aVL. Misplaced electrocardiographic leads are common. Some misplacements, such as arm lead reversal or both electrodes of a bipolar lead on the legs resulting in miniscule P, QRS, and T voltage in that lead, are easy to recognize, as are gross chest lead misplacements, such as placing the

V1 lead in the V6 position and vice versa or placing all of the chest leads on the right side of the chest. Many lead misplacements, however, go unrecognized. When the positions involved in lead misplacement can be recognized, an electrocardiographic diagnosis usually can be made.

REFERENCES

1. Milliken JA, Macfarlane FW, Lawrie TDV. Enlargement and hypertrophy. In: Macfarlane PW, Lawrie TDV, editors. Comprehensive Electrocardiology: Theory and Practice in Health and Disease. New York: Pergamon Press; 1989: Volume 1 :631–670. 2. Surawicz B, Knilans T. Chou’s Electrocardiography in Clinical Practice, Adult and Pediatric, 5th edition. Philadelphia: W B Saunders; 2001:44-74. 3. ibid. 28-43.

Dr. Glancy is a Professor and Dr. Jain is an Associate Professor in the Sections of Cardiology, Departments of Medicine, Louisiana State University Health Sciences Center and the Interim LSU Hospital, New Orleans.

J La State Med Soc VOL 166 November/December 2014 263 Journal of the Louisiana State Medical Society Radiology Case of the Month Uncommon Masses in Renal Disease

Juan S. Gomez, MD; Enrique Palacios, MD; FACR; Jeremy B. Nguyen, MD; Harold R. Neitzschman, MD (Section Editor)

CASE ONE

A 26 year-old female with fever, tachycardia and pain in her left lower extremity, presented to the Emergency Depart- ment. Past medical history is remarkable for hypertension, end stage renal disease requiring hemodyalisis and arteriovenous fistula (AVF). The AVF was performed in the left thigh undergoing superimposed infection. Physical examination revealed a fixed, non-erythematous tender mass at the left hip and an area of erythema, edema and induration at the surgical incision site of the arteriovenous access previously obtained at the left thigh. Blood chemistry values revealed hyperposphatemia and normocalcemia. Computer Tomography (CT) of the left hip with contrast was ordered.

Figure 1B

Figure 1A

Figure 1: Computed Tomography of the left hip without contrast. (A) Coronal, (B) axial and (C) sagittal projections. Fluid levels present in both (B) and (C).

Figure 1C

264 J La State Med Soc VOL 166 November/December 2014 CASE 2

A 38 year-old African American male with a past medical history of end stage renal disease due to hypertension since 1991, presented to our institution for a pre-transplant evaluation. The patient underwent a kidney transplant in 2001, however, due to non-compliance he developed progressive kidney rejection failure and has been on hemodyalisis since 2008. His blood chemistry laboratories values showed normal serum calcium levels. Chest radiographs at the time of examination were performed and compared with prior radiographs for further evaluation.

Figure 2A

Figure 2B

Figure 2: Chest radiographs. (A) Posteroanterior and (B) lateral views.

What is your diagnosis?

J La State Med Soc VOL 166 November/December 2014 265 Journal of the Louisiana State Medical Society

Radiology Case of the Month types: (1) Primary normophosphatemic Tumoral Calcino- Presentations are on pages 264 and 265 sis; in this type, patients have normal serum calcium and phosphate levels. (2) Primary hyperphosphatemic Tumoral RADIOLOGICAL DIAGNOSIS: Calcinosis characterized by a defect in phosphate resorption Tumoral Calcinois with Fluid-Fluid Levels and (3) Secondary Tumoral Calcinosis: these patients have a concurrent disease that causes soft tissue calcification such as chronic renal failure with a secondary hypervitaminosis D, hyperparathyroidism and bone destruction.5 Imaging and biopsy may confirm the diagnosis revealing yellow material containing calcium hydroxyapatite.

Imaging studies include Radiographic examinations, Computer Tomography (CT), and Magnetic Resonance (MR) IMAGING FINDINGS which can demonstrate dense nodular masses commonly with multiple fluid levels represented cystic structures with In the first case, CT of the left hip with contrast revealed sedimentation of calcium which may communicate with the an amorphus calcified soft tissue mass with multicystic fluid bursa of the adjacent joint. MR T1- weighted imaging shows levels located in the left proximal thigh Figure 1A, B and C inhomogenous lesions with low signal intensity; whereas on (arrows) consistent with the clinical setting as above with T2 weighted MR imaging, the lesion appears with a diffuse tumoral calcinosis secundary to end stage renal disease . nodular pattern with areas of high intensity associated with In the second case, prior chest radiographs demon- signal low intensity or signal voids. strated a small nonspecific ill-defined dense mass projected over the right upper chest wall. Follow-up radiographs Other entities that can have similar imaging findings seven years later revealed marked enlargement of the mass and that should be considered in the differential diagnosis which appears to be lobulated and nodular with small fluid of Tumoral Calcinosis include: Calcinosis Universalis, levels Figure 2 A and B (arrows). This was considered to be Calcinosis Cirumscripta, Calcific Tendonitis, Synovial consistent with Tumoral Calcinosis in the setting of long- Osteochondromatosis, Synovial Sarcoma, Osteosarcoma, standing renal disease. Myossitis Ossificans, Tophaceous Gout and Calcific Myo- necrosis. In 1989, Kaplan showed a correlation between Tumoaral Calcinosis and pseudoxanthoma elasticum6 and DISCUSSION in 1990, Martinez et al described an association between Tumoral Calcinosis and Calcific Myelitis.7 Tumoral Calcinosis is an uncommon familial disease secondary to a mutation in FGF23 (Fibroblast Growth Tumoral Calcinosis treatment is based on its underlying Factor 23), KL (Klotho) gene and the UDP-Nacetyl-D- cause, and is a combination between surgical excision and galactosamine:polypeptide N-acetylgalactosaminyltrans- phosphate decrease secondary to acetazolamide administra- 1 ferase 3 (GALNT3) gene.1 Tumoral Calcinosis was first tion. Acetazolamide increases calcium-phosphate solubility described by Giard and Duret in 1898 and in 1943, Inclan et by lowering the systemic pH, resulting in an increase of al named this entity as Tumoral Calcinosis Characterized phosphate excretion.1 Surgical excision is dependent on the by densely, lobular calcified benign masses in soft tissue of patient’s symptoms due to compromise of the adjacent struc- 1 the extensor surface of a bursa with characteristic imaging tures and further surgery for recurrence is recommended. of amorphous, multilobulated cystic calcifications in the musculoskeletal system commonly periarticularly.2 Currently, there are more than 300 cases of tumoral calcinosis have been described.3 It is most frequently seen REFERENCES in African Americans without sex predominance and usually appearing in childhood or young adulthood at the first 1. Finer G, Price HE, Shore RM, et al. Hyperphosphatemicfamilial tumoral calcinosis: Response to acetazolamide and postulated and second decade of life. Symptomatic manifestation is mechanisms. Am J Med Genet. PartA 2014; 164A:1545–1549. uncommon unless there is compressive neuropathy. Large 2. Jeong JJ, Ji JH, Shafi M. Hallux valgus deformity of foot with 1 periarticular lesions can result in reduced range of motion. tumoral calcinosis: An unusual presentation . Foot and Ankle Surg. The most common locations of Tumoral Calcinosis are the 2014; 20:15-18. shoulder, hip, elbow, foot and wrist, but the temporoman- 3. Topaz O, Shurman DL, Bergman R, et al. Mutations in GALNT3, diular joint, spine, hand and knee can also be involved. encoding a protein involved in O-linked glycosylation, cause The physical morbidity is based on repetitive trauma familial tumoral calcinosis. Nat Genet 2004; 36:579–581. 4. Mockel G, Buttgereit F, Labs K, Tumoral Calcinosis generating reparative impairment and initiation of osteo- revisited:patophysiology and treatment. Rheumatol Int 2005; 4 clastic activity. Smack et al, classified this entity into three 25:55-59.

