Tumefactive demyelinating lesions during etanercept treatment requiring decompressive hemicraniectomy

Introduction

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders including rheumatic and bowel inflammatory diseases. TNF-α antagonists (anti-TNF-α) have been successfully used for the treatment of these disorders. ¹ However, different central and peripheral neurological complications, systemic lupus erythematosus-like diseases and vasculitis have been described during their employment. ² Etanercept in particular, a TNF-α antagonist acting as a soluble TNF-α receptor, has been associated with neurological demyelinating disorders. ¹ We describe the first case of tumefactive demyelinating cerebral lesions which occurred during etanercept treatment requiring hemicraniectomy and associated with a favorable clinical recovery.

Case report

A 44-year-old man presented with an acute aphasia on 4 October 2010. He suffered from an HLA-B27 positive ankylosing spondylitis diagnosed in 2002 and subsequently treated with methotrexate until 2004, with leflunomid from 2004 to summer 2009 and then with etanercept (25 mg/2 weeks, from October 2009 to 26 September 2010). His recent history was negative for infections and vaccinations. On day 1 after admission, his neurological status assessment revealed a severe expressive aphasia and a mild facio-brachial hemiparesis: the patient developed a focal seizure with secondary generalization. Brain MRI showed multifocal tumefactive lesions with perilesional edema and partial contrast enhancement (Figures 1(a) and (b)). Cerebrospinal fluid (CSF) analysis revealed increased leukocyte (229/mm³, 85% granulocytes, 15% lymphocytes) and protein (946 mg/dl) counts. Empiric treatment with ceftriaxone, ampicillin, acyclovir and dexamethasone (4 mg intravenous (i.v.) every 6 hours) was initiated. CSF oligoclonal bands (OB) as well as an extensive infectious screening including John Cunningham Virus (JCV), Epstein-Barr Virus (EBV), Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Human Immunodeficiency Virus (HIV) Mycobacterium tuberculosis and M. pneumoniae were negative. Within 24 hours the patient became soporose and the right hemiparesis worsened. Based on clinical and radiological criteria, a diagnosis of probably drug-induced, acute demyelinating encephalopathy was made. A high dose steroid treatment (methylprednisolone i.v. 1 g/day) was started immediately (day 1 after admission). Three days after hospitalization, the CSF leukocyte count was significantly decreased (7/mm³). Mechanical ventilation and plasma exchange were started on day 4. A parenchymal intracranial pressure (ICP) monitoring system documented the ICP between 10 and 20 mm Hg. Despite treatment, on day 5, an ICP over 20 mm Hg associated with a clinical deterioration motivated a hemicraniectomy. An open field brain biopsy showed an acute demyelinating process (Figures 1(e)–(h)).

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Figure 1.

Tumefactive demyelinating lesions documented by MRI and histology: (a) and (b) axial MRI in the acute phase showed two (left fronto-temporal and right frontal) hyperintense pseudotumoral lesions on fluid attenuated inversion recovery (FLAIR) with open ring enhancement on gadolinium T1-weighed images (T1W); (c) and (d) show eight months follow-up after discontinuation of etanercept and a marked reduction of lesion size (FLAIR) without gadolinium enhancement on T1W. Figures 1(e)–(h) show open field biopsy specimens: (e) and (f) show perivascular hypercellularity and diffuse, infiltrating mononuclear cells (hematoxylin-eosin staining); (g) shows perivascular T lymphocyte infiltration (immunocytochemistry for CD3 antigen); and (h) shows perivascular infiltration of macrophages with phagocytic activity (immunocytochemistry for CD68 antigen). Scale bars: (e) and (g) 50 µm; (f) and (h) 25 µm.

Clinical evolution was progressively favorable and six months later the patient was able to communicate with verbal aids and could walk independently: a follow up MRI showed a dramatic regression of the cerebral inflammatory lesions (Figures 1(c) and (d)).

Discussion

We describe the first case of widely demyelinating brain lesions with tumefactive features which occurred during etanercept treatment and required decompressive hemicraniectomy. The clear temporal association between disease manifestation and administration of etanercept points to a direct causal effect of the drug. The severe clinical progression despite intensive medical treatment and the lack of recent infections or vaccinations point against an acute disseminated encephalomyelitis (ADEM). CSF pleiocitosis and absence of intrathecal IgG production argue also against a malignant monophasic multiple sclerosis variant (Marburg’s disease). Treatment with high dose methotrexate could lead to diffuse leukoencephalopathy. However this radiological picture has never been reported in cases of low dose methotrexate employed to treat ankylosing spondylitis. Moreover, methotrexate was suspended five years before symptom onset.

Tumefactive CNS demyelinating diseases have never been described following anti-TNF-α therapies but the association between anti-TNF-α therapies and neurological demyelinating disorders is known. Twenty cases associating demyelination with anti-TNF-α drugs were described ³ and 17 neurological events (14 with central demyelination) were reported from over 150,000 etanercept-treated patients ¹ but clinical symptoms were generally minor, MRI lesions small, and the prognosis often favorable. ² Experimental treatment of MS with anti-TNF-α agents has been associated with increased incidence of relapses and greater brain MRI activity. High levels of anti-TNF-α have also been found in MS plaques and CSF. ⁴ However, the patho-mechanisms by which anti-TNF-α drugs induce demyelination are not clearly established. Possible explanations include the enhancement of antigen presenting cell function, the increase of T-cell receptor signalling, the decrease of autoreactive T-cells apoptosis and the induction of pro-inflammatory cytokines including interferon-gamma, which is known to activate MS. ⁴

Decompressive hemicraniectomy has been described as life-saving procedure in the management of traumatic and ischemic brain injury and sub-arachnoid hemorrhage. Cases of successful treatment with decompressive hemicraniectomy in tumefactive demyelinating diseases such as ADEM and Marburg have seldom been reported. ^{5 –9}

Our case shows that central demyelinating disorders linked to anti-TNF-α treatments may also present with a severe clinical course. The favorable clinical outcome supports the use of aggressive treatments such as decompressive hemicraniectomy to overcome the acute clinical phase in similar cases.