Progressive multifocal leukoencephalitis in a patient with sarcoidosis on hydroxychloroquine with negative cerebrospinal fluid testing for the John Cunningham virus

Abstract

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system caused by the John Cunningham (JC) virus typically seen in immuno-compromised patients. Several drugs that suppress that immune system have already been known to cause PML such as natalizumab and rituximab. We present a patient with sarcoidosis who develops PML in the rare setting of minimal immunosuppression with only hydroxychloroquine. There was significant delay in the diagnosis due to negative cerebrospinal fluid testing for JC virus and concern for neuro-sarcoidosis, but eventually a diagnosis of PML was made via brain biopsy.

Flaccid Brachial Monoplegia As Initial Presentation in a Patient With Progressive Multifocal Leukoencephalopathy

“…Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by the reactivation of the polyomavirus John Cunningham (JC) virus (JCV) that causes lytic infection of glial cells [ 1 - 7 ]. PML most often occurs in patients who are immunosuppressed due to HIV, hematologic malignancies, solid organ transplants, or receive monoclonal antibodies for myriad conditions (natalizumab [multiple sclerosis (MS), Crohn’s], efalizumab [psoriasis], rituximab [systemic lupus erythematosus (SLE)], and alemtuzumab [MS]) [ 1 , 3 - 6 , 8 , 9 ]. PML is highly fatal, with a median survival of fewer than three months in patients without AIDS [ 3 ].…”

“…While JCV-specific antibodies are present in 50%-90% of the adult population worldwide, PML is an exceedingly rare complication with an incidence of 0.2-4.4 cases per 100,000 individuals in the general population [ 1 , 6 , 9 , 10 ]. Asymptomatic primary infection with JCV occurs in childhood and may subsequently reactivate from sites of latency and undergo sequential genomic rearrangements, spreading to the central nervous system in immunocompromised individuals [ 2 , 5 , 8 , 9 ].…”

“…While JCV-specific antibodies are present in 50%-90% of the adult population worldwide, PML is an exceedingly rare complication with an incidence of 0.2-4.4 cases per 100,000 individuals in the general population [ 1 , 6 , 9 , 10 ]. Asymptomatic primary infection with JCV occurs in childhood and may subsequently reactivate from sites of latency and undergo sequential genomic rearrangements, spreading to the central nervous system in immunocompromised individuals [ 2 , 5 , 8 , 9 ]. The American Academy of Neurology (AAN) Neuroinfectious Disease Section developed the criteria for the diagnosis of PML which may be confirmed by either (1) the typical neuropathologic histopathologic triad of demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei as well as the presence of JCV or (2) clinical and radiographic findings consistent with PML and not better explained by other disorders as well as the JCV by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) [ 1 , 6 , 9 - 11 ].…”

“…Presenting symptoms often comprise progressive weakness, sensory deficit, hemianopsia, cognitive dysfunction, aphasia, encephalopathy, incoordination, personality changes, and gait abnormalities [ 6 , 8 - 10 ]. Characteristic brain MRI findings include hyperintense lesions in the white matter without mass effect or edema on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images which are hypointense on T1-weighted images [ 3 , 6 , 9 , 10 ]. Lesions may also be located in the myelinated gray matter such as the basal ganglia or thalamus.…”

“…CSF evaluation often reveals JCV and excludes diagnoses such as other infections or tumors [ 10 , 12 ]. Few cases have been reported of JCV-negative CSF with subsequent PML confirmation requiring brain biopsy or autopsy [ 1 , 3 , 5 , 9 , 11 , 13 , 14 ]. Common brain biopsy findings of PML include the presence of oligodendrocytes with enlarged nuclei and atypical astrocytes, with the immunohistochemistry revealing positive reactivity for JCV-related antigens on abnormal glial cells [ 3 , 14 ].…”