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Radiology > BRAIN/SPINE
Progressive Multifocal Leukodystrophy
Article Last Updated: May 3, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 12  
Author: Manohar Aribandi, MD, Academic Chief, Section of Neuroradiology, Department of Radiology, Geisinger Medical Center
Manohar Aribandi is a member of the following medical societies: American Society of Neuroradiology
Coauthor(s):
Anil Kumar Aribandi, MD, MRCP, Registrar, Department of Hematology, Royal Hallamshire Hospital, UK
Editors: Mahesh R Patel, MD, Chief of MRI, Department of Radiology, Santa Clara Valley Medical Center; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Robert L DeLaPaz, MD, Director, Professor, Department of Radiology, Division of Neuroradiology, Columbia University; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; L Gill Naul, MD, Professor and Head, Department of Radiology, Texas A&M University College of Medicine; Chair, Department of Radiology, Chief, Section of Magnetic Resonance Imaging, Scott and White Memorial Hospital and Clinic
Author and Editor Disclosure
Synonyms and related keywords:
PML, progressive multifocal leukoencephalopathy, acquired immune deficiency, AIDS, multifocal demyelination, JC virus, Polyomavirus
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.
Clinical Details
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.
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)
Findings
Radiographs have no role in the diagnosis of PML.
Findings
CT scans usually show several bilateral, asymmetric hypoattenuating foci of various sizes without mass effect or enhancement. The lesions may involve the periventricular white matter, subcortical white matter, or both. Subcortical U-fiber involvement results in lesions having a lateral scalloped margin that follows the gray matter–white matter junction.
Degree of Confidence
Although lesions may be seen on CT scanning, MRI offers superior sensitivity in the detection and characterization of the lesions. The diagnosis may be suspected with CT, but MRI is needed for a more confident exclusion of other differential considerations.
False Positives/Negatives
Artifacts; chronic, ischemic white-matter changes; and chronic infarcts may mimic true white-matter lesions of PML.
Findings
Findings on T1- and T2-weighted and fluid-attenuated inversion recovery images
MRI has far greater sensitivity than other studies in detecting the lesions of PML and in defining their extent of involvement. On T2W images, lesions appear hyperintense and typically involve the periventricular and subcortical white matter, having a characteristic scalloped lateral margin when they involve the subcortical white matter. Lesions are more conspicuously visualized on fluid-attenuated inversion recovery (FLAIR) images, appearing hyperintense against a background of suppressed CSF signal intensity.
Lesions appear hypointense and well demarcated on T1-weighted (T1W) images, though they may be isointense in the initial phase of the disease. Although the disease may involve any part of the brain, lesions typically occur in the parieto-occipital lobes. Lesions appear to start in the subcortical white matter before extending to the periventricular white matter. Mass effect is infrequently described and usually minimal and correlated with shorter survival when seen on initial studies.
Distribution of lesions
A multifocal distribution pattern is seen. This pattern may be unilateral, but more often, it is bilateral and asymmetric. Lesions may start small, but they eventually enlarge and coalesce. Posterior-fossa involvement is common and is seen in up to one third of patients. Synchronous lesions are usually seen in the supratentorial compartment, though in 10% of patients, lesions are confined to the structures of the posterior fossa. PML may also appear to involve the basal ganglia and deep gray-matter nuclei because of white-matter fibers in these structures. When present, involvement of the gray matter is a secondary finding. In rare cases, lesions are single and can occur anywhere in the brain, including the brainstem.
Findings on contrast-enhanced images
The lesions typically do not enhance and do not have mass effect; however, some reports describe lesions with faint peripheral enhancement or diffuse enhancement with mass effect, especially in the early stages. Enhancement could suggest a relatively good immune response and hence an improved prognosis.
Findings on diffusion-weighted images
On diffusion-weighted images (DWI), lesions can show restricted diffusion, though this is uncommon. The extent of abnormal diffusion appears to be correlated with the speed of clinical progression. Areas with DWI abnormality may correspond to areas that are actively infected by the virus at the time of imaging, but this has been uncommonly reported.
