Progressive multifocal leukoencephalopathy

This page is about clinical aspects of the disease. For microbiologic aspects of the causative organism(s), see JC virus.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Progressive multifocal leucoencephalopathy, Multifocal leucoencephalopathy, Multifocal leukoencephalopathy, PML, PMLE

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Progressive multifocal leukoencephalopathy (PML), also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage (-pathy) or inflammation (-itis) of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal). It occurs almost exclusively in people with severe immune deficiency, e.g. transplant patients on immunosuppressive medications, or AIDS patients.

References

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Historical Perspective

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References

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Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pathophysiology

PML is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the white matter, which is mostly composed of axons from the outermost parts of the brain (cortex). Symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. PML is similar to another demyelinating disease, multiple sclerosis, but since it destroys the cells that produce myelin (unlike MS, in which myelin itself is attacked but can be replaced), it progresses much more quickly. Most patients die within four months of onset. PML destroys oligodendrocytes and produces intranuclear inclusions.

References

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Causes

This page is about microbiologic aspects of the organism(s). For clinical aspects of the disease, see Progressive multifocal leukoencephalopathy.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The JC virus (JCV) is a type of human polyomavirus (formerly known as papovavirus) and is genetically similar to BK virus and SV40. It was discovered in 1971 and named after the two initials of a patient with progressive multifocal leukoencephalopathy (PML). The virus is widespread, with 86% of the general population presenting antibodies, but it usually remains latent, causing disease only when the immune system has been severely weakened. The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS, or immunosuppression, as in organ transplant patients.

Epidemiology

The virus is very common in the general population, infecting 70 to 90 percent of humans; most people acquire JCV in childhood or adolescence ^[1]. It is found in high concentrations in urban sewage worldwide, leading some researchers to suspect contaminated water as a typical route of infection ^[2].

Minor genetic variations are found consistently in different geographic areas; thus, genetic analysis of JC virus samples has been useful in tracing the history of human migration ^[3].

Infection and pathogenesis

The initial site of infection may be the tonsils ^[4], or possibly the gastrointestinal tract ^[2]. The virus then remains latent in the gastrointestinal tract ^[5] and can also infect epithelial cells in the kidneys, where it continues to reproduce, shedding virus particles in the urine.

JCV can cross the blood-brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT_2A serotonin receptor ^[6]. It is found within the brain even in people with no symptoms ^[7].

When immunodeficiency or immunosuppression allows JCV to reactivate, it attacks the previously infected tissues. In the kidneys, this results in hemorrhagic cystitis and ureteral stenosis; in the brain, it causes the usually fatal progressive multifocal leukoencephalopathy or PML by destroying oligodendrocytes. Several studies since 2000 have suggested that the virus is also linked to colorectal cancer, as JCV has been found in malignant colon tumors, but these findings are still controversial ^[8].

References

↑ Padgett, B.L. and Walker, D.L. (1973). “Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy”. J. Infect. Dis. 127 (4): 467–470. PMID 4571704.
↑ ^2.0 ^2.1 Bofill-Mas, S., Formiga-Cruz, M., Clemente-Casares, P., Calafell, F. and Girones, R. (2001). “Potential transmission of human polyomaviruses through the gastrointestinal tract after exposure to virions or viral DNA”. J. Virol. 75 (21): 10290–10299. PMID 11581397.
↑ Pavesi, A. (2005). “Utility of JC polyomavirus in tracing the pattern of human migrations dating to prehistoric times”. J. Gen. Virol. 86 (Pt 5): 1315–1326. PMID 15831942.
↑ Monaco, M.C., Jensen, P.N., Hou, J., Durham, L.C. and Major, E.O. (1998). “Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection”. J. Virol. 72 (12): 9918–9923. PMID 9811728.
↑ Ricciardiello, L., Laghi, L., Ramamirtham, P., Chang, C.L., Chang, D.K., Randolph, A.E. and Boland, C.R. (2000). “JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract”. Gastroenterology. 119 (5): 1228–1235. PMID 11054380.
↑ Elphick, G.F., Querbes, W., Jordan, J.A., Gee, G.V., Eash, S., Manley, K., Dugan, A., Stanifer, M., Bhatnagar, A., Kroeze, W.K., Roth, B.L. and Atwood, W.J. (2004). “The human polyomavirus, JCV, uses serotonin receptors to infect cells”. Science. 306 (5700): 1380–1383. PMID 15550673.
↑ White, F.A., 3rd., Ishaq, M., Stoner, G.L. and Frisque, R.J. (1992). “JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy”. J. Virol. 66 (10): 5726–5734. PMID 1326640.
↑ Theodoropoulos, G., Panoussopoulos, D., Papaconstantinou, I., Gazouli, M., Perdiki, M., Bramis, J. and Lazaris, ACh. (2005). “Assessment of JC polyoma virus in colon neoplasms”. Dis. Colon. Rectum. 48 (1): 86–91. PMID 15690663.

