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First described in association with chronic lymphocytic leukemia and Hodgkin disease, progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the CNS that occurs in immunocompromised patients (925Astrom KE, Mancall EL, Richardson EP J. Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 1958;81:93-111.). It is caused by primary infection or reactivation of Jamestown Canyon virus (JCV), a ubiquitous polyoma virus. Most humans are infected with JCV early in life; 50% of children are seropositive by age 9-11 years, and seropositivity among adult women aged >25 years is 72% (926Stolt A., Sasnauskas K, Koskela P, et al. Seroepidemiology of the human polyomaviruses. J Gen Virol 2003;84(Pt 6):1499-504.). Infection results in chronic asymptomatic carriage in the kidneys, lymphoid tissue, bone marrow, and lymphocytes (927Rodrigues C, Pinto D, Medeiros R. Molecular epidemiology characterization of the urinary excretion of polyomavirus in healthy individuals from Portugal-a Southern European population. J Med Virol 2007;79:1194-8., 928Gu ZY, Li Q, Si YL, et al. Prevalence of BK virus and JC virus in peripheral blood leukocytes and normal arterial walls in healthy individuals in China. J Med Virol 2003;70:600-5.) ; in a patient with a weakened immune system, the virus may reactivate and spread to the brain by lymphocytes causing neurologic dysfunction and serious and life-threatening disease.

PML is an AIDS-defining illness in HIV-infected persons. PML has been rare in reports from large series of HIV-infected children (1Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001;20:40-8., 4Nesheim SR, Kapogiannis BG, Soe MM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics 2007;120:00 100–9., 929Ciuta ST, Boros S, Napoli PA, et al. Predictors of survival in children with acquired immunodeficiency syndrome in Italy, 1983 to 1995. AIDS Patient Care STDS 1998;12:629-37.), but cases have been reported in children (930Araujo AP, Pereira HS, Oliveira RH, et al. Progressive multifocal leukoencephalopathy in a child with acquired immunodeficiency syndrome (AIDS). Arg Neuropsiguiatr 1997;55:122-5., 931Robinson LG, Chiriboga CA, Champion SE, et al. Progressive multifocal leukoencephalopathy successfully treated with highly active antiretroviral therapy and cidofovir in an adolescent infected with perinatal human immunodeficiency virus (HIV). J Child Neurol 2004;19:35-8.,932Wilmshurst JM, Burgess J, Hartley P, et al. Specific neurologic complications of human immunodeficiency virus type 1 (HIV-1) infection in children. J Child Neurol 2006;21:788-94., 933Shah I, Chudgar P. Progressive multifocal leukoencephalopathy (PML) presenting as intractable dystonia in an HIV-infected child. J Trop Pediatr 2005;51:380-2., 934Berger JR, Scott G, Albrecht J, et al. Progressive multifocal leukoencephalopathy in HIV-1-infected children. AIDS 1992;6: 837-41., 935Liptai Z, Papp E, Barsi P, et al. Progressive multifocal leukoencephalopathy in an HIV-infected child. Neuropediatrics 2007;38:32-5.).

No symptoms are known to be associated with acute JCV infection. PML is the only disease caused by JCV. Cases in children are similar to those in adults.

Demyelination is at first patchy, involving subcortical regions, and then spreads to deep white matter in confluent pattern; thus, PML initially may present with focal neurologic deficits that can involve different brain regions. The established criteria for clinical diagnosis are focal signs and symptoms on neurologic examination, focal white matter lesions on MRI or CT without mass effect, and exclusion of other causes of the clinical and neuroradiologic findings (936Angelini L, Pietrogrande MC, Delle Piane MR, et al. Progressive multifocal leukoencephalopathy in a child with hyperimmunoglobulin E recurrent infection syndrome and review of the literature. Neuropediatrics 2001;32:250-5.). The disease has an insidious onset and produces a neurologic syndrome that steadily progresses over weeks or months, characterized by confusion, disorientation, lack of energy, loss of balance, cognitive dysfunction, dementia, seizures, ataxia, aphasia, cranial nerve deficits, visual abnormalities (e.g., blurred or double vision or loss of vision), hemiparesis or quadraparesis, and eventually coma. During the pre-HAART era, adults and children with PML had extremely poor survival (929Ciuta ST, Boros S, Napoli PA, et al. Predictors of survival in children with acquired immunodeficiency syndrome in Italy, 1983 to 1995. AIDS Patient Care STDS 1998;12:629-37.). Survival among adults has improved during the HAART era (937Antinori 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): 47-53., 938Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004;17:365-70., 939Berenguer JP, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047-52.). No comparable data exist for children.

