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Two-thirds of patients with systemic lupus erythematosus (SLE) develop neuropsychiatric manifestations. It is often difficult to delineate the etiology of neuropsychiatric presentation in a patient with a known diagnosis of SLE. Neuropsychiatric manifestation among patients with SLE may trigger investigations and/or even treatment for neuropsychiatric manifestations of SLE (NPSLE), in some cases with cytotoxic agents, based on high level of suspicion but without conclusive evidence of the diagnosis. We report a patient with active SLE who presented with progressive neurologic deficits, the underlying etiology of which was progressive multifocal leukoencephalopathy (PML) and not NPSLE. This differentiation was made by obtaining a brain biopsy sample. Although PML does not occur directly due to SLE, and therefore cannot be categorized within the realm of NPSLE, it can be considered a result of iatrogenic immunosuppression in patients receiving treatment for SLE. Health professionals may encounter PML more frequently in the current era of biologic therapy for autoimmune disorders. Therefore, there is a need to familiarize ourselves with the disease, its prognosis, and the evolving spectrum of conditions that it can be associated with. This case report presents the dilemmas in the diagnosis of PML and discusses the rare occurrence of PML in a patient with SLE.
A 49-year-old woman presented with a 10-day history of progressive right arm weakness. Her medical history was significant for SLE manifested as facial rash, photosensitivity, livedo reticularis, arthritis, serositis, seizures, and membranous lupus nephritis. She had been receiving treatment with prednisone 15 mg/day, azathioprine 75 mg/day, and hydroxychloroquine 200 mg/day for the past year. She developed mild leukopenia on this regimen, and azathioprine was discontinued, with normalization of white cell counts within 2 weeks. Mycophenolate mofetil at 500 mg/day was initiated 1 month prior to the visit, in place of azathioprine, due to arthralgias and as a steroid-sparing agent. Physical examination was unremarkable, except for mild confusion, malar rash, and decreased motor strength in the right upper extremity (4/5 strength in the arm flexors and extensors and decreased hand grip).
Serologies revealed normal complement levels (C3, C4), antinuclear antibodies (1:160 titer, speckled pattern), and anti–double-stranded DNA antibodies. Cerebrospinal fluid examination was normal for cell counts, protein, glucose, immunoglobulin index, oligoclonal bands, gram stain, and microbiologic polymerase chain reaction (PCR); cultures for bacteria, mycobacteria, Epstein-Barr virus, cytomegalovirus, herpes simplex, varicella-zoster virus, cryptococci, and other fungi were normal. The patient also tested negative for ribosomal P antibodies (normal <20 units). Magnetic resonance imaging (MRI) of the brain with gadolinium revealed white matter lesions in the left anterolateral temporal, parietal, and periventricular areas (high intensity on T2-weighted and low intensity on T1-weighted images), without contrast enhancement or mass effect (Figure 1). Magnetic resonance angiogram was reported as consistent with diffuse vasculitis. The diagnostic differential included lupus cerebritis and vasculitis, and pulsed intravenous methylprednisolone therapy (1 gm/day for 3 days) was initiated followed by oral prednisone at a dosage of 1 mg/kg, without any improvement.
A month later, the patient presented with increasing lethargy, confusion, and progressive weakness now also involving the right leg. Repeat MRI of the brain showed extension of the lesions now involving the left frontal regions (Figure 1). Due to a lack of any improvement with the current management, a conventional cerebral angiogram was performed to confirm the diagnosis of central nervous system (CNS) vasculitis. The angiogram result was normal. While taking steroids (60 mg/day), the patient's leukopenia returned (white cell count 1,800 cells /mm3, with 70% neutrophils, 20% lymphocytes, 6% monocytes, and 4% eosinophils). Mycophenolate mofetil treatment was stopped. Microbiologic workup remained negative. Granulocyte stimulating factor injections were administered.
Progressive neurologic decline continued. Due to rapidity of neurologic progression, 1 cycle of cyclophosphamide at a dosage of 500 mg/body surface area was administered intravenously, without any improvement. Antiphospholipid syndrome was also considered in the differential, and the patient was maintained on anticoagulant therapy. She became aphasic and nonresponsive. At this stage, a brain biopsy sample tested positive for JC virus by PCR and in situ hybridization (Figure 2). The histopathology demonstrated multifocal demyelination with atypical oligodendrocytes and swollen nuclei (Figure 3), consistent with PML.