266 J La State Med Soc VOL 166 November/December 2014 5. Smack D, Norton SA, Fitzpatrick JE. Proposal for a pathogenesis- based classification of tumoral calcinosis. Int J Dermatol 1996; 35:265–71. 6. Kaplan G, Vinceneux P, Grossin M, et al. Association of tumoral calcinosis and pseudoxanthoma elasticum: apropos of a case Rev Rhum Mal Osteoartic 1980;47:657–660. 7. Martinez S, Vogler JB, Harrelson JM, et al. Imaging of tumoral calcinosis: new observations. Radiology 1990; 174:215–222.

Dr. Gomez is Visiting Medical Student from Colombia SA. Dr. Palacios is professor of Neuroradiology at Tulane University Health Science Center in New Orleans, LA. Dr. Nguyen is Assistant professor at Tulane University Health Science Center in New Orleans, LA. Dr. Neitzschman is a Professor of Radiology and Chairman of the Department of Radiology at Tulane University Health Sciences Center in New Orleans, Louisiana. Donald Olivares is the Digital Imaging Specialist and Graphic Designer for the Department of Radiology at Tulane University Health Sciences Center in New Orleans, Louisiana.

J La State Med Soc VOL 166 November/December 2014 267 Journal of the Louisiana State Medical Society Clinical Case of the Month

A 63-Year-Old Woman With Rash and Proximal Muscle Weakness

Vaughan Washco, DO; Ross McCarron, MD; Lee S. Engel, MD, PhD; Sanjay Kamboj, MD; Fred A. Lopez, MD

A 63-year-old woman with a history of infiltrating ductal breast cancer, status post-mastectomy and chemotherapy, was in remission for 18 months prior to being admitted to the hospital with complaints of a pruritic erythematous macular rash involving her head, chest, and bilateral upper and lower extremities. Along with the dermatologic manifestations, physical exam revealed proximal symmetrical muscle weakness and bilateral axillary lymphadenopathy. Initial workup for muscle weakness revealed a creatine kinase of 2,200 IU/L (normal 20-180 IU/L). After administration of intravenous fluids for renal protection, serum sodium dropped to 121 mEQ/L (normal 135-145 mEQ/L). Computed tomography of the chest showed axillary and supraclavicular lymphadenopathy. Biopsy of a supraclavicular node revealed infiltrating ductal cancer with histologic and morphologic characteristics similar to her previous breast cancer. Following an extensive laboratory workup, we concluded that our patient’s myositis and hyponatremia were paraneoplastic syndromes secondary to her recurrent breast cancer.

CASE PRESENTATION Shortly after initiation of intravenous fluids for renal protection, serial metabolic panels revealed hyponatremia at a A 63-year-old woman with a history of hypertension, level as low as 121 mEQ/L (normal 135-145 mEQ/L). The hypothyroidism, and stage IIB poorly differentiated infil- patient was in a euvolemic state, with normal kidney and trating ductal breast cancer (hormone receptor and Her2/ liver function studies, and had no signs or symptoms to neu negative) that had been in remission for 18 months suggest heart failure. Serum osmolality was 260 mOsm/ following left mastectomy and chemotherapy presented kg (normal 275-295 mOsm/kg), urine osmolality was 674 to the emergency department with an acute pruritic ery- mOsm/kg (normal 50-1200 mOsm/kg), urine sodium was thematous macular rash (Figure 1). The rash had progres- 155 mEQ/L, and TSH was 1.78 IU/ml (normal 0.40-4.00 sively worsened over the past three weeks and involved IU/ml). She was not on any medications known to cause her head, chest, and bilateral upper and lower extremities. antidiuretic hormone release, and there were no clinical Associated symptoms included worsening fatigue, body features to suggest adrenal insufficiency. With the above cramps, and muscle weakness. Along with this rash, sym- findings, the cause of hyponatremia was determined to be metrical proximal muscle weakness and bilateral painless SIADH. The hyponatremia improved with fluid restriction. axillary lymph node enlargement were noted on physical Concern for an underlying malignant process prompted exam. A rheumatologic panel revealed a positive ANA. a computed tomography scan (CT) of the chest, which She was negative for Anti-SSA/SSB, Anti-DNA, Anti-sm, revealed bilateral axillary and supraclavicular lymphade- Anti-nRNP, Anti-Jo-1, Anti-histone, and Anti-Scl-70. Hepa- nopathy (Figure 2). A biopsy of her supraclavicular lymph titis panel was also negative, and complement C3 and C4 node confirmed the diagnosis of a high-grade carcinoma, levels were normal. Creatine kinase (CK) was elevated at which was hormone receptor and Her2/neu-negative like 2200 IU/L (normal 20-180 IU/L). She had no recent his- her previous cancer and shared the same histologic mor- tory of new medications known to cause an elevated CK, phology. MRI of the brain did not demonstrate metastatic nor recent trauma, ethanol, or illicit drug use. Based on the disease. Skin biopsy was negative for malignant cells but new onset of rash, proximal muscle weakness, and elevated revealed inflammatory changes characteristic of dermato- CK, a clinical diagnosis of dermatomyositis was suspected. myositis (Figure 3).

