– Christian Hoffmann –
PML is a severe demyelinating disease of the central nervous system. It is caused by JC virus (JCV), a polyoma virus found worldwide. JCV was named after the initials of the first patient John Cunningham, from which this simple DNA virus was first isolated in 1971 (Major 1992). Therefore, JC has no connection, as is often wrongly assumed, with Jakob-Creutzfeld syndrome. As seroprevalence is high, at up to 80%, latent persistent infection is assumed. Kidneys and bones seem to be important reservoirs. Only impaired cellular immunity leads to reactivation of JCV and manifestation of disease. It seems certain that JCV reaches the CNS via leukocytes, and then affects mainly oligodendrocytes and consequently the cells which comprise the myelin sheaths. Destruction of these is as macroscopically apparent as multifocal demyelination. The main focus of the disease is the white matter of the cerebral hemispheres, but in some cases, the cerebellum, the grey matter may also be affected.
PML is a classic opportunistic infection and can occur in patients with hematological diseases or during therapy with monoclonal antibodies such as rituximab, natalizumab or efalizumab (Yousry 2006, Carson 2009, Major 2010). However, HIV patients are by far the largest patient group. Severe immunodeficiency is frequently seen, but not obligatory for development of PML. In contrast to CMV or MAC infection, PML does not always indicate the final stages of HIV infection. Although CD4 T cells are usually below 100/µl at manifestation of disease, PML may also occur at above 200 CD4 T cells/µl. The decrease in incidence is not as marked as with other OIs. After cerebral toxoplasmosis, it is now probably the second most common neurological OI (Antinori 2001).
Prognosis was poor in the pre-HAART era. The median interval between the onset of the first symptoms and death was between 3 and 6 months. Patients usually died of secondary complications after being bedridden for many weeks. The prognosis is slightly better at CD4 counts above 200/µl (Berger 1998). Disease progression seems to be much slower under ART, and even complete remission seems possible (Albrecht 1998). However, these effects are not as impressive as for other OIs: in a Spanish study of 118 PML patients on ART, 64% were still alive 2.2 years after diagnosis (Berenguer 2003). Complete remissions are not the rule, even under sufficient ART. They mainly occur in cases of inflammatory PML, which occurs in the course of an immune reconstitution inflammatory syndrome (Du Pasquier 2003, Hoffmann 2003, Tan 2009). The number of CD4 T-cells and the JC-virus specific immune response seem to be relevant as prognostic markers, however the JCV viral load does not seem relevant (Khanna 2009, Marzocchetti 2009). Today PML is still the OI with the highest mortality (ART-CC 2009).
Signs and symptoms
Although there is a broad spectrum of PML symptoms due to the variety of localized areas of demyelination, the clinical signs and course of the disease have several common characteristics. In addition to cognitive disorders, which may range from mild impairment of concentration to dementia, focal neurological deficits are very typical of PML. Mono- and hemiparesis are observed most frequently, as well as speech and even visual deficits. We have seen several blind patients with PML. These deficits may be isolated and initially present as discrete changes in coordination, rapidly leading to considerable disabilities. Epileptic seizures may also occur. Loss of sensibility, fever, and headache are rare and are usually more typical of cerebral toxoplasmosis.
Clinical suspicion of PML should be rapidly confirmed radiologically. But beware: a CCT scan is not helpful – it does not clearly reveal hypodense lesions. A MRI is much more sensitive to detecting both the number and size of lesions than a CCT and usually shows high signal intensity lesions in T2-weighted imaging and in FLAIR sequence, which are hypointense in T1-w and often do not show gadolinium enhancement or mass effect. ART may result in inflammatory courses that involve significant enhancement (see IRIS). Exclusion of grey matter is typical – since this is a leukoencephalopathy. Furthermore, it should be noted that the lesions are almost always asymmetrical.
A MRI often allows distinction from cerebral toxoplasmosis or lymphoma. However, the huge, extensive lesions covering an entire hemisphere that are often shown in the literature are not always present. Every PML starts small – very discrete, localized, solitary lesions can occur and certainly do not exclude the diagnosis. PML can occur everywhere in the brain, and there are no typically susceptible areas. Lesions are often parieto-occipital or periventricular, but the cerebellum may also be involved. It is important that the images are assessed by a radiologist or clinician familiar with PML. Even then, it is difficult to distinguish PML from HHV-6 infection (Caserta 2004) or HIV leukoencephalopathy (Langford 2002).