Hydroxychloroquine was discontinued, and prednisone dosage was tapered to 20 mg/day to decrease immunosuppression. Investigative therapies were discussed. The patient entered hospice care at home and died 3 weeks later.
PML was first described neuropathologically by Astrom et al in 1958 (1). Viral etiology was pursued as the cause of this disease (2, 3). Viral particles with infected oligodendrocytes were subsequently identified by electron microscope (4, 5). In 1971, a novel papovavirus was isolated from the brain of a patient with PML (termed JC virus after the patient's initals) (6). Virtually all cases of PML are caused by JC virus, although a related virus (SV40) has been isolated in a few cases (7). JC virus is a widespread pathogen in human populations. Although it is recognized as the cause of PML, simple infection with the virus does not result in CNS disease. PML occurs exclusively in patients with primary or secondary immunosuppression and is caused by activation of a virus already present in the brain as a consequence of prolonged immunosuppression.
Patients present with insidious disturbances in motor function, vision, or mental status that progress. Asymmetrical involvement of the cerebral hemispheres is typical, but generally both hemispheres are affected. The cerebrospinal fluid examination is usually normal, although there may be slight elevation in protein or cell count. Neuroimaging demonstrates hypodense nonenhancing white matter lesions on computed tomography scans with prominent involvement of the corpus callosum.
PML typically occurs as a complication of chronic illness with secondary immunosuppression. In the era before acquired immunodeficiency syndrome, PML was most commonly associated with chronic lymphocytic leukemia, Hodgkin's lymphoma, organ transplants, and sarcoidosis. Recently, PML has been reported in patients with Crohn's disease and multiple sclerosis with the use of natalizumab, a humanized monoclonal antibody against α4 integrins (adhesion molecules) (8). Natalizumab appears to distinctively predispose recipients to PML relative to other infectious complications (9). Studies in these populations will be invaluable in understanding the mechanisms of disease pathogenesis. Serious consideration of this fatal infectious complication is needed in future trials involving the drugs selectively targeting the adhesion molecules (10). The number of reported cases of PML in patients with SLE remains low due to difficulty in distinguishing PML from CNS lupus (11–16), although iatrogenic immunosuppression may heighten the risk. Some patients with SLE with only maintenance doses of corticosteroids developed PML (16). Most patients with PML and SLE experienced dysarthria (16, 17).
The exact risk factors for PML in patients with SLE are not well known. The frequent use of MRI has increased the sensitivity of detecting demyelinating lesions in the white matter. Severe leukoencephalopathy from CNS NPSLE may sometimes mimic PML clinically and on MRI (17). A negative brain biopsy result for PML in such a situation may allow rapid escalation of therapy. Cerebrospinal fluid analyses, which are usually not within normal ranges in most cases of active CNS SLE, may also be helpful. However, as in our patient, knowing the patient's history of lupus may cause the radiologist to consider diagnoses other than PML. Brain biopsy can give a definitive diagnosis of PML when the virus is detected along with degenerated oligodendrocytes by electron microscopy and PCR.
Although cytarabine (18), cytosine arabinoside (16), and/or interferon-α (16, 18) have been shown to be effective in some cases, PML is often a fatal and untreatable disease. The serotonergic 5-hydroxytryptamine 2A receptor is the cellular receptor for JC virus on human glial cells (19), suggesting that a serotonin receptor antagonist may be useful in its treatment. Our case illustrates the importance of considering PML in patients with SLE with neurologic involvement and an unremarkable cerebrospinal fluid analysis result. Also, because etiology and treatment of CNS lupus and PML are drastically different from each other, it is important to differentiate between the 2 entities. Continued treatment with steroids or other cytotoxic drugs is not only unhelpful, but may also be detrimental in these patients. A brain biopsy may help prognosticate and avoid escalation of immunosuppression for presumed lupus cerebritis.
Dr. Jolly had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Acquisition of data. Govindappa, Hicks, Jolly.
Analysis and interpretation of data. Govindappa, Jolly.