Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus

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Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by a human polyomavirus designated JC virus. JC virus has been recognized as a major pathogen of opportunistic infections in patients receiving immunosuppressive treatment as well as in patients with human immunodeficiency virus (HIV) infection. Only a small number of cases of PML in patients with systemic lupus erythematosus (SLE) have been reported, even though patients with SLE usually receive immunosuppressive therapies. We present 3 cases of PML in patients with SLE who were treated at our hospital over the last 12 years.

A 21-year-old woman (patient 1; see ref. 1) with a 6-year history of SLE presented with a speech disturbance and right-hand clumsiness. A magnetic resonance imaging (MRI) examination revealed a low-intensity area on T1-weighted images and a high-intensity area on T2-weighted images in the white matter of bilateral cerebral and cerebellar hemispheres, consistent with PML. The intraspinal administration of interferon-β (IFNβ) seemed to slow the deterioration of her MRI and neurologic findings. However, she eventually developed decerebrate rigidity and died. JC virus DNA was detected in the autopsied brain using molecular cloning technique.

A 31-year-old woman (patient 2) had a 12-year history of SLE, accompanied by cutaneous vasculitis on her lower extremities. She developed dysarthria and ataxia in her right extremities; she had been taking 8 mg/day of methylprednisolone and 50 mg/day of azathioprine. An MRI examination revealed a low-intensity area on T1-weighted images and a high-intensity area on T2-weighted images in the deep white matter of the right cerebellum, extending into the pons (Figure 1A). A polymerase chain reaction (PCR) analysis of a cerebrospinal fluid (CSF) sample detected a PML-type JC virus DNA, confirming the diagnosis. The administration of cytosine arabinoside followed by IFNα caused liver dysfunction and did not improve her symptoms. However, her symptoms began to improve 2 weeks after the discontinuation of the treatment. She has recovered well except for moderate ataxia and dysarthria.

Figure 1.

A, Magnetic resonance imaging of the brain demonstrating white matter lesions in T2-weighted images. The lesion atypically involves the right cerebellum and the pons in patient 2. B, The lesion is located in the right front parietal and left parietal white matter in patient 3. The lesions demonstrate neither a mass effect nor contrast enhancement.

A 40-year-old woman (patient 3) had an 8-year history of SLE, along with leukocytopenia and a lupus profundus on her face and arms. She developed dysarthria, left-side hemiplegia, and a disturbance of consciousness; she had been taking 10 mg/day of prednisolone. An MRI examination revealed a low-intensity area on T1-weighted images and a high-intensity area on T2-weighted images in the right front parietal and left parietal white matter (Figure 1B). A PCR analysis of a CSF sample detected a PML-type JC virus DNA, confirming the diagnosis. Despite 4 times monthly administration of 250 mg of cidofovir, her neurologic findings worsened to those of a vegetative state. She died 20 months after the onset of her neurologic symptoms.

In all 3 patients, a CSF examination showed normal numbers of cells and normal levels of protein and glucose. The IgG index and albumin index were not elevated. Serologic testing for HIV yielded negative results. The patients were negative for antiphospholipid antibodies, and they did not have any episodes of thrombosis.

JC virus is a widespread pathogen in human populations. More than 70% of individuals are infected with JC virus asymptomatically during childhood. Although JC virus is usually not pathogenic in healthy individuals, it can cause PML in immunocompromised hosts, including patients with hematologic malignancies, organ transplant recipients, and patients treated with immunosuppressive drugs. Only 14 cases of PML associated with SLE have been reported (1–9). Between 10% and 60% of patients with SLE have CNS involvement (termed CNS lupus). These patients exhibit a variety of symptoms, including headache, psychosis, seizures, neuropathy, stroke, tremor, chorea, transverse myelopathy, aseptic meningitis, and cognitive impairment (10). PML should be considered within the differential diagnosis. In CNS lupus, a CSF examination shows increased numbers of cells, an elevated protein concentration, and an elevated IgG index, whereas in PML, the findings of the CSF examination are usually normal.

The characteristic MRI findings of PML include a lesion in the white matter of the brain, sparing the cortex and deep nuclei, that exhibits neither a mass effect nor contrast enhancement. As seen in patients in the present report and in some previous reports (1, 3, 5, 6, 8), lesions can appear atypically in the brainstem and cerebellum (Figure 1A).

The presence of antibodies to JC virus does not alone support a diagnosis of PML, because 80% of the human population is seropositive. Renal JC virus DNA carries the archetype regulatory region, whereas the CNS JC virus DNA of PML patients contains various regulatory regions, so-called PML-type regulatory regions. PCR analysis to identify JC virus DNA with PML-type regulatory region sequences in CSF has been reported to be useful for diagnosing PML with high sensitivity and specificity (82% and 100%, respectively) (11, 12). PML-type regulatory regions are generated from the archetype by deletions and/or duplications in infected individuals after the primary infection, and they differ from patient to patient (12, 13). Representative recombinant JC virus DNA clones detected in each patient were sequenced as described previously (12, 14). A comparison of the regulatory region sequences revealed that they were distinct from each other, and the positions and patterns of the deletions and duplications were case specific, since each had its own specific progenitor clones (Figure 2). These sequences were also distinct from those in patients with PML associated with HIV infection in our hospital (data not shown). These results confirmed that the patients reported here developed PML independently and not by horizontal nosocomial infection.

Figure 2.

Diagrammatic representation of the JC virus regulatory region sequences of 6 progressive multifocal leukoencephalopathy (PML)–type isolates from patients 1–3. The structure of the archetype regulatory region is shown schematically at the top. “Ori” and “TATA” indicate the origin of replication and TATA sequence, respectively. The start site of agnoprotein (Agno) is shown. The PML-type JC virus regulatory regions are shown with their deletions relative to the archetype as gaps. Duplication is displaced to the line below and to a position corresponding to that of the archetype sequence. The structures of Tky-2a and Tky-2b were drawn on the basis of the previously reported sequence data (14).

Most of the reported PML patients with SLE received aggressive immunosuppressive therapies. Unlike those previously observed patients, our patients developed PML while taking only a maintenance dose of corticosteroids (and 50 mg/day of azathioprine in the case of patient 2). Some risk factors for developing PML other than immunosuppression might be present. The serotonergic 5-hydroxytryptamine 2A receptor (5-HT2AR) has been shown to act as the cellular receptor for JC virus on human glial cells (15). There are reports of the surprising development of PML in 3 patients during treatment with natalizmab, a humanized monoclonal antibody against α4 integrins (16). These reports suggest that some cell surface molecules directly and indirectly (e.g., by preventing normal trafficking of lymphocytes) affect the PML-type JC virus infection.

No proven therapy for PML yet exists. Cidofovir was suggested to be effective (6), but a recent controlled prospective study in HIV patients with PML failed to demonstrate the benefit of this agent (17). The 5-HT2AR blockade may be useful (15). The symptoms of patient 2 improved, and her CSF became negative for viral DNA despite an incomplete antiviral therapy. We can only speculate that the amount of JC virus in the CNS possibly alters the prognosis.

In conclusion, PML should be considered within the differential diagnosis of neuropsychiatric symptoms in patients with SLE. Some factors other than immunosuppressive therapies might affect the development and prognosis of this condition.

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