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The clinical features of PML

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ABSTRACTThe symptoms associated with progressive multifocal leukoencephalopathy (PML) reflect the location of pathologic brain lesions. These symptoms include visual deficits, cognitive impairment, and motor weakness; in patients with acquired immunodeficiency syndrome (AIDS), presenting signs can also include gait disturbance, dysarthria, dysphasia, and ocular palsy. Recently, PML has been observed in patients treated with biologic agents; natalizumab recipients currently represent the second largest group of patients with PML (behind patients with AIDS). Although brain biopsy is the most accurate and reliable method for diagnosing PML, it is rarely used today. Diagnosis is usually based on detection of JC virus in the cerebrospinal fluid by polymerase chain reaction, the clinical presentation, and demonstration of PML brain lesions on magnetic resonance imaging. With immune reconstitution, the prognosis of PML has improved markedly.


 

References

Progressive multifocal leukoencephalopathy (PML) was a rare disease until the era of human immunodeficiency virus (HIV) infection, when the number of cases of PML markedly increased. We are now entering a new era in which PML is being observed in patients treated with biologic agents for diseases not associated with development of PML.

This article reviews the epidemiology and symptoms that characterize PML, the identification of lesions on radiographic imaging that support the diagnosis, the value of laboratory studies and immunocytochemistry in the diagnosis, and clinical outcomes.

CHANGING EPIDEMIOLOGY OF PML

Figure. Although certain findings are considered classic in progressive multifocal leukoencephalopathy (PML) patients, the percentage of patients affected has shifted as the disorder has evolved from the pre–acquired immunodeficiency syndrome (AIDS) era to PML associated with biologic therapies such as natalizumab. Prior to the AIDS era, nearly one-half of patients with PML were affected by visual deficits. Among patients with AIDS-related PML, motor weakness is a feature for more than one-half, while cognitive impairment is the most common clinical presentation of natalizumab-related PML, affecting nearly one-half of patients.1,2,6,9

The presentation and epidemiology of PML have evolved over the last several decades. Prior to the acquired immunodeficiency syndrome (AIDS) era, nearly one-half of patients with PML were affected by visual deficits. Among patients with AIDS-related PML, motor weakness is a feature for more than one-half, while cognitive impairment is the most common clinical presentation in natalizumab-related PML, affecting nearly one-half of patients (Figure).

The pre-AIDS era

Lesions of subcortical white matter characterize PML and the patient’s clinical manifestations reflect their location. Brooks and Walker1 reviewed 69 pathologically confirmed and 40 virologically and pathologically confirmed cases of PML in the era before AIDS, and categorized the neurologic signs and symptoms at onset and during disease progression; the clinical picture had three significant findings:

  • Impaired vision: Defective vision, most commonly homonymous hemianopsia, was the most frequent presenting sign, present in 35% to 45% of cases. At the time of diagnosis, 6% to 8% of the patients were cortically blind because of bioccipital pathology.
  • Motor weakness: Motor weakness was the initial sign in 25% to 33% of patients. At the time of diagnosis, hemiparesis or hemiplegia was present in nearly all patients.
  • Changes in mentation: A change in mentation, including personality change, difficulty with memory, emotional lability, and frank dementia, was the presenting sign in approximately one-third of cases and eventually involved most patients.

AIDS-related PML

The epidemiology of PML changed with the AIDS pandemic. From 1958 to 1984, Brooks and Walker1 identified 230 cases of PML; in the period from 1981 to 1994, Berger and colleagues2 described 154 cases of AIDS-related PML that had been identified by the University of Miami Medical Center and the Broward County medical examiner’s office. The frequency of PML from 1991 through 1994 was 12-fold greater than the frequency 10 years earlier, from 1981 through 1984. Among the patients with AIDS-related PML, the most common initial symptoms were weakness (42%), speech abnormalities (40%), cognitive abnormalities (36%), gait abnormalities (29%), sensory loss (19%), and visual impairment (19%), followed by seizures, diplopia, and limb incoordination. The most common findings at the time of initial physical examination were weakness (54%), followed by gait abnormalities (20%), cognitive abnormalities (20%), dysarthria (24%), aphasia (19%), sensory loss (19%), visual impairment (17%), and oculomotor palsy (6%). For about 5% of patients with PML, it is the heralding manifestation of AIDS.

Although clinical features consistent with cerebral hemisphere lesions are most common, brainstem and cerebellar findings are also observed. Among these are ataxia, dysmetria, dysarthria, and oculomotor nerve palsies.2–4 Other signs and symptoms associated with PML include headache, vertigo, seizures, sensory deficits, parkinsonism, 5 aphasia, and neglect syndromes.1–4 In some cases, the coexistence of encephalitis with HIV infection could have accounted for some of the symptoms.

