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Diagnosis and Treatment of Pediatric Acute Ayesha Ahmad, MD; Luis Seguias, MD; and Kathryn Ban, MD

cute transverse myelitis is a diagnosis. In addition to the clinical ticosteroids, plasma exchange (PLEX), rare, focal immune-mediated evaluation, magnetic resonance imag- intravenous immunoglobulin (IVIG), Adisease that affects the sensory ing (MRI) and cerebrospinal fluid (CSF) cytotoxic drugs, and other immuno- and motor pathways of the spinal cord. testing are common diagnostic tools modulatory agents; however, the use of It is characterized by a sudden clinical used as a first step in diagnosis. steroids followed by PLEX is the most onset of neurological motor dysfunction Children with ATM undergo differ- widely accepted treatment regimen. associated with sensory loss and auto- ent therapeutic modalities such as cor- ATM is commonly a monophasic ill- nomic disturbances. The following tetrad of symptoms has been classically described in acute transverse myelitis (ATM): 1) weakness in the arms/legs; 2) sensory symptoms such as numbness or tingling; 3) pain and discomfort; and 4) bladder dysfunc- tion and/or bowel motility problems. The etiology of ATM is diverse and includes infectious, post-infectious, vas- cular, collagen/autoimmune, neoplastic, and paraneoplastic causes. Clinical in- terview and careful neurological exami- nation are essential in making an ATM

Ayesha Ahmad, MD, is an Assistant Professor of Pediatrics, University of Texas Southwestern Medical Center. Luis Seguias, MD, is an Assistant Professor of Pediatrics, University of Texas South- western Medical Center. Kathryn Ban, MD, is an Assistant Professor of Pediatrics, University of Texas Southwestern Medical Center. Address correspondence to: Luis Seguias, MD, University of Texas Southwestern Medical Center, 5151 Harry Hines Boulevard, Dallas, TX 75390; email: [email protected]. Disclosure: The authors have no relevant fi- nancial relationships to disclose. doi: 10.3928/00904481-20121022-15 © Shutterstock

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increased drooling and trouble swallow- considered an immunologically “privi- ing. leged” organ. This old concept was based Initial clinical evaluation revealed on four principles: (1) the presence of a child with normal mental status and the blood–brain barrier; (2) the lack of severe truncal hypotonia. Her lower ex- constitutive expression of major histo- tremity muscle strength was markedly compatibility complex (MHC); (3) the decreased bilaterally with no antigrav- absence of lymphatic drainage; and (4) ity movement (grade: 2/5) and her upper the lack of T cell immune surveillance. extremity strength was also decreased However, it is now evident that most but to a lesser degree (grade: 3/5). Oth- of these assumptions were not valid. Re- Images courtesy of Ayesha Ahmad, MD. Reprinted with permission. Images courtesy of Ayesha Figure 1. MRI of brain showing swelling. erwise, vital signs and physical exami- cent studies have shown that activated T nation were unremarkable. Pertinent lymphocytes can penetrate the blood– diagnostic work-up included lumbar brain and the blood–nerve barriers and puncture revealing normal CSF indices, release cytokines that will engineer an and brain and spine MRI that demon- immune-response.2 Also, it has been strated swelling and marked T2 signal demonstrated that the nervous system prolongation of the spinal cord from microglial cells have the potential to act approximately C2 to T2-T3 suggestive as antigen presenters and regulate T-cell of an active inflammatory process (see activity.3 Figures 1 and 2). No optic nerve or brain Current research intends to elucidate demyelinating lesions were observed. the role of immune cells and immuno- She was admitted with the diagnosis of mediators in the initiation and progres- ATM for further diagnostic testing and sion of these neurological disorders.2 treatment. A comprehensive infectious and autoimmune work-up was obtained, HISTORY OF ATM Figure 2. MRI of spine showing marked T2 pro- with the only pertinent finding being a In 1882, H.C. Bastain, MD, reported longation of the spinal cord from C2 to T2-T3. positive