Progressive multifocal leukoencephalopathy

Edwina J. Wright: Department of Infectious Diseases Unit, Alfred Health and Monash University, Burnet Institute, Melbourne VIC
Phillip Chan : Department of Neurology, Queen Elizabeth Hospital, Hong Kong
Bruce J. Brew: HIV/Infectious Diseases Clinical Services Unit and Department of Neurology, St Vincent’s Hospital, Sydney NSW

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by a double-stranded DNA polyomavirus known as the John Cunningham virus (JCV). The JCV infects oligodendrocytes and leads to demyelination of the white matter of the brain (Figure 1.) and, rarely, the spinal cord. Serological evidence of infection with JCV is present in at least 80% of adults. Infection occurs during childhood and adolescence, following which JCV remains in the body, replicating within the kidneys,[1] peripheral blood mononuclear cells, the reticuloendothelial system, and, possibly, the brain.

PML usually manifests at the time of immunocompromise induced by human immunodeficiency virus (HIV) infection, organ transplantation, haematological malignancy, long-term immunosuppressive therapy[2] and idiopathic CD4 lymphocytopenia.[3] Administration of natalizumab therapy (a monoclonal antibody to alpha4 integrin that decreases adhesion of T cells) for Crohn’s disease or multiple sclerosis has been well documented as a risk factor for development of PML, with an estimated risk of 1 in 1000 treated patients.[4][5][6] Other immunomodulatory treatments including belatacept, brentuximab, efaluzimab, infliximab, rituximab, ruxolixinib and dimethyl fumarate have also been associated with PML. However, a sizeable number of patients have no discernible disturbance of their immune function.

Figure 1. Magnetic resonance imaging of the brain of a HIV-positive patient showing progressive multifocal leukoencephalopathy

Note: A confluent signal abnormality of the white matter is seen in the frontoparietal region of the brain. Source: Brew B. St Vincent’s Hospital, Sydney NSW. Used with permission.

PML occurred in 4% of acquired immune deficiency syndrome (AIDS) patients in Australia before the availability of combination antiretroviral therapy (cART.)[7] Despite the benefits of cART, there has not been a significant fall in the incidence of PML in parts of Europe,[8][9] nor has the USA seen a decrease in the incidence of PML as an AIDS-defining event.[10] In patients with HIV infection, PML is usually seen at the time of moderate or advanced immunosuppression. In studies from the pre-cART era, the median CD4 T-lymphocyte (CD4) cell count at diagnosis of PML was 53 cells/μL (range 0-420 cells/μL)11 in one study, and 30 cells/μL in an Australian study.[11] However, CD4 cell counts were somewhat higher in a post-cART study in which 60% of patients were receiving cART at the time of PML diagnosis (median 104 cells/μL, range 4-1030 cells/μL).[12] It is important to emphasise that PML can occur in HIV seropositive patients who have normal CD4 cell counts.

As a corollary, PML can occur in patients who have very low or undetectable plasma HIV viral loads and who are receiving cART: in one study, one-third of the patients diagnosed with PML had a plasma HIV viral load < 500 copies/mL.[13] In this same study, the overall median plasma HIV viral load was 3362 copies/mL (range < 500 copies –1.5 million copies/mL).[14]

Clinical features

The signs and symptoms of PML typically develop and progress over several weeks or, occasionally, over several months. Patients may present with cognitive impairment, headache, sensory and motor deficit of the limbs, or both, disturbance of gait, vision, speech and swallowing.[15][16] Clinical examination may reveal hemiparesis, hemineglect, visual field defects (including homonymous hemianopia), cerebellar signs and gait disturbance. Rarely there is evidence of brainstem and spinal cord involvement.

The presentation of PML is notable for the absence of fever in the patient and the infrequency of seizures.

Diagnosis

The key investigations that may be used in the diagnosis of PML include magnetic resonance imaging (MRI) of the brain, assessment of the cerebrospinal fluid (CSF) for JCV by polymerase chain reaction (PCR), and performance of a brain biopsy for histopathological review and JCV PCR. The typical findings of these and other investigations are discussed in Table 1.

