(See also Introduction to Brain Infections Introduction to Brain Infections Brain infections can be caused by viruses, bacteria, fungi, or, occasionally, protozoa or parasites. Encephalitis is most commonly due to viruses, such as herpes simplex, herpes zoster, cytomegalovirus... read more .)
Etiology of PML
Progressive multifocal leukoencephalopathy is caused by reactivation of the JC virus, a ubiquitous human papovavirus that is typically acquired during childhood and remains latent in the kidneys and possibly other sites (eg, mononuclear cells, central nervous system [CNS]). The reactivated virus has a tropism for oligodendrocytes.
Most patients who develop PML have depressed cell-mediated immunity due to
Reticuloendothelial system disorders (eg, leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more , lymphoma Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more )
Other conditions (eg, Wiskott-Aldrich syndrome Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome is an immunodeficiency disorder that involves a combined B- and T-cell defect and is characterized by recurrent infection, eczema, and thrombocytopenia. (See also Overview... read more , organ transplantation Overview of Transplantation Transplants may be The patient’s own tissue (autografts; eg, bone, bone marrow, and skin grafts) Genetically identical (syngeneic [between monozygotic twins]) donor tissue (isografts) Genetically... read more )
The risk in AIDS increases with increasing HIV viral load; prevalence of PML has decreased because of widespread use of more effective antiretrovirals.
Increasingly, PML is occurring as a complication of immunomodulatory therapy. The drugs most frequently implicated include
The monoclonal antibody natalizumab
The antibody-drug conjugate brentuximab vedotin
But PML has occurred in patients taking other drugs (eg, rituximab, fingolimod, dimethyl fumarate). Measuring serum antibodies to JC virus (JC virus index) may help assess the risk of PML in patients taking natalizumab; higher levels indicate higher risk.
Symptoms and Signs of PML
Clumsiness may be the first symptom of progressive multifocal leukoencephalopathy. Hemiparesis is the most common finding. Aphasia, dysarthria, and hemianopia are also common. Multifocal cortical damage produces cognitive impairment in two thirds of patients. Sensory, cerebellar, and brain stem deficits may be present.
Headaches and convulsive seizures are rare and occur most often in patients with AIDS.
Gradual, relentless progression culminates in death, usually 1 to 9 months after symptoms begin.
Diagnosis of PML
Cerebrospinal fluid (CSF) testing for JC viral DNA
Progressive multifocal leukoencephalopathy is suspected in patients with unexplained progressive brain dysfunction, particularly in those with depressed cell-mediated immunity.
Provisional diagnosis of PML is made by contrast-enhanced MRI, which shows single or multiple white matter lesions on T2-weighted images. A contrast agent enhances, usually faintly and peripherally, 5 to 15% of lesions. CT may show low-density, nonenhancing lesions but is significantly less sensitive than MRI.
CSF is analyzed for JC viral DNA using PCR; a positive result with compatible neuroimaging findings is nearly pathognomonic. Routine CSF analysis is usually normal.
Serologic tests are not helpful. Stereotactic biopsy can provide a definitive diagnosis but is rarely warranted.
Treatment of PML
Treatment of progressive multifocal leukoencephalopathy is mainly supportive.
Experimental use of drugs such as cidofovir and other antivirals has failed to provide benefit. Antiretroviral therapy (ART) in AIDS patients has improved outcome in PML, increasing the 1-year survival rate from 10 to 50%. However, patients treated with aggressive antiretroviral therapy may develop immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more (IRIS). In IRIS, the recovering immune system produces an intense inflammatory response against the JC virus, thus worsening symptoms. Imaging done after IRIS develops shows greater contrast enhancement of the lesions and may show significant cerebral edema. Corticosteroids may be helpful. Depending on the severity of IRIS and of AIDS, clinicians may decide to withdraw ART.
Withdrawal of immunosuppressants may result in clinical improvement. However, patients who stop taking these drugs are also at risk of developing IRIS.
If PML develops in patients taking natalizumab, another immunomodulatory drug, or an immunosuppressant, the drug should be stopped, and plasma exchange should be done to remove residual circulating drug.
Limited data suggest that treatment with the programmed cell death 1 (PD-1) inhibitors pembrolizumab or nivolumab (immune checkpoint inhibitors) may decrease viral load in the CSF, increase antiviral cellular immune activity, and lead to clinical improvement (1 Treatment references Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the JC virus. The disease usually occurs in patients with impaired cell-mediated immunity, particularly patients... read more , 2 Treatment references Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the JC virus. The disease usually occurs in patients with impaired cell-mediated immunity, particularly patients... read more ).
1. Cortese I, Muranski P, Enose-Akahata Y, et al: Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Engl J Med 380 (17):1597–1605, 2019. doi: 10.1056/NEJMoa1815039 Epub 2019 Apr 10.
2. Lambert N, El Moussaoui M, Maquet P: Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: Identifying relevant outcome factors. Eur J Neurol 2021 28 (11):3814–3819, 2021. doi: 10.1111/ene.15021 Epub 2021 Jul 26.
Reactivation of the ubiquitous JC virus, usually due to impaired cell-mediated immunity, leads to PML.
PML commonly causes clumsiness, hemiparesis, aphasia, dysarthria, hemianopia, and cognitive impairment.
Do MRI and test CSF for JC virus DNA in patients who have impaired cell-mediated immunity and unexplained progressive brain dysfunction.
Treat patients supportively, and manage underlying disorders as indicated (eg, by stopping natalizumab, another immunomodulatory drug, or an immunosuppressant or, in patients with AIDS, by initiating antiretroviral therapy and watching closely for development of immune reconstitution inflammatory syndrome).
Limited data suggest that treatment with pembrolizumab or nivolumab may decrease viral load in the CSF, increase antiviral cellular immune activity, and lead to clinical improvement.