parainfluenza virus type 3 on pathologic findings of several autopsies nasopharyngeal polymerase chain reac- from patients who died of “acute my- ness. Nevertheless, a small fraction of tion (PCR) swab. elitis” and divided the cases into those patients may have recurrence. Pediatric The patient was started on high-dose that he thought were due to “thrombotic outcomes are better than in adults, with intravenous followed by events to blood vessels supplying the children often regaining complete func- PLEX therapy per neuroimmunology spinal cord” and those that were due tion. recommendations. After completing five to acute . The “inflamma- PLEX sessions, she had significant re- tory” cases were postulated to be due to CASE SCENARIO covery of muscle strength, and was able an infectious or an allergic mechanism.4 A 1-year-old, previously healthy His- to sit and stand unassisted. Upon follow- In the early 1920s, health care pro- panic female presented to the emergency up visit 1 month after discharge, she was viders in England and Holland reported department (ED) with acute generalized reported to have a normal neurological multiple cases of “inflammation of the weakness. The sudden neurological exam. spinal cord and brain” after smallpox clinical picture was preceded by a 3-day immunization. At the time, clinical find- history of fever (Tmax: 38.8°C) and a SPECTRUM OF ings were interpreted as an “allergic” 2-week history of rhinorrhea and cough. NEUROIMMUNOLOGICAL post-vaccine .5 After picking her up from daycare at DISORDERS Several years later in 1928, Dr. Ford midday, the mother noticed that she re- The term neuroimmunological disor- theorized that many cases of acute my- fused to pull up or walk. The child had der refers to a group of illnesses that are elitis were post-infectious rather than previously been walking independently the result of acquired dysregulation of infectious in nature.6 A new terminology for 6 weeks. The mother tried repeatedly both the immune system and the central was introduced in 1948 by A.I. Suchett- to get her to sit-up alone, but she was un- nervous system (CNS)1 (see Sidebar 1, Kaye, MD, who described a case with able to do so. Also, the patient’s mother page 479). a “band-like” horizontal area of altered expressed concern about her daughter’s Historically, the CNS has long been sensation of the neck and torso. He

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named this entity “acute transverse my- ATM: 1) weakness in the arms/legs; 2) SIDEBAR 1. elitis.”7 sensory symptoms such as numbness or tingling; 3) pain and discomfort; and 4) Spectrum of Neuro- PATHOGENESIS/PATHOLOGY bladder dysfunction and/or bowel motil- immunologic Disorders ATM is a heterogeneous inflamma- ity problems. Central Nervous System tory disorder of the spinal cord. Using The distribution of these symptoms • Brain acute disseminated immunochemistry techniques, spinal may be either symmetric or asymmetric, (ADEM) cord histopathology of ATM patients has affecting either legs, arms, or both. • Multiple sclerosis (MS) demonstrated perivascular infiltration by There is often a clearly defined ros- • Acute transverse myelitis (ATM) T lymphocytes (+CD3 stain) and focal tral border of sensory dysfunction, and • Neuromyelitis optica (NMO) infiltration by macrophages (+HLA-Dr spinal MRI and lumbar puncture often • Optic neuritis (ON) 1,2 stain). These immunopathological show evidence of acute inflammation. • Pediatric autoimmune neuropsychiatric observations substantiate that ATM is Autonomic symptoms are variable, con- disorders associated with streptococcal an immune-mediated inflammatory dis- sisting of bowel or bladder incontinence, infection (PANDAS) ease. increased urinary urgency, difficulty or • Hashimoto’s encephalitis ATM is often preceded by an in- inability to void, incomplete evacuation, • Paraneoplastic encephalomyelitis fectious process, which has led to the or constipation.12 • Rasmussen’s encephalitis hypothesis of microbial superantigen- ATM has an incidence of one to four • Tropical spastic paraparesis mediated immune response. Molecular new cases per million people per year, • Stiff person syndrome “mimicry” by infectious agents has