Table 1 Investigational findings for patients with HIV infection with progressive multifocal leukoencephalopathy (PML)
Magnetic resonance imaging (MRI) of the brain (see Figure 1)
Key findings typically show several areas of T2-weighted high signal intensity in the subcortical white matter that have a scalloped appearance. Both unifocal and multifocal presentations have been reported. T1-weighted hypointensity is found in the corresponding areas. The frontal and parieto-occipital regions are most commonly involved. The presence of mass effect or contrast enhancement is very uncommon in PML, but can occur as a manifestation of an immune reconstitution inflammatory syndrome with the recent introduction of cART or with very aggressive JCV replication.[17][18] The MRI evidence of progression of PML includes increased hypointensity on T1-weighted images and increased high signal on fluid- attenuated inversion recovery/fast-spin echo (FLAIR-FSE) images.[19] In practice, MRI of the brain often plays a key role in the diagnosis of PML.
Computed tomography (CT) scan
Non-contrast CT brain scans typically reveal areas of hypointensity in the subcortical white matter that are not associated with mass effect and do not enhance with contrast. The lesions of PML on CT scans may mistakenly be interpreted as vasogenic oedema or infarction, especially if the diagnosis of underlying HIV infection is not known.
Cerebrospinal fluid JC virus polymerase chain reaction (PCR) assay
Qualitative JC virus PCR is readily available in Australia, but quantitative JC virus PCR assays are available in a few laboratories only. Sensitivity: over 90% in treatment cART naïve patients, but approximately 58% in cART exposed patients[20] Specificity: approximately 92-100% Positive predictive value: 88-100% Negative predictive value: 88.5-98.5%[21] In practice, the JC virus PCR in CSF may be positive in less than 50% of patients with PML.
Brain biopsy
The brain biopsy findings of PML on light microscopy show areas of demyelination in the subcortical white matter. Accompanying findings include enlarged oligodendrocytes, foamy macrophages and pleomorphic astrocytes.[22] Severe disease is characterised by intense demyelination that may lead to tissue destruction and cavitation.[23] If viral inclusions with a ground-glass appearance are found within the nuclei of oligodendrocytes, a diagnosis by light microscopy can be made. In practice, both the light microscopy findings and in situ hybridisation for JC virus are used for a tissue diagnosis of PML. Electron microscopy may also be used to secure a definitive diagnosis of PML. Overall, approximately 80% of PML patients who undertake a brain biopsy will be ascribed either a definite or probable diagnosis of PML.[24]

Typical clinical, radiological findings and positive JCV PCR from the patient’s CSF, are adequate to establish the diagnosis of PML.[25] Unfortunately, the clinician is often faced with the situation where the characteristic clinical and radiological features of PML are present, but there is a negative CSF JCV PCR, and the patient either declines a brain biopsy or a brain biopsy is technically unfeasible. Failure to detect JCV by PCR in CSF has increased in the cART era (10% in pre-cART era to 40% post cART era), and the test is also more likely to be negative in those with higher CD4 cell counts.[26] This increased false-negative rate is also reported in PML related to natalizumab treatment.[27] This rate is probably due to a lower viral load in CSF, below the threshold of detection in commonly used assays. High sensitivity PCR assays can detect a viral load down to 10 copies/mL, but this technique is usually only available in specialised laboratories. Occasionally a repeat CSF analysis will be positive for JCV PCR in this setting. Otherwise the practitioner must consider other possible causes of the clinical and MRI findings (see differential diagnoses below): if the original CSF analysis was negative for cytomegalovirus (CMV), varicella- zoster virus (VZV) and herpes simplex virus (HSV), and the CSF cytology was normal, then it is reasonable to have increased confidence in the diagnosis of PML.