268 J La State Med Soc VOL 166 November/December 2014 Figure 1: Erythematous macular rash of the face (A), arms (B), and legs (C).

Prior to discharge, she was started on high-dose pred- are most often associated in women.11 The Bohan and Pe- nisone, which mildly improved her skin lesions and muscle ter criteria are most widely used to make the diagnosis of weakness. Shortly after discharge, she followed up with dermatomyositis.12 These criteria take into consideration the oncology and chemotherapy consisting of carboplatin and physical findings of symmetrical proximal muscle weak- gematabine was initiated. After several cycles of chemo- ness, elevated skeletal muscle enzyme levels, myopathic therapy, positron emission tomography showed progression changes on electromyography, and skin lesions characteris- of metastatic lymphadenopathy with new hypermetabolic tic of dermatomyositis. Meeting all four of the above criteria retroperitoneal lymph nodes. Several months later, her indicates a definite diagnosis, three out of four a probable symptoms of muscle weakness progressively worsened diagnosis, and two out of four a possible diagnosis of dis- along with her performance status, and she passed away ease.12 Skin and muscle biopsy is also helpful in making the while under the care of home hospice. diagnosis, with hallmark features of peri-fascicular atrophic regeneration, degenerating myofibers, and the presence of DISCUSSION perivascular inflammation in the muscle.13 Treatment of this paraneoplastic syndrome is directed towards the underly- Paraneoplastic syndromes associated with breast cancer ing cancer. However, as seen in our patient, steroids have are uncommon. There have been several reports that discuss been shown to provide some symptomatic relief. If there myositis associated with breast cancer1-3 and a few cases of is a poor response to steroids, immunomodulating therapy SIADH associated with breast cancer.4-7 To our knowledge, may be warranted.8 this is the first report describing SIADH and dermato- Paraneoplastic SIADH arises from tumor cell produc- myositis simultaneously as paraneoplastic syndromes with tion of antidiuretic hormone and atrial natriuretic peptide. recurrent breast cancer. Occurrence of these concurrent Antidiuretic hormone leads to increased free-water reab- paraneoplastic syndromes in recurrent breast cancer is rare, sorption, whereas atrial natriuretic peptide has natriuretic and therefore, we can only speculate about their prognostic and antidiuretic properties. These combined actions lead to impact on staging or treatment of recurrent malignancy. a hypoosmotic, euvolemic hyponatremia. Common symp- Myositis associated with malignancy includes derma- toms are nonspecific and include muscle cramps, lethargy, tomyositis and polymyositis. Dermatomyositis presents nausea, vomiting, gait disturbances, seizures, and altered with proximal muscle weakness and skin changes with mental status.8,14,15 SIADH affects 1% to 2% of all patients classic findings of a heliotrope rash and gottron papules.8 with cancer, with small cell lung cancer accounting for most The pathophysiology of dermatomyositis associated with of these cases.8 SIADH rarely occurs in breast cancer.4-7 The cancer is not clearly understood; however, it is likely multi- diagnosis is one of exclusion and includes a euvolemic state, factorial. The main contributing factor is thought to be an low serum osmolarity, and a urine osmolarity greater than immune system imbalance with a failure in immunological appropriate considering the plasma tonicity. Before mak- surveillance.8-10 Polymyositis and dermatomyositis associ- ing the diagnosis, it is essential to rule out other causes of ated with malignancy typically occur in adults, with an euvolemic hyponatremia such as hypothyroidism, adre- incidence peak from age 40 to 60 years. In 60% of cases, they nal insufficiency, primary polydipsia, or drug-associated precede the clinical onset of neoplasm. Lung, prostatic, and anti-diuretic release.14-15 The mainstay treatment of mild to gastrointestinal cancers are the most frequently associated moderate hyponatremia in SIADH is water restriction.8,15 neoplasms in men, while breast and gynecological cancers Five hundred to 1,000 ml of free water restriction per day

J La State Med Soc VOL 166 November/December 2014 269 Journal of the Louisiana State Medical Society

Figure 2: CT of the chest with contrast showing abnormal appearing adenopathy seen within the bilateral axillary regions in coronal cuts (A&B) and a sagittal view (C). Arrows measure the short axis of the lymph nodes.

is sufficient to correct hyponatremia. When life threaten- numerous side effects. Newer pharmacologic agents of inter- ing conditions such as seizures, cerebral edema, or coma est that have been studied in euvolemic and hypervolemic are present, treatment with hypertonic saline is indicated. hyponatremia are vasopressin-2 receptor blockers, referred When administering 3% saline, serum sodium levels must to as aquaretics.14 These drugs are competitive inhibitors of be monitored closely, and the correction should be gradual vasopressin, with the effective dose dependent on vasopres- (<10 mEq/day) due to the risk of osmotic demyelination.8,14 sin serum levels. Vasopressin levels are often unknown If sodium levels are resistant to the above measures, dem- and not constant. With the potential for overdiuresis or eclocycline is a therapeutic option. This medication inter- inadequate diuresis, serum sodium must be monitored feres with the anti-diuretic hormone effects on the kidney; closely in this setting. however, its effects are sometimes unpredictable and it has

270 J La State Med Soc VOL 166 November/December 2014 Figure 3: Punch biopsy of the skin extending to the level of the deep reticular dermis with findings consisting of dermatomyositis. The epidermis is ulcerated with associated fibrinoid necrosis, cellular debris, and a chronic inflammatory infiltrate (A). The deep dermis contains increased dermal mucin and a mild perivascular lymphohistiocytic inflammatory infiltrate (B).