been affecting individuals of all ages with bi- •  acknowledged as a pathogenic mecha- modal peaks between the ages of 10 and Peripheral Nervous System nism in neurological disease (eg, Guil- 19 years and 30 and 39 years.12 There • Peripheral nerve chronic inflammatory 9,10 lain-Barré syndrome). In ATM, this may be a third peak involving children demyelinating polyneuropathy idea of cross-reactive immune activation aged younger than 3 years, as evidenced • Acute inflammatory demyelinating poly- against self-tissue is also embraced.2 by a recent study of 47 pediatric cases of neuropathy (Guillain-Barré syndrome) In addition, the humoral reaction to ATM, with 38% of their patients being Neuromuscular Junction microbial molecular “mimicry” could younger than the age of 3.9 It is estimat- • Myasthenia gravis trigger the production of autoautibod- ed that 20% to 30% of ATM cases occur • Lambert-Eaton myasthenic syndrome ies. This autoimmune response against in children. The number of affected male Muscle neuronal surface proteins could induce and female children is approximately •  neural injury by altering cellular signal- equal among cases of pediatric ATM.9 • Dermatomyositis ing and/or metabolism. 1 Recent identification of novel CSF DIAGNOSTIC CRITERIA Source: Adapted from Krishnan et al biomarkers associated with ATM (eg, A diagnosis of ATM requires evi- interleukin-6 and protein 14-3-3) might dence of inflammation within the spinal lead to better understanding of the spec- cord, as determined by spinal MRI and presentations of disease. Accordingly, trum of this disease. In the future, de- CSF analysis. Diagnosis should require all patients presenting with ATM should tection of these biomarkers could grant that all of the inclusion criteria and none also be investigated for the presence of potential therapeutic targets and give of the exclusion criteria are fulfilled (see systemic inflammatory disease. prognostic value.11 Sidebar 2, page 480).12 Key historical information should be obtained regarding the presence of - CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION OF es, oral or genital ulcers, night sweats, EPIDEMIOLOGY ACUTE MYELOPATHIES shortness of breath, sicca symptoms, ATM is an inflammatory disorder of Differentiating ATM resulting from pleuritic pain, or hematuria. Physical ex- the spinal cord, characterized clinically an underlying disease from the idio- amination should include evaluation for by of neurologic pathic form is essential. Many systemic oral or genital ulcers, uveitis or retinitis, dysfunction that result in motor weak- inflammatory disorders (eg, SLE, sar- skin , lymphadenopathy, hepa- ness, sensory loss, and autonomic dys- coidosis, Behçet’s disease, Sjogren’s tosplenomegaly, or pericardial friction function with acute or subacute onset.11 syndrome) may also involve the CNS, rub. Laboratory studies should include There are four classic symptoms of and ATM may be one of the potential complete blood count with differential

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SIDEBAR 2. disorders, vascular, and neoplastic/para- neoplastic. The first three are considered Criteria for Diagnosis of Acute Transverse Myelitis inflammatory disorders. Inclusion criteria In demyelinating disorders (eg, MS, • Development of sensory, motor, or autonomic dysfunction attributable to the spinal cord. NMO, ADEM), typically the onset of • Bilateral signs and/or symptoms (though not necessarily symmetric). neurological symptoms occurs over • Clearly defined sensory level. days, with both sensory and motor • Inflammation within the spinal cord demonstrated by CSF pleocytosis or elevated IgG index or symptoms and bladder and bowel distur- gadolinium enhancement (If none of the inflammatory criteria is met at symptom onset, repeat MRI and LP evaluation between 2-7 days following symptom onset). bances. They usually occur in individu- als who are otherwise healthy and are Exclusion criteria sometimes preceded by a nonspecific • History of previous radiation to the spine within the past 10 years. viral illness. • Clear arterial distribution clinical deficit consistent with thrombosis of the anterior spinal artery. In multiple sclerosis, lesions