Clinical Vignette

A 65-year-old man with a history of follicular lymphoma initially treated with conventional chemotherapy 4 years previously was given three courses of rituximab for maintenance therapy because of persistence of clonal changes in his bone marrow. He developed confusion, dysarthria, and aphasia after the third course. MRI revealed nonenhancing lesions in the posterior and frontal lobes and left centrum semiovale. Peripheral blood PCR was positive for JC virus, but CSF was negative.

Brain biopsy demonstrated changes characteristic of progressive multifocal leukoencephalopathy (PML). His peripheral blood demonstrated a CD4 count of 100. Treatment with cidofovir was ineffective as the patient’s clinical condition worsened with progressive aphasia and confusion, urinary and fecal incontinence, flaccid paralysis of the left arm, accompanied by radiologic progression with mass effect. He died 3 months after presentation.

Epidemiology

JC virus is a human polyomavirus (a small nonenveloped virus with a circular, double-stranded DNA genome). Infection is acquired during childhood and persists in the kidney. JC virus is the cause of PML, a rare demyelinating disease of immunosuppressed patients. PML causes rapidly progressive focal neurologic deficits without signs of increased intracranial pressure. PML is most often an AIDS-defining illness, although it occurs in other immunocompromised settings such as long-term corticosteroid or methotrexate (MTX) therapy. Although one may usually consider such in more chronic settings of the immunocompromised, we have seen one instance of an individual who developed and subsequently died of PML 9 months after commencing MTX therapy. Recently, several cases of PML are reported in patients treated with the monoclonal antibodies natalizumab for multiple sclerosis and Crohn disease as well as rituximab. This has significantly limited the utilization of natalizumab, a medication that initially was felt to be the most promising therapy ever developed for MS patients. The incidence of PML in HIV-infected patients has decreased after the introduction of highly active antiretroviral therapy (HAART) therapy; however, HAART may “uncover” PML, with it developing within 6 months of commencement of this therapy.

PML occurs most commonly in systemic lupus erythematosus among the various rheumatologic disorders.

Clinical Presentation

PML has a variable presentation depending on which part of the brain is initially infected. The temporal profile and clinical symptomatology are no different in HIV patients than in those with other immunodeficiencies, such as acute leukemias. Common neurologic scenarios include a progressive hemiparesis, visual field deficits, aphasia, and cognitive impairment. Occasional patients present with a pure cerebellar truncal and/or appendicular ataxia, or cranial nerve deficits. Late in the course of PML, affected patients develop severe neurologic deficits, including cortical blindness, quadriparesis, profound dementia, and coma.

Lesions may be primarily located in the cerebral white matter or sometimes in the cerebellum and brainstem (Fig. 51-1). Spinal cord involvement is rare but is reported. However, survival remains poor once PML is diagnosed. As there is no specific antiviral medication effective for PML, the main focus should be on prophylactic measures to avoid immunodeficiency.

Figure 51-1 Progressive Multifocal Leukoencephalitis.

Diagnosis

MRI scans reveal hypodense, nonenhancing lesions of the cerebral white matter. The severity of clinical findings is often greater than is suggested by the extent of involvement on computed tomographic (CT) scan. The latter may even be normal. MRI typically helps to differentiate brain tumors, especially lymphoma, or abscesses in the immunocompromised. A spongiform encephalopathy caused by a prion, Creutzfeldt–Jakob disease, is a fatal infectious disease that sometimes presents with a progressive cerebellar syndrome or various focal cerebral lesions. However, this does not have a predilection for immunocompromised hosts.

PCR has been used to amplify JC virus DNA in CSF samples (sensitivities range from 60% to 100%). CSF cell count and chemistry results are usually normal. EEG may reveal focal slowing or may be normal early in the course of PML.

A definitive diagnosis of PML requires identification of the characteristic pathologic changes on brain biopsy: multiple asymmetric foci of demyelination at various stages of evolution in the cerebral white matter. The oligodendrocytes demonstrate characteristic cytopathic effects, including nuclear enlargement, loss of normal chromatin pattern, and intranuclear accumulation of deeply basophilic homogenous staining material. Electron microscopy reveals polyomavirus particles in enlarged oligodendrocyte nuclei (see Fig. 51-1).

Therapy

Unfortunately, there is no specific antiviral therapy effective for PML. Although there were some preliminary studies suggesting that cidofovir, a nucleoside analog active against polyomaviruses, might have therapeutic potential, recent results from a large multi-institutional trial are disappointing. We continue to have an overriding need for an effective PML therapy. Marked clinical and radiographic improvement in HIV-infected patients with PML has been seen after treatment with combination HAART regimens that include a protease inhibitor. Aggressive antiretroviral treatment of underlying HIV infection seems to be the most reasonable therapeutic approach to management in HIV-infected patients, as patients receiving HAART therapy have a lower incidence of PML. The opportunity for treatment may be better with the natalizumab-induced PML patient in that steroid pulse therapy led to clinically significant recovery in one patient. Unless the accompanying underlying immune deficit can be reversed as noted above, PML typically progresses to death fairly rapidly.