CONCLUSION 10) Aggarwal R, Oddis C. Paraneoplastic Myalgias and Myositis. Rheum Dis Clin N Am 2011;37:607–621. A combination of paraneoplastic syndromes as the 11) Minisini A, Pauletto G, Bergonzi P, et al. Paraneoplastic presenting signs of recurrent breast cancer has not been well neurological syndromes and breast cancer. Regression of documented. Further studies concerning the relationship of paraneoplastic neurological sensorimotor neuropathy in a patient with metastatic breast cancer treated with capecitabine: a case recurrent breast cancer with the development of paraneo- study and mini review of the literature. Breast Cancer Res Treat plastic syndrome are warranted. 2007;105:133–138. 12) Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J REFERENCES Med 1975;292:403-7. 13) Raychaudhuri S, Mitra, A. Polymyositis and dermatomyositis: 1) Xi L, Wanshou Q, Yong H, et al. Invasive ductal breast cancer Disease spectrum and classification. Indian J Dermatol. 2012 Sep- associated polymyositis causing respiratory failure. Breast Cancer Oct; 57(5): 366–370. Res Treat 2011;126:211–214. 14) Esposito P, Piotti G, Bianzina S, et al. The Syndrome of Inappropriate 2) Sandhu N, Zakaria S, Degnim A, et al. Dermatomyositis presenting Antidiuresis: Pathophysiology, Clinical Management and New as a paraneoplastic syndrome due to underlying breast cancer. Therapeutic Option. Nephron Clin Pract 2011;119:c62–c73. BMJ Case Reports 2011;doi:10.1136/bcr.10.2010.3416. 15) Sorensen J, Andersen M, Hansen H. Syndrome of inappropriate 3) Primiano G, Plantone D, Sauchelli D, et al. Resolution of secretion of antidiuretic hormone (SIADH) in malignant disease. Muscle Inflammation After Tumor Removal in a Woman with Journal of Internal Medicine 1995;238:97-110. Paraneoplastic Dermatomyositis. J Rheumatol 2012;39:2359-2360. 4) Hashida H, Honda T, Morimoto H, et al. Breast cancer presenting with the syndrome of inappropriate secretion of antidiuretic hormone after simple mastectomy. Intern Med 2001;40(9)911-4. Dr. Washco is a third-year Internal Medicine Resident at the Louisiana State University Health Sciences Center in New Orleans. Dr. McCarron 5) Andersen MK, Sorensen JB. Development of syndrome of is an Assistant Professor of Clinical Medicine at LSUHSC-New inappropriate secretion of antidiuretic hormone during Orleans. Dr. Engel is an Associate Professor of Clinical Medicine and Acta Oncol progression of metastatic disease. 1997;36:535-537. the Associate Program Director of the Internal Medicine Residency 6) Howard AC, Laing RW, Hussein FN. Breast carcinoma Program at LSUHSC-New Orleans. Dr. Kamboj is an Assistant Professor presenting with inappropriate ADH secretion. Letter. Eur J Cancer of Internal Medicine at LSUHSC-New Orleans. Dr. Lopez is the 1993;29A:2339. Richard Vial Professor of Medicine and Vice Chair for Education in 7) Gupta A, Sasarula S, Rao PV. The syndrome of inappropriate the Department of Medicine at LSUHSC-New Orleans. secretion of antidiuretic hormone in a case of carcinoma of the breast. JAPI 1986;34:44-2. 8) Pelosof L, Gerber D. Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment. Mayo Clin Proc. 2010;85(9):838-854. 9) Levine Stuart M. Cancer and myositis: new insights into an old association. Current Opinion in Rheumatology 2006;18:620–624.

J La State Med Soc VOL 166 November/December 2014 271 Journal of the Louisiana State Medical Society Pathology Image of the Month

Autopsy Findings in an Adult with Down Syndrome

Ellen E. Connor, MD, PhD; Ally Darga; Robin R. McGoey, MD

Emergency medical responders were activated to the home of a 59-year-old African-American male in distress and with known Down syndrome complicated by Alzheimer’s disease. He was found to be unresponsive and subsequently became pulseless. Advanced cardiac life support protocols were initiated and continued for two hours in the emergency department. Due to family request, efforts were eventually ceased and the patient was declared dead. Full, unrestricted autopsy examination was conducted under the coroner’s authorization. The cause of death was determined to be a pulmonary thromboembolus in the main pulmonary artery with extension into the bilateral pulmonary arteries. Additional external findings included alopecia universalis, penoscrotal hypospadias, ostium secundum type of atrial septal defect, right ventricular cardiac dilatation, diffuse cerebral atrophy, facial features compatible with Down syndrome, and generalized patches of skin depigmentation over the hands as seen in Figure 1 but also over the feet, lips, areola, and trunk. Microscopic findings included features of pulmonary hypertension. A microscopic image from a section of the thyroid is seen in Figure 2.

What two additional co-morbid conditions can be diagnosed from these images?

Figure 1: (left) External image of the right hand at autopsy showing broad areas of depigmentation. Additional areas of similar depigmentation were seen over the lips, areola, trunk, and both feet. Furthermore, there was no scalp hair, facial, axillary, chest, genital region, or extremity hair. Eyebrows and eyelashes were absent.

Figure 2: (right) Histologic section taken from thyroid at autopsy demonstrating marked glandular infiltration by lymphocytes forming lymphoid follicles containing germinal centers. Thyroid follicles are reduced in number and size, and colloid is depleted. Thyroid follicular epithelium has undergone oxophilic (Hurthaloid) change characterized by an increased size and abundant granular, eosinophilic cytoplasm (40x, Hematoxylin and Eosin stain).