are usu- • Extra-axial compressive etiology by neuroimaging (MRI of spine preferred; CT myelography accept- ally small (<2 vertebral segments in able; X-ray, CT of spine are not adequate). length) and peripheral, and therefore • Abnormal flow voids on the surface of the spinal cord consistent with arteriovenous malformation. cause asymmetric signs and symptoms. • Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behçet’s disease, Sjogren’s syndrome, systemic erythematosus, mixed connective tissue disorder, etc). CSF oligoclonal bands are present in • History of clinically apparent optic neuritis. more than 90% of patients, and a raised • CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, mycoplasma, other viral infection (eg, HSV- immunoglobulin IgG index is seen in 1, HSV-2, VZV, EBV, CMV, HHV-6, enteroviruses). more than 60%.8 • Progression to nadir in less than 4 hours from symptom onset. Early in relapse, symptoms usually • Symptom progression continues beyond 21 days from symptom onset. resolve in a few weeks to months. Neu- • Brain and spinal cord MRI abnormalities suggestive of MS and presence of oligoclonal bands in CSF. romyelitis optica is most commonly a

CMV = cytomegalovirus; CNS = central nervous sytem; CSF = cerebrospinal fluid; CT = computed tomography; EBV = Epstein- relapsing demyelinating condition of the Barr virus; HHV = human herpesvirus; HSV = herpes simplex virus; IgG = immunoglobulin G; LP = lumbar puncture; MRI = CNS affecting primarily the optic nerves magnetic resonance imaging; MS = multiple slcerosis; VZV = varicella zoster virus. and spinal cord. Lesions are typically 11 Source: Adapted from Transverse Myelitis Consortium Working Group long (>3 vertebral segments), centrally located, and necrotic, leading to more and smear, antinuclear antibody, SS-A enhancement on MRI, CSF pleocytosis, systemic signs and symptoms, greater and SS-B antigens, erythrocyte sedi- or elevated CSF immunoglobulin index, disability than multiple sclerosis, and mentation rate, and complement levels. one needs to determine whether there less complete recovery. The first step in diagnostic evaluation is a possible infectious cause. The third ADEM is a monophasic disorder that is to rule out a compressive lesion. If a step is to define the area and distribution affects the brain and occasionally the myelopathy is suspected, a gadolinium- of demyelination within the CNS, since spinal cord. Often, there is a history of enhanced MRI of the spinal cord should there are several disorders (eg, multiple a preceding viral or other infectious ill- be obtained as soon as possible. If there sclerosis or acute disseminated encepha- ness. The brain and spinal cord show de- is no structural lesion such as a spinal lomyelitis) that may present with ATM myelinating lesions that are generally of mass or spondylolisthesis, then the sec- as the initial presentation of disease or the same age. ADEM may evolve over ond step is to identify the presence or in the setting of multifocal disease. To the course of up to 3 months and is more absence of spinal cord inflammation check for these entities, a gadolinium- common in children. with lumbar puncture. The absence of enhanced brain MRI should be ordered. Viral, bacterial, fungal, and parasitic pleocytosis would lead to the consid- The absence of multifocal areas of de- infections can also cause acute myelitis. eration of noninflammatory causes of myelination would suggest the diagnosis Patients typically are systemically ill myelopathy such as arteriovenous mal- of isolated ATM and lead to appropriate with fever and meningeal signs. Com- formation (AVM), fibrocartilaginous treatment measures. mon organisms include HSV, VZV, embolism, radiation, epidural lipoma- CMV, EBV, HHV-6, enteroviruses, in- tosis, or possibly early inflammatory DIFFERENTIAL DIAGNOSES fluenza, dengue, West Nile, mycoplas- myelopathy (ie, a false-negative CSF). There are five groups of disorders ma, Lyme, and syphilis.1,13 In the presence of an inflammatory that present as acute myelopathy: demy- Connective tissue disorders may process, as evidenced by gadolinium elination, infections, other inflammatory present with acute or subacute myelitis.

