Progressive multifocal leukoencephalopathy (PML) is a rare, life-threatening disease that is characterized by focal neurological deficits. It is caused by the John Cunningham virus (JC virus), which is usually contracted during childhood but is asymptomatic until the virus is reactivated later in life due to weakened immune status. The clinical manifestations are consistent with findings on brain imaging or biopsy. Since this disease is fatal, early diagnosis and prompt treatment are imperative.
The clinical course of PML is gradual and progressive as it develops over several weeks to months . The features of this disease include visual deficits, aphasia, gait ataxia, motor impairment, and possibly headaches and seizures. Patients also suffer from cognitive function decline that may result in dementia. If left untreated, PML is associated with high rates of morbidity and mortality.
It is important to consider the risk factors. This viral infection is most prevalent in patients with HIV/AIDS. Additionally, it may manifest in immunocompromised individuals with leukemia, Hodgkin's disease, organ transplant, or genetic immunodeficiencies. Patients receiving treatment with natalizumab  and other monoclonal antibodies , long-term steroid therapy, methotrexate, cyclosporine, and other immunosuppressants are also at increased risk for developing PML .
Remarkable findings on the neurological exam include ataxia, hemiparesis, limb apraxia, and possibly head tremor. Altered mental status is also observed. Visual assessment may be notable for conjugate gaze deficits and other abnormalities.
Entire Body System
- Hodgkin Lymphoma
The first case is a 50-year-old man recently treated with chemotherapy including rituximab for non-Hodgkin's lymphoma. The second case is a 64-year-old woman with human immunodeficiency virus (HIV) infection. [ncbi.nlm.nih.gov]
Twelve months later she died of aspiration pneumonia caused by the bulbar lesion. At autopsy, the histological examination suggested the presence of demyelinating foci with numerous foamy macrophages. [ncbi.nlm.nih.gov]
ROS Word finding difficulties Lethargy Loss of balance POH Pseudophakia OU PMH Hyperlipidemia (HLP) Prostate cancer s/p prostatectomy Obstructive sleep apnea (OSA) Pneumonia with persistent cough Married Attorney C/A/D: + cigars/ 1-2 alcoholic beverages [eyewiki.aao.org]
Other causes of death included aspiration pneumonia and respiratory failure. Twelve of the surviving patients were left with severe disability, while nine had moderate and four had mild disability. [medpagetoday.com]
Aspirative pneumonia was the direct cause of death in most of the cases. [academic.oup.com]
- Visual Impairment
Clinical Presentation of Progressive Multifocal Leukoencephalopathy Insidious onset and steady progression of focal symptoms that include behavioral, speech, cognitive, motor, and visual impairment. [medcaretips.com]
[…] concentration deficits, and visual impairment. [n.neurology.org]
The median time from the onset of PML symptoms to the first seizure was 5.4 months (range 0-159) and 64 % of patients with seizures had them within the first year. [ncbi.nlm.nih.gov]
Focal and generalized seizures are an infrequent complication. CSF is usually normal. The EEG often demonstrates nonspecific diffuse slowing. CT and MRI reveal white-matter abnormalities. Treatment There is no definitive treatment. [epilepsy.com]
We report the case of a 15-year-old girl with progressive multifocal leukoencephalopathy and AIDS who presented with nystagmus, dysarthria and ataxia. [ncbi.nlm.nih.gov]
Physical exam Remarkable findings on the neurological exam include ataxia, hemiparesis, limb apraxia, and possibly head tremor. Altered mental status is also observed. [symptoma.com]
- Neurologic Manifestation
The rapid onset of his neurologic manifestations and the initial neuroimaging studies suggested acute disseminated encephalomyelitis (ADEM), and a brain biopsy was needed for the diagnosis of PML. [pediatrics.aappublications.org]
Neuro-ophthalmological disorders in HIV infected subjects with neurological manifestations 2004;88: 1455-1459. Tan CS, Koralnik IJ. JC, BC, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy. [eyewiki.aao.org]
Neurological manifestations of human immunodeficiency virus infection in adults. Neurology in Clinical Practice. 2004. 2: 1581-1602. Focosi D, Marco T, Kast RE, Maggi F, Ceccherini-Nelli L, Petrini M. [emedicine.com]
Three years later, she presented with a 3-week history of progressive walking impairment associated with twitching of her facial muscles and abnormal sensation all over her body that was associated with left hemi-paresis and sensory changes, in addition [ncbi.nlm.nih.gov]
A neurological examination revealed subconjunctival erythema in the left eye and vesicular-papular lesions in the region of the left ophthalmic branch of the V cranial nerve, dysarthria and paresis of the right arm. [ehoonline.biomedcentral.com]
At entry into the study in October 2002, he had an old left afferent pupillary deficit, mild right lateral rectus palsy, right-sided lower-motor-neuron facial paresis, mild ataxia, a score on the Kurtzke Expanded Disability Status Scale of 2 (scores can [doi.org]
- Speech Disorder
Symptoms vary, depending on which part of the brain is affected, but may include speech disorders, paralysis of one side of the body, or loss of an area of vision. [catie.ca]
Complaints of weakness and of gait and speech disorders were the most common symptoms reported by patients with PML, and the most common signs were limb weakness, alterations of speech, and lack of coordination ( table 2 ). [academic.oup.com]
The workup consists of a careful assessment of the clinical picture, history, risk factors as well as a detailed physical exam and appropriate tests. Immunosuppressed patients with worsening manifestations and progressive deterioration should raise suspicion for PML.
