Thrombotic Microangiopathy and Purtscher-like Retinopathy as a Rare Presentation of Juvenile Dermatomyositis

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Thrombotic Microangiopathy and Purtscher-like

Retinopathy as a Rare Presentation of Juvenile

Dermatomyositis

abstract

Juvenile dermatomyositis is a rare systemic vasculopathy that may sometimes present with acute complications. We report here the case of a 7-year-old boy with severe dermatomyositis associated with throm-bocytopenia and blurry vision. The presence of schistocytosis and the secondary occurrence of hemolytic anemia were consistent with a di-agnosis of thrombotic thrombocytopenic purpura (TTP). Further inves-tigations demonstrated the association of TTP with muscular microangiopathy and Purtscher-like retinopathy. Retinal and hemato-logic involvements dramatically improved after the initiation of plasma exchange in emergency. This report emphasizes that early recognition of TTP and prompt plasmapheresis are important in a child with severe juvenile dermatomyositis associated with thrombocytopenia.Pediatrics

2012;129:e821–e824 AUTHORS:Brigitte Bader-Meunier, MD,a_Dominique

Monnet, MD, PhD,b_{Christine Barnerias, MD,}c_Isabelle

Halphen, MD,d_{Karen Lambot-Juhan, MD,}e_Martin

Chalumeau, MD, PhD,d_{Nathalie Costedoat-Chalumeau, MD,}

PhD,f_{Jean-Antoine Ribeil, MD, PhD,}g_{Christine Bodemer,}

MD, PhD,h_{and Romain Gherardi, MD, PhD}i

a_{Departments of Pediatric Immunology and Rheumatology,} c_{Pediatric Neurology,}e_{Pediatric Radiology,}d_Paediatrics, g_{Biotherapy, and}h_{Dermatology, Paris Descartes University,} Necker Hospital, AP-HP, Paris, France;b_{Department of} Ophthalmology, Cochin Hospital, AP-HP, Paris, France; f_{Department of Internal Medicine, La Pitié-Salpêtrière Hospital,} AP-HP, University Paris 6, Paris, France; andi_{Department of} Pathology, Henri Mondor Hospital, AP-HP, Paris-Est University, Créteil, France

KEY WORDS

juvenile dermatomyositis, thrombotic thrombocytopenic purpura, Purtscher-like retinopathy

ABBREVIATIONS

DM—dermatomyositis JDM—juvenile dermatomyositis MAC—membrane attack complex TMA—thrombotic microangiopathy TTP—thrombotic thrombocytopenic purpura

www.pediatrics.org/cgi/doi/10.1542/peds.2011-0338

doi:10.1542/peds.2011-0338

Accepted for publication Oct 27, 2011

Address correspondence to Brigitte Bader-Meunier, MD, Hôpital Necker, Pediatrics, 149 rue de Sèvres, Paris, France 75015. E-mail: brigitte.bader-meunier@nck.aphp.fr

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

FINANCIAL DISCLOSURE:The authors have indicated they have noﬁnancial relationships relevant to this article to disclose.

FUNDING:No external funding.

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Juvenile dermatomyositis (JDM) is a rare systemic vasculopathy, compris-ing ∼85% of the pediatric idiopathic inﬂammatory myopathies.1_{It primarily} affects skeletal muscle and skin, and may sometimes present with acute complications, especially resulting from digestive or cardiac involvement.1_Here we describe the case of a patient who presented with thrombotic thrombocy-topenic purpura (TTP) and ischemic ret-inopathy (Purtscher-like) associated with severe JDM, and was dramatically re-sponsive to plasma exchange. This case demonstrates the clinical challenges faced in the early detection of TTP in children with JDM.

CASE REPORT

A 7-year-old boy presented with a 3-week history of febrile myalgia and proximal muscular weakness that gradually worsened, with a progressive increase of serum creatine kinase levels of 2500 IU/L (normal: 30–180 IU/L). He was referred to our department for workup of the progression of the muscle weakness and abrupt onset of facial edema and dysphonia. Physical eval-uation revealed (1) a severe proximal weakness on muscular manual testing and childhood muscle assessment, with values of 48/80 and 40/52 re-spectively, and (2) a mild scaly, red rash on the knuckles and the elbows and facial swelling. Body temperature was 38.9°C. Laboratory studies showed a white blood cell count of 5800/mL with a differential count of 75% neu-trophils and 12% lymphocytes, a he-moglobin level of 11.6 g/dL, platelet count of 50 000/mL, serum creatine ki-nase level of 6000 IU/L, glutamine oxa-loacetic transaminases of 1200 IU/L (normal 9–45 IU/L), and lactate de-hydrogenase of 2300 IU/L (normal 310– 615 IU/L). Peripheral blood smear showed 3% schistocytes and no blast cells. A bone marrow aspirate revealed a hypercellular marrow. C-reactive

protein and erythrocyte sedimenta-tion rate were normal. Renal funcsedimenta-tion tests and urinalysis were unremark-able. Serologic test for cytomegalovirus, toxoplasmosis, and Epstein-Barr virus were negative. Antinuclear, anti-DNA, anticardiolipin, and anti-b2-glycoprotein 1 antibodies were absent, and serum complement levels were within normal range. The patient’s blood and urine cultures remained negative.

