Bone Marrow Transplantation (2014) 49, 854–856 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Acute disseminated encephalomyelitis following allo-SCT: central nervous system manifestation of GVHD Bone Marrow Transplantation (2014) 49, 854–856; doi:10.1038/ bmt.2014.29; published online 17 March 2014
Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system (CNS). It characteristically occurs in children and is putatively autoimmune in nature, triggered by environmental stimuli in susceptible individuals. A monophasic clinical presentation with multifocal neurological symptoms and encephalopathy is typical. Diagnosis is on the basis of a constellation of clinical and radiological features (Table 1).1 The principal differential diagnoses include multiple sclerosis, characterized by recurrent episodes of CNS demyelination, optic neuritis, transverse myelitis and neuromyelitis optica. ADEM is often preceded by infection (occasionally immunisation), typically 1 month before neurological dysfunction. The pathogenesis is not fully understood, although the principal hypothesis implicates myelin proteins serving as autoantigens sharing antigenic determinants with an infectious agent.2 One study demonstrated a 10-fold greater reactivity of T lymphocytes directed towards myelin basic protein in those with ADEM, compared with normal controls and encephalitis patients.3 Antimyelin-associated glycoprotein (anti-MAG) and anti-myelin basic protein (anti-MBP) antibodies have been detected in cerebrospinal fluid (CSF).4 Immunomodulation in the form of steroids, i.v. Ig and plasmapheresis is the mainstay of treatment.5 The occurrence of ADEM in adults following allo-SCT is rare and its diagnosis is challenged by a wide differential.6 However, prompt recognition is essential as neurological sequelae can be debilitating, whereas appropriate treatment can result in rapid resolution. We report an adult case of ADEM occurring 92 days after a reduced intensity conditioning (RIC) matched unrelated donor allo-SCT for p53 deleted CLL and discuss the possible pathogenesis. A 63-year-old man with CLL, diagnosed 9 years previously, presented with Richter’s transformation in a retroperitoneal mass (classical Hodgkin lymphoma histology) and concurrent BM progression of CLL, with a new p53 deletion. Before this, he had received a single-agent chlorambucil on three separate occasions. On this occasion he was treated with six cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) followed by 12 weeks of Alemtuzumab consolidation, without significant toxicity. A complete metabolic remission on computerized tomography–positron emission tomography was achieved but low-level (15%) CLL persisted in his BM. In view of the poor risk features, he proceeded to an allo-SCT from an unrelated donor, a 10/10 match by high-resolution typing. Both the donor and recipient were negative for CMV on serology. He received lowdose total body irradiation (2 Gy) and fludarabine (30 mg/m2 × 3) as conditioning. GVHD prophylaxis comprised CsA and mycophenolatemofetil (MMF). Thirty-six days post transplant, he presented with IBMTR Grade B acute GVHD (stage 2 skin GVHD and stage 1 gut GVHD) that responded well to a short course of prednisolone 40 mg, which was rapidly weaned.7 On day 92 post transplant, although still taking CSA and prednisolone 5 mg, but not MMF, he presented with dizziness and blunted mentation. He was unsteady on his feet and had mild
cognitive impairment. Neurological assessment revealed ocular flutter, a fine tremor, bilateral upper limb ataxia and a positive Romberg’s sign. Systemic examination was otherwise normal. At this time, full blood count and a broad biochemistry profile including liver function tests were unremarkable. There was no evidence of thrombocytopenic thrombotic purpura. DNA chimaerism analysis on whole blood confirmed 100% donor origin. The differential diagnoses considered were viral encephalitis, drug toxicity, fungal infection or an alloimmune inflammatory process. Magnetic resonance imaging (MRI) of the brain demonstrated multifocal subcortical and juxtacortical white matter lesions with slight mass effect (Figures 1a and b). Neither the MRI findings nor the clinical picture were thought to be typical for CsA-associated leukoencephalopathy, and no other drugs were thought to be implicated. CSF analysis revealed an elevated protein concentration 1097 mg/L (150–450 mg/L) but no abnormal cells. He was empirically treated for infective causes with Meropenem, Foscarnet and Ambisome. Cerebral biopsy was considered too risky. CSF was negative for HSV, VZV, CMV, EBV, HHV6, HHV7, JC, BK and adenovirus by PCR, as was galactomannan antigen assay. An interval MRI scan 1 week later showed progression with multiple periventricular, subcortical and brainstem hyperintense lesions, both supra- and infra-tentorially (Figures 1c and d), although there was no further clinical deterioration. By this time point, his stage I acute liver GVHD had recurred with a bilirubin of 2.2 mg/dL and stage 2 mucocutaneous GVHD had developed with a maculopapular rash affecting approximately a third of his body surface area alongside mucositis and gingivitis affecting the mouth. Therefore, in the absence of CNS infection, a diagnosis of ADEM was considered. Antimicrobial therapy was discontinued and corticosteroid therapy (prednisolone 0.5 mg/kg daily) was commenced, while maintaining therapeutic cyclosporin levels. Progressive improvement in neurological signs ensued over 2 weeks and repeat MRI corroborated this improvement (Figures 1e and f). A slow steroid taper was initiated 35 days after the initial
Table 1.
