eMedicine Specialties > Radiology > Brain/Spine

Progressive Multifocal Leukodystrophy

Author: Manohar Aribandi, MD, Academic Chief, Section of Neuroradiology, Department of Radiology, Geisinger Medical Center
Coauthor(s): Anil Kumar Aribandi, MD, MRCP, Registrar, Department of Hematology, Royal Hallamshire Hospital, UK
Contributor Information and Disclosures

Updated: May 3, 2006

Introduction

Background

Progressive multifocal leukoencephalopathy (PML) is a fatal subacute progressive demyelinating disease seen in persons with impaired cell-mediated immune response. PML predominantly occurs in patients with AIDS. Before the AIDS epidemic, PML was rare and associated with immunocompromised conditions, such as leukemia, lymphoma, systemic lupus erythematosus (SLE), organ transplantation, Wiskott-Aldrich syndrome, and severe combined immunodeficiency (SCID).

At present, PML develops in as many as 5% of all patients with AIDS. This demyelinating disease results from infection with the JC virus, which belongs to the genus Polyomavirus of the Papovaviridae family of viruses.

Anstrom et al first described PML in 1958, and Zurhein and Chou initially demonstrated the association of PML with a viral infection. In 1971, Padgett et al confirmed the viral etiology by isolating a virus from the brain of a patient who had died from PML. The patient's initials were J.C.; hence, the virus is known as the JC virus.

PML is characterized by 3 cardinal histopathologic features: demyelination, enlarged nuclei of oligodendrocytes, and bizarre astrocytes.

Pathophysiology

The JC virus is believed to produce infection after it enters the tonsillar tissue during an upper respiratory tract infection. After infection, the virus becomes latent in the spleen, the reticuloendothelial system, and the medulla of the kidney. The JC virus is thought to be undetectable in the brain tissue.

Antibodies (immunoglobulin G [IgG]) to the JC virus are common in most Western populations. Seroconversion is seen in 10% of the children by the age of 5 years, in 40-60% by 10 years, and in up to 90% of young adults. Acute infection is usually not noticed. After several years of latency, reactivation occurs under appropriate conditions of immunocompromise.

Approximately 50-80% of all PML cases occur in patients with HIV infection, whereas cases are rare in patients with organ transplantation. This difference may indicate the need for an interaction between the JC virus and HIV for PML to develop rather than just an underlying setting of decreased immune function. Although reactivation of JC virus may be necessary, this itself is insufficient to cause PML. A specific deficiency in cellular immune response to the JC viral antigen is probably required in addition to the general cellular immunodeficiency in persons with PML.

Reactivation of the virus occurs in the kidney and bone marrow, usually in the setting of immunosuppression. Infected lymphocytes (B cells) then cross the blood-brain barrier and pass infection to astrocytes at the border of vessels. The infection may then be augmented by multiplication and eventual infection of adjacent oligodendrocytes. Oligodendrocytes are responsible for forming and maintaining the myelin sheath. Infection of the oligodendrocytes causes destruction of the cells and loss of the myelin sheath. The axons are usually spared.

Histopathology

On microscopy, the cardinal feature of PML is demyelination, which is usually multifocal. The lesions may occur in any location in the white matter, and they range from 1 mm to several centimeters in size.

The histopathologic hallmarks of PML include a triad of multifocal demyelination, hyperchromatic enlarged oligodendroglial nuclei, and enlarged bizarre astrocytes with lobulated and hyperchromatic nuclei. Electron microscopy reveals JC virus in the oligodendroglial cells. Gross examination reveals gray or brown discoloration of the affected brain as a result of loss of myelin.

Frequency

United States

The prevalence of PML in patients with HIV infection is 1-5% in clinical studies, though postmortem data show a rate of up to 8%. The prevalence of this disease initially increased with the rising incidence of HIV infection, but more recently, the incidence has decreased with the widespread use of highly active antiretroviral therapy (HAART), which has reversed immunosuppression in many patients with AIDS (see subsection on Prognostic utility of MRI in PML). For unknown reasons, PML rarely affects children with HIV infection.