External links

MS drug Tysabri link to JC virus and progressive multifocal leukoencephalopathy, or PML.

de:JC-Virus nl:JC-virus

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References

Differentiating Progressive multifocal leukoencephalopathy from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Differentiating Progressive multifocal leukoencephalopathy from other Diseases

Progressive multifocal leukoencephelopathy (PML) is more common among immunocompromised patients who are at high risk for other fungal, bacterial, and viral infections. It should be differentiated from the following diseases:

Disease	Differentiating signs and symptoms	Differentiating tests
CNS lymphoma^[1]	Patient is immunocompetent Focal symptoms indicative of a mass lesion Seizure	Single solitary ring enhancing lesion on CT or MRI
Disseminated tuberculosis^[2]	Prior history of residence in an endemic area Chronic cough, weight loss, hemoptysis	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli CXR shows cavitations
Aspergillosis^[3]	Pulmonary lesions in addition to CNS lesions Symptoms may include cough, chest pain, and hemoptysis	CSF fungal culture, galactomannan
Cryptococcosis	Symptoms include cough, chest pain, and hemoptysis	Cryptococcal antigen from CSF and serum CSF fungal culture
Chagas disease^[4]	History of residence in Central or South America Acute infection is rarely symptomatic Encephalitis or focal brain lesions Myocarditis Chronic infections in immunocompromised patients develop into encephalitis with necrotic brain lesions causing a mass effect	Trypanosoma cruzi in blood, tissue, or CSF, PCR of tissue or body fluids, and serologic tests
CMV infection^[5]	Most common CNS opportunistic infection in AIDS patients Presents with encephalitis, retinitis, progressive myelitis, or polyradiculitis In disseminated disease, it involves both the liver and kidneys	Brain CT/MRI/biopsy: location of lesions is usually near the brain stem or periventricular areas PCR of CSF with detectable virus is diagnostic Brain biopsy with + staining for CMV or evidence of owl’s eyes is also diagnostic, but it is rarely performed because of the location of brain lesions
HSV infection^[6]	Seizures, headache, confusion and/or urinary retention can be seen in disseminated disease, which usually affects only the immunocompromised or acute infections In pregnant women, it may be associated with concurrent genital/oral lesions; can be spread to the neonate during acute infection in the mother, or via viral shedding in the birth canal Neonatal HSV can range from localized skin infections to encephalitis, pneumonitis, and disseminated disease	Brain CT/MRI/biopsy: location of lesions is usually the medial temporal lobe or the orbital surface of the frontal lobe. PCR of CSF with detectable virus is diagnostic
Varicella Zoster infection^[7]	Multifocal involvement has subacute course, usually only in immunosuppressed, with headache, fever, focal deficits, and seizures. Unifocal involvement is more typically seen in immunocompetent hosts, occurring after contralateral cranial nerve herpes zoster, with mental status changes, TIAs, and stroke Disseminated varicella zoster virus can occur in adults during primary infection, presenting with pneumonitis and/or hepatitis Disease is a vasculopathy with hemorrhage and stroke	PCR of CSF with detectable virus is diagnostic
Brain abscess^[8]^[9]	Associated with sinusitis (abutting the sinuses) or with bacteremia Signs and symptoms includes fever and necrotizing brain lesions with mass effect	CSF culture or culture of brain abscess
Progressive multifocal leukoencephalopathy^[10]	Symptoms are often more insidious in onset and progress over months. Symptoms include progressive weakness, poor coordination, with gradual slowing of mental function. Only seen in the immunosuppressed. Rarely associated with fever or other systemic symptoms	PCR of CSF for JC virus Biopsy reveals white matter lesions and not well-circumscribed lesions.