272 J La State Med Soc VOL 166 November/December 2014 Answers: Vitiligo and Hashimoto thyroiditis

Table 1: Reported prevalence of medical complications in adults with DS Medical Complication Prevalence in Adult DS Population Hearing loss <70%4 Obstructive sleep apnea 50%4 Congenital Heart Defects 40 - 50% Seizures 46% over 50 years5 Thyroid disfunction 10%-40%6,7 Alzheimer’s disease 10% by 40 years8 75% by 70 years Mitral valve prolapse 57%9 Celiac disease 10%10 Cataract 8%-13%11 Alopecia 3%12

Down syndrome (DS) is the most common chromosome ism to autoimmune thyroiditis, including both Graves and abnormality among liveborn neonates, occurring in 1 out Hashimoto disease.7,15 Hashimoto thyroiditis, or chronic of nearly every 700 live births.1 Individuals with DS have a lymphocytic thyroiditis, as seen in the current case, however, specific combination of phenotypic features that universally is by the far the most common acquired thyroid disorder includes mental retardation. In 95% of cases, the cause of DS in DS and typically causes hypothyroidism with or without is chromosomal aneuploidy, Trisomy 21, but rare cases of detectable serum anti-thyroid antibodies at a median age of DS can arise from either chromosomal translocation or from onset of 12.3 years and with an equal distribution in both mosaicism.2 DS is characterized by a wide variety of well- male and female DS individuals.16 recognized dysmorphic features and many, well-known, The link between DS and vitiligo is less well-defined and congenital malformations including congenital heart defects appears to be tied not only to the concomitant presence of in 40%-50% of cases. Though life expectancy in DS is shorter cutaneous alopecia areata (AA) but also to thyroiditis. The than that in the general population, survival has improved milder AA is reported in nearly 9% of DS individuals, while substantially, with a median age at death nearly doubling the more severe form of alopecia universalis, as was seen in over the past 20 years to 56.8 years.3 As such, awareness of the current case, is relatively rare at only 2% of DS patients.12 adult-onset conditions and provision of medical services The mechanism behind the autoimmune predisposition for adults with DS are becoming increasingly important. in the DS population has yet to be determined; however, The patient reported here and the documented findings at there are two proposed mechanisms that implicate the autopsy further substantiate the need for a review of the additional copy of chromosome 21.15 There is a strong as- more common pathologic features potentially seen in the sociation between autoimmune hypothyroidism and the adult DS population. A listing of medical problems, and coding genes for the major histocompatibility complex their estimated prevalence, found more frequently in the (MHC) antigens expressed on B cells. While the MHC gene adult DS population is shown in Table 1. family region occurs on chromosome 6, it is postulated that A wide array of immunologic abnormalities have been genes on chromosome 21 participate in the upregulation of associated with DS, including thymic atrophy, susceptibility the MHC gene complex.15 The second proposed mechanism to infections, and a higher incidence of autoimmune diseases involves the autoimmune regulatory gene (AIRE) located that affect both endocrine (thyroid, pancreas, adrenal) and on chromosome 21. This gene is selectively expressed in the nonendocrine (stomach, small bowel) organs, including thymic medulla and is hypothesized to be a protector against thyroiditis, diabetes, Addison disease, autoimmune hepa- organ specific autoimmune disease. Inactivating mutations titis, primary sclerosing cholangitis, and alopecia areata in the AIRE gene cause the rare autosomal recessive disease (occasionally in combination with vitiligo).12-14 autoimmune polyendocrine syndrome type 1, a condition The link between DS and thyroid dysfunction is well with a similar autoimmune profile to Down syndrome. established as the most common endocrine disorder in the Despite the additional AIRE gene copy in the DS, AIRE DS population.6 Studies suggest a lifetime prevalence of expression has recently been found to be paradoxically thyroid disorders on the order of 25%-30%, compared to a reduced in DS.13,17 prevalence in the general population of less than 2%.7 The The current case illustrates many of the comorbid condi- variety of disorders ranges from congenital hypothyroid- tions known to challenge the adult DS community, which is

J La State Med Soc VOL 166 November/December 2014 273 Journal of the Louisiana State Medical Society

expanding due to an improved life expectancy and a com- related diseases associated with Down’s syndrome: a record munity more vigilant health surveillance. The cause of death linkage study. Arch Dis Child. 2004;89:1014-1017. in the current case is a large pulmonary thromboembolus 15. Graber E, Chacko E, Regelmann MO. Down syndrome and thyroid (PTE). A single case report of a fatal PTE in a postoperative function. Endocrinol Metab Clin N Amer. 2012;41:735-745. 16. Popova G, Paterson WF, Brown A, et al. Hashimoto’s thyroiditis DS adolescent is described in the literature, making the in Down’s syndrome: clinical presentation and evolution. Horm 18 premise of inherent hypercoagulability unlikely. As such, Res. 2008;70:278-284. the role that the ostium secundum atrial septal defect played, 17. Lima FA, Moreira-Filho CA, Ramos PL, et al. Decreased AIRE along with the finding of right ventricular cardiac dilatation expression and global thymic hypofunction in Down syndrome. and pulmonary hypertension, is unclear but leaves open J Immunol. 2011;187:3422-3430. the possibility for the development of a right-to-left cardiac 18. Mohan UR, Mangat JS, Sutaria N, et al. Saddle arterial embolus in shunt and subsequent pulmonary arterial thrombus forma- a patient with Down syndrome. Pediatr Cardiol. 2006;27:117-121. tion.19 Continued awareness of comorbid conditions in the 19. Silversides CK, Granton JT, Konen E, et al. Pulmonary thrombosis in adults with Eisenmenger syndrome. J Amer Coll Cardiol. adult down syndrome poplulation is critical to continuing 2003;42:1982-1987. efforts at establishing practice guidelines and improving care.

ACKNOWLEDGEMENTS In the Department of Pathology at Louisiana State University’s School of Medicine in New Orleans, Dr. Connor is a second-year Pathology Resident; Ms. Darga is a third-year Medical Student; and Dr. McGoey The authors would like to gratefully acknowledge the is an Associate Professor of Pathology and Residency Program Director. support of the Orleans Parish Coroner’s Office for providing the case material for this report.