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SLE, Behçet’s, Sjogren’s, , munomodulatory and cytotoxic drugs preventing recurrence, there is insuf- mixed connective tissue disorder, and such as , , and cy- ficient evidence to warrant the use of sarcoidosis have all been associated with clophosphamide, although there is not immunosuppressive at this myelitis; however, it is uncommon for sufficient evidence in the literature to time.12 myelitis to be the presenting symptom. support their routine use.12 In one large In addition to pharmacologic thera- Invariably, classic systemic features of retrospective study of adult patients with pies, the importance of physical and oc- the disease will be present before the de- ATM, patients with the most severe level cupational therapy in the care of patients velopment of myelitis. of disability at nadir, and those with a with ATM cannot be overlooked and Vascular disorders can also lead to history of did show should be included as early as possible in spinal cord infarction, imitating myelitis. some benefit from IV cyclophospha- their care. Arterial occlusions are rare and develop mide after corticosteroids. acutely over minutes. AVMs usually In that same study, another subgroup NATURAL HISTORY AND progress slowly due to gradual ischemia of patients receiving IV corticosteroids PROGNOSIS resulting from venous congestion. followed by PLEX fared better than The progression of symptoms in Metastatic disease and compressive those who received IV corticosteroids ATM often slows within 2 to 3 weeks tumors (eg, neurofibromas and menin- alone, further supporting the use of ste- of onset, with a corresponding improve- giomas) are common causes of acute or roids followed by PLEX as the widely ment in CSF and MRI abnormalities. acute-on-chronic myelopathy. Several accepted standard of care.14 In terms of Evidence of at least some recovery is paraneoplastic antibodies are also as- sociated with subacute myelopathies. Radiation-induced myelopathies are usually slowly progressive but may oc- cur up to 15 years after the completion of radiation treatment.13

TREATMENT OPTIONS ATM is a rare disease; randomized placebo-controlled studies to support evidence-based management are not available. Decision-making is often guided by clinical experience and treat- ment of related disorders. At the Johns Hopkins Transverse Myelitis Center, high-dose (1 g IV daily for 3-7 days) is typically first-line THE STRENGTH TO HEAL treatment.1 The decision to extend ste- and protect the health of roids or provide additional treatment those who protect our country. modalities is based both on the clinical course and MRI findings after comple- Physicians and surgeons on the U.S. Army health care team take pride in caring for our Soldiers and tion of steroids. their families. They take pride in being members PLEX is often added to the regimen of one of the world’s most advanced health care systems. They take pride in the fact that their if a patient shows little clinical improve- skills and experience will continue to grow along ment after the standard steroid course. with their nation’s gratitude. To learn more about the U.S. Army health PLEX can be considered as initial treat- care team, call 855-276-9660 or visit ment if a patient has moderate to severe healthcare.goarmy.com/info/q462. ATM symptoms on presentation (eg, is ©2012. Paid for by the United States Army. unable to ambulate, sensory loss in low- All rights reserved. er extremities, or significant autonomic dysfunction).1 Other therapeutic options include im-