Clinicoradiological diagnosis is therefore not definitive. Examination of cerebrospinal fluid is essential. Generally, if there is no other co-infection, then unspecific inflammatory signs are absent, although the total protein content is usually slightly elevated. Pleocytosis is rarely seen, and more than 100/3 cells make PML unlikely. CSF should always be tested for JCV. Newer PCR methods have a sensitivity of around 80% and a specificity of over 90%. A CSF sample should be sent to a JCV-experienced laboratory.
PML is very probable in cases of clinicoradiological suspicion and positive JCV PCR. In such cases, brain biopsies are no longer recommended today. Nevertheless, negative PCR does not exclude the diagnosis. Levels of JCV viral load may vary significantly and do not correlate with the extent of lesions (Eggers 1999, Garcia 2002, Bossolasco 2005). Unfortunately, JCV PCR is even less useful – many patients with PML have a low or undetectable JCV CSF viral load under ART (Bossolasco 2005). Stereotactic brain biopsy may become necessary in individual cases.
A specific PML treatment is not available. Foscarnet, interferon, immune stimulants, steroids or cytosine-arabinoside are not effective (Hall 1998). Cidofovir and camptothecin are the two new drugs currently being discussed. It is feared that these drugs will have a similar fate in controlled studies. Camptothecin is an alkaloid cytostatic, which inhibits topoisomerase I, a nuclear enzyme that is required for DNA and therefore also JCV replication (O’Reilly 1997). Currently, only data from case studies and a small series of patients exist in which 3 out of 12 patients experienced clinical improvement under the camptothecin-derivate topotecan (Vollmer-Haase 1997, Royal 2003). However, one patient died under topotecan, which shows high hematoxicity. Results of randomized studies are missing and this approach can not be recommended outside clinical studies.
The nucleotide analog cidofovir, which is licensed for cmv retinitis showed some positive effects. According to an analysis of 370 patients from numerous studies (De Luca 2008), a real benefit has not been proven Observed experiences have been rather disappointing and, in a retrospective analysis of 35 patients, cidofovir was even associated with a poorer prognosis. However, this chiefly reflects the frustration of patients and clinicians – cidofovir was mainly used in cases of progressive disease (Wyen 2004). Furthermore, the opinion exists that there is no longer an argument for the use of cidofovir in PML patients.
In recent years, 5-HT2a-inhibitors and/or serotonin receptor antagonists have been proposed for PML treatment. It has been shown that the serotonergic receptor 5HT2AR could act as the cellular receptor for JCV on human glial cells (Elphick 2004); the blockade could represent thus a therapeutic goal. Case studies for some agents such as risperidone and mirtazapine, which block serotonergic receptors, exist already (Verma 2007, Focosi 2007+2008, Cettomai 2009). However, controlled studies are missing. This is also the case for mefloquine (Brickelmeier 2009).
The absolute priority should currently be to optimize ART in cases of PML. Improvement of the JC virus-specific immune response which is often observed within immune reconstitution determines the patient’s further progress to a large extent (Khanna 2009, Marzocchetti 2007+2009). Our early observation that prognosis significantly improved under ART (Albrecht 1998) was confirmed by several other groups (Clifford 1999, Dworkin 1999, Gasnault 1999+2008, Tantisiriwat 1999, Berenguer 2003, Khanna 2009). Since synergism between HIV and JCV has been demonstrated in vitro, maximal HIV suppression should at least be achieved. Although progression of disease has been described under sufficient antiretroviral therapy, ART often remains the only real hope for patients today. There is also some evidence that intracerebral penetrating antiretroviral agents such as AZT, FTC, abacavir, nevirapine and lopinavir are more efficient on survival of PML patients (Gasnault 2008).
Treatment/prophylaxis of PML
|Treatment of choice||ART||The most important goal is maximal HIV suppression and immune reconstitution. Use intracerebral penetrating agents such as AZT, FTC, abacavir, nevirapine and lopinavir|
|Experimental||Only within clinical trials (risperidone? mirtazapine?)|
There is none. Exposure prophylaxis is also not possible.
Albrecht H, Hoffmann C, Degen O, et al. HAART significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. AIDS 1998, 12:1149-1154.
Antinori A, Ammassari A, Giancola ML, et al. Epidemiology and prognosis of AIDS-associated progressive multifocal leukoencephalopathy in the HAART era. J Neurovirol 2001, 7:323-8.
