660 Postgrad Med J 2000;76:660–662 Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from SELF ASSESSMENT QUESTIONS

A case of migratory lymphadenopathy and cutaneous anergy in an Asian woman

Haider M Al Attia, Yasser H Al Ahmed, Afaf El Hag, Rima N El Abassi

Answers on p 663. A 40 year old Pakistani woman presented with virus-1, herpes simplex and hepatitis B and C, one month history of fever, night sweats, and as well as serum immunoglobulins were progressive and painful swelling in the right normal or negative. Assays for antinuclear fac- side of the neck. She was febrile (temperature tors, anti-dsDNA, neutrophil cytoplasmic anti- 38–40ºC). Right deep cervical, occipital, and bodies, and rheumatoid factor were also nega- jugulodiagastric lymph nodes were palpable, tive. Computed tomography of the chest and firm, and tender. Save for a moderately severe abdomen showed normal findings. Cervical asymmetrical arthralgia of right wrist, shoulder lymph node biopsy showed an intact architec- and proximal interphalangeal joints, the rest of ture and a reactive proliferation of histiocytes, Department of her physical examination was unremarkable. transformed lymphocytes of CD8 phenotype Internal Medicine and Laboratory data showed, mild leucopenia of and plasma cells, surrounding areas of karyor- Histopathology, 3.6 × 109/l with 64% neutrophils, 26% lym- rhectic necrosis without neutrophils. There Mafraq Hospital, Abu phocytes (no atypical form), and 10% mono- were no demonstrable organisms on special Dhabi, United Arab Emirates cytes, erythrocyte sedimentation rate (ESR) 64 stains. A periadenitis was present together with H M Al Attia mm/hour, and C reactive protein of 105 mg/l a vasculities with no fibrinoid necrosis present Y H Al Ahmed (normal <10 mg/l). A skin test for tuberculin (fig 1). A diagnosis was made and she was AElHag reactivity was negative. Results of chest radio- treated accordingly. There was rapid resolution R N El Abassi graphy, blood chemistry, urine and stool analy- of fever and arthralgia within 24 hours, and the Correspondence to: sis, throat swab, blood cultures, Venereal lymphadenopathy in two weeks. Follow up at Dr Haider M Al Attia, Disease Research Laboratory test, test for HIV, three months was uneventful. Mafraq Hospital, PO Box heterophil antibodies, and serological studies After being well for two years, she presented 2951, Abu Dhabi, UAE for salmonella serotypes, brucellosis, toxo- again in June 1998 with a one month history of Submitted 9 March 1999 plasmosis, Lyme disease, Epstein-Barr virus, the same symptoms, but this time there was a Accepted 14 October 1999 cytomegalovirus, human T cell leukaemia non-tender, left supraclaviular, posterior trian- gle, and jugulodigastric lymphadenopathy. Leucopenia of 3.1 × 109/l with 7% monocytes http://pmj.bmj.com/ and ESR of 36 mm/hour were documented. All the tests that had been carried out during her previous admission were repeated. The results showed no abnormal findings. The tuberculin test was again negative. Biopsy of a left deep cervical node showed identical changes to those of the previous biopsy. She was conserva-

tively managed with bed rest and administra- on September 30, 2021 by guest. Protected copyright. tion of paracetamol. The fever subsided completely after 10 days and lymphadenopathy resolved in two weeks. The patient remains well to date. During the follow up, the tuberculin test was repeatedly found to be positive.

Questions (1) What was the overall diagnosis? (2) What two unusual features are described Figure 1 Area of karyorrhectic necrosis (arrow) surrounded by histiocytes (pale zone), lymphoctyes, and plasma cells (dark zone). in this case?

www.postgradmedj.com Self assessment questions 661 Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from Multiple focal lesions in liver and spleen in acute leukaemia

Sangeet Ghai, Sanjay Thulkar, Prakash Neduvelil Purushothaman, Sanjay Sharma

Answers on p 664. An 18 year old girl presented with a two month history of fever and bleeding tendency. On examination, she had multiple petechial haemorrhages all over her body. There

Figure 3 Computed tomogram shows multiple, low attenuation, rounded lesions in the spleen. One of the lesions (arrow) also shows a central nidus of high attenuation.

Figure 1 Sonogram of the spleen shows multiple, rounded was no organomegaly or peripheral lympha- hypoechoic lesions, some with typical bull’s eye appearance. denopathy. Systemic examination was Institute Rotary unremarkable. Total leucocyte count was Cancer Hospital, All 117 × 109/l and platelet count 45 × 109/l. India Institute of Peripheral smear showed presence of blast Medical Sciences, New cells. Bone marrow biopsy revealed 60%–70% Delhi 110 029, India: myeloblasts. The patient was diagnosed as Department of Radio-diagnosis having myeloid leukaemia. After two cycles of S Ghai chemotherapy, the patient went into remis- http://pmj.bmj.com/ S Thulkar sion. S Sharma After three weeks, she became febrile again and developed diVuse upper abdominal ten- Department of derness and jaundice. Abdominal sonography Medical Oncology P N Purushothaman (fig 1) and computed tomography (figs 2 and 3) were performed. Total leucocyte count at Correspondence and reprint this time was 9.5 × 109/l. requests to: Dr Sanjay on September 30, 2021 by guest. Protected copyright. Sharma, A-86, Inderpuri, New Delhi 110012, India Questions (email: (1) What are the findings on ultrasound and [email protected]) Figure 2 Computed tomogram of the upper abdomen computed tomography? showing multiple small low attenuation lesions in the liver Submitted 1 June 1999 and spleen. Incidentally old calcified granulomas are also (2) What is the radiological diagnosis? Accepted 8 October 1999 seen in liver and spleen. (3) How can the diagnosis be confirmed?

