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HIV-associated PML: Changing epidemiology and clinical approach

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ABSTRACTDespite the availability of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) infection, there has not been a dramatic decrease in the frequency of progressive multifocal leukoencephalopathy (PML) in the HIV-infected population. Usually a multifocal progressive disease of nonenhancing lesions in white matter, PML can have distinct characteristics in HIV-infected patients, including unifocal static lesions of faint contrast enhancement on imaging and involvement of gray matter. A syndrome of cerebellar degeneration has been described in association with HIV infection in patients positive for JC virus, the papovavirus responsible for PML. The standard of care for HIV-associated PML is HAART to achieve immunologic recovery and optimal HIV virologic control. The prognosis of PML has improved greatly since the advent of HAART.


 

References

The appearance of progressive multifocal leukoencephalopathy (PML) as a complication of human immunodeficiency virus (HIV) infection dates to shortly after the first description of acquired immunodeficiency syndrome (AIDS). The advent of highly active antiretroviral therapy (HAART) dramatically altered the nature of HIV infection, resulting in a substantial decline in mortality and, in essence, turning AIDS into a chronic disease. As patients lived longer with HIV infection, one consequence was an increased incidence of neurologic complications. By the early 1980s, AIDS was well recognized as an underlying disorder that predisposed to PML.

As many as 70% of HIV patients will eventually have involvement of either the peripheral or central nervous system (CNS). Most patients with HIV are managed by primary care clinicians, including those in the fields of family practice, internal medicine, or infectious disease, and the complexity of the neurologic disorders associated with HIV often results in either delayed diagnosis or misdiagnosis. For example, the evolution of HIV in the plasma, where most clinicians measure it, may differ from its evolution in the spinal fluid and brain. An emerging issue is that of hepatitis C coinfection, which may itself be associated with central and peripheral neurologic complications.

Treatment of HIV with antiretroviral agents has numerous neurologic implications. These include the potential ability of these agents to penetrate the blood-brain barrier, their efficacy in both treating and preventing cognitive impairment and other CNS disorders, and their toxic effects in the CNS and peripheral nervous system.

NEUROLOGIC COMPLICATIONS OF AIDS

Neurologic disease in AIDS patients can be classified in several ways. One of the most logical, particularly for primary care clinicians, is the separation of primary from secondary neurologic disorders:

  • Primary neurologic disorders are enigmatic and difficult to characterize; they include HIV-associated neurocognitive disorders in adults, encephalopathy in children, myelopathy or spinal cord disease, and peripheral neuropathy.
  • Secondary complications are related to progressive immunosuppression. These include opportunistic infections such as cytomegalovirus, toxoplasmosis, or cryptococcal meningitis; and neoplasms such as primary CNS lymphoma. Opportunistic infections and neoplasms have declined in incidence in the HAART era.
The prevalence of neuropathy as a neurologic complication of HIV/AIDS is as high as 57%, while PML affects 5% or fewer of HIV-infected patients (Table). PML in these patients is often associated with advanced disease, as reflected by low CD4+ cell counts and increased plasma HIV viral loads.

AT-RISK POOLS FOR PML

The AIDS epidemic significantly changed the epidemiology of PML, turning a formerly rare disease into a much more common one. In South Florida, the incidence of PML in patients with AIDS increased by 12 times from the 5-year period 1981 to 1984 compared with 1991 to 1994. Only two non-AIDS cases of PML were reported in South Florida during this 15-year period.1

At present, nonimmunosuppressed, healthy individuals account for fewer than 1% of all cases of PML. Non-HIV–related PML represents 10% to 20% of all PML cases. Cancer survivors and patients with rheumatoid arthritis who are treated with immunotherapy constitute the largest at-risk pools among this group. PML related to HIV represents 80% to 90% of PML cases, drawing from a pool of 1.2 million HIV-infected individuals in the United States.

UNIQUE PRESENTATION OF HIV-ASSOCIATED PML

The brain lesion in PML is classically a nonenhancing focal lesion, preferentially in white matter, but lesion characteristics often depart from this characteristic picture. For example, relatively faint contrast enhancement of lesions on magnetic resonance imaging has been observed, as well as involvement of white matter and gray matter. The distribution and character of brain lesions in PML may also differ from the classic picture. For example, the lesion may not be focal, particularly when PML is combined with the symmetric white matter abnormalities that are seen in HIV encephalopathy; this nonclassic presentation can cause difficulty in radiologic differentiation of PML and HIV encephalopathy.

Cerebellar degeneration

A unique presentation of PML is possible in HIV-infected patients. In 1998, Tagliati et al2 described a syndrome of degeneration of the cerebellum in 10 HIV-infected patients. One patient had JC virus (JCV) detected by polymerase chain reaction (PCR) in cerebellar biopsy tissue. The authors proposed the possibility of latent JCV infection of cerebellar granular cells in HIV-infected patients with cerebellar atrophy, lacking further evidence of other features of PML.

Figure. Magnetic resonance imaging demonstrates diffuse cerebellar atrophy (A, arrow) without areas of enhancement and white matter abnormalities (B, arrow) in a patient with JC virus–associated cerebellar degeneration.3

In 2005, Koralnik et al3 described a case of JCV granule cell neuronopathy in a patient with JCV-associated cerebellar degeneration. Clinical symptoms included gait and limb ataxia, dysmetria, dysarthria, and nystagmus. Magnetic resonance imaging demonstrated diffuse cerebellar atrophy and occasional subtle white matter abnormalities within the cerebellum (Figure). Immunohistochemistry showed preservation of Purkinje cells, and in situ PCR revealed selective depletion of cerebellar granule cells and JCV infection of granule cell neurons.

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