Diagnostic criteria for ADEM
Clinical features
First attack of inflammatory/demyelinating disease in the CNS Acute or subacute onset Multifocal CNS involvement Polysymptomatic presentation including encephalopathy Acute behavioural change and/or alteration in consciousness Absence of alternative aetiologies
MRI with FLAIR/T2
Large (>1–2 cm) multifocal, hyperintense lesions Supra- and/or infra-tentorial white matter and/or grey matter foci (basal ganglia and thalamus often involved) Rarely, large single white matter lesions seen Confluent intramedullary lesions in spinal cord No radiological evidence of previous destructive white matter changes
Abbreviations: ADEM = acute disseminated encephalomyelitis; CNS = central nervous system; MRI = magnetic resonance imaging.
Letter to the Editor
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a
c
e
b
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f
Figure 1. Sequential MRI head images with T2 weighting: demonstrating progression from images a and b to images c and d (interval of 1 week) and improvement from images c and d to images e and f (interval of 2 weeks).
presentation, with no recrudescence of neurological signs. Over the following weeks, the patient went on to develop chronic mucocutaneous GVHD (NIH Consensus Score—Moderate) with progressive onset from this acute episode for which he required Rituximab.8 Twelve months after diagnosis, the patient is well and now off all immunosuppression except a small dose of prednisolone. This patient presented with features of an acute encephalomyelopathy, occurring early post allo-SCT. A monophasic presentation with characteristic clinical and radiological features, with exclusion of infective causes, prompted a diagnosis of ADEM. A sustained response to corticosteroid therapy was achieved. Isolated reports of ADEM have been described following SCT.4,6 Limited information has been available on ADEM occurring in adults following allo-SCT and particularly lacking in RIC allo-SCT protocols. Available data support the contention that ADEM is an autoimmune phenomenon,2–4 although the precise immunopathogenesis remains unknown. Immune dysregulation following allo-SCT is common and a range of autoimmune conditions have been reported in this context.9 Although chimaerism analysis was not specifically performed on the T-cell fraction, whole blood chimaerism was always 100% donor. In the context of coincident GVHD, it is possible that the aetiology of ADEM in this case was alloimmune; mediated by donor immune cells infiltrating the CNS resulting in acute cerebral GVHD. Re-initation of corticosteroid therapy resulted in prompt improvement of both neurological and mucocutaneous symptoms. This is consistent with the presumed T-cell-mediated pathogenesis of autoimmune ADEM.3 A number of disparate reports support the notion that donor T cells may invade the host CNS, resulting in a spectrum of neurological disease. Cerebral angiitis10 and a chronic demyelinating polyneuropathy have both been reported in association with chronic systemic GVHD.11 Interestingly, brain biopsies from two patients with severe neurological impairment following allo-SCT displayed a perivascular lymphocytic infiltrate composed of donor © 2014 Macmillan Publishers Limited
T cells.12 Data from animal models are also consistent with T-cellmediated reactions in the CNS.13 Taken together, it seems likely that CNS-GVHD is a genuine entity and potentially underdiagnosed. The optimal management of ADEM following alloSCT remains uncertain, although the clinical outcome in our case, in keeping with the pathogenesis, supports the use of immunosuppressants. Consideration of ADEM within the wide differential for patients presenting with CNS dysfunction following allo-SCT is essential. Histological confirmation of the diagnosis should be considered and exclusion of infective causes, before augmenting immunosuppression, is critical.
CONFLICT OF INTEREST The authors declare no conflict of interest.
CM Harvey1, R Gottipati1, S Schwarz2, D Auer2, M O’Donoghue3, NH Russell1 and CP Fox1 1 Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK; 2 Department of Radiology, Nottingham University Hospitals NHS Trust, Nottingham, UK and 3 Department of Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK E-mail:
[email protected]
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