References

↑ Gerstner ER, Batchelor TT (2010). “Primary central nervous system lymphoma”. Arch. Neurol. 67 (3): 291–7. doi:10.1001/archneurol.2010.3. PMID 20212226.
↑ von Reyn CF, Kimambo S, Mtei L, Arbeit RD, Maro I, Bakari M, Matee M, Lahey T, Adams LV, Black W, Mackenzie T, Lyimo J, Tvaroha S, Waddell R, Kreiswirth B, Horsburgh CR, Pallangyo K (2011). “Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality”. Int. J. Tuberc. Lung Dis. 15 (8): 1087–92. doi:10.5588/ijtld.10.0517. PMID 21740673.
↑ Latgé JP (1999). “Aspergillus fumigatus and aspergillosis”. Clin. Microbiol. Rev. 12 (2): 310–50. PMC 88920. PMID 10194462.
↑ Rassi A, Rassi A, Marin-Neto JA (2010). “Chagas disease”. Lancet. 375 (9723): 1388–402. doi:10.1016/S0140-6736(10)60061-X. PMID 20399979.
↑ Emery VC (2001). “Investigation of CMV disease in immunocompromised patients”. J. Clin. Pathol. 54 (2): 84–8. PMC 1731357. PMID 11215290.
↑ Bustamante CI, Wade JC (1991). “Herpes simplex virus infection in the immunocompromised cancer patient”. J. Clin. Oncol. 9 (10): 1903–15. doi:10.1200/JCO.1991.9.10.1903. PMID 1919640.
↑ Hambleton S (2005). “Chickenpox”. Curr. Opin. Infect. Dis. 18 (3): 235–40. PMID 15864101.
↑ Alvis Miranda H, Castellar-Leones SM, Elzain MA, Moscote-Salazar LR (2013). “Brain abscess: Current management”. J Neurosci Rural Pract. 4 (Suppl 1): S67–81. doi:10.4103/0976-3147.116472. PMC 3808066. PMID 24174804.
↑ Patel K, Clifford DB (2014). “Bacterial brain abscess”. Neurohospitalist. 4 (4): 196–204. doi:10.1177/1941874414540684. PMC 4212419. PMID 25360205.
↑ Tan CS, Koralnik IJ (2010). “Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis”. Lancet Neurol. 9 (4): 425–37. doi:10.1016/S1474-4422(10)70040-5. PMC 2880524. PMID 20298966.

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Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Epidemiology and Demographics

About 2-5% of AIDS patients develop PML. It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests that the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects (Berger, 2003).

There are case reports of PML being caused by pharmacological agents, although there is some speculation this could be due in part to the existing impaired immune response or ‘pharm combos’ rather than individual drugs. Rituxan and Natalizumab (branded Tysabri).

References

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Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Risk Factors

Anyone with a weakened immune system, however, are at greater risk of developing PML. Causes of a weakened immune system include:

AIDS (less common now because of better AIDS treatments).
Certain medications used to treat multiple sclerosis, rheumatoid arthritis, and related conditions.
Leukemia and lymphoma.

References

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Natural History, Complications and Prognosis

Patients with Progressive Multifocal leukoencephalopathy(PML) have a long-term neurological sequelae and is often fatal. The mortality rate is 30%-50% ^[1] in early months of diagnosis. Those who are immunocompromised are at significant risk of reactivation.

COMPLICATIONS

PML may complicate into the following :

Neurologic Dysfunction
Dementia
Blindness
Seizures

PROGNOSIS

The prognosis is variable and depends on the underlying severity of PML.
Impairment of immune system (eg. HIV) or use of immunosuppressants may worsen prognosis and leads to rapid progression of the disease.^[1]
Patients who survive have substantial morbidity and severe neurological disabilities.^[2]

Reference

Progressive Multifocal Leukoencephalopathy Information Page. NIH-National Institute of Neurological Disorders and Stroke. 29 July 2019. Retrieved 12 June 2021.
Castle, D., & Robertson, N. P. (2019). Treatment of progressive multifocal leukoencephalopathy. Journal of Neurology, 266(10), 2587–2589. https://doi.org/10.1007/s00415-019-09501-y

Diagnosis

Treatment

Medical Therapy | Surgery | Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case #1

Related Chapters

Leukoencephalopathy with vanishing white matter

Template:Viral diseases de:Progressive multifokale Leukenzephalopathie nl:Progressieve multifocale leukoencefalopathie

Template:WikiDoc Sources

[Padget-1] Padgett, B.L. and Walker, D.L. (1973). “Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy”. J. Infect. Dis. 127 (4): 467–470. PMID 4571704.

[Bofill-2] 2.0 ^2.1 Bofill-Mas, S., Formiga-Cruz, M., Clemente-Casares, P., Calafell, F. and Girones, R. (2001). “Potential transmission of human polyomaviruses through the gastrointestinal tract after exposure to virions or viral DNA”. J. Virol. 75 (21): 10290–10299. PMID 11581397.

[Pavesi-3] Pavesi, A. (2005). “Utility of JC polyomavirus in tracing the pattern of human migrations dating to prehistoric times”. J. Gen. Virol. 86 (Pt 5): 1315–1326. PMID 15831942.