PEDIATRIC ANNALS 41:11 | NOVEMBER 2012 Healio.com/Pediatrics | 481 FEATURE expected to begin within 6 months; Early systemic corticosteroids +/- 7. Suchett-Kaye AI. Acute transverse myelitis most patients show some improvement PLEX are the current treatment modal- complicating pneumonia. Lancet. 1948;255- 417. in neurologic function within 8 weeks, ity of choice. Pediatric outcomes are 8. Borchers A, Gershwin E. Transverse myelitis. although recovery can take a more pro- better than in adults, with children often Autoimmun Rev. 2012;11:231-248. longed course of up to 2 years. About regaining complete function. 9. Kerr D, Ayetey H. Immunopathogenesis of acute transverse myelitis. Curr Opin Neurol. one-third of patients will show minimal 2002;15:339-347. (eg, mild urinary symptoms, minimal REFERENCES 10. Pittock S, Lucchinetti C. “Inflammatory sensory deficits and upper 1. Krishnan C, Kaplin A, Deshpande D, Pardo transverse myelitis: evolving concepts.” Curr C, Kerr D. Transverse myelitis: pathogen- Opin Neurol. 2006;19:362-368. signs) to no permanent effects. Another esis, diagnosis and treatment. Front Biosci. 11. Transverse Myelitis Consortium Working one third will have a moderate degree 2004;9:1483-1499. Group. Proposed diagnostic criteria and no- of disability (eg, mild spasticity, but 2. Kawakami N, Bartholomaus I, Pesic M, Mues sology of acute transverse myelitis. Neurol- still ambulating independently, urinary M. An odyssey: how autoreac- ogy. 2002;59:499-505. tive T cells infiltrate into the CNS.Immunol 12. Scott TF, Frohman EM, De Seze J, et al. urgency +/- constipation, some sensory Rev. 2012;248(1):140-155. Evidence-based guideline: clinical evaluation symptoms). The remaining one third 3. Almolda B, Gonzalez B, Castellano B. Anti- and treatment of transverse myelitis. Report will be left with severe disabilities (eg, gen presentation in EAE: role of microglia, of the Therapeutics and Technology Assess- macrophages and dendritic cells. Front Bios- ment Subcommittee of the American Acade- inability to walk or severe disturbance in ci. 2011;1(16):1157-1171. my of . Neurology. 2011;77:2128- gait, lack of sphincter control).1 4. Bastian HC. Thrombotic softening of the spi- 2134. The majority of patients with ATM nal cord: a case of so-called “acute myelitis”. 13. Jacob A, Weinshenker B. An Approach to the Lancet. 1910;1531-1534. diagnosis of acute transverse myelitis. Semin have monophasic disease without re- 5, Rivers TM. Viruses. JAMA. 1929;92:1147- Liver Dis. 2008;28(1):105-120. currence.1 It is generally accepted that 1152. 14. Greenberg BM, Thomas KP, Krishnan C, pediatric outcomes are better than in 6. Ford FR. The nervous complications of mea- Kaplin AI, Calabresi PA, Kerr DA. Idiopathic adults, with children often regaining sles: with a summary of literature and pub- transverse myelitis – corticosteroids, plasma lications of 12 additional case reports. Bull exchange, or . Neurology. 10 complete function. Studies in adults Johns Hopkins Hosp. 1928;43:140-184. 2007;68:1614-1617. and children have identified several risk factors for unfavorable outcomes at presentation, including rapid progres- sion to maximal neurologic deficit (<24 AD INDEX hours), severe motor weakness, spinal shock, back pain as the initial com- ABBOTT NUTRITION plaint, and sensory disturbances at the 625 Cleveland Avenue, Columbus, OH 43215 cervical level.1,10 PediaSure...... C2 In terms of recurrence, findings of ACTAVIS multifocal lesions within the spinal Turmstrasse 24, CH-6300 Zug, Switzerland FeverAll...... 439 cord, demyelinating lesions in the brain, oligoclonal bands in CSF, evidence of AMERICAN LIFELINE 138 First Street, Baraboo, WI 53913 mixed connective tissue disorders, and Florajen...... 445 serum (especially SS-A) GLAXOSMITHKLINE all seem to be significant predictors of 5 Moore Drive, Research Triangle Park, NC 27709 a possible multiphase disease course.1,10 Menhibrix...... C4 SLACK INCORPORATED CONCLUSION 6900 Grove Road, Thorofare, NJ 08086 Curbside Consultation...... 476 ATM is a rare, but serious acute in- Infectious Diseases in Children Education Lab...... C3 flammatory neurological disorder of the Healio.com/Pediatrics...... 457 spinal cord characterized by four classic symptoms: 1) weakness in the arms/legs; While every precaution is taken to ensure accuracy, Pediatric Annals cannot guarantee against occasional changes 2) sensory symptoms such as numbness or omissions in the preparation of this index. or tingling; 3) pain and discomfort; and 4) bladder dysfunction and/or bowel motility problems.

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