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