REFERENCES

1. Parker SE, Mai CT, Canfield MA, et al. Updated National birth prevalence estimates for selected birth defects in the Unites States, 2004-2006. Birth Defects Res A. 2010;88:1008-1016. 2. Tyler C, Edman JC. Down syndrome, Turner syndrome, and Klinefelter syndrome: primary care throughout the life span. Prim Care. 2004; 31:627-648. 3. Englund A, Jonsson B, Zander CS, et al. Changes in mortality and causes of death in the Swedish Down syndrome population. Am J Med Genet A. 2013;161:642-649. 4. Smith DS. Health care management of adults with Down syndrome. Am Fam Physician. 2001;64:1031-1038. 5. McVicker RW, Shanks OE, McClelland RJ. Prevalence and associated features of epilepsy in adults with Down’s syndrome. Br J Psychiatry. 1994;164:528-532. 6. Hawli Y, Nasrallah M, El-Hajj Fuleihan G. Endocrine and musculoskeletal abnormalities in patients with Down syndrome. Nat Rev Endocrinology. 2009;5:327-334. 7. Prasher VP. Down syndrome and thyroid disorders: a review. Downs Syndr Res Pract. 1999;6:25-42. 8. Head E, Powell D, Gold BT, et al. Alzheimer’s disease in in Down syndrome. Eur J Neurodegener Dis. 2012;1:353-364. 9. Goldhaber SZ, Brown WD, Robertson N, et al. Aortic regurgitation and mitral valve prolapse with Down’s syndrome: a case-control study. J Ment Defic Res. 1988;32:333-336. 10. Cohen WI. Health care guidelines for individuals with Down syndrome. Down Syndrome Quarterly. 1999;4:1-15. 11. Berk AT, Saatci AO, Ercal MD, et al. Occular findings in 55 patients with Down’s syndrome. Opthalmic Genet. 1996; 12. Madan V, Williams J, Lear JT. Dermatological manifestations of Down’s syndrome. Clin Exper Dermatol. 2006;31:623-629. 13. Gimenez-Barcons M, Casteras A, del Pilar Armengol M, et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol. 2014;193:3872-3879. 14. Goldacre MJ, Wotton CJ, Seagroatt V, et al. Cancers and immune

274 J La State Med Soc VOL 166 November/December 2014 Volume 166: Author Index

Abdehou, Sophia T. (2) 67, (5) 203 Gonzalez-Toledo, Eduardo Nesbitt Jr., Lee T. (4) 154 Abide Jr., William P. (1) 36 (2) 56, (3) 119 Newman, William P. (2) 92 Akkus, Nuri I. (6) 251 Greenlund, Andrew C. (6) 254 Nguyen, Jeremy (4) 149, (5) 193, Allen, Laveil (2) 70 Guillory, Shane G. (3) 129 (6) 264 Al Asfari, Aya (2) 53 Guo, Baofeng (3) 97 Noah, Sabrina L. (2) 73, (4) 175 Al-Mawed, Saleem (4) 138 Gupta, Jagan D. (1) 38 Nuttli, Theresa (1) 46 Alquist, Caroline R. (4) 143 Hadi, Christiane M. (1) 28 Ojemakinde, Oluwayemisi (2) 56 Ambekar, Sudheer (4) 160 Hamidian Jahromi, Alireza (2) 53, Oncale, Andrew (2) 78 Arbour, Adrienne (5) 224 (5) 207 O’Neal Jr., Hollis (6) 239 Austin, Tracy (1) 38 Hamilton, Craig S. (2) 60 Ong, Menchu (5) 200 Ballard, David H. (2) 50 Happel, Kyle (5) 221 Ory, Bridget (5) 213 Barbeau, James M. (1) 28 Hauch, Adam (5) 213 Palacios, Enrique (1) 38, (2) 70, 78; Bauer, Arielle (4) 179 Hebert, Catherine (1) 41 (4) 149, (5) 193, (6) 264 Bentley, Gail (1) 2 Hutchings, John J. (3) 129 Palomino, Jamie (6) 258 Berry, Susan (3) 109 Jahromi, Alireza H. (6) 248, (6) 251 Paramesh, Anil (5) 213 Bhavsar, Vedang (5) 197 Jain, Neeraj (6) 262 Parsons, Chris (5) 224 Billiodeaux, Seth (2) 60 Jordan, Matthew D. (3) 129 Patel, Brijesh (6) 251 Bordelon, Curley J. (4) 176 Kahn, Azheem (6) 239 Patel, Stavan (5) 200 Bordlee Jr., Bruce (2) 78 Kamboj, Sanjay (6) 268 Paul, Timir (5) 197 Caffery, Terrell (2) 63, (6) 239 Kaskas, Nadine (6) 236 Pointer Jr., David T. (1) 15 Carpenter, Elizabeth J. (1) 28 Khaled Soufi, Mohamad (4) 138 Previgliano, Carlos (2) 53, (2) 56 Carter, John (3) 100 Khandekar, Alim (4) 138 Ramirez, Sandra (2) 53 Caruthers, Carrie (4) 182 Kheir, Fayez (6) 258 Ramnaryan, Paragi Gururaja (1) 10 Cascio, Brett M. (2) 50 Khouzam, Rami N. (4) 138 Rao, Vyas (6) 251 Castillo-Jorge, Sarah (4) 149, (5) 193 Klair, Ikrita K. (6) 258 Ratard, Raoult (4) 168 Celebi, Murat M. (2) 75 Ladia, Vatsal (5) 197 Reddy, Threta (2) 56 Connor, Ellen E. (6) 272 Le, Crystal P. (2) 70 Revis, Brian (1) 26 Cotelingam, James (5) 200 LeLorier, Paul A. (2) 75 Richey, Lauren E. (1) 28 Darga, Ally (6) 272 Liang, Jackson J. (6) 254 Richmond, Nicole (3) 109 Daroca, Philip (4) 149 Lopez, Fred A. (1) 41, (3) 129, Rigby, Perry G. (1) 10 Davis, William (2) 81 (4) 182, (5) 224, (6) 268 Roberts III, Evans (5) 224 Dewenter, Tracy (4) 143 Mabry, Christian (5) 221 Robichaux, Camille (5) 200 Diaz, James H. (3) 103, (4) 154, Maffei, Joanne (4) 182 Robinson, Danny (6) 239 (5) 186 Manix, Marc (1) 21 Rodriguez, Kimsey (3) 100 Dies, David (5) 207 Manning, David (4) 179 Rosenberg, Michael (2) 70 DiGiorgio, Catherine (6) 236 Maronge, Genevieve F. (1) 10 Safley, Matthew L. (1) 41, (3) 129 Dupin, Charles L. (1) 15 Martinez, Jorge A. (1) 41 Saketoo, Leslie A. (3) 129 El Hajj, Stephanie C. (4) 176 McCarron, Ross (6) 268 Salama, Laura (4) 138 Engel, Lee S. (2) 81, (4) 143, (6) 268 McGoey, Robin R. (1) 46, (2) 92, Salerno, Daniel A. (6) 258 Englert, Daniel (5) 224 (3) 134, (4) 188, (5) 231 Samuelson, Christian G. (2) 60 Erbil, Jen (5) 221 (6) 272 Sanders, Charles V. (4) 182 Fallahzadeh, Mohammad Kazem McShurley, Timothy D. (5) 219 Sangster, Guillermo (2) 53, (2) 56 (1) 26, (2) 67, (5) 203, 207 Mermilliod, Julie (6) 236 Scheeringa, Michael S. (6) 242 Fauria-Robinson, Christian (4) 149, Mickman, Carl (4) 182 Schiro, Ron (4) 182 (5) 193 Moore II, Kevin (3) 119 Seal, Paula (5) 224 Feng, Zhuang (1) 2, (3) 97 Morris, Liam (6) 251 Self II, Ronnie (4) 149 Foy, Matthew (2) 63 Moses, Michael H. (1) 15 Sharma, Mayur (4) 160 France, Joel (5) 231 Musa, Faisal (1) 41 Shokouh-Amiri, Hosein (2) 67; Gelpi, Brian (2) 60 Musso, Mandi (6) 239 (5) 203, 207 Glancy, D. Luke (1) 36, (2) 75, Nagalingam, Shiva (3) 125 Simoncini, Alberto (2) 53 (3) 121, 123; (4) 176, Nanda, Anil (1) 21, (4) 160 Sin, Anthony (1) 21 (5) 219, (6) 262 Neitzschman, Harold (1) 38, (2) 78, Singh, Manpreet (2) 75 Gomez, Juan S. (6) 264 (4) 179, (5) 221, (6) 264 Singh, Neeraj (1) 26, (5) 207