Berenguer J, 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.
Berger JR, Levy RM, Flomenhoft D, et al. Predictive factors for prolonged survival in AIDS-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998, 44:341-9.
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, 40:738-44.
Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 2009, 53:1840-9.
Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project. Blood 2009 Mar 5.
Caserta MT. Human Herpesvirus 6 Infection of the Central Nervous System. Curr Infect Dis Rep 2004, 6: 316-321.
Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol 2009, 66:255-8.
Clifford DB, Yiannoutsos C, Glicksman M et al. HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 1999, 52:623-5.
De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS 2008, 22:1759-67.
Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003; 9 Suppl 1:25-31.
Dworkin MS, Wan PC, Hanson DL, Jones JL. Progressive multifocal leukoencephalopathy: improved survival of HIV-infected patients in the protease inhibitor era. J Infect Dis 1999, 180:621-5.
Eggers C, Stellbrink HJ, Buhk T, Dorries K. Quantification of JC virus DNA in the cerebrospinal fluid of patients with HIV-associated PML – a longitudinal study. J Infect Dis 1999, 180:1690-4.
Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004;306:1380-3.
Engsig FN, Hansen AB, Omland LH, et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis 2009, 199:77-83.
Falcó V, Olmo M, del Saz SV, et al. Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: results of an observational multicenter study. J AIDS 2008, 49:26-31.
Focosi D, Kast RE, Maggi F, Ceccherini-Nelli L, Petrini M. Risperidone-induced reduction in JC viruria as a surrogate marker for efficacy against progressive multifocal leukoencephalopathy and hemorrhagic cystitis. J Clin Virol 2007; 39:63–4.
Focosi D, Kast RE, Maggi F, et al. 5-HT2a inhibitors for progressive multifocal leukoencephalopathy: old drugs for an old disease. J Infect Dis 2008, 197:328.
Garcia De Viedma D, Diaz Infantes M, Miralles P, et al. JC virus load in progressive multifocal leukoencephalopathy: analysis of the correlation between the viral burden in cerebrospinal fluid, patient survival, and the volume of neurological lesions. Clin Infect Dis 2002, 34:1568-75.
Gasnault J, Lanoy E, Bentata M, et al. Intracerebral penetrating ART are more efficient on survival of HIV+ patients with progressive multifocal leucoencephalopathy. Abstract 385, 15th CROI 2008, Boston.
Gasnault J, Taoufik Y, Goujard C, et al. Prolonged survival without neurological improvement in patients with AIDS-related PML on potent combined antiretroviral therapy. J Neurovirol 1999, 5:421-9.
Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with HIV infection. N Engl J Med 1998, 338:1345-51.
Hoffmann C, Horst HA, Albrecht H, Schlote W. Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 2003;74:1142-4.
Khanna N, Elzi L, Mueller NJ, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis 2009, 48:1459-66.
Khanna N, Wolbers M, Mueller NJ, et al. JCV-specific immune responses in hiv-1 patients with progressive multifocal leukoencephalopathy. J Virol 2009 Feb 11. [Epub ahead of print]
Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 2002, 16:1019-29.
Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 1992, 5:49-73.
Marzocchetti A, Sanguinetti M, Giambenedetto SD, et al. Characterization of JC virus in cerebrospinal fluid from HIV-1 infected patients with progressive multifocal leukoencephalopathy: insights into viral pathogenesis and disease prognosis. J Neurovirol 2007;13:338-46.
Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009, 73:1551-8.
O’Reilly S. Efficacy of camptothecin in progressive multifocal leucoencephalopathy. Lancet 1997, 350:291.
Royal W 3rd, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003; 9:411-9.
Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection. Clinical manifestations and treatment with steroids. Neurology 2009 Jan 7.
Tantisiriwat W, Tebas P, Clifford DB, et al: Progressive multifocal leukoencephalopathy in patients with AIDS receiving HAART. Clin Infect Dis 1999, 28:1152-4.
Verma S, Cikurel K, Koralnik IJ, et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis 2007;196:709-11.
Vollmer-Haase J, Young P, Ringelstein EB. Efficacy of camptothecin in progressive multifocal leucoencephalopathy. Lancet 1997, 349:1366.
Wyen C, Hoffmann C, Schmeier N, et al. Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death. J AIDS 2004, 37:1263-1268.
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006, 354:924-33.