[Monaco-4] Monaco, M.C., Jensen, P.N., Hou, J., Durham, L.C. and Major, E.O. (1998). “Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection”. J. Virol. 72 (12): 9918–9923. PMID 9811728.

[Ricardiello-5] Ricciardiello, L., Laghi, L., Ramamirtham, P., Chang, C.L., Chang, D.K., Randolph, A.E. and Boland, C.R. (2000). “JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract”. Gastroenterology. 119 (5): 1228–1235. PMID 11054380.

[Elphick-6] Elphick, G.F., Querbes, W., Jordan, J.A., Gee, G.V., Eash, S., Manley, K., Dugan, A., Stanifer, M., Bhatnagar, A., Kroeze, W.K., Roth, B.L. and Atwood, W.J. (2004). “The human polyomavirus, JCV, uses serotonin receptors to infect cells”. Science. 306 (5700): 1380–1383. PMID 15550673.

[White-7] White, F.A., 3rd., Ishaq, M., Stoner, G.L. and Frisque, R.J. (1992). “JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy”. J. Virol. 66 (10): 5726–5734. PMID 1326640.

[Theodoropoulos-8] Theodoropoulos, G., Panoussopoulos, D., Papaconstantinou, I., Gazouli, M., Perdiki, M., Bramis, J. and Lazaris, ACh. (2005). “Assessment of JC polyoma virus in colon neoplasms”. Dis. Colon. Rectum. 48 (1): 86–91. PMID 15690663.

[pmid20212226-1] Gerstner ER, Batchelor TT (2010). “Primary central nervous system lymphoma”. Arch. Neurol. 67 (3): 291–7. doi:10.1001/archneurol.2010.3. PMID 20212226.

[pmid21740673-2] von Reyn CF, Kimambo S, Mtei L, Arbeit RD, Maro I, Bakari M, Matee M, Lahey T, Adams LV, Black W, Mackenzie T, Lyimo J, Tvaroha S, Waddell R, Kreiswirth B, Horsburgh CR, Pallangyo K (2011). “Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality”. Int. J. Tuberc. Lung Dis. 15 (8): 1087–92. doi:10.5588/ijtld.10.0517. PMID 21740673.

[pmid10194462-3] Latgé JP (1999). “Aspergillus fumigatus and aspergillosis”. Clin. Microbiol. Rev. 12 (2): 310–50. PMC 88920. PMID 10194462.

[pmid20399979-4] Rassi A, Rassi A, Marin-Neto JA (2010). “Chagas disease”. Lancet. 375 (9723): 1388–402. doi:10.1016/S0140-6736(10)60061-X. PMID 20399979.

[pmid11215290-5] Emery VC (2001). “Investigation of CMV disease in immunocompromised patients”. J. Clin. Pathol. 54 (2): 84–8. PMC 1731357. PMID 11215290.

[pmid1919640-6] Bustamante CI, Wade JC (1991). “Herpes simplex virus infection in the immunocompromised cancer patient”. J. Clin. Oncol. 9 (10): 1903–15. doi:10.1200/JCO.1991.9.10.1903. PMID 1919640.

[pmid15864101-7] Hambleton S (2005). “Chickenpox”. Curr. Opin. Infect. Dis. 18 (3): 235–40. PMID 15864101.

[pmid24174804-8] Alvis Miranda H, Castellar-Leones SM, Elzain MA, Moscote-Salazar LR (2013). “Brain abscess: Current management”. J Neurosci Rural Pract. 4 (Suppl 1): S67–81. doi:10.4103/0976-3147.116472. PMC 3808066. PMID 24174804.

[pmid25360205-9] Patel K, Clifford DB (2014). “Bacterial brain abscess”. Neurohospitalist. 4 (4): 196–204. doi:10.1177/1941874414540684. PMC 4212419. PMID 25360205.

[pmid20298966-10] Tan CS, Koralnik IJ (2010). “Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis”. Lancet Neurol. 9 (4): 425–37. doi:10.1016/S1474-4422(10)70040-5. PMC 2880524. PMID 20298966.

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Progressive multifocal leukoencephalopathy

Overview

References

References

Pathophysiology

References

Overview

Epidemiology

Infection and pathogenesis

References

External links

References

Differentiating Progressive multifocal leukoencephalopathy from other Diseases

References

Epidemiology and Demographics

References

Risk Factors

References

COMPLICATIONS

PROGNOSIS

Reference

Treatment

Case Studies

Related Chapters

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