J La State Med Soc VOL 166 November/December 2014 275 Journal of the Louisiana State Medical Society Volume 166: Author Index

Sivagnanam, Kamesh (5) 197 Wright, Howard W. (6) 248 Smith, David (1) 41 Yandle, Gretchen (5) 221 Spiegel, Jaclyn (4) 182 Yang, Christina (3) 100 Spieler, Bradley M. (3) 129 Youssef, Asser (3) 119 St. Hilaire, Hugo (1) 15, (3) 100 Zakhary, Joseph (5) 207 Stalder, Mark W. (1) 15 Zhang, Zhenzhen (3) 97 Stark, Chris (1) 38 Zhou, Jun (1) 2 Stone, Jonathan (2) 78 Zibari, Gazi B. (2) 67; (5) 203, 207 Straif-Bourgeois, Susanne (4) 168 Summers, Jeffery (5) 197 Telang, Pavan R. (2) 60 Thelin, Camille (4) 143 Thomas, Louise (4) 188 Thurston, Scott (6) 239 Tsao, Christin (3) 134, (4) 188 Tran, Tri (3) 109 Valenzuela, Alejandra A. (2) 70 Veillon, Diana (5) 200 Vincent, Bethaney (6) 236 Walia, Suneeta (6) 236 Wan, Siu-Hin (6) 254 Washco, Vaughan (6) 268 Weidenhaft, Mandy (3) 125 Weiss, Ashley (6) 242 Welliko, Adam (2) 56 Wellman, Greg (2) 67, (5) 207 Willett, Addison (3) 119 Winters, Ryan (3) 100 Wong, Ryan (1) 15

Volume 166: Subject Index

Abdominal imaging (5) 197 Anesthetics, Local (2) 60 Atrioventricular dissociation (5) 219 Abdominal pain (5) 197 Aneurysm (4) 160 Autopsy (1) 46, (2) 92, (5) 231 Acarophobia (4) 154 Anterior mediastinal mass (2) 78 Bayou virus (5) 186 Accelerated idioventricular rhythm Anticoagulation (5) 197 Bile ducts (5) 203 (5) 219 Antipsychotics (6) 242 Biliary tract (5) 203 Acute coronary syndrome (6) 251 Aortic dissection (6) 251 Bisphosphonates (5) 200 Acute esophageal necrosis (4) 188 Aortic root thrombi (4) 138 Black creek canal virus (5) 186 acute respiratory distress Aquaculture-related fish infections Black esophagus autopsy (4) 188 syndrome (6) 248, 258 (3) 103 Black pigmentation (3) 134 Adenocarcinoma (4) 143 Aquatic infections (3) 103 Black thyroid (3) 134 Adult (2) 60 Arteries (5) 221 Blastic nature killer cell (1) 2 Airways (2) 56 Arthroscopy (2) 50 Blastic plasmacytoid dendritic cell Alcohol abuse (2) 92 Ascending aorta (6) 251 neoplasm (1) 2 Alcoholic liver disease (1) 46 Aspergillus (2) 92 Blindness (2) 70 Altered mental status (1) 46 Aspergillosis (2) 92 Brachial Plexus/ultrasonography American hantaviruses (5) 186 Atrial tachycardia (3) 123 (2) 60 Anatomic variation (5) 203 Atrioventricular block (2) 75 Brain contusions (3) 119 Anatomy (2) 53 Atrioventricular conduction (2) 75 Branching hyphae (2) 92