www.postgradmedj.com 662 Self assessment questions Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from A pregnant patient with bilateral ischaemic limbs

N B Teo, N Mamode, D P Leiberman

Answers on p 666. A 29 year old pregnant woman, at 35 weeks’ The electrocardiogram showed ST changes gestation, was admitted with a three day history in the septal leads with R waves in V1 sugges- of a painful left thigh and calf which was exac- tive of right ventricular hypertrophy as well as erbated by walking. She also complained of T wave inversion in the anterolateral leads paraesthesiae, muscle weakness, and coldness thought by the cardiologist to be suggestive of pulmonary thromboembolism. Chest radio- of the left foot which at times became graphy showed cardiomegaly. Full blood cyanosed. These symptoms were associated count, concentrations of urea and electrolytes, with dyspnoea on exertion. and thrombophilia screen were normal. When admitted to the obstetric ward, the left On review by the vascular team, it was noted lower limb pulses were impalpable. The left that apart from a very weak right femoral pulse, lower leg was mottled and cold but was viable. there was absence of pulses in both lower limbs, which were significantly ischaemic. After cardiological review, a transthoracic echocardiogram showed a large right ventricle with a dilated pulmonary artery. No atrial sep- tal defect was seen and there was no evidence of thrombus. Doppler ultrasound showed a 10 cm left Peripheral Vascular popliteal venous thrombus as well as occlusion Unit, Royal Infirmary of bilateral common femoral and superficial Glasgow, Glasgow, UK arteries. This was followed by a transradial NBTeo arteriogram that showed the thrombus causing N Mamode a left common iliac occlusion and a right com- D P Leiberman mon femoral arterial occlusion (fig 1). Correspondence to: Mr N B Teo, Pathology Questions Department, University of (1) What is the diagnosis? Liverpool, Duncan Building, Daulby Street, Liverpool (2) Describe the pathogenesis of this clinical L69 3GA, UK condition? (email: (3) How should the diagnosis be made? [email protected]) (4) Describe the most recent development in http://pmj.bmj.com/ Submitted 27 August 1999 Figure 1 Transradial arteriogram: left common iliac and the diagnosis of this condition? Accepted 8 October 1999 right common femoral arterial occlusions. (5) What is the treatment?

Severe symptomatic hypercalcaemia on September 30, 2021 by guest. Protected copyright.

José María Calvo-Romero, María del Carmen Bonilla-Gracia

Answers on p 668. A 49 year old man had a six week history of and albumin 43 g/l. The blood calcium was 4.8 depression, constipation, proximal muscle mmol/l, confirmed by repeated determinations. weakness, anorexia, and weight loss of about 20 The 24 hour urinary calcium excretion was 12.3 kg. The patient was not taking any medication mmol. An electrocardiogram revealed sinus Internal Medicine and there was no history of nephrolithiasis, rhythm and shortened QT interval. Free thyrox- Service, Infanta Cristina University peptic ulcer, headache, or visual defects. Physi- ine and thyrotrophin serum concentrations were Hospital, Badajoz, cal examination showed light proximal muscle normal. Serum intact parathyroid hormone was Spain weakness without atrophy, dehydration, and no 488 µg/l (normal values 10–65 µg/l). J M Calvo-Romero other remarkable findings. The blood pressure M C Bonilla-Gracia was 140/85 mm Hg. The patient’s blood Questions chemical values were: glucose 5.2 mmol/l, urea (1) What is your diVerential diagnosis for this Correspondence to: José María Calvo-Romero, nitrogen 13.2 mmol/l, creatinine 141 µmol/l, case? Héroes de Cascorro 9, 31A, sodium 136 mmol/l, potassium 4.1 mmol/l, (2) What further investigations would you 06004 Badajoz, Spain chloride 101 mmol/l, phosphorus 1.3 mmol/l, perform? Submitted 7 July 1999 magnesium 0.98 mmol/l, alkaline phosphatase (3) What is the therapy for the severe hyper- Accepted 8 October 1999 115 U/l, creatine kinase 82 U/l, protein 76 g/l, calcaemia in this case?