PML associated with monoclonal antibody therapy

Natalizumab is an alpha-4-beta-1 integrin inhibitor approved for the treatment of relapsing-remitting multiple sclerosis (MS); patients taking natalizumab represent the second largest group with PML (the largest group is patients with AIDS). Natalizumab-associated PML has some noteworthy features. The most common clinical presentations are cognitive disorders (48%), motor abnormalities (37%), language disturbances (31%), and visual defects (26%). Lesions are often monofocal rather than multifocal and the most common site of involvement is the frontal lobe.6 Among MS patients with natalizumab-associated PML, 30% to 40% have gadolinium-enhancing lesions on magnetic resonance imaging (MRI) at the time of diagnosis.

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME

The immune reconstitution inflammatory syndrome (IRIS) is a paradoxical clinical deterioration that typically occurs in the face of immunologic recovery (Table).7,8 Although not unique to PML or opportunistic infections, it is frequently observed in the setting of HIV infection and natalizumab-associated PML, and it may be concurrent with the diagnosis of PML.6,9

Among patients with HIV, predictors for the development of IRIS include antiretroviral naiveté, profoundly low CD4 lymphocyte counts (< 50 cells/mm3), a rapid decrease in HIV load, and the presence of active or subclinical opportunistic infections at the time of initiation of combined antiretroviral therapy. Tan and colleagues8 have reported the largest series to date. Of the 54 patients in their series, 36 developed PML and IRIS simultaneously, and 18 had worsening of preexisting PML. Although some investigators have recommended corticosteroid therapy for PML-IRIS, no controlled trials have been conducted and caution has been advised, particularly in patients without contrast enhancement on MRI or mass effect.

DIAGNOSTIC TESTING: NEUROIMAGING, CEREBROSPINAL FLUID ANALYSIS

Neuroimaging, including computed tomography (CT) and MRI, is a useful diagnostic tool for investigating a patient with PML. Cerebrospinal fluid (CSF) analysis for the presence of JC virus (JCV) may play a significant role, but it primarily serves to rule out other illnesses.

Computed tomography: lesion size may not reflect clinical status

On CT, demyelinating lesions appear as subcortical hypodensities, often with a propensity for parietooccipital areas that are confined to the white matter at the junction interface of the gray-white junction of the cortex.9–11 Lesions may be seen in the corpus callosum, thalamus, and basal ganglia,9 but changes in the size of lesions observed on CT do not necessarily reflect clinical progression.12 Prior to the availability of highly active antiretroviral therapy (HAART) for the treatment of AIDS, mass effect was exceptionally rare. However, the development of IRIS with PML, typically in AIDS patients following the use of HAART, may be associated with edema.13 Single-dose intravenous contrast and delayed, double-dose contrast CT scanning enhancement is observed in a minority of patients, typically fewer than 10%.8 This enhancement is generally faint and peripherally located.

Magnetic resonance imaging may show lesions before clinical disease

MRI is vastly more sensitive than CT in detecting the demyelinating lesions of PML.9,14 On rare occasions, MRI will clearly demonstrate pathology when CT is normal. In fact, MRI may show lesions in advance of clinically apparent disease.15 The characteristics of these lesions are hyperintensity on T2-weighted imaging, fluid-attenuated inversion recovery sequences, and hypointensity on T1-weighted image. Apparent diffusion coefficients (ADC) on MRI are typically normal to low in new lesions and at the advancing edge of lesions; the ADC was typically higher in the center of lesions.16

As observed on CT, approximately 10% of patients exhibit a faint rim of gadolinium enhancement.2,9 Enhancement is more common with PML-IRIS, and the distribution of lesions parallels what is seen pathologically. Enhancement PML lesions have altered signal characteristics compared with the surrounding white matter.9,17–19 In contrast, 15% of HIV-associated PML showed gadolinium enhancement on MRI at the time of diagnosis.6,9

Cerebrospinal fluid analysis

With the exception of polymerase chain reaction (PCR) for JCV, the primary utility of lumbar puncture in the setting of possible PML is to exclude the presence of other illnesses, including treatable infections.

CSF findings in patients with PML are nonspecific, with most patients demon strating a normal profile. A mild lymphocytic pleocytosis, which is rarely (if ever) more than 25 leukocytes/mL, occurs in 15% of patients. Total protein level is mildly elevated in approximately 20% to 30% of patients.

The CSF examination in HIV-infected patients with PML may reflect changes associated with HIV: low-grade lymphocytic pleocytosis (< 20 cells/mm3), mildly elevated protein (< 65 mg/dL), and elevated immunoglobulin G and oligoclonal bands. These abnormalities should not be attributed to PML.

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