Mortality/Morbidity

• The median survival of patients with PML as a complication of AIDS is 6 months. In 10% of patients, survival exceeds 12 months. The longest reported survival is 92 months from the onset of illness.
• PML is an AIDS-defining illness. Patients whose MRIs show enhancement, which is rare, and those with an increased CD4 count appear to have a better prognosis than that of other patients; these findings probably represent their relatively good immune status.

Sex

Before the AIDS epidemic, men and women were affected in a male-to female ratio of 3:2, and lymphoproliferative disease was the most common cause. At present, HIV infection is most common cause, with a male-to-female ratio of 7:1

Age

• PML chiefly affects homosexual or bisexual men aged 25-50 years.
• For unknown reasons, PML rarely affects children with HIV infection.

Anatomy

The white matter of the brain is usually involved. Lesions of PML may occur anywhere in brain, but the frontal lobes and parieto-occipital regions are commonly affected. Isolated involvement of basal ganglia, external capsule, and posterior-fossa structures may be seen.

Presentation

Symptoms

Progressive focal neurologic deficit is the clinical hallmark. Weakness and disturbance of speech are most common symptoms. Other symptoms include cognitive abnormalities, headaches, gait disorders, visual impairment, and sensory loss.

Headaches are most common in the HIV-infected population, and visual disturbances are most common in those without HIV infection. About 10% of patients have seizures. Cognitive deficits do not persist in isolation for long and distinguish PML from HIV dementia. PML seems to have a more aggressive course in persons with HIV disease than in persons with other predisposing conditions.

Signs

Most common physical sign is limb weakness, which occurs in more than 50% of patients. Cognitive disturbances and gait disorders affect 25-33%, and diplopia affects 9%. Optic-nerve disease does not occur with PML, and spinal-cord involvement is rare.

Laboratory findings

Severe cellular immunosuppression, as defined by a CD4 lymphocyte count of 200 cells/µL, is observed in most patients. The mean CD4 count is 84-104 cells/µL.

Results of CSF examination are usually normal or show slightly elevated protein levels. CSF study is not helpful in diagnosis except that it may help in excluding other diagnoses. Cell counts are usually less than 20 cells/µL.

Several studies demonstrated that polymerase chain reaction (PCR) study of the CSF has high sensitivity and specificity for JC virus in PML, with some investigators reporting 95% sensitivity and 100% specificity.

An additional test of the CSF involves measurement of an antibody to the major structural protein of the JC virus known as VPI. The criterion standard for the diagnosis remains histologic confirmation by means of tissue biopsy. However, with a characteristic clinical and MRI pattern and a positive PCR result for JC virus in the CSF, brain biopsy is often avoided.

Preferred Examination

Imaging studies

Radiographic imaging strongly supports the diagnosis of PML in the appropriate clinical context. MRI is sensitive to white matter lesions and shows hyperintense lesions on T2-weighted (T2W) images in affected regions. Therefore, MRI is the preferred form of imaging.

MRI is the preferred diagnostic test. Because of its superior contrast resolution, it can be used to detect subtle white matter abnormalities, whereas CT depicts the lesions at an advanced stage.

Imaging findings

Lesions are found at the gray matter–white matter interface and tend to involve the subcortical white matter. This predilection accounts for the scalloped margins of the lesions. Lesions are initially multiple and discrete, but they eventually may coalesce into large lesions. The lesions may occur anywhere, but are most often seen in the parieto-occipital and frontal lobes.

Limitations of Techniques

CT is often the first neuroimaging technique used, but is not as sensitive as MRI in the detection of white-matter lesions.

MRI offers superior sensitivity in the detection of white-matter lesions of PML, but it is contraindicated in patients with a cardiac pacemaker, in those with MRI-incompatible implants, and those with intraocular metallic foreign bodies.

Differential Diagnoses

Toxoplasmosis, CNS

Other Problems to Be Considered

Encephalomalacia
Chronic infarcts
HIV leukoencephalopathy
Focal cerebritis
Multiple sclerosis
Acute disseminated encephalomyelitis (ADEM)
CNS lymphoma
White-matter demyelination due to chemotherapy and/or radiotherapy
Posterior reversible encephalopathy syndrome (PRES)

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