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A case of migratory lymphadenopathy dilemma; a situation that would have not been and cutaneous anergy in an Asian woman settled without a second lymph node biopsy. Such a migratory characteristic, however, has Q1: What was the overall diagnosis? not been specifically referred to in the previous Histiocytic necrotising lymphadenitis (Kikuchi literature. KFD should be considered in the Fujimoto disease) diVerential diagnosis of any clinical setting with migratory lymphadenopathy. The repeatedly Q2: What two unusual features are negative tuberculin test during acute illness described in this case? was another issue of interest. Unless the cellu- (1) The transient cutaneous anergy during the lar mediated immune reaction is stunted, the acute phase of the illness and (2) the migratory tuberculin test is expected to be positive in an pattern of lymphadenopathy after a prolonged Asian adult, even in the absence of active remission. tuberculous disease. Thus, the negative reac- tion in our patient was likely to be a sign of Discussion transient cutaneous anergy possibly induced by Histiocytic necrotising lymphadenitis or the disease activity and recovered during Kikuchi Fujimoto disease (KFD) is an uncom- remission. To the best of our knowledge this mon, self limiting disease that primarily aVects phenomenon was also not reported before, and the cervical lymph nodes in young adults, is worthy of further study in future cases. mainly females. The aetiology seems unknown but an infective origin seems likely. Though the Final diagnosis condition commonly aVects patients of Asian Histiocytic necrotising lymphadenitis (Kikuchi descent, it has been more and more seen in Fujimoto disease). other populations.12 KFD is a peculiar condition with broad 1 Simonsen K, StormT L. Histiocytic necrotizing lymphad- morphological spectrum that can readily be enitis (Kikuchi’s disease). Ugeskr Laeger 1991;153:2836–7. 2 Depree C, Pelte MF, Delacretaz F, et al. Histiocytic mistaken for malignant lymphoma or lupus,3 necrotizing lymphadenitis or Kikuchi’s disease. Anatomo- clinical study of 4 cases. Nouv Rev Fr Hematol 1990;32:241– thus an accurate distinction is crucial. Patients 7. usually develop painless, often unilateral cervi- 3 Kuo TT.Kikuchi’s disease (histiocytic necrotizing lymphad- enitis). A clinicopathologic study of 79 cases with an analy- cal lymphadenopathy in the context of fever, sis of histologic subtypes, immunohistology, and DNA 4 night sweats, arthralgia, rash, and asthenia. ploidy. Am J Surg Pathol 1995;19:798–809. Painful lymphadenopathy may also develop.3 4 Dylewski J, Berry G, Pham-Dang H. An unusual cause of cervical lymphadenitis: Kikuchi-Fujimoto disease. Rev Inf Generalised lymphadenopathy occurs Dis 1991;13:823–5. 3 5 Bataille V, Harland CC, Behrens J, et al. Kikuchi disease infrequently and has recently been associated (histiocytic necrotizing lymphadenitis) in association with http://pmj.bmj.com/ with human T cell leukaemia virus-1 HTLV 1. Br J Dermatol 1997;136:610–12. infection.5 The true nature of the lesion 6 Kung IT, Ng WF, Yuen RW, et al. Kikuchi’s histiocytic lym- phadenitis. Diagnosis by fine needle aspiration. Acta becomes evident on a lymph node biopsy Cytolocica 1990;34:323–6. 6 7HoVman A, Kirn E, Kuerten A, et al. Active human rather than fine needle aspiration samples. herpesvirus-6 (HHV-6) infection associated with Kikuchi- Other infectious agents of possible relevance to Fujimoto disease and systemic lupus erythematosus. In vivo pathogenesis include herpes virus 6, Epstein- 1991;5:265–9. 8 Yen A, Fearneyhough P, Raimer SS, et al. EBV- associated Barr virus, cytomegalovirus, parvovirus B-19, Kikuchi’s histiocytic lymphadenitis with cutaneous manifes- 7–12 tations. J Am Acad Dermatol 1997;36:342–6. , and brucella species. on September 30, 2021 by guest. Protected copyright. Yersinia enterocolitica 9 Biasi D, Caramaschi P, Carletto A, et al. Three clinical KFD has been repeatedly linked with systemic reports of Kikuchi’s lymphadenitis combined with systemic lupus erythematosus3–13 and described in as- lupus erythematosus. Clin Rheumatol 1996;15:81–3. 10 Yufu Y, Matsumoto M, Miyamura T, et al. Pavovirus sociation with Hashimoto’s thyroiditis,13 B19-associated haemophagocytic syndrome with lymphad- Sweet’s syndrome,14 and Still’s disease.15 The enopathy resembling histiocytic necrotizing lymphadenitis (Kikuchi’s disease). Br J Haematol 1997;96:868–71. condition has a low recurrence rate of 3%–4% 11 Heikens J, Tel W, van de Stadt J, et al. Kikuchi’s and rarely recurs after a prolonged remission. lymphadenitis: report of a Yersinia enterocolitica-associated case and an overview of aetiology and clinical outcome. Neth The acute phase of illness usually responds to JMed1992;41:222–8. 12 Rodr’iguez Martorell J, Mart’in MV, B’aez JM, et al. bed rest and symptomatic treatment. The Kikuchi-Fujimoto necrotizing lynphadenitis associated with symptoms resolve within 1–4 months; however brucellosis. Sangre 1992;37:201–4. 3 13 Bousquet E, Tubery M, Brousset P, et al. Kikuchi syndrome, there have been cases that recurred or Hashimoto thyroiditis and lupus serology. A propos of a 4 persisted as long as a year. case. Rev Med Interne 1996;17:836–8. In this case the migratory pattern of cervical 14 Itoh H, Shimasaki S, Nakashima A, et al. Sweet’s syndrome associated with subacute necrotizing lymphadenitis. Intern lymphadenopathy, which was painful and Med 1992;31:686–9. 15 Ohta A, Matsumoto Y, Ohta T, et al. Still’s disease tender at first presentation and painless on associated with necrotizing lymphadenitis (Kikuchi’s relapse, has led to a clinical diagnostic disease): report of 3 cases. J Rheumatol 1988;15:981–3.