Differential diagnoses

In the setting of advanced immunodeficiency, HIV encephalitis (HIVE) and CMV encephalitis (CMVE) are potential differential diagnoses of PML, as they also present with white matter T2 hyperintensity in MRI. However, the signal changes in HIVE are usually diffusely symmetrical in nature (rather than multifocal). In CMVE, the T2 signal changes mainly concentrate in the periventricular areas (rather than subcortical). The presence of meningeal or ependymal contrast enhancement also suggests the diagnosis of CMVE rather than PML.[28] In encephalitis related to reactivation of VZV, multifocal lesions can be observed on MRI due to multi-vessel vasculopathy.[29] However, the nature of these lesions is that of ischaemic or haemorrhagic infarcts rather than a demyelinating nature. Negative CSF PCR results for CMV and VZV, and a close review of the MRI findings, should help to exclude these entities in individual patients.

CNS lymphoma may present as a diffuse leukoencephalopathy even without contrast enhancement.[30] However, in HIV patients, primary or secondary lymphoma is associated with contrast enhancement in the majority of cases. Mass effect or peri-focal oedema are frequently associated with CNS lymphoma. Moreover, heterogeneity and ring-like contrast enhancement are features suggestive of primary CNS lymphoma.[31] A positive CSF PCR test for Epstein-Barr virus (EBV) in this setting is very useful .

Another condition which is also related to opportunistic JCV infection is granular cell neuronopathy (GCN). Its presentations are predominantly cerebellar in nature, including ataxia, tremor, nystagmus and dysarthria. The key feature in imaging is cerebellar atrophy. Microscopy shows extensive loss of the granular cell layer in the cerebellum rather than demyelineation as seen in PML. However, it is important to note that GCN can present alone or in combination with PML.[32][33][34]

Cyclosporine, tacrolimus, levamisole, fludarabine and 5-fluorouracil[35] have been reported to cause PML. Although these case reports have not come from the HIV setting, 5-fluorouracil is used in HIV infection to treat gastrointestinal malignancy.

Prognosis

Age is a characteristic associated with prognosis of PML in patients with HIV: one study found that patients younger than 45 years had improved survival.[36]

Baseline levels of CSF JCV viral load significantly predict survival in patients with HIV infection treated with cART,[37] and clearance of JCV from the CSF is associated with prolonged survival.[38][39][40] A high CD4 cell count (> 100 cells/μL) in patients treated with cART at the time of diagnosis of PML[41][42][43] and a rise in CD4 cell count following commencement of cART[44] are associated with increased survival in PML. Recent research has suggested that patients who can mount a specific cellular immune response to JCV have an increased chance of prolonged survival after diagnosis with PML.[45] Up to 10% of patients may experience spontaneous remission and prolonged survival.

Management

An overview of the treatment of PML with cART

The use of cART to treat PML in patients with HIV infection has been associated with prolonged survival in several studies.[46][47][48] In one study the median survival of patients who did not receive cART was 80 days compared with 246 days in those patients who did receive cART.[49]

The use of cART in the treatment of PML may be associated with a prompt clinical response, including complete recovery in some patients.[50] The median time to clinical improvement in PML after commencement of cART is not well documented, but, in one small study, clinical improvement was typically not evident until week four of therapy.[51] In the authors’ experience, patients who do improve generally do so within the first 4 to 12 weeks of cART, and they may go on to experience subtle symptomatic and objective improvements over the next 12 to 24 months, or occasionally longer.

Unfortunately, the benefits of cART may not extend to all patients with PML. A review of 118 patients with HIV infection with PML showed that up to one-third failed to respond to cART, dying within a median time of 12 weeks from diagnosis.[52] In this large study, the baseline CD4 cell count was significantly-associated with survival. Additionally, in the same review, residual neurological deficit occurred in approximately 50% of survivors, an observation made by other authors.[53]

PML-associated immune reconstitution inflammatory syndrome

PML-associated immune reconstitution inflammatory syndrome associated (PML-IRIS) is a frequently reported complication of using cART in HIV patients with PML. It is related to a profound inflammatory reaction resulting from restoring immunity towards JCV or viral proteins. Pathological studies reveal an inflammatory reaction with reactive gliosis, multinucleated histiocytes and intraparenchymal infiltration by CD8+ lymphocytes.[54][55] The cardinal feature of PML-IRIS is a clinical (in terms of original symptoms or development of new symptoms and signs) and radiological deterioration despite ongoing improvement in laboratory parameters, including decreasing plasma HIV viral load and increasing CD4 cell count after cART. PML-IRIS can be paradoxical in nature, in which deterioration occurs in a patient with diagnosed PML, or unmasking, when the development of symptoms after initiation of cART leads to the diagnosis of underlying PML.

