Progressive multifocal leucoencephalopathy: progress in the AIDS era

Progressive multifocal leucoencephalopathy (PML) has been described as a complication in various conditions which result in impaired cellular immunity—these include lymphoproliferative disorders and chronic granulomatous disorders such as sarcoidosis. Iatrogenic immunosuppression in post-transplant patients and patients undergoing cancer chemotherapy, as well as those with autoimmune disorders, is also a risk factor. The occasional case has been described in pregnant women which some may regard as being an immunosuppresssed state. A review in 1984 of 230 patients found that 69% were due to lymphoproliferative or myeloproliferative disorders, 7% granulomatous disorders, 6% postrenal transplant, and 4% occurred in patients with the acquired immunodeficiency syndrome (AIDS). About 6% of all patients with PML had no identifiable evidence of immunosuppression. These were all anecdotal reports from the early 1970s. Since the onset of the AIDS epidemic in 1981, the incidence of PML has increased significantly and now human immunodeficiency virus (HIV) associated cases account for up to 85% of all cases of PML. Before the introduction of highly active antiretroviral therapy (HAART), the estimated incidence in patients infected with HIV was 4%. HAART is the term used for a combination of three or four anti-HIV drugs from the following classes—nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transciptase inhibitors, and protease inhibitors. The widespread availability and uptake, at least in the developed world, of HAART has had a dramatic impact on morbidity and mortality of patients infected with HIV. This is, in part, due to reduction in incidence of opportunistic infections. In the period 1995 to 1997, one United States study documented a fall in the combined incidence of Pneumocystis carinii pneumonia, Mycobacterium avium complex, and cytomegalovirus infection from 21.9 per 100 person-years to 3.7 per 100 person-years. In one London hospital, the number of cases of toxoxplasmosis fell from 19 cases in 1996 to five in 1998. Reports pertaining to the incidence of PML since the introduction of HAART have, to date, been conflicting. Progressive multifocal leucoencephalopathy (PML) is an acquired demyelinating disorder of the CNS caused by the JC virus. This DNA virus, so labelled after the initials of the patient whose tissue was used to isolate it, is a member of the genus Polyomavirus in the family Papovaviridae, which also includes BK virus and SV 40 virus. The clinical presentation of PML is usually one of a progressive neurological deficit resulting in a monoparesis or hemiparesis, hemianopia, or ataxia (table). Despite its name, the disease is not restricted to cerebral white matter as the presentation may be with cortical deficits such as dysphasia, cortical blindness, or seizures. Cortical involvement may also be evident on MRI and in the neuropathological findings. Patients may also present with a dementing disorder with focal neurological signs. By contrast with the other causes of focal abnormalities in patients infected with HIV—toxoplasmosis and primary CNS lymphoma—there are no symptoms or signs of raised intracranial pressure or of systemic infection. There has been only one description of spinal cord involvement diagnosed at necropsy but not antemortem. In the appropriate clinical setting, MR scans have some characteristic features—the lesions, which may be single or multiple, involve mainly white matter and may depict a scalloping at the grey/white interface due to involvement of the arcuate fibres (figure A and B).The parieto-occipital and frontal areas of the brain are most often aVected. Less often, abnormalities are found in the posterior fossa, corpus callosum, thalamus, and basal ganglia. The aVected areas are of low signal intensity on T1 weighted sequences. The hyperintense lesions on T2 weighted images are much more obvious and occasionally dramatic. Cranial CT shows hypodense lesions. Contrast enhancement and mass eVect are seen only rarely on imaging studies. Occasionally, HIV encephalopathy may cause diagnostic confusion but clinical focal signs are rare and on imaging the abnormalities tend to be more symmetric and less discrete than in PML. On T1 weighted MRI images the low signal lesions due to PML are much more obvious than in HIV related changes. Before and in the early years of the AIDS epidemic, a definitive diagnosis of PML was only possible by brain biopsy. The typical histological features are of areas of Table 1 Clinical signs and symptoms (%) of patients with PML