www.postgradmedj.com 664 Self assessment answers Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from Multiple focal lesions in liver and spleen in acute leukaemia Box 1: Various patterns of candidal infection of liver and spleen on Q1: What are the findings on ultrasound ultrasound and computed tomography? x Pattern 1a: wheel within wheel Abdominal ultrasound shows multiple hypo- appearance echoic focal lesions in the spleen, some of them x Pattern 1b: wagon wheel appearance having central echogenic foci producing bull’s eye or target configuration. Contrast enhanced x Pattern 2: bull’s eye appearance/target computed tomography shows multiple, non- configuration enhancing, hypodense focal areas in liver in x Pattern 3: pure hypoechoic defect addition to the spleen. Few of the splenic x Pattern 4: echogenic lesion with a lesions demonstrate central hyperdense foci. varying intensity of posterior acoustic Incidentally, a few old healed calcified foci are shadow also seen in the liver and spleen.

Q2: What is the radiological diagnosis? The image morphology of liver and splenic Box 2: DiVerential diagnosis of lesions in this immunocompromised patient is multiple hypodense/hypoechoic splenic strongly suggestive of fungal infection. and liver lesions x Lymphoma Q3: How can the diagnosis be confirmed? Image guided fine needle aspiration and x Leukaemia microscopic examination of the aspirate can be x Metastatic disease done to confirm the diagnosis. An aspirate x Bacterial infection from the centre of the focal lesion is most likely to yield a positive result as the fungal elements x Fungal infection are most abundant in these central necrotic x Parasitic infection areas. Blood and tissue cultures may be falsely x Sarcoid negative, particularly with candidal infections. In our patient, ultrasound guided fine needle aspiration was performed. The aspirate dem- hypoechoic nidus. In the wagon wheel appear- onstrated mycelia and budding yeast cells con- ance, echogenic radial strands are seen which firming the diagnosis of hepatosplenic candi- imitate the spokes of a wheel. These “spokes” diasis. represent the inflammatory process, whereas hypoechoic regions between the spokes is the Discussion fibrous component. The axis of the wheel is Fungal infections of the liver and spleen occur formed by hypoechoic, necrotic nidus. almost exclusively in individuals with underly- Pattern 2, manifested by the “bull’s eye” or ing defects of host immune defence mech- target configuration, lacks the central necrotic http://pmj.bmj.com/ anism. The most commonly implicated organ- hypoechoic nidus. The lesion consists of the ism is Candida albicans, but infections with inflammatory process forming the echogenic other fungi such as aspergillus and cryptococ- centre, which is surrounded by fibrosis seen as cus may also occur.1 The presenting symptoms the hypoechoic rim.3 Pattern 3 is characterised are generally non-specific, consisting of fever, by a purely hypoechoic lesion. It is seen when pain referable to the area of involvement, the inflammatory process is being replaced by tenderness on direct palpation, enlargement of fibrosis.3 Later this hypoehoic lesion is trans- liver and/or spleen, and rarely, jaundice. formed into a completely echogenic lesion on September 30, 2021 by guest. Protected copyright. Usually both liver and spleen are involved, (pattern 4) with a varying degree of posterior though either organ may be aVected in acoustic shadow. This sonographic appearance isolation.2 is produced by scar tissue with or without cal- Initially hepatomegaly and/or splenomegaly cification. This echogenic lesion is usually are present. Subsequently focal lesions develop smaller than pattern 2 or 3 lesions and may that later spread throughout the parenchyma. even disappear completely in the course of the They may be single or multiple. When healing process.3 multiple, they tend to be located adjacent to In acute phase of the disease, lesions of pat- one another or may become partially terns 1 and 2 prevail. As disease progresses, confluent.3 Their size varies from 0.3 cm to 4.0 pattern 3 lesions are identified, however, cm and they have relatively well defined pattern 1 and 2 lesions may still be present. borders. Five sonographic patterns of hepato- When pattern 4 lesions appear, pattern 1 is no splenic candidiasis have been described.3 Pat- longer seen and the lesions of other patterns tern 1 represents an early active phase of the regress in size. This is recognised late in the disease in which ultrasound demonstrates course of the disease.3 either a “wheel within wheel” (type a) or Fungal abscesses in liver and spleen of neu- “wagon wheel” (type b) appearance. In the tropenic patients are not always detectable on former appearance, the outer hypoechoic rim is sonography, even in the presence of dissemi- formed by fibrosis while the inner hyperechoic nated infection. The lesions become apparent rim is composed of the inflammatory process. when the neutrophil count returns to normal.4 In the centre of the inner hyperechoic zone, It is important to identify pattern 1 or 2 in at there is an area of necrosis identified as the least one lesion, as these appear only when the

