Progressive Multifocal Leukoencephalopathy in HIV 

Progressive multifocal leukoencephalopathy (PML) is characterized by widespread demyelinative lesions due to infection of oligodendrocytes by a human papovavirus. It occurs almost exclusively in immunosuppressed individuals, such as patients with AIDS, leukemia, or tumors or those undergoing organ transplants. PML has also been reported in patients receiving immune therapy with monoclonal antibodies (eg, natalizumab, rituximab).^[1] PML is associated with both HIV-1 and HIV-2.^{[2, 3]}

HIV-associated PML also occurs during immune recovery following the initiation of highly active antiretroviral therapy (HAART).^[4] Such cases are associated with an inflammatory reaction in brain lesions and contrast enhancement on neuroimaging studies. The outcome of inflammatory PML is more variable than that of PML in end-stage AIDS.^[5]

Unlike some of the other HIV-associated opportunistic infections of the CNS, which are almost wholly prevented when CD4+ counts are maintained above 100–200 cells/μL, PML can occur in patients with high CD4+ counts.^{[6, 7]} For example, Mascarello et al reported a case of PML in an HIV-infected patient receiving successful long-term HAART, with a CD4+ count greater than 700/µl and an undetectable HIV viral load.^[8]

Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the endemic JC papovavirus (ie, polyomavirus). As many as 90% of healthy individuals have serum antibodies to this virus, but less than 10% show any evidence of ongoing viral replication. In cases associated with the initiation of highly active antiretroviral therapy (HAART), immune recovery may uncover pre-existing subclinical PML.^[9]

According to a study of HIV-negative controls and HIV-positive patients with or without PML, a third of individuals from all subgroups had JC virus DNA in the urine.^[10] In the same study, JC virus DNA was detected in 43% of lymphocyte samples and in 63% of plasma samples in HIV-positive patients with PML. In HIV-positive patients without PML, however, JC virus DNA was detected in only 13% of lymphocyte samples and in 22% of plasma samples. In HIV-negative controls, no lymphocyte or plasma samples harbored JC viral DNA.

The site of viral replication remains to be determined. Candidate locations include bone marrow and the reticuloendothelial system. Whether PML develops when resident virus in the brain is reactivated or when the virus is reactivated and seeds the brain via blood lymphocytes or in free form is unclear.

HIV gene products, such as Tat, may be able to transactivate the JC viral promoter directly. This provides an additional pathogenic mechanism beyond general immunosuppression.

A United States study of 9,675 cases of PML from 1998-2005 found that 82% of cases were associated with HIV infection.^[11]

The incidence of PML is low in India and Africa, possibly due to diagnostic challenges and differences in JC virus isolates.

Before the advent of highly active antiretroviral therapy (HAART), PML occurred in as many as 4% of AIDS cases. Unlike other HIV/AIDS-related opportunistic tumors and infections, the incidence of PML has not changed significantly in the HAART era.^[12] According to the Italian NeuroAIDS study 2000-2002 (IRINA), PML is the third most common cause of encephalopathy in HIV-infected patients, after Toxoplasma encephalitis and HIV encephalopathy.^[13]

In the United States, the mortality associated with PML has decreased significantly since 1996, when HAART became the standard of care. The PML-associated death rate decreased from 2.76 deaths per 1 million population in 1992-1995 to 0.66 in 2002-2005, in large part because of fewer deaths among HIV-infected patients.^[14]

In the pre-HAART era, the prognosis in patients with PML was dismal, with death occurring within 4-6 months after diagnosis in most cases. Approximately 8% of patients experienced spontaneous recovery.

With the widespread adoption of highly active antiretroviral therapy (HAART), the incidence of PML decreased substantially. In addition, several case series have shown prolonged survival for patients receiving HAART.^[15] In a series of 118 consecutive patients from Spain, 63.6% survived for a median of 114 weeks (2.2 y) after diagnosis of PML.^[16]

CD4⁺ T-cell counts less than 100/μL at baseline are associated with a higher mortality rate. Death may result not from the neurologic condition but from end-stage immune deficiency.

In a recent clinical outcome study of 60 patients with PML (73% HIV+) who were prospectively evaluated for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood, estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV-negative patients with PML. The presence of JCV-specific CTLs was associated with a trend toward longer survival in patients with PML.^[17]

A study by Lima et al of 24 PML patients whose survival exceeded 5 years found that by the end of the follow-up period, 33% of patients had no significant disability despite persistent symptoms; 25% had slight disability and were living independently; 21% were moderately disabled, requiring some help during activities of daily living; and 21% had moderately severe disability, requiring constant help or institutionalization.^[18]

Patients with progressive multifocal leukoencephalopathy (PML) typically experience insidious onset and steady progression of focal symptoms that include behavioral, speech, cognitive, motor (eg, head tremor^[19] ), and visual impairment. Unlike other major opportunistic disorders that produce focal brain lesions (eg, cerebral toxoplasmosis, primary CNS lymphoma), which characteristically progress over the course of hours or a few days, PML evolves over several weeks.^[7] However, PML demonstrates more rapid progression than AIDS dementia complex (ADC).

As individual lesions expand, either concentri­cally or along white matter tracts, manifestations may worsen and involve a larger territory. For example, initial weakness of one leg may progress to hemiparesis.^[7]

Although seizures have been considered a rare manifestation of PML, Lima et al found that seizures occurred in 18% of PML patients.^[20] Many of the PML patients presenting with seizures had demyelinating lesions immediately adjacent to the cortex. Seizures usually responded well to treatment and did not affect survival.