A confirmed diagnosis of PML requires a compatible clinical syndrome and radiographic findings coupled with brain biopsy demonstrating a characteristic triad of pathologic foci of demyelination, enlarged hyperchromatic oligodendrocytes with enlarged nuclei and basophilic-staining intranuclear material, and enlarged astrocytes with bizarre hyperchromatic nuclei. When only two of these features are present, JCV can be demonstrated by in situ hybridization or by electron microscopy for definitive diagnosis.

Although brain biopsy remains the confirmative test for diagnosis of PML, brain scans such as MRI or CT can reveal lesions in the brain. The radiologic features of PML are typically noninflammatory (unless associated with HAART-related IRIS). Typical CT abnormalities include single or multiple hypodense, nonenhancing cerebral white matter lesions; cerebellum and brain stem occasionally are involved. MRI depicts white matter lesions of low T1 signal intensity and high proton density on T2 weighted images with absence of edema or mass effects, as might be seen with cerebral toxoplasmosis or lymphoma. Postcontrast enhancement is unusual and, when present, usually is sparse, with a thin or reticulated appearance adjacent to the edge of the lesions.

PML diagnosis is now facilitated by use of PCR to detect JCV DNA in CSF, which may obviate the need for brain biopsy in patients with a compatible clinical syndrome and radiographic findings. Nested JCV PCR on CSF is highly sensitive (90%-100%) and specific (92%-100%) for PML (940Mamidi A, DeSimone JA, Pomerantz RJ. Central nervous system infections in individuals with HIV-1 infection. J Neurovirol 2002;8: 158-67.). Measurement of JCV DNA levels in CSF samples can be a useful virologic marker for managing PML in patients receiving HAART (941Bossolasco 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;40:738-44.).

No means of primary prophylaxis of JCV infection or development of PML have been demonstrated.

Neurologic stability or improvement and prolonged survival are associated with reduced JCV DNA and appearance of JCV-specific antibody in CSF of HAART-treated PML patients (946Giudici B, Vaz B, Bossolasco S, et al. Highly active antiretroviral therapy and progressive multifocal leukoencephalopathy: effects on cerebrospinal fluid markers of JC virus replication and immune response. Clin Infect Dis 2000;30:95-9.).

When antiretroviral therapy is initiated and CD4 counts rise, certain patients will experience neurologic improvement and others might become neurologically stable; however, reports have documented worsening neurologic manifestations after initiation of HAART (939Berenguer JP, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047-52.). In certain instances, this worsening is caused by IRIS (939Berenguer JP, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047-52., 947Safdar A, Rubocki RJ, Horvath JA, et al. Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 2002;35:1250-7., 948Cinque P, Koralnik IJ, Clifford DB. The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus terminology. J Neurovirol 2003;9(Suppl 1):88-92., 949D'Amico R, Sarkar S, Yusuff J, et al. Immune reconstitution after potent antiretroviral therapy in AIDS patients with progressive multifocal leukoencephalopathy. Scand J Infect Dis 2007;39:347-50.), examples of which have occurred in children (21Nuttall JJ, Wilmshurst JM, Ndondo AP, et al. Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitution inflammatory syndrome. Pediatr Infect Dis J 2004;23:683-5.). Other cases may represent the natural history of PML. The underlying etiology and trigger of HAART-associated PML is controversial. One hypothesis postulates a reduction in inhibitory cytokines (e.g., interferonalfa and interleukin-12) after HAART, thus promoting JCV reactivation within the brain or, by increasing trafficking of JCV-infected peripheral lymphocytes, into the brain (950Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9(Suppl 1):25-31.). JCV infection occurring coincidental to HAART initiation resulting in a beneficial inflammatory response with lack of disease progression is another hypothesis (950Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9(Suppl 1):25-31.), particularly given that JCV infection in children with perinatal HIV infection most often would be acquired during childhood. The overall prevalence of IRIS in children is not known. Inflammatory PML should be suspected in HAART-treated children with advanced HIV disease who show acute neurologic deterioration and contrast-enhancing demyelinating lesions on MRI.

PML remission with HAART may take several weeks, and no criteria exist that define progression of disease. A working definition used for HIV-infected adults is continued clinical worsening and continued detection of CSF JCV at 3 months (see Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults) (16CDC. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.). Some patients' PML worsens despite HAART, either because of IRIS or the natural history of PML. In both cases, HAART should be continued. If HAART fails to suppress HIV RNA or to boost the CD4 count, then attention should focus on modifying and optimizing the antiretroviral treatment (AII). However, in HIV-infected children responding well to HAART but with continued worsening PML, an expert in pediatric HIV infection should be consulted.

On the basis of its role in reversing the disease, the main preventive measure is an effective antiretroviral regimen that suppresses HIV viremia and maintains CD4 count (AII).

No means of secondary prophylaxis of JCV infection or PML have been demonstrated.