www.postgradmedj.com Self assessment answers 665 Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from neutrophil count in a previously neutropenic bacterial and fungal infection, and sarcoid. patient is returning to normal and infection is Most of these diseases give rise to non-specific active.5 This fact suggests that the inflamma- focal hypoechoic lesions on sonography. Target tory response of the host plays a part in defin- lesions may however be seen in metastatic dis- ing the characteristic appearance.6 Pattern 3 ease, although metastatic disease is unusual in and 4 lesions occur later in course of the the spleen. Deposits of lymphoma and leukae- disease and suggest that the infection is mia show rapid regression after cytostatic subsiding.5 treatment, a fact which may help to diVerenti- Computed tomography may demonstrate ate them from the lesions of other aetiologies.6 similar appearances. Pastakia et al reported that To summarise, the detection of focal hepatic pattern 1 lesions were not seen on computed and splenic lesions with characteristic image tomograms and pattern 2 lesions were demon- morphology should suggest a possible underly- strated only occasionally.5 Pattern 3 lesions ing fungal disease in a febrile leukaemic (multiple rounded areas of decreased attenua- patient. Apart from the aetiological diagnosis tion scattered throughout the liver and spleen) of fungal infection, the imaging features also were most common. Pattern 4 lesions, repre- provide understanding of their evolution over senting areas of calcification, were seen late in time. course of the disease. In our patient, no focal hepatic lesion could be detected on ultrasound, Final diagnosis while computed tomography showed multiple Multiple candidal abscesses in liver and spleen pattern 3 and one pattern 2 lesion in the liver in acute myeloid leukaemia. and multiple pattern 2 and 3 lesions in the spleen. Similar observation was also made by 1 Berlow ME, Spirit BA, Weil L. CT follow-up of hepatic and Pastakia et al. A computed tomogram is more splenic fungal micro-abcesses. J Comput Assist Tomogr sensitive in detecting the focal lesions; however, 1984;8:42–5. 2 Maxwell AJ, Mamtora H. Fungal liver abcesses in acute it is less specific as the characteristic pattern 1 leukemia—a report of two cases. Clin Radiol 1988;39:197– and 2 lesions are demonstrated only occasion- 201. 3 Grunebaum M, Ziv N, Kaplinsky C, et al. Liver ally. Periportal areas of increased attenuation candidiasis—the various sonographic patterns in the immu- seen on computed tomography are also re- nocompromised child. Pediatr Radiol 1991;21:497–500. 4 Chew FS, Smith PL, Barboriak D. Candidal splenic ported which correlate pathologically with abcesses. AJR Am J Roentgenology 1991;156:474. focal linear fibrosis in these immunocompro- 5 Pastakia B, Shawker TH, Thaler M, et al. Hepatosplenic 5 candidiasis: wheels within wheels. Radiology 1988;166:417– mised patients. 21. The usual diVerential diagnosis of multiple, 6 Gorg C, Wiede R, Schwerk WB, et al. Ultrasound evaluation of hepatic and splenic microabscesses in the immunocom- focal lesions in liver and spleen include promised patient: sonographic patterns, diVerential diagno- lymphoma, leukaemia deposits, metastasis, sis and follow-up. J Clin Ultrasound 1994;22:525–9. http://pmj.bmj.com/ on September 30, 2021 by guest. Protected copyright.

www.postgradmedj.com 666 Self assessment answers Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from A pregnant patient with bilateral Q5: What is the treatment? ischaemic limbs Our patient was started on intravenous heparin infusion. She was taken to theatre for an emer- Q1: What is the diagnosis? gency caesarean section and bilateral femoral The patient has paradoxical embolism and embolectomies. The baby was delivered un- patent foramen ovale. eventfully. Anticoagulation was continued postoperatively and the mother made an Q2: Describe the pathogenesis of this uncomplicated recovery. It is planned to close clinical condition? the atrial septal defect in the near future. A favourable right to left pressure gradient, As part of acute management,3 most authors secondary to raised right atrial pressure (RAP), agree that immediate anticoagulation should must exist to promote shunting of venous be started in the absence of any contradiction. thrombi through the intracardiac defect. Pul- Thrombolysis or embolectomy is indicated to monary thromboembolism is the most com- treat peripheral embolism which threatens limb mon cause of acute elevation of RAP. Occlu- viability. In suspected cases of paradoxical sion of left pulmonary artery causes a rise in embolism, thrombolysis is indicated in the mean pulmonary arterial pressures with a presence of both pulmonary thromboembo- simultaneous fall in systemic arterial pressure. lism and acute cor pulmonale. Favourable pressure gradient only exists when Thrombolysis can reduce RAP and minimise at least one third of the pulmonary arterial tree recurrence of paradoxical embolism.1 As for is occluded or when the mean pulmonary arte- the patient who is haemodynamically compro- rial for right to left shunting at least 30 mm mised, pulmonary embolectomy should be Hg.1 performed if indicated and feasible. Rarely, impending paradoxical embolism is best man- Q3: How should the diagnosis be made? aged with intracardiac embolectomy and clo- Four criteria have to be met for diagnosis: (1) sure of patent foramen ovale.1 deep vein thrombosis and/or pulmonary Current long term therapeutic options are: thromboembolism, (2) an abnormal communi- (1) long term anticoagulation therapy, (2) long cation between the venous systemic circula- term antithrombotic therapy, (3) surgical tion, (3) clinical, angiographic, and pathologi- closure of patent foramen ovale either open cal evidence for systemic embolism, and (4) heart surgery or transcatheter placement of the pressure gradient allowing right to left shunting double umbrella device, or (4) inferior vena at some point in the cardiac cycle.1 Clinically, cava (Greenfield) filter. Until now, there has the diagnosis of paradoxical embolism is been little information regarding the long term presumptive, relying on circumstantial evi- outcome of any particular treatment modality.1 dence as well as a high index of suspicion. Pre- morbid diagnosis of patent foramen ovale is Discussion usually made by transthoracic or transoesopha- For venous thromboses to travel into the