In PML related to immune reconstitution, onset may occur weeks to months after the initiation of antiretroviral therapy.

Physical examination

Focal neurologic signs include aphasia, hemiparesis, ataxia, cortical blindness, and, less frequently, head tremor. Focal signs tend to be related to posterior brain (eg, occipital lobes).

Conjugate gaze abnormalities are common. This is the initial presentation in more than 30% of patients. Abnormalities may progress to quadriparesis and coma. Occasionally, neurologic signs are diffuse rather than focal.

In a patient with steadily progressive focal neurologic deficits consistent with progressive multifocal leukoencephalopathy (PML), neuroimaging is indicated. The combination of a characteristic clinical picture and typical imaging findings supports a confident presumptive diagnosis of PML.^[7]

Computed tomography or magnetic resonance imaging

With CT scan or MRI of the brain, single or multiple confluent lesions without mass effects are seen, most frequently in the parieto-occipital white matter. Occasional infratentorial lesions are usually asymmetrical. Sparing of subcortical U fibers is characteristic. Subcortical gray matter or spinal cord may be involved, but rarely. Gray matter involvement has a scalloped appearance.

PML sometimes can resemble lymphoma, toxoplasmosis, or HIV encephalitis. However, the absence of a mass effect or displacement of normal structures is more consistent with PML than these other disorders.^[7]

CT scan may show hypodense lesions. On MRI, PML lesions characteristically are hypointense on T1-weighted images; this finding may be subtle but can help distinguish PML lesions from those of other diseases (eg, white matter lesions of HIV encephalitis). On T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, PML lesions are characteristically hyperintense (see the image below).^[7]

Neuroimaging in patients with inflammatory PML may demonstrate atypical features, including a mass effect of the PML lesions with surrounding edema. Con­trast enhancement, which is uncommon in classic PML and tends to be sparse when it does occur, may be striking in patients with inflammatory PML.^[7]

Lumbar puncture

Cerebrospinal fluid (CSF) is usually normal, but protein may be elevated slightly. Normal CSF findings serve to rule out other etiologies.

Polymerase chain reaction (PCR) of the CSF has been shown to be highly specific (92-99%) and sensitive (74-93%) for the detection of JC virus in patients with PML.^[21] Measuring CSF JC virus DNA load is a reliable marker of disease activity in patients receiving HAART and has a potential use in drug trials. Conceivably, this test could eliminate the need for brain biopsy. However, the detection of JC virus in CSF may be less likely in patients with inflammatory PML.^[7]

Brain biopsy has a sensitivity of 74-92% and a specificity of 92-100% in progressive multifocal leukoencephalopathy (PML). Mild cortical atrophy may be seen on biopsy specimens.

Multiple demyelinative foci may be seen in the cerebral, cerebellar, and brainstem white matter and at the gray-white matter junction; in severe cases, such foci may be seen in the cortical gray matter. Foci may become confluent (see the images below).

Perivascular inflammatory infiltrates are observed. Necrotic and cystic lesions may be present but are rare.

Nuclear inclusions may be seen in large ballooned oligodendrocytes and rarely in astrocytes, both of which show bizarre-looking nuclei. The inclusions contain viruses as identified by electron microscopy and immunohistochemistry.

All treatments are experimental in progressive multifocal leukoencephalopathy (PML). The principal approach is antiretroviral therapy. Treatment guidelines for PML recommend (1) starting antiretroviral therapy immediately in patients with PML who are not on therapy and (2) optimizing the antiretroviral regimen for virologic suppression in patients who are receiving antiretroviral therapy but who remain HIV-viremic because of antiretroviral resistance.^[7]

Intensive treatment with 4 classes of antiretroviral drugs, including enfuvirtide, has been reported as providing a possible survival benefit in PML patients with undetectable plasma HIV. Currently, evidence is insufficient to support a recommendation for or against this approach.^[7]

The use of drugs that block the serotonergic 5HT2a receptor (eg, olanzapine, zisprasidone, mirtazapine, cyproheptadine, risperidone) has been suggested as treatment for PML, on the basis of a report indicating that this receptor can serve as the cellular receptor for JCV. Only anecdotal reports of this approach are available, however, and its routine use is not considered justified.^[7]

In some individuals, especially those with very low CD4⁺ counts, worsening of PML or new-onset PML can be observed after the initiation of highly active antiretroviral therapy (HAART). This is thought to be secondary to immune reconstitution inflammatory syndrome (IRIS). IRIS is considered as a paradoxical deterioration of a preexisting infection that is related to the recovery of the immune system. It is suggested to occur due to an imbalance of CD8⁺/CD4⁺ T cells.

Anecdotal case reports of use of pulsed methylprednisolone have shown rapid improvement in IRIS-associated PML.^[22] Treatment guidelines consider the use of corticosteroids justified in this setting (B rating).^[7]

Treatment trials have been conducted with cidofovir (used in AIDS patients with CMV),^[23] topotecan (topoisomerase inhibitor), and interferon-alfa.^[24] Results have been inconclusive, however, and treatment guidelines do not recommend the use of any of those agents.^[7]

In a multicenter trial, cytarabine did not improve prognosis in patients with PML^[25] ; consequently, its use is a not recommended.^[7]

The treatment of HIV-2–associated PML is challenging because HIV-2 is not susceptible to nonnucleoside reverse transcriptase inhibitors (NNRTIs). Two nucleoside reverse transcriptase inhibitors (NRTIs) combined with protease inhibitors (PIs) can be tried. Further studies are under way.