Category Archives: Progressive multifocal Leukoencephalopathy

Progressive multifocal Leukoencephalopathy

– 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
Acute therapy    
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?)
Prophylaxis   Not available


There is none. Exposure prophylaxis is also not possible.


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