276 J La State Med Soc VOL 166 November/December 2014 Volume 166: Subject Index

Brachial Plexus/ultrasonography (5) 186 Marine animal injuries (3) 103 (2) 60 Heart failure (6) 254 Marine bacteria (3) 103 Brain contusions (3) 119 Hematology (1) 10 Marine infections (3) 103 Branching hyphae (2) 92 Hemodialysis (1) 26 Marine injuries (3) 103 Bronchopleural fistula (6) 258 Histology (2) 92 Marine mammal pathogens (3) 103 Bursitis (4) 182 HIV epidemiology (1) 28 Medical home (3) 109 Calvarial mass (4) 149 HIV testing (1) 28 Mental (1) 41 Cancer (1) 38, (2) 50 Homicide (4) 168 Middle cerebral artery (4) 160 Castleman’s disease (2) 78 Hounsfield units (3) 119 Minocycline (3) 134 Catheter (1) 26 Hyaline vascular (2) 78 Mitral stenosis (1) 36 Catheter migration (1) 21 Hyperammonemia (1) 46 Morgellons disease (4) 154 Celiac trunk (2) 53 Hypercalcemia (3) 97 Mortality (1) 46, (2) 92 Celiacomesenteric trunk (2) 53 Hypertension (5) 221 Mycobacterium infections (4) 182 Central nervous system (1) 41 Hypervascular lymphoid hyper- Mycobacterium kansasii (4) 182 Children (3) 109 plasia (2) 78 Multiple myeloma (4) 149 Cirrhosis (2) 92 Hypothermia (3) 97 Necrosis (4) 188 Clear cell (4) 143 Human immunodeficiency virus Neoplasm metastasis (4) 143 Climatic factors (5) 186 (4) 182, (5) 224 Nerve Block/instrumentation (2) 60 Clinical abstracts (2) 81 Humans (2) 60 Nerve Block/methods (2) 60 Clipping (4) 160 Inclusion Body Myositis (6) 254 Neuroimaging (4) 149 Coiling (4) 160 Infectious disease outbreaks (5) 186 Neuromelanin (3) 134 Colorectal neoplasms (4) 143 Inferoposterior acute myocardial New world hantaviruses (5) 186 Computed tomography (2) 53, (2) 56 infarction (5) 219 Newborn (3) 97 Congenital anomaly (2) 53 Infestations, delusional (4) 154 Non-alcoholic liver disease (1) 46 Conn’s syndrome (5) 221 Intermediate filament (1) 46 Non-Caucasian (2) 56 Cough (4) 179 Intraoperative complications (5) 203 Nontuberculosis (4) 182 Cutaneous blastomycosis (6) 248 Invasive aspergillosis (2) 92 Nontuberculous mycobacterium Cutaneous lymphoma (1) 2 Invasive fungal infection (2) 92 (5) 213 Cytarabine (6) 236 Ischemia (4) 188 Oncology (1) 10 Dehiscence (2) 70 Jaw (5) 200 Osteochondromatosis (3) 125 Delirium (6) 242 Joint (3) 125 Osteonecrosis (5) 200 Determining culprit artery in infero- Juvenile (3) 100 Oxidation (3) 134 posterior infarct (5) 219 Kaposi sarcoma (5) 224 Palatoplasty (1) 15 Digitalis (3) 123 Knee (3) 125 Pancreas (2) 67 Dizziness (2) 75 Kidney transplantation (5) 207 Pancreas transplantation (5) 207 Doxycycline (3) 134 Laparoscopic cholecystectomy Pancreatic neoplasms (2) 67 Duodenum (5) 207 (5) 203 Papillary thyroid carcinoma (3) 134 Dyspnea (6) 254 Left atrial enlargement (1) 36 Parasitosis, delusional (4) 154 Echocardiography (6) 240, 241 Leptospira interrogans (5) 186 Pathology (2) 92, (4) 188 Ectoparasitosis, delusional (4) 154 Leptospirosis (5) 186 Pediatric (3) 109 Elbow (2) 50 Lesion (3) 100, (5) 193 Percutaneous coronary intervention Ekbom’s syndrome (4) 154 Leukemia cutis (6) 236 (5) 219 Embolization (4) 138 Lhermitte-Duclos disease (5) 193 Peritoneal dialysis (5) 213 Endoscopy (5) 207 Linkage to care (1) 28 Physician (1) 10 Erosion (2) 70 Lipofuscin (3) 134 Plasma cell (2) 78 Exit-site infections (5) 213 Liver (3) 129 Plasmacytoid dendritic cell (1) 2 Fatty liver (1) 46 Louisiana (1) 10, (4) 168 Plasmacytoma (2) 63 Fibroma (3) 100 Magnetic resonance spectrocopy Plexiform lesion (5) 231 Firearm deaths (4) 168 (5) 193 Plexogenic arteriopathy (5) 231 Fish pathogens (3) 103 Male (2) 60 Primary biliary cirrhosis (3) 129 Gastrointestinal neoplasms (4) 143 Mallory bodies (1) 46 Prostate (1) 38 Graft rejection (5) 207 Mallory Denk bodies (1) 46 Psychosomatic medicine (6) 242 Hantavirus (5) 186 Mallory hyaline (1) 46 Pulmonary arterial hypertension Hantavirus pulmonary syndrome Malposition (1) 21 (5) 231

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Volume 166: Subject Index

Pulmonary emboli (4) 176 Pulmonary hypertension (5) 231 Pulmonary langerhans cell histio-cytosis (4) 179 Rectus sheath hematoma (5) 197 Relapsing polychondritis (2) 56 Respiratory failure (6) 254 Respiratory Paralysis/prevention & control (2) 60 Rib (2) 63 Rodent-borne (5) 186 Solitary plasmacytoma (4) 149 Shortage (1) 10 Sickle cell disease (5) 231 Sin nombre virus (5) 186 Skin lesions (6) 248 Slurring of speech (1) 38 Sphenoid sinusitis (2) 70 Stab wound (6) 239 Steatosis (1) 46 Subcutaneous fat necrosis (3) 97 Submucous cleft (1) 15 Sudden unexplained death (2) 92 Suicide (4) 168 Superior mesenteric artery (2) 53 Supernormal (2) 75 Surgery (2) 67 Synovial metastasis (2) 50 Synovial osteochondromatosis (3) 125 Systemic embolus (1) 36 Tachycardia (3) 123 Thoracotomy (6) 239 Toxic erythema of chemotherapy (6) 236 Toxoplasmosis (1) 41 Tracheobronchomalacia (2) 56 Transaminitis (1) 46 Transcutaneous Electric Nerve Stimulation/methods (2) 60 Traumatic brain injury (3) 119 Treatment outcome (2) 60 Trends (4) 168 Turbinate (3) 100 Ultrasonography, Interventional (2) 60 Velopharyngeal incompetence (1) 15 Ventriculo-peritoneal shunt (1) 21 Ventricular septal defect (6) 239 Weil’s disease (5) 186 White Coat ceremony (3) 121

278 J La State Med Soc VOL 166 November/December 2014