geal colour Doppler echocardiography (TTE systemic circulation the clot has to bypass the http://pmj.bmj.com/ or TOE). Studies as well as our case confirm pulmonary bed by passage through an abnor- the superiority of TOE over TTE in detecting mal communication. This may be a fixed atrial patent foramen ovale.12 For the diagnosis, septal defect or a patent foramen ovale which Chen et al reported that TOE had a sensitivity allows right to left shunting when the right of 100% and a specificity of 97%, while they atrial pressure RAP is raised by a pulmonary were 63% and 78% respectively for TTE.2 thromboembolism.1 It was first diagnosed in In this case, postoperative TOE revealed a 1877 by Cohnheim,4 and although cases are large atrial septal defect with a free left to right not infrequently reported, it was rarely de- on September 30, 2021 by guest. Protected copyright. flow and thrombus in the right middle pulmo- scribed in pregnancy.5 nary artery. Aburahma reported that 56% of cases of emboli had probable or possible paradoxical Q4: Describe the most recent embolism,3 while Caplan et al reported that development in the diagnosis of this 36% of embolic strokes had an unidentifiable condition? cardiac source.6 Importantly, Lechat et al It was suggested that contrast echocardio- showed that patent foramen ovale was found in graphy is a useful and probably more eVective 40% of patients with unexplained embolic manoeuvre to exclude patent foramen ovale.1 It stroke compared with 10% in a control group.7 involves high pressure injection into the venous Patent foramen ovale occurs in 11% to 35% of circulation of a saline solution containing the normal population and grows larger with microbubbles in suspension. A valsalva ma- age.8 noeuvre can increase the sensitivity of the con- In our case, the clinical features were trast study. However, it was also reported that strongly suggestive of a large pulmonary the cough test is superior to the valsalva thromboembolism in association with acute manoeuvre in the contrast study. peripheral arterial ischaemia, giving a strong Recently, contrast transcranial Doppler suspicion of the diagnosis of paradoxical (TCD) was shown to have a sensitivity and embolism. It is interesting that the TTE did specificity of 100% in comparison with con- not suggest paradoxical embolism but the trast TOE.1 Therefore, contrast TCD can be postoperative TOE did show the atrial septal an alternative method for detection of right to defect and clot in the pulmonary artery. This is left shunting. in keeping with studies which have shown the

www.postgradmedj.com Self assessment answers 667 Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from as the pelvic veins were patent on ultrasound, it Learning points was considered unnecessary. After successful x Prevalence of paradoxical embolism as delivery, the TOE confirmed atrial septal the cause of peripheral or cerebral defect and the patient is awaiting surgical embolic events has been under-estimated closure at present. The complexity of this x There is right to left shunting through case—which requires specialist obstetric, imag- atrial septal defect or patent ductus ing, surgical, intensive care, and anaesthetic arteriosus when right atrial pressure is expertise—could be used as an argument for elevated by pulmonary locating obstetric units within general hospital thromboembolism centres. It is interesting to speculate about the x Transoesophageal echocardiogram is outcome if the peripheral embolus had lodged superior to transthoracic in the right internal iliac as well as the left. The echocardiogram in detecting patent uterine artery supplying the placenta would foramen ovale have been occluded with a probable intrauter- x Angiography is safe in the third trimester ine death. Fortunately, however, this was not and magnetic resonance arteriography is the case and both the mother and baby have less invasive done well. x Thrombolysis reduces right atrial The high prevalence of clinically occult deep pressure and prevents recurrence of vein thrombosis and the presence of patent patent ductus arteriosus foramen ovale in up to 35% of the population highlights the fact that paradoxical embolism In pregnancy, surgical embolectomy is a x may be the cause of a peripheral or cerebral safer option embolic event more often than is currently x Acute management requires a high index suggested. of suspicion, early diagnosis, and timely The key points of management are the need intervention with a multidisciplinary for high index of suspicion, early diagnosis, and approach timely intervention with a multidisciplinary approach. The long term treatment of para- doxical embolism is less well defined. More superiority of TOE against TTE in detecting studies are needed to assess the risk of patent foramen ovale.2 recurrent arterial ischaemic events in the pres- The contrast echocardiogram, especially ence of patent foramen ovale as well as to with the valsalva manoeuvre and cough test, is examine the long term outcome of the respec- useful for excluding patent foramen ovale.1 tive treatment strategies. Contrast transcranial Doppler can be an alter- native method for detection of right to left Final diagnosis shunting. We showed the extent of the periph- Paradoxical embolism and patent foramen ovale.