Owing to the muscular and cutaneous involvement, we suspected a JDM with edema. Electromyogram showed myo-pathic changes. Deltoid muscle biopsy showed necrotizing myopathy with microvascular changes and minute inflammation. There was neither obvi-ous perifascicular atrophy nor micro-infarcts, but CD56/neural cell adhesion molecule (NCAM) immunostaining re-vealed extensive regeneration more marked in the perifascicular regions (Fig 1). Individual myofibers showed conspicuous myofibrillar alterations including occasional cytoplasmic body formation, myosinolysis with punch-out vacuoles, and empty necrotic fibers with a rim of regenerative myoblasts, as typically observed in dermatomyo-sitis (DM).2 _{There were some CD68+} macrophages in the vicinity of necrotic

ﬁbers and perimysium, but lymphocytes were absent. Major histocompatibility

complex class 1 antigens were diffusely reexpressed by myofibers with peri-fascicular reinforcement. Microvascu-lar changes included capilMicrovascu-laries with thick walls, gaping lumens, and marked membrane attack complex (MAC) de-posits. Microthrombosis was observed and confirmed byfibrinogen immuno-staining. As previously documented in thrombotic microangiopathies, thrombi colocalized with microvascular depos-ition of both immunoglobulin M and several complement fractions,3_including C1q, C3, and C4d, in addition to MAC (C5b9). Together, these findings

con-ﬁrmed the diagnosis of JDM and dem-onstrated its association with TTP. Treatment with intravenous methyl-prednisolone at a dosage of 4 mg/kg per day was initiated promptly.

Despite rapid fever resolution and improvement of myalgia, the patient developed blurry vision, which pro-gressively worsened in both eyes, 2 days after admission. On ophthalmo-logic examination, his visual acuity was 3/10 in the right eye and 2/10 in the left eye. Slit lamp examination was un-remarkable. The funduscopic exam-ination showed multiple conﬂuent cotton-wool spots centered around the optic nerve head, and including the macula. We also observed some su-perﬁcial hemorrhages in the right eye

FIGURE 1

Deltoid muscle biopsyfindings (Magnification3500). A, Gomori trichrome staining showing a necrotic myofiber. B, Diffuse reexpression of major histocompatibility complex class 1 antigens by myofibers with reinforcement in perifascicular degeneratingfibers. C, MAC deposits in endomysial capillaries. D–F, Immunofluorescence assessing microthrombosis (fibrinogen) (D), immunoglobulin M (E) but not immunoglobulin G (F) vascular deposits.

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(Fig 2). Optical coherence tomography indicated central macular thickness of 415µm in the right eye and 397µm in the left eye (normal ,200µm), and showed the presence of serous sub-retinal ﬂuid. Fluorescein angiography demonstrated precapillary occlusion. All these features were consistent with the diagnosis of Purtscher-like reti-nopathy. Concurrently, platelet count and hemoglobin level dropped to 40 000/mL and 8.2 g/dL, respectively, whereas the reticulocyte count was 250 000/mL with persistent schizo-cytosis. Haptoglobin was ,0.10 g/L (normal 0.34–2.00 g/L), and a direct antiglobulin test was negative. Fibrin-ogen level decreased to 1.5 g/L (normal 2.0–4.0 g/L). Renal function and urinal-ysis remained normal. Owing to the di-agnosis of TTP, further workup, including disintegrinlike metalloproteinase with thrombospondin type 1 motif 13 activ-ity and serum factor H and I measure-ments were normal. Plasma exchange was initiated in emergency. General condition and visual and hematologic abnormalities began to improve im-mediately. The platelet count, hemo-globin, andﬁbrinogen levels returned to normal limits within 1 week. Left and right visual acuity increased to 10/10 and 7/10 within 4 weeks, respectively. Ten plasmaphereses were administrated within 4 weeks and prednisone therapy

progressively tapered. Six months af-ter theﬁrst plasma exchange, the pa-tient received prednisone at a dosage of 0.3 mg/kg per day, and had normal muscular testing, blood cell count, and fundoscopic evaluation.

