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Hemophagocytic lymphohistiocytosis with leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma: a case report
© The Author(s). 2016
Received: 30 October 2015
Accepted: 27 June 2016
Published: 2 August 2016
Hemophagocytic lymphohistiocytosis associated with autoimmune diseases is seen in patients with systemic juvenile idiopathic arthritis, adult-onset Still’s disease, and systemic lupus erythematosus, whereas it is rarely seen in patients with dermatomyositis. In addition, central nervous system involvement with dermatomyositis is rare. To the best of our knowledge, this is the first case of hemophagocytic lymphohistiocytosis complicated by leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma.
A 17-year-old Asian male adolescent with dermatomyositis and hemophagocytic lymphohistiocytosis that were controlled with corticosteroid therapy presented to our hospital with high fever and altered consciousness. Brain magnetic resonance imaging revealed multiple cerebral lesions. We diagnosed the central nervous system lesions as leukoencephalopathy secondary to dermatomyositis and hemophagocytic lymphohistiocytosis. Because corticosteroid and cyclophosphamide pulse therapy was ineffective, he was treated with a modified hemophagocytic lymphohistiocytosis-2004 protocol, which resulted in the disappearance of the lesions of his central nervous system.
Our findings suggest that the hemophagocytic lymphohistiocytosis-2004 protocol including etoposide should be initiated immediately in patients with hemophagocytic lymphohistiocytosis who respond poorly to treatment for the underlying disease. Moreover, irrespective of the underlying disease, patients with hemophagocytic lymphohistiocytosis with central nervous system lesions might require bone marrow transplantation.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome associated with a variety of underlying conditions. The hereditary form of HLH is caused by defects in the transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes, and it can manifest in childhood or adulthood. The acquired forms of HLH are caused by infectious diseases, autoinflammatory and autoimmune diseases, malignancies, and acquired immune deficiency . HLH associated with autoimmune diseases is seen in patients with systemic juvenile idiopathic arthritis, adult-onset Still’s disease, and systemic lupus erythematosus, whereas it is rarely seen in patients with dermatomyositis (DM) . HLH is usually treated with intensive immunosuppressive therapy, including immunomodulatory and immunosuppressive agents. The therapy aims to suppress hypercytokinemia and to eliminate activated and infected cells. The protocol based on HLH-1994/HLH-2004 (with or without cyclosporine A in the first 8 weeks) is currently regarded as the standard of care [3, 4]. Patients with hereditary HLH can be cured only with hematopoietic stem cell transplantation, while patients with acquired HLH have shown improved survival when treated with reduced-intensity conditioning regimens .
DM is an idiopathic acute inflammatory disorder, characterized by inflammation of skeletal muscle, progressive symmetrical proximal myopathy, and classical cutaneous manifestations. The disease is associated with a connective tissue disease or a malignancy . Central nervous system (CNS) involvement with DM is rare, and to the best of our knowledge, only five cases have been reported that were associated with juvenile DM, which is a rare, serious autoimmune condition of childhood involving systemic small vessel vasculopathy. It typically affects skin and muscle, but it can also involve the joints, gut, lung, heart, and other internal organs .
He was administered sedative drugs to produce a state of calmness, to help him sleep, and to prevent acts of violence caused by his altered state of consciousness that lasted for 5 months. The medications were eventually discontinued because altered consciousness was no longer observed. However, disturbances of his higher cerebral functions remained. Five months after his initial admission, he could speak and walk like a very young child. Corticosteroid therapy was successfully tapered without a relapse of his symptoms (including fever and altered consciousness), and without changes in his laboratory and MRI findings.
Eight months after admission, a follow-up brain MRI revealed a recurrence of the CNS lesions (Fig. 2), although these recurrent lesions were different from the previous lesions, considering that there was no fever and no altered consciousness. Moreover, his laboratory findings were normal. We hypothesized that the pathology of the new CNS lesions differed from the pathology of the previous lesions and presumed that they were caused by progressive multifocal leukoencephalopathy or drug-induced (tacrolimus) leukoencephalopathy. However, a PCR analysis for the John Cunningham virus in his CSF (to diagnose progressive multifocal leukoencephalopathy) was negative, and no improvement in CNS lesions was observed when tacrolimus was discontinued.
One month after the recurrence of the CNS lesions, his abilities to walk and speak deteriorated. A MRI revealed a progression of the CNS lesions; therefore, a brain biopsy of his right frontal lobe was performed on day 297. On day 325, a diagnosis of peripheral T-cell lymphoma (PTCL) was made based on the T-cell receptor rearrangement seen in the tumor cells of his brain specimen. Therefore, on day 330, chemotherapy combined with high-dose methotrexate and cytarabine was initiated. A follow-up MRI on day 345 revealed that his CNS lesions had increased in size, suggesting that the chemotherapy regimen was ineffective, and he died of sepsis on day 348.
The patient presented here had a combination of several very rare diseases (DM, HLH, and CNS lesions). His condition was refractory, but it could be improved through intensive chemotherapy including etoposide (the modified HLH-2004 protocol).