eral clot in our patient by angiography, which is http://pmj.bmj.com/ safe for the fetus in the third trimester, but we 1 Robert RM III, A Stacey H, Michael SB, et al. Impending had considered magnetic resonance angio- PDE. Arch Intern Med 1998;158:438–48. graphy, which is less invasive and also safe in 2 Chen W, Kuan P, Lien W, et al. Detection of patent foremen ovale by contrast transechocardiogram. Chest 1992;101: pregnancy.9 1515–20. 3 Aburahma AF, Lucentre FC, Boland JP. Paradoxical Normally, management of patients with embolism: an under-estimated entity—a plea for compre- paradoxical embolism would be determined by hensive workup.J Cardiovasc Surg (Torino) 1990;31:685–92. the need to re-establish peripheral flow, if pos- 4 Cohnheim J. Thrombose und Embolid. Vorlesungen Uber Allgemeneine Pathogie.Vol 1. Berlin: Hirschwald, 1877: 136.

sible; to prevent further arterial embolisation; 5EVeney DJ, Krupski WC. Paradoxical embolism in on September 30, 2021 by guest. Protected copyright. pregnancy: an usual thromboembolic event. West J Med and to reduce the haemodynamic threat from 1984;140:287–8. the pulmonary embolus. This may require that, 6 Caplan LR, Hier DB, D’Cruz I. Cerebral embolism in the in addition to immediate anticoagulation, both Michael Reese Stroke Registry. Stroke 1983;14:530–6. 7 Lechat P, Mas JI, Lascault G, et al. Prevalence of patent venous and peripheral thrombolysis should be foramen ovale in patients with stroke. N Engl J Med 1988;318:1148–52. considered. We felt that thrombolysis, which 8 Hagen PT, Scholz DG, Edwards WD. Incidence and size of has been advocated to reduce RAP and patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc minimise recurrence of paradoxical embolism, 1984; :12–20. 10 59 would threaten the pregnancy, and that surgi- 9 Dizon-Townson D, Magee KP, Twickler DM, et al. Coarcta- cal embolectomy and caesarean delivery would tion of the abdominal aorta in pregnancy: diagnosis by mag- netic resonance imaging. Obstet Gynecol 1995;85(5 pt oVer the safest solution. Placement of an infe- 2):817–19. 10 Turrentine MA, Braems G, Ramirez MM. Use of thrombo- rior vena cava filter before section to prevent lytics for the treatment of thromboembolic disease during further pulmonary emboli was considered but pregnancy. Obstet Gynecol Surv 1995;50:534–41.

www.postgradmedj.com 668 Self assessment answers Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from Severe symptomatic hypercalcaemia remains asymptomatic and blood calcium and intact PTH are normal. Q1: What is your diVerential diagnosis for Surgery, with its risks, for all patients with this case? primary hyperparathyroidism now seems un- The highly sensitive and specific immunomet- wise when many will have no features of meta- ric assays for intact parathyroid hormone bolic bone or renal disease.8 When done by an (PTH) separates hyperparathyroidism from all experienced parathyroid surgeon, parathyroid- other causes of hypercalcaemia.1 With few ectomy is curative in more than 90% of cases.1 exceptions, non-parathyroid causes of hyper- Medical treatment is intended to lower blood calcaemia are accompanied by low serum con- calcium to less dangerous levels. However, it is centrations of intact PTH. Chronic treatment not necessary to obtain normal levels of with lithium may produce hypercalcaemia that calcium, and surgery must be carried out as is associated with high serum intact PTH, a soon as the patients’s clinical condition and 7 clinical picture indistinguishable from primary metabolism improve suYciently. Emergency hyperparathyroidism.2 Familial hypocalciuric neck exploration should be reserved for hypercalcaemia must be considered in healthy unusual patients in whom hypercalcaemia can- patients who have had hypercalcaemia since not be controlled medically and the clinical 6 the first decade of life; they usually have hypo- picture is severe. calciuria and normal serum concentrations of intact PTH.3 Discussion A solitary parathyroid adenoma is the Hypercalcaemia in an adult who is asympto- underlying pathology in more than 80% of matic is usually due to primary hyperparathy- 45 roidism and severe hypercalcaemia suggests cases of primary hyperparathyroidism. Dif- 1 fuse hyperplasia of all parathyroid glands cancer or parathyroid carcinoma. The clinical occurs in about 15%–20% of patients and may picture of our case suggests malignancy. Muscle weakness is not common in primary in about half of these be part of a multiple hyperparathyroidism but is common in acute endocrine neoplasia (MEN).1 Multiple adeno- primary hyperparathyroidism, due to the se- mas and parathyroid cysts are uncommon, and vere hypercalcaemia.67 The serum creatinine parathyroid carcinoma is very rare (<1%).1 wasn’t particularly raised, which is a surprise in Acute primary hyperparathyroidism is an unu- view of the very high level of serum calcium; sual form of the disease characterised by life 67 this suggests that our patient’s hypercalcaemia threatening hypercalcaemia. was of short duration. The proportion of symptom-free patients with primary hyperpar- Q2: What further investigations would athyroidism has increased since the introduc- you perform? tion of the multichannel autoanalyser.45 Our Ultrasonography demonstrated a nodule of 3 case had acute primary hyperparathyroidism cm diameter in the left lower parathyroid caused by a parathyroid adenoma, an unusual gland. Abdominal radiography and ultrasonog- form of the disease. Acute primary hyperpar- raphy did not reveal nephrocalcinosis or neph- athyroidism, also called parathyroid intoxica- http://pmj.bmj.com/ rolithiasis. Bone series were normal. Plasma tion, parathyroid storm or parathyroid crisis, is calcitonin was 29 ng/l (normal <50 ng/l) and characterised by symptomatic marked hyper- fasting plasma gastrin was 44 ng/l (normal calcaemia with very high serum PTH levels <150 ng/l). The 24 hour urinary free catecho- and with polyuria, dehydration, reduced renal lamines, dopamine, epinephrine, and nore- function, and worsening hypercalcaemia.67 pinephrine were normal. In our case, there Most cases of acute primary hyperparathy- were no family history, clinical or laboratory roidism are due to a parathyroid adenoma.67 findings of MEN 1 (primary hyperparathy- Some authors do not exclude the parathyroid on September 30, 2021 by guest. Protected copyright. roidism, tumours of the pituitary and pancreas, carcinoma from the acute primary often associated with Zollinger-Ellison syn- hyperparathyroidism.7 Remarkable increases of drome) or MEN 2A (primary hyperparathy- PTH are characterisitc of acute primary hyper- roidism, pheochromocytoma, and medullary parathyroidism, up to values 30 times normal carcinoma of the thyroid). levels.67 It has excluded autonomous PTH secretion as a possible cause of acute primary Q3: What is the therapy for the severe hyperparathyroidism, and it has been sug- hypercalcaemia in this case? gested that a sudden increase in the set point of The patient was treated with saline rehydra- the diseased parathyroid cells in the presence of tion, low doses of intravenous frusemide (after a huge cell mass accounts in large part for both rehydration), intravenous clodronate, and sub- the marked hypercalcaemia and elevated PTH cutaneous calcitonin. Four days after, the levels in these patients.9 Infections, recent sur- blood calcium was 2.2 mmol/l and the gery, immobilisation, dehydration, and trauma creatinine was 61.9 µmol/l. Parathyroid surgi- appear to play a prominent part in the acute cal exploration revealed an enlarged left lower primary hyperparathyroidism.67 parathyroid gland. The other three glands were Frusemide must be used for therapy of the normal. Removal of the left lower parathyroid hypercalcaemia after rehydration and with gland was performed, and the histopathologi- caution as it counteracts the eVects of rehydra- cal examination demonstrateda3cmdiameter tion. Saline rehydration reverses the increased parathyroid adenoma. Seven days after surgery, proximal tubular calcium reabsorption, and intact PTH was 43 µg/l and blood calcium calcitonin inhibits the distal tubular calcium remained normal. Six months later, the patient reabsorption.

