D26 Progressive multifocal leukoencephalopathy
Background and epidemiology
Progressive multifocal leukoencephalopathy (PML) is a potentially fatal demyelinating disease caused by JC virus (JCV), a human double-stranded DNA virus of the polyoma family. Primary infection occurs during late childhood and the infection is usually asymptomatic. More than 85% of adults have detectable antibody to JCV indicating previous exposure. The virus remains latent in the bone marrow, spleen and kidneys in a proportion of exposed individuals. PML occurs as a result of the reactivation of latent JCV when there is severe cellular immunodeficiency, as in patients with leukaemia, lymphoma, organ transplantation, or receiving corticosteroid or monoclonal antibody-based immune therapy such as natalizumab or rituximab. It has a particular preponderance to occur in AIDS patients, possibly due to direct upregulation of JCV transcription by the HIV tat protein.
Reactivated JCV spreads through the blood stream to enter the central nervous system (CNS) and causes lytic infection of the oligodendrocytes, leading to multifocal demyelination. PML tends to involve the periventricular white matter and subcortical U-fibres which are located at the grey-white matter junction. The lesions are preferentially localised in the frontal and parieto-occipital lobes and may also involve the brainstem and cerebellum. The lesions are initially discrete and with progressive increase in number and extent may coalesce into large confluent lesions.
PML is one of the important opportunistic diseases affecting the CNS in HIV-infected patients. In the United States, PML is the AIDS-defining illness (ADI) in less than 1% of HIV-infected individuals and the prevalence is 2-4%. The incidence did not show as significant a decline in comparison with other opportunistic infections in the era of highly active antiretroviral therapy (HAART). In Hong Kong, PML was the ADI in 8 of the cumulative 1959 AIDS patients up to the end of Sep 2018. (Department of Health statistics). A summary of the approach to managing PML is given at Algorithm 26.
The clinical presentation of PML is determined by the localisation of the demyelination and can result in focal neurological signs and symptoms such as hemiparesis, cortical visual impairment, speech disturbance, cerebellar ataxia and cognitive decline. Seizure may occur in a small proportion of patients. There are no symptoms of raised intracranial pressure or systemic infection. The time course is insidious with symptom onset and progression evolving over weeks to months. It generally occurs in the setting of relatively advanced HIV infection with CD4 lymphocyte count of below 100/μL although there had been isolated reports of HIV-infected patients developing PML at higher CD4 level. Alternatively the patient may present with symptoms of PML for the first time or have deterioration in PML-related symptoms shortly after commencing HAART, due to immune reconstitution inflammatory syndrome (IRIS, see below and Chapter C17).
Computed tomography (CT) may show the lesions as areas of hypodensity with clear demarcation but the findings may not be prominent until more advanced stages. On magnetic resonance imaging (MRI), white matter lesions appear hypointense on T1 and hyperintense on T2 and fluid-attenuated inversion recovery (FLAIR) sequences. The lesions are asymmetrical, multifocal and may coalesce to result in extensive involvement. While different parts of the brain can be affected, there is preponderance for involvement of the posterior region, especially the parieto-occipital lobe, the cerebellum and brainstem. Due to involvement of the subcortical U-fibres, the lateral margin tends to have a characteristic scalloped appearance. Typically there is no mass effect, oedema or contrast enhancement, which helps to differentiate PML from other intracranial focal mass lesions such as toxoplasma encephalitis, tuberculoma, fungal abscess and CNS lymphoma. The main differential diagnosis is HIV encephalitis in which the white matter changes are more diffuse, bilateral, symmetrical, mainly distributed over the periventricular region and uncommon in involvement of the posterior fossa.[Box 26.1]
Box 26.1. Radiological features of PML
|PML||Toxoplasma encephalitis||HIV encephalitis|
|Lesion morphology||Discrete white matter lesions that may coalesce into confluent lesions||Multiple discrete lesions||Diffuse predominantly white matter lesions|
|Mass effect and oedema||Typically absent||Usually present||Typically absent|
|Contrast enhancement||Typically absent||Usually present||Typically absent|
|Lesion location||Subcortical (U-Fibre), periventricular, frontal, parieto-occipital, posterior fossa||Basal ganglia, corticomedullary junction, posterior fossa||Periventricular, (posterior fossa involvement uncommon)|
Routine cerebrospinal fluid (CSF) tests and culture generally yield unremarkable findings apart from slight increase in the protein level, while the glucose level and CSF pressure are normal. Various studies have shown that nested PCR for JCV in the CSF has high positive detection rate of over 75% and specificity of up to 99% for the diagnosis in untreated PML, although the performance may not be as favourable in patients already on antiretroviral therapy and PML associated with IRIS.