Typically, most CNS lesions that appear acutely during immunosuppressive therapy are caused by infection. However, in this case, no infectious diseases were identified. Next, we suspected that the CNS lesions were caused by DM; however, his brain MRI findings revealed no evidence of vasculopathy or vasculitis, which are often seen in CNS lesions due to juvenile DM [7, 8]. Neuropsychiatric systemic lupus erythematosus was also excluded through blood and CSF examinations. Finally, we considered that the patterns of the CNS lesions on MRI closely resembled CNS lesions in patients with hereditary HLH who exhibit diffuse leptomeningeal and perivascular enhancement (corresponding to meningeal and perivascular infiltrations of histiocytes and lymphocytes), patchy areas of increased T2 signal intensity in the white matter of both cerebral hemispheres, and a diffuse parenchymal volume loss of the cerebrum and cerebellum . Henter and Elinder described cases of progressive encephalopathy (termed CNS-HLH in their report) that were diagnosed on brain necropsy. The pathophysiology of CNS-HLH has been characterized as a perivascular infiltration of lymphocytes and histiocytes in the cerebral parenchyma .
CNS involvement is commonly seen in patients with hereditary HLH . However, CNS involvement is less commonly seen in patients with autoimmune-associated HLH than in patients with malignancy-associated and viral infection-associated HLH. Gupta et al. reported that HLH was associated with rheumatic disease, malignancy, and viral/other complications by CNS disease in 14 %, 38 %, and 31 % of cases, respectively . In our patient, natural killer cell activity was normal, and protein levels of Munc13-4, Munc18-2, syntaxin 11, and integrin αIIβ were normal; mutations in the genes coding for these proteins are associated with the onset of hereditary HLH . Kim et al. reported that CNS involvement was associated with poor outcomes in patients with HLH and emphasized that the timely administration of chemotherapy (especially the early use of cyclosporine) was important for improving survival .
Yamashita et al. reported a case of HLH associated with DM complicated by CNS lesions; this case was identified on a postmortem examination . Similar to our case, induction therapy, a combination of DEX pulse therapy and cyclophosphamide pulse therapy, and cyclosporine therapy was used in their patient. However, in contrast to Yamashita et al.  who used corticosteroids, cyclosporine, and cyclophosphamide, we used etoposide in accordance with the modified HLH-2004 protocol. We believe that the CNS lesions caused by HLH in our case improved owing to the early treatment based on the HLH-2004 protocol.
Haddad et al. have described the poor outcomes of CNS disease in patients with HLH. According to the results of their study, bone marrow transplantation (BMT) appears to be the only available treatment procedure capable of preventing HLH CNS disease progression and that can cure the patient when performed early after remission . BMT was not performed after the recurrence of the CNS lesions in our case. In hindsight, considering the results, we should have performed BMT after the CNS lesions disappeared. The reason that we did not perform BMT was that there was no evidence for the effectiveness of BMT for HLH associated with autoimmune diseases complicated by CNS lesions, and those lesions had completely disappeared on MRI. Patients with DM are often known to have malignancies . In our case, no malignancies were found on the PET-CT examination at the time of diagnosis of DM and HLH. We could not confirm the coexistence of PTCL on the day of admission because PET-CT examination and brain biopsy were not performed. Nevertheless, considering that the CNS lesions disappeared after the initial therapy and that PTCL cannot be controlled by immunochemotherapy according to the HLH-2004 protocol, we speculate that the initial CNS lesions were not from PTCL. If the CNS lesions had been derived from PTCL, it is unlikely that the CNS lesions would have disappeared with treatment following the HLH-2004 protocol. To the best of our knowledge, there is no report in the literature that PTCL complicated by CNS lesions could be cured by treatment following the HLH-2004 protocol. Therefore, we hypothesize that our patient experienced T-cell lymphoma either as an adverse effect of immunosuppressant therapy or due to chronic inflammation during his clinical course.
Our findings show that it is necessary to immediately administer additional intensive immunosuppressive therapies, such as those indicated in the HLH-2004protocol, including etoposide, to patients with corticosteroid-resistant acquired HLH due to autoimmune disease. In addition, a biopsy should be performed as early as possible for brain lesions of unknown origin. Patients with HLH with CNS lesions might require BMT to achieve good clinical outcomes.
BMT, bone marrow transplantation; CK, creatine kinase; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; DEX, dexamethasone; DM, dermatomyositis; HLH, hemophagocytic lymphohistiocytosis; mPSL, methylprednisolone; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PET-CT, positron emission tomography-computed tomography; PTCL, peripheral T-cell lymphoma
We thank Dr Yuji Nakatsuji, Department of Neurology, Osaka University Graduate School of Medicine for his professional opinion of the patient.
We would like to thank Editage (www.editage.jp) for English language editing.
STe participated in the sequence alignment and drafted the manuscript. YK participated in the sequence alignment. YM participated in the sequence alignment. MY participated in the sequence alignment. EK-T participated in the sequence alignment. STs participated in the sequence alignment. YHa participated in the sequence alignment. MM participated in the sequence alignment. SO participated in the sequence alignment. KW participated in the sequence alignment. TK participated in the sequence alignment. YHo participated in the sequence alignment. YS conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript. All members were involved in the daily evaluation and treatment of this patient.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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