Progressive multifocal leucoencephalopathy isolated to the posterior fossa in a patient with systemic lupus erythematosus

R. P. White, S. Abraham1, S. Singhal, H. Manji and C. R. A. Clarke

National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG and
1 Department of Rheumatology, Whipps Cross Hospital, London E11 1NR, UK

SIR, Progressive multifocal leucoencephalopathy (PML) may complicate immunosuppressive states other than HIV infection. Its presentation as an isolated posterior fossa lesion is uncommon. We describe here ante-mortem diagnosis on cerebellar biopsy of PML in a patient with systemic lupus erythematosus (SLE) immunosuppressed with prednisolone and azathioprine. The case illustrates both that immunosuppression, other than that induced by HIV, may be complicated by PML and that this devastating opportunistic viral infection should be considered in the differential diagnosis of isolated progressive posterior fossa white matter disease.

A 41-yr-old Asian man presented with right-sided ataxia, right trigeminal sensory and motor palsy, bilateral abducens palsies and mild right lower motor facial palsy. He had a history of microbiologically proven tuberculous pleuritis 8 yr previously, which was treated with a 6-month anti-tuberculous course. A year later he developed recurrent pleuritis with lymphadenopathy, splenomegaly and elevated erythrocyte sedimentation rate (ESR). He was given a further anti-tuberculous course, but no mycobacteria were isolated. One year later, he developed a pleural effusion and right lower lobe collapse. At this point he was positive for antinuclear antibody titre (1:2560), had a high double-stranded DNA binding level (150 IU) and was negative for extractable nuclear antigen. A diagnosis of SLE was made and he was started on prednisolone (15 mg once daily) and azathioprine (50 mg twice daily). He remained in SLE remission for 5 yr prior to neurological presentation. His ophthalmologist documented bilateral abducens palsies shortly after his SLE diagnosis.

On admission he had lymphopenia with a raised mean corpuscular volume of 105.4 and a reduced platelet count of 140x109/l, consistent with azathioprine treatment. ESR was normal. HIV serology was negative. CD4 levels were reduced at 144/µl, with CD8 levels of 533/µl. Antineutrophil cytoplasmic antibodies (ANCA) and anticardiolipin antibodies were negative. Double-stranded DNA titre was elevated at 172 IU. Complement C3 levels were reduced at 0.73 (0.9–1.8) g/l but C4 levels were normal. Magnetic resonance imaging (MRI) of the brain showed an arachnoid cyst over the inferior vermis with right cerebellar atrophy and low T1 signal, and a rim of T2 high signal within the pons (Fig. 1Go). There was no gadolinium enhancement. Cerebrospinal fluid (CSF) analysis was normal. Oligoclonal bands unmatched to serum were found in the CSF. Syphilis serology was negative. CSF cryptococcal antigen was negative.



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FIG. 1.  Axial T2 MRI image through the posterior fossa prior to biopsy, illustrating pontine and right cerebellar hemisphere demyelination.

 
Central nervous system (CNS) lupus was considered within the differential diagnosis and a course of intravenous methylprednisolone (500 mg/day for 3 days) and a pulse of cyclophosphamide (500 mg) were given. Over the course of 4 weeks the patient's neurology deteriorated, with worsening of his ataxia and progressive pseudobulbar palsy. Repeat MRI demonstrated marked pontine and cerebellar demyelination. Repeated CSF analysis was normal. Formal biopsy of the right cerebellar hemisphere showed a characteristic appearance of PML with oligodendrocyte nuclear inclusions, foamy macrophages and white matter necrosis. In situ hybridization was positive for JC 40 virus in the brain. Azathioprine and prednisolone were discontinued and interferon {alpha} (3 MU/day subcutaneously), was given from the time of histological diagnosis. The patient died 7 months after presentation.

PML is a progressive fatal demyelinating disorder associated with oligodendroglial infection by the human papovavirus JC. PML typically presents with focal subcortical neurological deficits, and its presentation confined to isolated brainstem and cerebellum lesions is unusual. It is seen as a complication of many immunocompromised states [1]. Occasional cases are described in pregnancy [2] and 6% of cases may have no identifiable evidence of immunosuppression [3]. A limited number of reports in the world literature describe its association with systemic lupus erythematosus [48]. Whilst diagnostic suspicion is high in the setting of HIV, the diagnosis of PML in SLE is seldom ante-mortem [5, 8] (five cases).

SLE is associated with a number of neurological complications, including vasculopathy with focal ischaemia, cranial neuropathies, neuropsychiatric disturbance and a progressive neurological syndrome resembling multiple sclerosis. In this case there was no evidence of significant SLE disease activity systemically at presentation, and the absence of gadolinium enhancement on MRI was against a CNS vasculopathy. Treatment of his SLE was followed by rapid neurological decompensation with florid imaging changes.

Diagnosis of PML may be difficult. Because 80% of the population are seropositive, the presence of antibodies to JC is not of diagnostic value. CSF identification of JC virus by polymerase chain reaction is useful, and studies suggest a sensitivity of 95% and specificity of 90–99% [9]. The MRI findings are characteristic in PML, with a high T2 signal and a low T1 signal, which does not enhance with gadolinium and has no mass effect. Brain biopsy is the only definitive way to make the diagnosis.

Recent reports of improved outcome following aggressive highly active anti-retroviral therapy (HAART) in HIV [10] and specific JC antiviral treatment with interferon {alpha} or cidofovir [11, 12] favour early diagnosis. PML should be considered in all patients with an underlying disease process associated with altered cell-mediated immunity, where there is a progressive neurological picture that is possibly, but not definitely, of multifocal origin. If JC virus is absent in the CSF, brain biopsy should be considered.

Notes

Correspondence to: R. P. White, Department of Neurology, Hammersmith Hospital, Du Cane Road, London W12 ONS, UK. Back

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Accepted 7 January 2002