Neuro-Behcet’s disease in a patient with thrombotic thrombocytopenic purpura

Neuro-Behcet’s disease in a patient with thrombotic thrombocytopenic purpura Rheumatology key message Unrelated novel autoimmune diseases should be considered in patients with an established autoimmune disease. Sir, a 31-year-old Caucasian male was referred for recurrent headaches and febrile temperatures. His past medical history consisted of recurrent thrombotic thrombocytopenic purpura (TTP) first diagnosed 8 years ago with two subsequent relapses treated with plasmapheresis and repeated rituximab infusions (last treatment 9 months ago). Two months prior to the current presentation he had already been admitted because of febrile temperatures and headaches. At this time a cerebral MRI had not shown any abnormalities. Cerebrospinal fluid (CSF) analysis revealed elevated nucleated cells (254/μl) and protein (1972 mg/l). Although both bacterial culture and viral testing were negative he had been treated empirically with broad-spectrum antibiotics and antivirals. Two weeks later he developed an acute uveitis anterior that was successfully treated with low-dose prednisolone. The patient also reported occasional oral aphthous lesions. Laboratory analysis revealed elevated lactate dehydrogenase (LDH); however, platelets, haptoglobin and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, antigen and antibody were within the normal range. Five days after admission the patient developed acute aphasia and right-sided hemiplegia. A cerebral MRI showed no evidence for ischaemic or haemorrhagic stroke but instead revealed multiple bilateral periventricular contrast-enhancing focal lesions (Fig. 1A). An open-brain biopsy of a right-sided subepidymal lesion was performed and the corresponding histology is shown in Fig. 1B. Fig. 1 View largeDownload slide MRI and histology showing cerebral vasculitis (A) Gadolinium-enhanced MRI demonstrated oedematous bilateral periventricular enhancing lesions on T2-weighted images. (B) Histological examination of brain biopsy tissue showed predominantly lymphocytic infiltrates (lymphocytic vasculitis pattern) of small cerebral arteries and veins. The inflammatory cells infiltrated all parts of the vessel walls, causing fragmentation of vessel wall layers, focal vessel occlusion (upper image, scale bar 100 µm; lower image, scale bar 100 µm). Inflammatory infiltration of vessel walls was characterized by mainly CD45+CD3+ T lymphocytes (data not shown). Fig. 1 View largeDownload slide MRI and histology showing cerebral vasculitis (A) Gadolinium-enhanced MRI demonstrated oedematous bilateral periventricular enhancing lesions on T2-weighted images. (B) Histological examination of brain biopsy tissue showed predominantly lymphocytic infiltrates (lymphocytic vasculitis pattern) of small cerebral arteries and veins. The inflammatory cells infiltrated all parts of the vessel walls, causing fragmentation of vessel wall layers, focal vessel occlusion (upper image, scale bar 100 µm; lower image, scale bar 100 µm). Inflammatory infiltration of vessel walls was characterized by mainly CD45+CD3+ T lymphocytes (data not shown). Given the patient’s history of relapsing TTP, a recurrence with neurological manifestation was suspected. TTP in adults is caused by autoantibody-mediated depletion of the von Willebrand factor–cleaving protease ADAMTS13 leading to accumulation of ultralarge von Willebrand factor multimeres inducing thrombotic microangiopathy. Neurological symptoms are common in TTP and a thrombotic episode can occur without evidence of haemolysis [1]. In this case, elevation of