Brain magnetic resonance imaging (MRI) in patients with PML reveals unifocal or multifocal lesions that are hypointense on T1 images but hyperintense on T2 and FLAIR (fluid attenuated inversion recovery) sequences. Moreover, these foci are likely to develop in the parietooccipital white matter although white matter changes may also appear in the cerebellum, brain stem or peduncles.
Computed tomography (CT) brain scan is another imaging modality that can be used to evaluate these patients. However, it is usually less sensitive than MRI .
Confirmation of PML is through detection of the JC virus in cerebrospinal fluid, which is obtained through a lumbar puncture (LP). Polymerase chain reaction (PCR) analysis of the sample requires technical expertise since testing for the JC virus is complex. Since DNA PCR may be negative in the initial phases of PML, LP should be repeated in patients with progressive clinical and radiographic signs suggestive of PML.
A brain biopsy can definitively establish the diagnosis as well, in which immunohistochemistry and in situ hybridization analysis of the tissue demonstrates the presence of the JC virus. This test is associated with a sensitivity as high as 95% and 100% specificity.
Postmortem brain examination also confirms the diagnosis.
- White Matter Lesions
All patients had SWI hypointensities in cortex and/or U-fibers adjacent to the white matter lesions. QSM always suggested a paramagnetic effect. [ncbi.nlm.nih.gov]
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. [emedicine.com]
PML patients require prolonged multidisciplinary rehabilitation treatment, and considerable progress can be achieved. [ncbi.nlm.nih.gov]
In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis. [ncbi.nlm.nih.gov]
We will discuss the potential etiologies of mild and transient immunosuppression that can lead to PML with non-apparent immunosuppression. [ncbi.nlm.nih.gov]
Etiology PML lesions are secondary to progressive demyelination due to John Cunningham (JC) virus (usually reactivation) which infects oligodendrocytes. [radiopaedia.org]
You are here › All Topics › JC Virus - Progressive Multifocal Leukoencephalopathy JC virus (JCV) is a human neurotropic polyomavirus that is the etiologic agent of progressive multifocal leukoencephalopathy (PML). [arupconsult.com]
The epidemiology of neurologic disease. In: Clinical Neurology. Harper & Row: Philadelphia, PA, pp 1–14. Google Scholar Lane JH, Sasseville VG, et al (1996). [doi.org]
In this chapter changes to the epidemiology are discussed along with an update in its pathogenesis and treatment. [ncbi.nlm.nih.gov]
Further prospective studies are needed to understand the pathophysiology and treatment of this disease. [ncbi.nlm.nih.gov]
Pathophysiology PML is caused by reactivation of the polyomavirus (JC virus), that usually leads to death or severe disability. [eviq.org.au]
[…] from market due to PML risk) Ocrelizumab – multiple sclerosis (suspected risk due to medication class) Alemtuzumab – select lymphomas, relapsing MS Brentuximab – select lymphomas Mycophenolate mofetil – immunosuppression following organ transplantation Pathophysiology [arupconsult.com]
Until the pathophysiologic mechanism of this and other autoimmune encephalopathies is better characterized, they conclude that descriptive terms that reflect an association rather than causation are most appropriate. [mayo.edu]
To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. [ncbi.nlm.nih.gov]
Can PML be prevented? It is unclear how the JC virus is transmitted, so currently there are no ways to prevent infection. However, the best way to prevent PML disease is by keeping the immune system healthy. [poz.com]
The NINDS supports research on demyelinating disorders of the nervous system such as PML aimed at increasing scientific understanding of these disorders, and finding ways to prevent, treat, and cure the disease utilizing state of the art molecular diagnostic [web.archive.org]
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- Bartt RE. Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy. Curr Opin Neurol. 2006;19(4):341-9.
- Whiteman ML, Post MJ, Berger JR, Tate LG, Bell MD, Limonte LP. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology. 1993;187(1):233-40.