Prognostic utility of MRI in PML
Post et al (1999) studied the prognostic utility of MRI in PML. None of the MRI variables was predictive of patient survival, with the exception of mass effect, which was usually minimal, infrequent, and associated with decreased survival. Serial MRI studies showed progression of disease in 1-24 weeks, and a more rapid change was seen in many patients in just 9 weeks.
The authors suggested that findings of increasing atrophy, increasing confluence and extent of white-matter lesions, spread of disease across the corpus callosum, and increasing hypointensity of the lesions on follow-up T1W MRIs may be poor prognostic indicators or as failure of response to therapy. Stabilization or a decrease in the size of the lesion, clinical improvement, and loss JC viral detection on CSF PCR testing may indicate a response to therapy. However, improvements on MRI can lag clinical improvement by 2-6 months or even indicate temporary worsening.
In PML patients undergoing HAART, MRIs can show initial worsening in the first few months followed by stabilization and regression by 12 months. HAART consists of a combination of 3 or 4 anti-HIV drugs from the following classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors.
Thurnher et al (2001) reported 2 patients with long-term responses to HAART, apparent increased mass effect and enhancement before eventual improvement, and atrophy of the involved brain parenchyma. T1W MRIs but not FLAIR MRIs showed hypointensity. Two nonresponders initially had extensive changes, without enhancement or mass effect after the start of therapy. Their T1W MRIs also showed hypointense areas that were hyperintense on FLAIR images.
This increasing hypointensity on T1W MRIs might have been due to increasing demyelination, which appears hyperintense on FLAIR images. This finding might indicate a worsened prognosis. Increased T1W hypointensity in responders was due to gliosis and necrosis seen in burned-out lesions; this finding is hypointense on FLAIR images.
Berger et al (Ann Neurol, 1998) found enhancement in 8.9% of short-term survivors in contrast to 50% in long-term survivors. Enhancement suggests an improved immune response and hence an improved prognosis.
In a study by Collazos et al (1999), contrast enhancement was seen on images in patients with PML treated with HAART only when their CD4+ count increased. In these patients, the PML lesions changed from enhancing to nonenhancing on follow-up MRI after 3-6 months of therapy. Larger studies than this are needed to clearly identify the MRI changes after therapy and to confirm the utility of MRI in assessing the patient's prognosis and response to therapy.
Magnetic resonance spectroscopy
Evaluation of the PML lesions with magnetic resonance (MR) spectroscopy reveals reduced N-acetylaspartate (NAA) and creatine levels, increased choline levels, and an excess of lipids and sometimes of myo-inositol. In some cases, lactate is present. Cell membrane and myelin breakdown is the presumed cause of elevated choline levels, neuronal loss leads to decreased NAA concentrations, and glial-cells proliferation elevates myo-inositol values. The mild elevation of lactate and lipid levels may be due to the activity of macrophages and the breakdown products of myelin.
The elevation of choline and myo-inositol values is seen in the early phase of the disease. In the later phase all the metabolites are decreased. These metabolic abnormalities are not specific for PML and may be similar in other lesions complicating HIV disease.
Magnetization transfer imaging
PML lesions appear to have strongly reduced magnetization transfer ratios. According to Ernst et al (1999), these features may help in distinguishing lesions from white-matter lesions of HIV leukoencephalopathy. Large prospective studies are needed to assess the utility of newer MR techniques, such as MR spectroscopy and magnetization transfer imaging, in the diagnosis and follow-up of PML.
Degree of Confidence
MRI has far greater sensitivity than that of other studies in depicting the lesions of PML and in defining their extent of involvement. Although MRI results may suggest the diagnosis of PML in the appropriate clinical setting, typical features of PML are often nonspecific, and other differential considerations, such as ischemic changes, HIV leukoencephalopathy, and gliotic changes from previous trauma, must be considered. When the lesions of PML are atypically enhancing or when they have mass effect, other lesions, such as those due to toxoplasmosis, lymphoma, or other intracranial masses should be considered.
The presence of multiple pathologies in immunocompromised conditions adds to the complexity of image interpretation. Infection coexisting with other opportunistic infection may be responsible for some atypical manifestations of the disease and for an apparent response to some form of therapy in some patients.
False Positives/Negatives
It is unusual for a normal variant to mimic PML lesions on MRI.
