Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by reactivation of John Cunningham virus (JCV). This rare condition is associated with advanced immunosuppression almost exclusively – malignancy, HIV, organ transplantation, and immunomodulatory agents.

Clinical features

The demyelination involves white matter and can involve grey matter. In classical PML, the signs and symptoms typically develop and progress over several weeks or months. As in the name, the multifocal involvement results in a myriad of neurological deficits including cognitive impairment, sensory or motor deficits, gait disturbance, visual disturbance, speech changes, seizures, difficulty swallowing, and altered mentation. Clinical examination may reveal hemiparesis, hemineglect, visual field defects (including homonymous hemianopia), cerebellar signs and gait disturbance. The presentation of PML is notable for the absence of fever in the patient.  Classical PML is usually progressive and fatal.

Other forms of potentially “milder” JC virus infection are increasingly recognised such as those with a single lesion, JCV encephalopathy, JCN meningitis, and JCV cerebellar granule cell neuronopathy.

Diagnosis

MRI brain and CSF analysis for JCV by polymerase chain reaction (PCR) are key to the diagnosis of PML. Typical clinical and radiological findings alongside a positive JCV PCR in the CSF are adequate for a probable diagnosis of PML. The degree of JCV viral load may have prognostic implications.

A brain biopsy may be necessary to confidently exclude other pathologies, particularly in atypical cases or those with unifocal lesions. The insidious nature of PML raises the possibility of concurrent HIV encephalopathy, primary CNS lymphoma or concurrent OIs such as toxoplasmosis – features on MRI brain, the presence of JCV, Epstein-Barr virus (EBV), Toxoplasma PCR, HIV viral load, and ultimately a brain biopsy can help distinguish these conditions.

Management

Unfortunately, there is no specific treatment for PML. Overall prognosis is poor. PWH who are ART- naïve and develop PML should commence ART (preferably with good CNS penetration). ART serves to immune restore and has in some cases led to modest clinical response, noting the risk of PML-IRIS.

A repeat LP to look for a drop of JCV viral load may guide treatment response. The timing of follow-up assessments should be guided by clinical progress.

Agents such as maraviroc, mirtazapine, mefloquine have been tried with no obvious benefit. Of late, there has been interest in considering checkpoint inhibitors such as nivolumab and pembrolizumab (13), and JCV-specific T-cells therapy (14). These remain under investigation and require expert discussion.

Early discussions on goals-of-care and symptomatic and supportive care are encouraged.

Timing of antiretroviral therapy commencement

As discussed above, ART should be commenced early in the setting of HIV-PML co-infection as this is key to immune restoration.

Neurological deterioration post-ART commencement

Patients with PML can continue to progressively deteriorate despite ART. It can be difficult distinguishing natural progression of PML from PML-IRIS, where the latter may benefit from steroid therapy. PML-IRIS typically has MRI changes suggestive of progressive oedema

If a patient continues to have progressive CNS decline despite virological and immunological response to ART, consideration should be given to a brain biopsy, particularly if the initial diagnosis of PML was presumptive and not virologically proven.

Summary

The diagnosis and management of CNS OIs can be complex. Please seek help from local and international experts where needed.