LDH was suggestive for active TTP, but normal haptoglobin, platelets and ADAMTS-13 parameters made active TTP highly unlikely. Differential diagnosis in this immune-compromised patient with a history of maintenance rituximab infusions and persistent B cell depletion included infectious and malignant diseases. PET-CT scan demonstrated ubiquitous lymph node enrichment suggestive of reactive lymphadenopathy. Cases of progressive multifocal leucoencephalopathy caused by JC virus (JCV) in patients on rituximab therapy have been reported. CSF JCV PCR was negative in our patient, but negative CSF JCV PCR has been reported in progressive multifocal leucoencephalopathy [2]. In addition, rituximab treatment has been associated with a non-vasculitic autoimmune meningoencephalitis [3]. A brain biopsy was performed in order to differentiate a cerebral neoplastic disease from an infectious meningoencephalitis (including JCV) or cerebral vasculitis. Histology demonstrated a severe small vessel vasculitis (Fig. 1B). The aetiology of cerebral vasculitis is broad and includes paraneoplastic diseases. Of note, the patient had mentioned recurrent oral aphthous lesions. In addition, 2 months prior he presented with acute anterior uveitis and retinal scanning demonstrated active retinal vasculitis. These symptoms strongly suggest neuro-Behçet’s disease (BD) [4]. BD is an autoimmune vasculitis characterized by recurrent oral and genital ulcers and uveitis. CNS involvement is not uncommon. Based on these disease manifestations and the histology, a diagnosis of neuro-BD with cerebral vasculitis, anterior and posterior uveitis and oral aphthous lesions was established. The presence of more than one autoimmune disease in a single patient is not rare and was recently termed polyautoimmunity [5]. Interestingly, this patient had a positive family history for different autoimmune diseases. Following treatment with prednisolone, IVIG and CYC the patient recovered fully from all clinical symptoms. MRI after completion of 3 monthly cycles of CYC showed regression in size and contrast enhancement of the cerebral lesions. In addition, CSF analysis displayed improvement, with fewer nucleated cells (12/μl) and less protein (1416 mg/l). The case illustrates that in patients with established autoimmune diseases presenting with unusual symptoms, apparently unrelated autoimmune diseases should be considered besides the signs and symptoms of the primary disease and the consequences of immunosuppression. Funding: No specific funding was received from any source in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest. References 1 Downes KA, Yomtovian R, Tsai HM et al.   Relapsed thrombotic thrombocytopenic purpura presenting as an acute cerebrovascular accident. J Clin Apher  2004; 19: 86– 9. Google Scholar CrossRef Search ADS PubMed  2 Kuhle J, Gosert R, Bühler R et al.   Management and outcome of CSF-JC virus PCR-negative PML in a natalizumab-treated patient with MS. Neurology  2011; 77: 2010– 6. Google Scholar CrossRef Search ADS PubMed  3 Hadley I, Jain R, Sreih A. Nonvasculitic autoimmune meningoencephalitis after rituximab: the potential downside of depleting regulatory B cells in the brain. J Clin Rheumatol  2014; 20: 163– 6. Google Scholar CrossRef Search ADS PubMed  4 Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s Disease. Lancet  1990; 335: 1078– 80. PubMed  5 Anaya J-M. The diagnosis and clinical significance of polyautoimmunity. Autoimmun Rev  2014; 13: 423– 6. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Neuro-Behcet’s disease in a patient with thrombotic thrombocytopenic purpura