www.postgradmedj.com Self assessment answers 669 Postgrad Med J: first published as 10.1136/pmj.76.900.661 on 1 October 2000. Downloaded from 1 Potts JT Jr. Diseases of the parathyroid gland and other Learning points hyper- and hypocalcemic disorders. In: Fauci AS, Braun- wald E, eds. Harrison’s principles of internal medicine.New x Hypercalcaemia with normal or high York: McGraw-Hill, 1998: 2227–47. 2 Mallete LE, Khouri K, Zengotita H, et al. Lithium treatment PTH levels occurs in primary increases intact and midregion parathyroid hormone and hyperparthyroidism, familial parathyroid volume. J Clin Endocrinol Metab 1989;68:654– 60. hypocalciuric hypercalcaemia and 3 Heath HI. Familial benign (hypocalciuric) hypercalcemia: a chronic treatment with lithium troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723–40. x Acute primary hyperparthyroidism is an 4 Heath HWI, Hodgson SF, Kennedy MA. Primary unusual form of the disease hyperparathyroidism: incidence, morbidity and potential economic impact in a community. N Engl J Med 1980;302: characterised by life threatening 189–93. hypercalcaemia 5 Mollerup CL, Bollerslev J, Blichert-Toft M. Primary hyperparathyroidism: incidence and clinical and biochemi- x Severe hypercalcaemia suggests cancer cal characteristics: a demographic study. Eur J Surg 1994;160:485–9. or parathyroid carcinoma, and acute 6 Fitzpatrick LA, Bilezikian JP. Acute primary hyperparathy- primary hyperparthyroidism constitutes roidism. Am J Med 1987;82:275–82. 7 Sarfati E, Desportes L, Gossot D, et al. Acute primary an exception of this assertion hyperparathyroidism: experience of 59 cases. Br J Surg 1989;76:979–81. 8 Potts JT Jr, Fradkin JE, Aurbach GD, et al. Proceedings of the NIH Consensus Development Conference on Diagnosis and Management of Asymptomatic Primary Hyperparathy- Final diagnosis roidism. J Bone Miner Res 1991;6(suppl 2):1–165. 9 Schachter PP, Christy MD, Avigad IS, et al. Non-autonomy Acute primary hyperparathyroidism, caused by of parathyroid hormone secretion in acute primary hyper- a solitary parathyroid adenoma. parathyroidism. Clin Endocrinol (Oxf) 1992;37:565–9. http://pmj.bmj.com/ on September 30, 2021 by guest. Protected copyright.

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