DISCUSSION

This case was characterized by the occurrence of TTP revealed by throm-bocytopenia as an early complication of JDM. The patient had a diagnosis of deﬁnite JDM according to the Bohan and Peter criteria.1 _{Its presentation} was a diagnostic challenge given the unusual presentation of TTP and the rarity of its association with JDM. JDM primarily affects skeletal muscle and skin and usually presents with normal blood cell count.1_{TTP is a rare but} po-tentially life-threatening cause of thrombocytopenia in childhood. When both typical microangiopathic hemo-lytic anemia and thrombocytopenia are present, with or without renal failure or neurologic abnormalities, the diag-nosis can be straightforward4_; how-ever, anemia may be absent at onset of TTP. Still, evaluation of the peripheral blood smear to search for schistocytes is crucial in patients with thrombocy-topenia.5_{In our patient, TTP manifested} only as thrombocytopenia at onset. Thus, theseﬁndings highlight that the search for schistocytosis should be included in a serial workup for un-explained thrombocytopenia during the course of severe JDM. Thrombotic microangiopathy (TMA) occurred in 1% to 6% of adult patients with connec-tive tissue disease (CTD), especially in patients with systemic lupus eryth-ematosus and systemic sclerosis.6 TMA is less likely to complicate DM in adults,6,7_{and has never been reported} in children with JDM. At least 2 sub-types of CTD-TMAs have been described: a majority population with normal or moderately reduced activity,6_as ob-served in our patient, and a minority

population with deﬁcient disintegrin-like metalloproteinase with thrombo-spondin type 1 motif 13 activity caused by neutralizing autoantibodies. In these latter patients, the underlying mecha-nism of TMA is speculative. In JDM, it might be related in part to the high von Willebrand factor plasma level and in changes of the microvasculature.

In the present report, some of the mus-cular changes and retinal involvement may be viewed as a consequence of TTP. Muscle biopsy was reminiscent of a rare condition known as“necrotizing myopathy with pipestem capillaries, microvascular deposition of the com-plement MAC, and minimal cellular

in-ﬁltration,”which most likely belongs to the DM spectrum.8 _{Thrombi may be} occasionally observed in muscles of patients with DM. Here, TMA was likely associated with the activation of the classic complement activation pathway, as assessed by detection of both C1q and C4d deposits. This activation, as well as platelet-induced activation of the downstream complement cascade,9 are suggested by deposition of the ter-minal lytic C5b-9 fraction.

Purtscher retinopathy is caused by microembolization of retinal and cho-roidal arterioles by fat emboli after severe trauma10_{and is characterized} by retinal ischemia and hemorrhages. Purtscher-like retinopathy shows the same clinicalﬁndings, but is associated with other diseases, including mostly acute pancreatitis and chest compres-sion, and less frequently chronic renal failure, fat embolism syndrome,10 sys-temic lupus erythematosus,11_adult-onset Still disease,12_{and cryoglobulinemia,} as well as in idiopathic TTP or hemo-lytic and uremic syndrome.13–17_Acute fundus abnormalities include large edema peripapillary cotton-wool spots, intraretinal hemorrhages, optic disk swelling, and, in some cases, charac-teristic Purtscher ﬂecken, consisting of multiple, discrete areas of retinal

FIGURE 2

Initial ophthalmologic examination of the right eye Fundus photographs taken at the initial ophthalmologic examination showed multiple conﬂuent cotton wool spots centered around the optic nerve head, and including the macula, and some superﬁcial hemorrhages.

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whitening in the superﬁcial aspect of the inner retina, between the arterioles and venules. Fluorescein angiography typically shows multifocal lesions re-stricted to the posterior pole, and occlusion of the retinal vessels.10 The pathogenesis of Purtscher and Purtscher-like retinopathy remains spec-ulative, and might involve complement activation in some conditions.10 _The concurrent occurrence of Purtscher-like retinopathy and idiopathic TTP or hemolytic uremic syndrome,13_–17 _and the description of lesions mimicking Purtscher retinopathy resulting from platelet aggregate microembolization of the retinal system in an experimental

porcine model, also support a relation-ship between TTP and Purtscher reti-nopathy.14_{Thus, in our patient,} Purtscher-like retinopathy may be viewed as a retinal vascular involvement resulting from TTP rather than as a retinal com-plication of JDM, which itself is rare and usually mild.18

Patients with TTP require plasma ex-change, which has been reported to dramatically increase their survival.2 Visual outcome is variable in patients with Purtscher retinopathy, and may depend on the retinopathy’s primary cause. Most patients with trauma, acute pancreatitis, or chronic renal failure show variable visual recovery

without specific treatment, but occa-sional case reports suggest possible benefit from intravenous methylpred-nisolone.10_{In view of the fact that the} Purtscher-like retinopathy was proba-bly a manifestation of TTP, we suggest that plasma exchange might have been beneficial for the retinal involvement in our patient.

CONCLUSIONS

This report emphasizes that physicians must consider the diagnosis of TTP in patients with severe JDM associated with thrombocytopenia. Early recognition and prompt plasmapheresis are warranted.

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DOI: 10.1542/peds.2011-0338 originally published online February 6, 2012;

2012;129;e821

Pediatrics

Jean-Antoine Ribeil, Christine Bodemer and Romain Gherardi

Karen Lambot-Juhan, Martin Chalumeau, Nathalie Costedoat-Chalumeau,

Brigitte Bader-Meunier, Dominique Monnet, Christine Barnerias, Isabelle Halphen,

Presentation of Juvenile Dermatomyositis

Thrombotic Microangiopathy and Purtscher-like Retinopathy as a Rare

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