Published: September 2012

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PML: A Rare but Serious Disease

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Prescriber Update 33(3): 21-23
September 2012

Conjointly prepared by Medsafe and the Australian Therapeutic Goods Administration

Immunomodulatory medicines have emerged as a class of medicines associated with the development of progressive multifocal leukoencephalopathy (PML).

Awareness of risk factors and early recognition of symptoms is important as early diagnosis is likely to improve the prognosis¹.

What is PML?

PML is a rare, but often fatal, demyelinating disease of the central nervous system (CNS). PML is caused by lytic infection of oligodendrocytes and astrocytes resulting in multiple areas of demyelination in the CNS.

PML lesions are typically asymmetrical demyelinated plaque areas with irregular borders, surrounded by macrophages and irregular astrocytes with large, multiple nuclei². On magnetic resonance imaging (MRI), the lesions usually do not show oedema, mass effect or gadolinium enhancement, which are common in multiple sclerosis².

Patients with PML can have a variety of symptoms including muscle weakness, sensory deficit, cognitive dysfunction, language impairment and/or coordination and gait difficulties³.

What causes PML?

PML is caused by a human polyomavirus, the JC virus. The virus was named after the patient from whom the virus was initially cultivated, John Cunningham. Approximately 50% of the world's population are infected with the virus by the time they reach age 20, although most remain asymptomatic⁴. After initial virus infection, the virus remains quiescent in the kidneys, bone marrow and lymphoid tissue³.

In immunocompromised individuals the quiescent virus can reactivate, enter the blood-stream and then gain entry to the CNS where it infects oligodendrocytes and astrocytes. Infection of these cells leads to cell death, and the resulting demyelination produces the neurological signs and symptoms of PML⁵.

Viruses isolated from the brains of individuals with PML have a genomic rearrangement in the regulatory region that is not found in the strains responsible for initial infection^{4, 5}.

What are the risk factors?

Patients who are immunosuppressed or have a malfunction of the immune system are at higher risk of developing PML. Cell-mediated immunity disorders are the major immunological disorders that predispose individuals to the development of PML⁴.

PML cases have been reported in patients with HIV, lymphoproliferative disorders, malignancies, patients on immunosuppressive therapy after solid organ transplantation and in rheumatic diseases such as systemic lupus erythematosus^{6, 7}.

Immunosuppressive medications that have been associated with PML include cyclophosphamide, corticosteroids, mycophenolate mofetil and monoclonal antibodies including natalizumab (Tysabri), rituximab (Mabthera) and alemtuzumab (MabCampath)⁸.

How is PML diagnosed?

Diagnosis should be considered in any patient with risk factors who presents with progressive neurological signs or symptoms and has MRI evidence of multiple characteristic lesions. The early signs of PML are often related to cognitive dysfunction, manifesting as mental slowness, disorientation and behavioural changes². Motor and sensory disturbance, characterised by lack of coordination, gait disturbance, ataxia, hemiparesis or visual deficits may also be found at the time of presentation². Seizures, language difficulties and headaches can occur but are less common. These signs and symptoms progress over the course of a few weeks and death can occur weeks to months after diagnosis.

The diagnosis can be confirmed by detection of JC virus DNA or proteins by in situ hybridization or immunohistochemistry on a brain biopsy sample, or by detection of JC virus DNA in the CSF by quantitative PCR³. However, a negative PCR result does not exclude the diagnosis of PML, particularly early in the disease.

How many cases have been reported?

A search of the Australian and New Zealand adverse event databases found 27 reports of PML (Table 1). Many of these reports had multiple risk factors including prior or concomitant immunosuppression therapies, underlying disease and chemotherapy. The majority of reports were associated with the monoclonal antibodies, rituximab and natalizumab. However, this may be due to greater awareness of PML in association with these particular medicines.

Table 1: Australian and New Zealand reports of PML associated with immunomodulatory medicines to June 2012

How is PML treated?

Improved chance of survival is associated with early diagnosis, younger age at diagnosis and if the disease is limited to one lobe of the brain¹.

Current treatment of PML is limited and is generally supportive in nature. The current treatment strategy for PML in HIV-negative patients is to restore the host adaptive immune response by stopping or decreasing immunosuppression³. There are currently no specific antiviral drugs for the JC virus.

Recovery of the immune system can trigger immune reconstitution inflammatory syndrome (IRIS). In HIV-negative patients with PML-IRIS, the current treatment is corticosteroids to reduce the inflammatory response³.

References

1. Vermersch P, Kappos L, Gold R, et al. 2011. Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 76: 1697-704.
2. Major EO. 2010. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annual Review of Medicine 61: 35-47.
3. Tan CS, Koralnik IJ. 2010. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurology 9: 425-37.
4. Berger JR, Khalili K. 2011. The pathogenesis of progressive multifocal leukoencephalopathy. Discovery Medicine 12: 495-503.
5. Tyler KL. 2010. Progressive multifocal leukoencephalopathy: can we reduce risk in patients receiving biological immunomodulatory therapies? Annals of Neurology 68: 271-4.
6. Molloy ES, Calabrese LH. 2009. Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis and Rheumatism 60: 3761-5.
7. Holman RC, Torok TJ, Belay ED, et al. 1998. Progressive multifocal leukoencephalopathy in the United States, 1979-1994: increased mortality associated with HIV infection. Neuroepidemiology 17: 303-9.
8. Piccinni C, Sacripanti C, Poluzzi E, et al. 2010. Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents. European Journal of Clinical Pharmacology 66: 199-206.