Progressive multifocal leukoencephalopathy

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Classification according to ICD-10
A81.2 Progressive multifocal leukoencephalopathy
ICD-10 online (WHO version 2019)

The progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system (CNS) caused by the genus of the polyoma viruses belonging JC virus is caused. The name of the virus is derived from the initials of the patient from whom it was first isolated. The disease occurs almost exclusively in severely compromised people. It is an acute , progressive disease in which numerous functional changes in the nervous system, such as motor and cognitive disorders, can occur.

Epidemiology

PML occurs rarely and then almost exclusively in people with weakened immune systems who have a significant defect in T-cell immunity . Immunocompetent people or people who only have deficits in the humoral defense system (antibody and complement system) do not usually develop PML. People with relevant T-cell immunodeficiency either suffer from diseases of the immune system or have received immunosuppressive treatment for another disease. Immunosuppression can occur as a side effect - for example in the chemotherapy of tumors - or as a desired effect of drugs - after organ transplants or for the treatment of autoimmune diseases . PML occurs more frequently after bone marrow transplants .

The majority of PML cases occur in the context of acquired immunodeficiency syndrome (AIDS) in stage C3 - around 80–90% of PML patients are also infected with AIDS. In 1980 the prevalence of PML among AIDS patients was still over 5%, but seems to have been falling continuously since then, which is mainly attributed to the fact that highly active antiretroviral therapy (HAART) is now widespread. According to the classification of the Centers for Disease Control and Prevention, PML is one of the "AIDS-defining diseases".

The disease rarely occurs in the context of tumors of the lymphoreticular system - especially in Hodgkin's disease - as well as in chronic inflammatory diseases, after organ transplants and as an undesirable effect of immunosuppressive drugs (especially with natalizumab , but also rarely with rituximab , efalizumab , fingolimod and Dimethyl fumarate ), which are increasingly used. The ingestion of fumaric acid ester can possibly promote the development of PML, as four case reports in the New England Journal of Medicine (2013; 368: 1657–1661) show. In a statement by two dermatologists in Dt. Ärzteblatt, however, this is questioned.

Pathogenesis and pathology

Immunohistochemical detection of JC virus protein (stained brown) in a brain biopsy

The disease is a reinfection through reactivation of the JC virus. The initial or primary infection with the virus is asymptomatic. The infection already begins in childhood and reaches an infection rate of 40–60% in adults. The pathogen persists for life.

In T-cell immunocompromised people, the JC virus probably gets from the site of its persistence (possibly kidney tissue and / or bone marrow) via leukocytes to the central nervous system and replicates in the white matter in the cerebrum , the brain stem , the cerebellum and the spinal cord . It is a demyelinating disease, that is, the nerve sheaths (myelin sheaths) of the oligodendrocytes , which surround the nerve processes (axons) of the neurons , are attacked and degenerate . Since the gray matter consists mainly of nerve cell bodies and only a small proportion of axons, it is hardly affected by the infection. Histologically , it is an inflammatory demyelinating with perivascular leukocyte infiltration. In particular, the pronounced polymorphism of the infected glial cells is typical. The neuropathological diagnosis is confirmed by the detection of JC virus protein in immunohistochemistry or the detection of JC virus genome in the in situ hybridization.

Symptoms

The symptoms of PML depend on the location of the demyelinating foci in the central nervous system. If, for example, these are in the language center, speech disorders ( aphasia ) occur, if the sensitive tracts are affected, sensory disorders; if the motor tracts are affected, motor failures in the form of fine motor disorders or paralysis occur. If the visual pathway is affected , visual field defects ( e.g. hemianopsia ) occur. As the disease progresses, cognitive disorders, concentration disorders, confusion and even dementia can occur. Also epileptic seizures may occur in the disease process.

diagnosis

T2-weighted MRI image

A relatively reliable diagnosis is only possible through the detection of the JC virus DNA in the cerebrospinal fluid using the polymerase chain reaction (PCR). The detection of the virus in the urine does not show any connection with the disease, as around 20% of the population shed the virus permanently. The relatively unspecific foci of demyelinating, which can be detected with magnetic resonance imaging (MRI, magnetic resonance imaging), can contribute to the suspected diagnosis. The foci are hypointense on T1 weighting, hyperintense on T2 and Flair sequences and do not absorb any contrast medium . Surface confluent and symmetrical signal changes with the cerebral cortex cut out are typical. These are often parietal. A differentiation from other changes of the same appearance ( e.g. in multiple sclerosis (MS) or posterior reversible encephalopathy syndrome (PRES)) is not possible without a medical history based on the MRI findings alone. The virus can also be detected in brain tissue using an electron microscope.

