Progressive Multifocal Leukoencephalopathy

Background

Classic PML

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of latent infection with JC virus, a polyomavirus that infects and lyses oligodendrocytes. Demyelination can occur along any part of the white matter, and often does so at multiple sites (hence the term multifocal). The severity of symptoms increases as demyelination progresses.

Among HIV-infected patients, PML occurs classically and most frequently in those with CD4 counts of <100 cells/µL. They typically present with multiple focal deficits of the cerebrum and brainstem, such as cognitive decline, focal weakness, and cranial nerve palsies, with one focal deficit often predominating. Symptoms typically progress over the course of several weeks. Imaging studies show noninflammatory, nonenhancing white matter lesions, without mass effect, with an anatomical location that maps to deficits on the neurological examination. A presumptive diagnosis of PML often can be made on the basis of the patient's clinical presentation and results of neuroimaging studies. Cerebrospinal fluid (CSF) often tests positive for JC virus DNA by polymerase chain reaction (PCR), although brain biopsy is sometimes needed for definitive diagnosis.

Although PML classically occurs in patients not receiving antiretroviral therapy (ART), it can occur in patients on ART, with suppressed HIV RNA but low CD4 counts. Among untreated patients, the interval between the first manifestation of neurologic symptoms and death may be as short as 3-4 months. Although the prognosis for patients with PML has improved with the use of potent ART, there is no specific treatment for PML, and mortality rates remain high. Patients who survive PML are likely to have permanent neurologic deficits.

Inflammatory PML

Whereas PML in the absence of ART usually is not an inflammatory condition, initiation of ART may cause an immune reconstitution-like syndrome, involving new or worsening neurologic deficits and inflammatory changes seen on brain imaging and biopsy specimens. (See chapter Immune Reconstitution Inflammatory Syndrome.) The initiation of ART in a patient with late-stage HIV-related disease may even reveal previously undetected PML. Although many patients with inflammatory PML improve or at least stabilize, some suffer exacerbation of symptoms, rapid progression of disease, cerebral edema, herniation, and death.

S: Subjective

The patient or a caregiver may note symptoms such as weakness, gait abnormalities, difficulties with speech, visual changes, altered mental status, personality changes, and seizures. Hemianopia, ataxia, dysmetria, and hemiparesis or hemisensory deficits are often seen. The onset is likely to be subacute, with progression over the course of weeks, though neurologic disturbances may become profound. PML is not associated with headache or fever; this may help to distinguish it from other opportunistic illnesses of the CNS.

O: Objective

• Measure vital signs.
• Perform a full physical examination, including a thorough neurologic and mental status evaluation. Look for focal or nonfocal neurologic deficits, particularly cranial nerve abnormalities, visual field defects, weakness, gait abnormalities, and abnormalities in cognitive function, speech, or affect; deficits are likely to be multiple. The patient typically is alert.
• Review previous laboratory values, particularly CD4 count (usually <100 cells/µL in patients with PML).

A: Assessment

Rule out other causes of the patient's neurologic changes. A partial differential diagnosis includes the following:

• CNS lymphoma
• Toxoplasmosis
• HIV encephalopathy
• HIV dementia
• Other (non-HIV) forms of dementia
• Cerebrovascular disease
• Neurosyphilis
• CNS opportunistic infection (e.g., tuberculosis, cryptococcosis, and cytomegalovirus)
• Multiple sclerosis

P: Plan

Diagnostic Evaluation

Definitive diagnosis requires a brain biopsy and identification of characteristic pathological changes, or detection of JC virus DNA in CSF of patients with radiographic and clinical findings consistent with PML.

Presumptive diagnosis of PML often is made on the basis of clinical presentation, brain imaging, and laboratory tests. A brain biopsy should be considered with patients for whom a diagnosis is unclear.

Radiographic Studies

CNS imaging may reveal changes typical of PML, but is nonspecific. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) for detecting PML. Classic PML presents as single or multiple hypodense lesions in the subcortical white matter, with no surrounding edema. On MRI, lesions show increased T2 signal and little or no enhancement with gadolinium. On CT, PML lesions typically are nonenhancing. In some patients, and particularly in patients taking ART, PML lesions may show inflammatory changes, such as enhancement, and there may be cerebral edema.

CSF Evaluation

• CSF cell count, protein level, and glucose level generally are normal or show mild pleocytosis and slightly elevated protein.
• JC virus PCR assays are approximately 75-85% sensitive; detection of JC virus in a patient whose clinical presentation and radiographic imaging results are consistent with PML is adequate to make a diagnosis. A negative result with JC virus PCR does not rule out PML.

Other Studies

• Other diagnostic tests should be performed as indicated to rule out other potential causes of the patient's symptoms.
• A brain biopsy should be considered if the diagnosis is unclear.

Treatment

• There is no specific treatment for JC virus. Potent ART with maximal virologic suppression and effective immune reconstitution is the only treatment that may be effective for patients with PML. Even with ART, however, mortality rates approach 50%, and neurologic deficits are unlikely to be reversible.
• Initiate ART for patients who are not already receiving treatment. It is not clear whether antiretroviral agents with good CNS penetration are more effective than those that are less likely to cross the blood-brain barrier.
• For patients who are on ART with incomplete virologic suppression, change the ART regimen appropriately to achieve virologic suppression, if possible. For patients on ART with poor immunologic response, consider changing or intensifying therapy with the goal of improved immunologic recovery. (See chapter Antiretroviral Therapy.)
• If symptoms are caused by immune reconstitution, consider adding corticosteroids (e.g., dexamethasone) to help decrease inflammation.
• The following agents have been proposed as specific therapy for PML, but have not been shown to be effective by prospective studies and are not recommended for treatment: cidofovir, cytarabine, topotecan, interferon-alfa, and inhibitors of the serotonergic 5-HT2a receptor.
• Depending on the patient's cognitive and physical status, he or she may need a care provider in the home to assure that medications are taken on schedule.
• The patient is likely to need supportive care for personal hygiene, nutrition, safety, and prevention of accidents or injury; refer as indicated.

Patient Education

• Most patients diagnosed with PML will need supportive treatment for an undetermined period of time, and hospice referral should be considered if the patient does not show clinical improvement in response to ART.
• If the patient is receiving ART, be sure that caregivers, family members, and friends are taught about the medications and are able to help the patient with adherence.
• When a diagnosis of PML has been established or suspected, initiate a discussion of plans for terminal care (including wills, advanced directives, and supportive care and services) with the patient and family members or caregivers.

References

• Aksamit AJ. Review of progressive multifocal leukoencephalopathy and natalizumab. Neurologist. 2006 Nov;12(6):293-8.
• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol. 2004 Jun;17(3):365-70.
• Wyen C, Lehmann C, Fatkenheuer G, et al. AIDS-related progressive multifocal leukoencephalopathy in the era of HAART: report of two cases and review of the literature. AIDS Patient Care STDS. 2005 Aug;19(8):486-94.