Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease which results from the reactivation of John Cunningham virus (JC virus) infecting oligodendrocytes in patients with compromised immune systems. It is considered the most common clinical manifestation of John Cunningham virus (JC) virus infection in the brain 7, and is seen in three clinical contexts:
- PML due to immunocompromised state
- PML-s-IRIS: simultaneous development of Immune Reconstitution Inflammatory Syndrome (IRIS) and PML due to immune reconstitution
- PML-d-IRIS: immune reconstitution worsens pre-existing PML
Progressive multifocal leukoencephalopathy is strongly associated with immunosuppressed states, particularly AIDS, but also can occur in patients with bone marrow or solid organ transplants, leukemia, solid organ malignancies, inflammatory diseases and isolated CD4 lymphocytopenia 4,17. The incidence in the non-HIV settings is thought to be increasing. Primary PML developing in an immunocompetent patient is very rare.
In AIDS, it typically develops in patients with CD4 counts of 50-100 cells/μL and is found in approximately 5% of autopsies of patients who died from AIDS 2.
More recently it has also been associated with natalizumab (TysabriTM), an IgG monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis 5.
In addition to being seen in immunocompromised patients, it is also seen in patients whose immune function is recovering, and PML is one of the classic conditions encountered in immune reconstitution inflammatory syndrome (IRIS) 16.
Patients with progressive multifocal leukoencephalopathy present with various neurological symptoms. It typically spares the optic nerve and the spinal cord. The most frequently encountered symptoms include:
- altered mental status
- motor deficits
- limb and gait ataxia
- visual symptoms (diplopia and hemianopia)
- seizure (as PML can also involve the grey matter in late stage)
The final diagnosis is established with brain biopsy (specificity: 100%, sensitivity: 65-95%).
PML lesions are secondary to progressive demyelination due to John Cunningham (JC) virus (usually reactivation) which infects oligodendrocytes. In PML seen in HIV/AIDS, reactivation is typically seen when CD4 cell count drops below 100/μL 17.
Lesions tend to have a confluent, bilateral but asymmetrical supratentorial white matter and thalamic involvement 7. However, basal ganglia, brainstem and cerebellum also can be involved. Subcortical frontal and parieto-occipital regions are common locations. However, isolated posterior fossa involvement has also been reported 15. While the condition invariably involves white matter, subcortical U-fibers and in late stages of disease grey matter involvement is also seen 6.
Histology reveals demyelinating plaques involving the white matter and subcortical U-fibers. Other findings include infected oligodendrocytes with enlarged amphophilic nuclei located at the periphery of the lesions, macrophages containing phagocytosed cellular debris and myelin, and reactive gliosis with enlarged astrocytes 13.
Asymmetric focal zones of low attenuation involving the periventricular and subcortical white matter. This is in contradistinction to more symmetrical hypoattenuation seen in HIV encephalopathy.
Typically seen as multifocal, asymmetric periventricular and subcortical involvement. There is little, or no mass effect or enhancement 10 and the subcortical U-fibers are commonly involved with a predilection for the parieto-occipital regions 17. Corpus callosum may be involved 17.
- T1: involved regions are usually hypointense
- T2: involved regions are hyperintense
T1 C+ (Gd)
- typically there is no enhancement 10
- enhancement can be seen in PML-IRIS, AIDS with HAART, and in patients on natalizumab 16,17
- when enhancement is present, it may be associated with improved survival 3,17
- MR spectroscopy: according to one study, spectra of PML lesions were characterized by significantly reduced NAA, lactate presence, and by significantly increased choline and lipids compared with control group values 8
- ADC/DWI: peripheral patchy diffusion restriction particularly at the leading edge 14
- elevated at the leading edge of lesions
- most commonly seen in progressive non-IRIS PML 18
A characteristic imaging finding has recently been described by Bezuidenhout et al. termed the barbell sign. It refers to a coalescent bilateral parieto-occipital T2 and FLAIR hyperintense lesion with involvement of the splenium of the corpus callosum reminiscent of a barbell (see case). This lesion has minimal or no mass effect, no post-contrast enhancement and a thin rim of peripheral diffusion restriction reflecting the typical imaging findings seen in PML 19.
Treatment and prognosis
Prognosis is generally poor with an inexorable neurologic decline leading to coma and death occurring in the majority of patients with PML 9. If untreated, PML is usually fatal within one year, often within 2 to 6 months 17. Treatment with highly active antiretroviral therapy (HAART) may prolong survival, although in some instances this leads to PML-IRIS. High-dose glucocorticoid therapy is recommended for patients with PML-IRIS. Some reports also state some benefit with cytarabine or mirtazapine, the latter especially in natalizumab-associated PML.
- HIV/AIDS encephalopathy: often diffuse white matter disease, with atrophy
- posterior reversible encephalopathy syndrome (PRES)
- differing clinical history (e.g. hypertension)
- can involve both grey and white matter
- acute disseminated encephalomyelitis (ADEM)
- differing clinical history (e.g. recent infection/vaccination)
- can involve both grey and white matter
- lesions usually enhance
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