Differential diagnosis

Before suspecting PML in the context of AIDS, the more common encephalitides caused by toxoplasmosis or cryptococcosis , CNS lymphoma , HIV encephalopathy , but also leukodystrophies and, in children, subacute sclerosing panencephalitis (SSPE) must be ruled out. If PML is suspected during treatment of multiple sclerosis with natalizumab , an MS flare-up is the most important differential diagnosis.

therapy

The most effective treatment of PML at the moment are measures to restore immune competence :

  • In AIDS patients, the mortality and severity of the disease could be reduced by high-dose antiretroviral therapy (HAART), as the number of T cells increases again in the course of such treatment.
  • Treatment should be discontinued in patients receiving immunosuppressive therapy. For drugs with a long biological action, measures to remove the drug are recommended.
  • In patients treated with immunosuppressive drugs for an organ transplant, the transplanted organ may need to be removed.

There is no causal treatment of PML. Individual case reports or small case series have been published on the effects of some drugs ( e.g. foscarnet , cytosine arabinoside , cidofovir , interferon, cortisone ), but their review in larger patient populations was disappointing.

A case report from 2010 describes successful treatment with mefloquine , an anti-malarial drug that appears to have an inhibitory effect on the JC virus. Elimination of the virus particles from the patient's body and prevented progression of PML have been reported.

forecast

The prognosis is currently poor. If it is not possible to improve the function of the immune system adequately, PML leads to death within an average of 3 to 20 months.

literature

Web links

Individual evidence

  1. ↑ BL Padgett, DL Walker, GM Zu Rhein et al .: Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. In: The Lancet . 1971; 1, pp. 1257-1260. PMID 4104715
  2. ↑ a b J. M. Kean, S. Rao u. a .: Seroepidemiology of human polyomaviruses. In: PLoS pathogens. Volume 5, number 3, March 2009, p. E1000363, doi : 10.1371 / journal.ppat.1000363 , PMID 19325891 , PMC 2655709 (free full text).
  3. ↑ a b A. Egli, L. Infanti u. a .: Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. In: The Journal of Infectious Diseases . Volume 199, Number 6, March 2009, pp. 837-846, PMID 19434930 .
  4. ^ IJ Koralnik et al .: Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 14-2004. A 66-year-old man with progressive neurologic deficits. In: N Engl J Med . 2004; 350, pp. 1882-1893. PMID 15115835
  5. ↑ JR Berger et al: Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. In: Ann Intern Med . 1987; 107, pp. 78-87. PMID 3296901
  6. ↑ N. Sacktor: The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. In: J Neurovirol. 2002; 8 (Suppl 2), pp. 115-121. PMID 12491162 .
  7. ^ FDA Drug Safety Communication
  8. ↑ KR Carson, D. Focosi, EO Major et al .: Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. In: Lancet Oncol. 2009; 10, pp. 816-824. PMID 19647202
  9. ↑ Fumaric acid ester: PML in psoriasis treatment. In: Dt. Medical journal. April 26, 2013. Retrieved July 18, 2013.
  10. ↑ H. Albrecht, C. Hoffmann, O. Degen et al .: Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. AIDS . 1998; 12, pp. 1149-1154. PMID 9677163
  11. ↑ a b O. Stüve, CM Marra, PD Cravens et al: Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions. In: Arch Neurol . 2007; 64, pp. 169-176. PMID 17296831
  12. ^ TE Gofton, A. Al-Khotani, B. O'Farrell, LC Ang, RS McLachlan: Mefloquine in the treatment of progressive multifocal leukoencephalopathy. In: Journal of Neurology, Neurosurgery, and Psychiatry . Volume 82, Number 4, April 2011, pp. 452-455, ISSN  1468-330X . doi: 10.1136 / jnnp.2009.190652 . PMID 20562463 .