PML and JCV titers

Progressive multifocal leukoencephalopathy (PML), caused by John Cunningham virus reactivation, often follows immunomodulatory therapy or HIV. It presents with neurological deficits, diagnosed via MRI and lumbar puncture. Treatment focuses on restoring immune response, especially effective antiretroviral therapy in HIV. Prognosis is generally poor, with high mortality.

Progressive Multifocal Leukoencephalopathy (PML) Overview:

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disorder of the central nervous system. PML is caused by reactivation of John Cunningham virus (JCV). JCV infects cortical and subcortical white matter and causes demyelinating lesions of PML. (1, 2)

Predisposing Factors for PML:

The development of PML is usually predisposed by underlying malignancy, HIV infection or immunomodulatory therapies, such as, natalizumab, rituximab, brentuximab vedotin, eculizumab. (3, 4)

Clinical Manifestations of PML:

PML usually manifests as subacute neurological deficits including altered mental status, limp weakness, gait ataxia and visual symptoms, such as, hemianopia and diplopia. Atypical presentation with seizures could occasionally happen. Also, at early stage, it might be asymptomatic and could only be discovered by MRI brain. (5, 6)

Other JCV Infections:

Apart from PML, JCV infection could also lead to cerebellar granule cell neuronopathy (ataxia, incoordination, dysarthria), meningitis and encephalopathy. (7)

Diagnosis of PML:

Patients with suspected PML should have a brain MRI, lumber puncture, JCV index and polymerase chain reaction (PCR) for JCV. Brain biopsy remains the gold standard in ambiguous circumstances. JCV index is negative if <0.9 and positive if >1.5. (8)

Treatment Approach for PML:

PML has no specific treatment. The main approach is restoring the host adaptive immune response, a strategy which appears to prolong survival.

Management of HIV-Associated PML:

In patients with HIV infection who have PML, initiation of effective ART is the best therapeutic option. (10)

Management in Non-HIV Patients:

In patients without HIV infection, it is advisable to discontinue any potential medication. Also, high dose glucocorticoid therapy (methylprednisolone 1g daily for five days) and plasma exchange every other day for a total of 5 days might help. (11)

Prognosis of PML:

Mortality is high in PML, with a median survival of 3 months. Favourable prognostic markers include younger age at diagnosis, lower JCV load, less disability prior to PML and localised brain lesions on MRI. (12)

References

1- Olsson T, Achiron A, Alfredsson L, et al. Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort. Mult Scler. 2013;19:1533– 1538

2-Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003; 9 Suppl 1:47.

3-Antinori A, Ammassari A, Giancola ML, et al. Epidemiology and prognosis of AIDS-associated progressive multifocal leukoencephalopathy in the HAART era. J Neurovirol 2001; 7:323.

4-Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009; 361:1075.

5-Dahlhaus S, Hoepner R, Chan A, et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013; 84:1068.

6-Bossolasco S, Calori G, Moretti F, et al. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 2005; 40:738.

7-Koralnik IJ, Wüthrich C, Dang X, et al. JC virus granule cell neuronopathy: A novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 2005; 57:576.

8- Plavina T, Subramanyam M, Bloomgren G, et al. JCV antibody index stratifies PML risk in natalizumab-treated MS patients. Available

at: https://cmscactrims.confex.com/cmscactrims/ 2013/webprogram/ Paper1642.html. Accessed November 25, 2013.

8-Pavlovic D, Patera AC, Nyberg F, et al. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord 2015; 8:255.

9-Elliot B, Aromin I, Gold R, et al. 2.5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy. Lancet 1997; 349:850.

10- Major EO, Frohman E, Douek D. JC viremia in natalizumab-treated patients with multiple sclerosis. N Engl J Med. 2013;368:2240–2241.

11-Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009; 72:1458.

12-Vulliemoz S, Lurati-Ruiz F, Borruat FX, et al. Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry 2006; 77:1079.