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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1462-0324
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1462-0332
D.O.I.
10.1093/rheumatology/kex533
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Abstract

Rheumatology key message Unrelated novel autoimmune diseases should be considered in patients with an established autoimmune disease. Sir, a 31-year-old Caucasian male was referred for recurrent headaches and febrile temperatures. His past medical history consisted of recurrent thrombotic thrombocytopenic purpura (TTP) first diagnosed 8 years ago with two subsequent relapses treated with plasmapheresis and repeated rituximab infusions (last treatment 9 months ago). Two months prior to the current presentation he had already been admitted because of febrile temperatures and headaches. At this time a cerebral MRI had not shown any abnormalities. Cerebrospinal fluid (CSF) analysis revealed elevated nucleated cells (254/μl) and protein (1972 mg/l). Although both bacterial culture and viral testing were negative he had been treated empirically with broad-spectrum antibiotics and antivirals. Two weeks later he developed an acute uveitis anterior that was successfully treated with low-dose prednisolone. The patient also reported occasional oral aphthous lesions. Laboratory analysis revealed elevated lactate dehydrogenase (LDH); however, platelets, haptoglobin and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, antigen and antibody were within the normal range. Five days after admission the patient developed acute aphasia and right-sided hemiplegia. A cerebral MRI showed no evidence for ischaemic or haemorrhagic stroke but instead revealed multiple bilateral periventricular contrast-enhancing focal lesions (Fig. 1A). An open-brain biopsy of a right-sided subepidymal lesion was performed and the corresponding histology is shown in Fig. 1B. Fig. 1 View largeDownload slide MRI and histology showing cerebral vasculitis (A) Gadolinium-enhanced MRI demonstrated oedematous bilateral periventricular enhancing lesions on T2-weighted images. (B) Histological examination of brain biopsy tissue showed predominantly lymphocytic infiltrates (lymphocytic vasculitis pattern) of small cerebral arteries and veins. The inflammatory cells infiltrated all parts of the vessel walls, causing fragmentation of vessel wall layers, focal vessel occlusion (upper image, scale bar 100 µm; lower image, scale bar 100 µm). Inflammatory infiltration of vessel walls was characterized by mainly CD45+CD3+ T lymphocytes (data not shown). Fig. 1 View largeDownload slide MRI and histology showing cerebral vasculitis (A) Gadolinium-enhanced MRI demonstrated oedematous bilateral periventricular enhancing lesions on T2-weighted images. (B) Histological examination of brain biopsy tissue showed predominantly lymphocytic infiltrates (lymphocytic vasculitis pattern) of small cerebral arteries and veins. The inflammatory cells infiltrated all parts of the vessel walls, causing fragmentation of vessel wall layers, focal vessel occlusion (upper image, scale bar 100 µm; lower image, scale bar 100 µm). Inflammatory infiltration of vessel walls was characterized by mainly CD45+CD3+ T lymphocytes (data not shown). Given the patient’s history of relapsing TTP, a recurrence with neurological manifestation was suspected. TTP in adults is caused by autoantibody-mediated depletion of the von Willebrand factor–cleaving protease ADAMTS13 leading to accumulation of ultralarge von Willebrand factor multimeres inducing thrombotic microangiopathy. Neurological symptoms are common in TTP and a thrombotic episode can occur without evidence of haemolysis [1]. In this case, elevation of LDH was suggestive for active TTP, but normal haptoglobin, platelets and ADAMTS-13 parameters made active TTP highly unlikely. Differential diagnosis in this immune-compromised patient with a history of maintenance rituximab infusions and persistent B cell depletion included infectious and malignant diseases. PET-CT scan demonstrated ubiquitous lymph node enrichment suggestive of reactive lymphadenopathy. Cases of progressive multifocal leucoencephalopathy caused by JC virus (JCV) in patients on rituximab therapy have been reported. CSF JCV PCR was negative in our patient, but negative CSF JCV PCR has been reported in progressive multifocal leucoencephalopathy [2]. In addition, rituximab treatment has been associated with a non-vasculitic autoimmune meningoencephalitis [3]. A brain biopsy was performed in order to differentiate a cerebral neoplastic disease from an infectious meningoencephalitis (including JCV) or cerebral vasculitis. Histology demonstrated a severe small vessel vasculitis (Fig. 1B). The aetiology of cerebral vasculitis is broad and includes paraneoplastic diseases. Of note, the patient had mentioned recurrent oral aphthous lesions. In addition, 2 months prior he presented with acute anterior uveitis and retinal scanning demonstrated active retinal vasculitis. These symptoms strongly suggest neuro-Behçet’s disease (BD) [4]. BD is an autoimmune vasculitis characterized by recurrent oral and genital ulcers and uveitis. CNS involvement is not uncommon. Based on these disease manifestations and the histology, a diagnosis of neuro-BD with cerebral vasculitis, anterior and posterior uveitis and oral aphthous lesions was established. The presence of more than one autoimmune disease in a single patient is not rare and was recently termed polyautoimmunity [5]. Interestingly, this patient had a positive family history for different autoimmune diseases. Following treatment with prednisolone, IVIG and CYC the patient recovered fully from all clinical symptoms. MRI after completion of 3 monthly cycles of CYC showed regression in size and contrast enhancement of the cerebral lesions. In addition, CSF analysis displayed improvement, with fewer nucleated cells (12/μl) and less protein (1416 mg/l). The case illustrates that in patients with established autoimmune diseases presenting with unusual symptoms, apparently unrelated autoimmune diseases should be considered besides the signs and symptoms of the primary disease and the consequences of immunosuppression. Funding: No specific funding was received from any source in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest. References 1 Downes KA, Yomtovian R, Tsai HM et al.   Relapsed thrombotic thrombocytopenic purpura presenting as an acute cerebrovascular accident. J Clin Apher  2004; 19: 86– 9. Google Scholar CrossRef Search ADS PubMed  2 Kuhle J, Gosert R, Bühler R et al.   Management and outcome of CSF-JC virus PCR-negative PML in a natalizumab-treated patient with MS. Neurology  2011; 77: 2010– 6. Google Scholar CrossRef Search ADS PubMed  3 Hadley I, Jain R, Sreih A. Nonvasculitic autoimmune meningoencephalitis after rituximab: the potential downside of depleting regulatory B cells in the brain. J Clin Rheumatol  2014; 20: 163– 6. Google Scholar CrossRef Search ADS PubMed  4 Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s Disease. Lancet  1990; 335: 1078– 80. PubMed  5 Anaya J-M. The diagnosis and clinical significance of polyautoimmunity. Autoimmun Rev  2014; 13: 423– 6. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

RheumatologyOxford University Press

Published: Feb 12, 2018

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