PML-IRIS has been reported to occur from the first week to months after initiation of cART. [56][57][58][59][60] The clinical and radiological deterioration during the first four weeks of cART may be followed by recovery and stabilisation, or progressive deterioration. [61][62][63][64] It is thought that the inflammatory nature of PML-IRIS leads to contrast enhancement in radiological studies. [65][66][67][68] However, contrast enhancement has been reported in only 56% of PML-IRIS cases.[69] Practitioners are increasingly treating patients who have PML-IRIS with corticosteroids while maintaining patients on their cART regimen[70][71][72]Corticosteroids are recommended for patients who develop significant neurological deterioration and have radiological evidence of disease progression including features of cerebral oedema. Recommended regimens include dexamethasone 32 mg daily in four divided doses, or intravenous methylprednisolone 1mg daily for 5 days. Following administration of either dexamethasone or methylprednisolone the steroids should be weaned slowly over a number of weeks.

Use of the CCR5 inhibitor maraviroc in the setting of HIV-related PML-IRIS was associated with an improved outcome in one case report,[73] but not in another.[74] We recommend that any use of maraviroc should be made on a case-by-case basis.

Recommended combination antiretroviral therapy regimens

Patients who develop PML and who are antiretroviral-naïve or receiving suboptimal antiretroviral therapy should commence or change cART regimens, respectively. As restoring the T-cell immunity is the mainstay of PML treatment and any HIV replication in the brain will augment JCV replication through Tat, it is reasonable to employ, where possible, a cART regimen with good CNS penetration efficacy (CPE) in order to achieve maximum viral suppression in CNS (or most often CSF).[75] The use of cART regimens with high CPE scores in the late versus early cART eras was not associated with superior outcomes for neurological disorders including PML, presumably because the potency of the cART regimens was so high, irrespective of the CPE scores.[76]

Cytosine arabinoside, interferon-alpha and cidofovir

Intravenous cytosine arabinoside was not beneficial in the treatment of HIV-related PML in a large, placebo-controlled, randomised study,[77]and is rarely used. Subcutaneous interferon-alpha was associated with improved survival in a retrospective study,[78] but has not yet been tested in clinical trials. It is not used routinely to treat PML, because of its potentially significant toxicity. Cidofovir has proved disappointing in two studies of cART alone versus cART plus cidofovir to treat PML: there was no survival benefit, nor any benefit in neurological outcome.[79][80]

There are reports about the success in treating non-HIV related PML with psychotropic agents like mirtazapine[81][82] and risperidone[83] because of their 5HT2A blocking property. However, a systematic trial is necessary to justify their usefulness. A recent trial with mefloquine was negative although it was underpowered.[84] Other agents that have been suggested as potential treatment for PML include the thiazolidenones,[85] and the antipsychotic agents such as olanzapine.[86]

Monitoring

The monitoring of a patient with PML is summarised in Figure 2. Patients diagnosed with PML should be reviewed weekly during the first month of commencing cART to monitor for deterioration in symptoms and signs during this period. Following this procedure, the patient should be seen every 2 to 4 weeks for the first 3 months.

If the JCV is detected in the CSF at baseline, then a repeat lumbar puncture may be performed to look for JCV clearance at 6 to 12 weeks. Quantitation of CSF JCV DNA may be a useful guide to monitor treatment response if the test is available.

Repeat MRI should be performed at 6, 12 and 24 weeks after cART initiation or switch. It should also be noted that some patients improve significantly without any obvious change in MRI abnormalities.

If a patient deteriorates despite a successful virological and immunological response to cART, then consideration should be given to a brain biopsy if the diagnosis of PML was presumptive and not virologically proven.

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