Diagnosis of PML
A definitive diagnosis of PML is established by histological examination through brain biopsy. Apart from the presence of demyelination, there are intranuclear inclusions in enlarged ballooned oligodendrocytes and the JCV can be demonstrated by electron microscopy and immunohistochemistry. However, brain biopsy is an invasive procedure and the white matter lesions may be deeply located near vital structure and not readily accessible.
A presumptive diagnosis of PML can be made in a patient with characteristic clinical presentation and MRI findings. MRI is the diagnostic modality of choice and has superior sensitivity in detecting more subtle lesions. It should be recognised that atypical radiological features may be present in PML associated with IRIS, with more prominent mass effect, oedema and contrast enhancement.
CSF examination should be performed to exclude other treatable opportunistic infections of the CNS. The CSF should be sent for examination by nested polymerase chain reaction (PCR). The detection of JCV DNA in the CSF in a patient with characteristic clinical presentation and MRI findings can also establish the diagnosis of PML. Patients with presumptively diagnosed PML but repeated negative nested PCR for JCV DNA may be empirically treated after other infections have been excluded by CSF examination, reserving brain biopsy for those who continue to deteriorate.
Treatment and prognosis
There is no definitive curative treatment available for PML. Untreated patients have a median survival of 4 to 6 months. Various antiviral agents including cytarabine and cidofovir have been studied but did not show any conclusive evidence of efficacy. Other therapies that have been tried and failed to show benefits include heparan sulfate, interferon-α and -β, topotecan (topoisomerase inhibitor), and serotonergic receptor inhibitors.
The mainstay of PML treatment is immune restoration. Patients with PML should have early initiation of antiretroviral therapy and for those who are already on treatment, the regimen should be optimised to achieve full HIV suppression. With widespread rollout of HAART, survival of patients with PML had significantly improved with at least 60% achieving longer-term survival. It has been shown that the JCV DNA level in the CSF would significantly decline in patients with PML who had improvement following antiretroviral therapy but not in untreated or non-responsive patients. It was also found that a CD4 lymphocyte count of less than 100/μL is a poor prognostic indicator for response to antiretroviral therapy.
Up to 50% of the surviving patients on antiretroviral therapy have moderate to severe degree of residual neurological deficit. The outcome with HIV-associated PML may be improved if the diagnosis can be made earlier and if HAART is initiated in asymptomatic infected individuals at higher CD4 level. In the treatment of PML, one must be on the alert for IRIS. Although most forms of IRIS are paradoxical ‘exacerbation’ of previously diagnosed PML, some are newly diagnosed cases that follow HAART-induced immune recovery. Systemic steroid may be considered for immediate management of severe reactions, while withdrawal of HAART is exceptional.
Algorithm 26. Diagnosis and management of an HIV-infected patient with clinical suspicion of progressive multifocal leucoencephalopathy (PML)
- Ferenczy MW, Marshall LJ, Nelson CD, Atwood WJ, Nath A, Khalili K, Major EO. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 2012;25(3):471-506. link
- Berenguer J, Miralles P, Arrizabalaga J, Ribera E, Dronda F, Baraia-Etxaburu J, Domingo P, Márquez M, Rodriguez-Arrondo FJ, Laguna F, Rubio R, Lacruz Rodrigo J, Mallolas J, de Miguel V; GESIDA 11/99 Study Group. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36(8):1047-52. link
- Marzocchetti A, Di Giambenedetto S, Cingolani A, Ammassari A, Cauda R, De Luca A. Reduced rate of diagnostic positive detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy. J Clin Microbiol 2005;43(8):4175-7. link
- Bossolasco S, Calori G, Moretti F, Boschini A, Bertelli D, Mena M, Gerevini S, Bestetti A, Pedale R, Sala S, Sala S, Lazzarin A, Cinque P. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 2005;40(5):738-44. link
- Tassie JM, Gasnault J, Bentata M, Deloumeaux J, Boué F, Billaud E, Costagliola D. Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV. AIDS 1999;13(14):1881-7. link
- Dworkin MS, Wan PC, Hanson DL, Jones JL. Progressive multifocal leukoencephalopathy: improved survival of human immunodeficiency virus-infected patients in the protease inhibitor era. J Infect Dis 1999;180(3):621-5. link
- Drake AK, Loy CT, Brew BJ, Chen TC, Petoumenos K, Li PC, Wright EJ. Human immunodeficiency virus-associated progressive multifocal leucoencephalopathy: epidemiology and predictive factors for prolonged survival. Eur J Neurol 2007;14(4):418-23. link