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Progressive Multifocal Leukoencephalopathy

Progressive Multifocal Leukoencephalitis

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.


Presentation

The clinical course of PML is gradual and progressive as it develops over several weeks to months [1]. 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 [2] and other monoclonal antibodies [3], long-term steroid therapy, methotrexate, cyclosporine, and other immunosuppressants are also at increased risk for developing PML [4].

Physical exam

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.

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]
  • "Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin's lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy". Ann Hematol. 81 (7): 410–3. doi : 10.1007/s00277-002-0481-4. PMID 12185517.[en.wikipedia.org]
Pathologist
  • Accordingly, pathologists should keep this disease in mind in the differential diagnosis when neural symptoms newly emerge in patients who are treated with these drugs.[ncbi.nlm.nih.gov]
Walking with a Cane
  • Able to walk with a cane. Speech remains slightly slurred.[doi.org]
Intravenous Administration
  • Regularly check the level of immunoglobulins and the CD4 : CD8 T-cell ratio, intravenous administration of immunoglobulins should be considered when recording their reduction. 2.[ncbi.nlm.nih.gov]
Seizure
  • 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]
Ataxia
  • 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]
  • 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]
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]
Hemianesthesia
  • Case Report In 1983, a 23-year-old right-handed man had a month-long episode of right hemianesthesia, his first symptom of what proved to be relapsing–remitting multiple sclerosis.[doi.org]
Paresthesia
  • The patient experienced additional paresthesia on the left side of her face and swallowing difficulties. Cytarabine was added to cidofovir based on previously reported successful treatment results [8].[karger.com]

Workup

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.

Imaging

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 [5].

Procedures

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.

Staphylococcus Aureus
  • The patient's hospital course was further complicated by methicillin-resistant Staphylococcus aureus bacteremia, urosepsis, upper gastrointestinal bleeding, elevated concentrations of serum aminotransferases, transient hyponatremia, and transient lymphopenia[doi.org]
Ischemic Changes
  • 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[emedicine.com]

Treatment

  • Development of fulminant PML is rare and treatment options are limited.[ncbi.nlm.nih.gov]

Prognosis

  • 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]

Etiology

  • 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]

Epidemiology

  • 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]
Sex distribution
Age distribution

Pathophysiology

  • 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]
  • Pathophysiology of Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy is caused by reactivation of the endemic JC virus, a type of papovavirus.[medcaretips.com]

Prevention

  • 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]

Patient Information




References

Article

  1. Masur H, Brooks JT, Benson CA, et al. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014; 58 (9):1308-11.
  2. Hartung HP. New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol. 2009;8(1):28–31.
  3. Pugashetti R, Koo J. Efalizumab discontinuation: a practical strategy. J Dermatolog Treat. 2009;20(3):132–6.
  4. Bartt RE. Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy. Curr Opin Neurol. 2006;19(4):341-9.
  5. 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.

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Last updated: 2019-07-11 19:56