PML must be distinguished from HIV leukoencephalopathy. PML tends to be multifocal, with bilateral, asymmetric, and predominantly subcortical involvement. In comparison, HIV leukoencephalopathy tends to produce lesions that are usually diffuse, bilateral, and symmetric; these predominantly affect the periventricular white matter.
Diffuse cortical atrophy and ventricular dilatation are not predominant findings of PML and may be helpful in distinguishing from HIV leukoencephalopathy, which is usually associated with substantial atrophy. Lesions appear well defined and hypointense on T1W images, whereas they appear isointense and poorly defined in HIV leukoencephalopathy. Clinical correlation may be helpful, as patients with PML have progressive focal motor and sensory neurologic deficits, whereas those with HIV leukoencephalopathy present with global cognitive changes and dementia.
Findings
Ultrasonography currently has no role in the diagnosis of PML.
Findings
Nuclear medicine studies do not play a major role in the diagnosis of PML. However, Port et al (1999) described a case of PML in a patient with AIDS in whom MRIs of the lesion showed enhancement and mass effect, with increased thallium-201 uptake on single photon emission CT (SPECT). O'Mally et al (1994) had reported a case of PML with no uptake on 201Th SPECT.
Degree of Confidence
On thallium SPECT, photopenic lesions can be caused by any previous insult to the brain parenchyma, and hence, the differential considerations include a wide variety of causes. The uncommon observation of increased radiotracer uptake may be seen with lymphoma and is atypically found in some infections.
False Positives/Negatives
No anatomic variants have been described to mimic the lesions of PML, but cold lesions (eg, arachnoid cyst, porencephalic cyst) can conceivably appear as photopenic lesions similar to the lesions of PML.
Findings
Angiography has no role in the diagnosis of PML. However, Nelson et al (1999) reported angiographic findings in 6 patients with PML. In 4, angiograms showed abnormal parenchymal blush of the affected region in the early to mid arterial phase and persisting into the venous phase. Associated arteriovenous shunting was also present. In only 1 of the 4 patients did MRI demonstrate enhancement.
On pathologic evaluation, intense perivascular inflammatory cellular infiltrates, angiogenesis, and gliosis were found in the patients with angiographic abnormalities, whereas changes were minimal in patients who did not have angiographic abnormalities.
Degree of Confidence
The findings of vascular blush and arteriovenous shunting on angiography are nonspecific and can be seen with infectious, neoplastic, vascular, and ischemic etiologies.
False Positives/Negatives
No known anatomic variants mimic the lesions of PML.
As of now, radiographically guided intervention has no role in the treatment of PML.
An antiretroviral regimen containing protease inhibitors has been successful in prolonging the survival of patients with HIV infection and PML. Topotecan and cidofovir are promising drugs presently under evaluation. The role of splenectomy remains unproven, though reports have described remission in association with HAART.
| Media file 1:
T2-weighted MRI in a patient infected with HIV demonstrates a hyperintense lesion in the left frontoparietal region in the subcortical and periventricular white matter. Biopsy confirmed progressive multifocal leukodystrophy. |
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Media type: MRI
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| Media file 2:
Contrast-enhanced T1-weighted MRI demonstrates a hypointense lesion predominantly in a subcortical, left frontoparietal location. Note the characteristic absence of enhancement and lack of mass effect. |
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Media type: MRI
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| Media file 3:
Fluid-attenuated inversion recovery (FLAIR) MRI corresponding to Image 1 shows the PML lesion with improved contrast after the suppression of cerebrospinal fluid signal intensity. |
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Media type: MRI
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| Media file 4:
Nonenhanced CT of the head shows a hypoattenuating lesion in the subcortical white matter. Note the characteristic scalloped lateral margin. |
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Media type: CT
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| Media file 5:
Fluid-attenuated inversion recovery (FLAIR) images in a patient with HIV infection presenting with visual defects, aphasia, and balance problems. Patchy, confluent, and hyperintense lesions are seen in the left occipitotemporoparietal lobes in the subcortical and periventricular white matter. The patient's clinical and radiologic features suggested progressive multifocal leukodystrophy, though cerebrospinal fluid results for the JC virus were negative. |
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Media type: MRI
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Progressive Multifocal Leukodystrophy excerpt Article Last Updated: May 3, 2006
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