Not a Disease of the Past: A Case Series of Progressive Multifocal Leukoencephalopathy in the Established Antiretroviral Era

Abstract

Progressive multifocal leukoencephalopathy (PML) and PML immune reconstitution inflammatory syndrome (PML-IRIS) can be devastating neurological processes associated with HIV, but limited knowledge of their characteristics in the established antiretroviral therapy (ART) era is available. We conducted a case series to evaluate the clinical course of PML and PML-IRIS at our urban safety-net hospital in Atlanta, GA. All HIV-positive individuals with a positive John Cunningham virus DNA polymerase chain reaction in the spinal fluid between were identified from the electronic health records (EHRs) using the HIV Disease Registry. Demographics, symptom presentation, laboratory data, imaging results, treatment, and outcomes were abstracted from the EHR. PML and PML-IRIS were defined using the American Association of Neurology criteria. Of the 32 individuals identified, 6 (19%) were felt to have asymptomatic positive results. Of the remainder, 15 (58%) HIV-positive patients had PML and 11 (42%) PML-IRIS (2 with an unmasking presentation and 9 with a paradoxical presentation). The most common presenting symptoms were motor weakness (18, 69%), cognitive deficits (15, 58%), and dysarthria (11, 42%). Corticosteroids were used in 12 patients and maraviroc in 3 patients. Outcomes were dismal with 7 (47%) patients with PML and 9 (82%) with PML-IRIS dying or being referred to hospice, with median survival times of 266 days in the PML group and 109 days in the PML-IRIS group. Despite widespread access to ART, patients with PML continue to have poor outcomes, particularly among those who develop PML-IRIS. More research is needed to understand the risks for and prevention of PML-IRIS.

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease

“…Two presentations of IRIS have been described, on the basis of the timing of the clinical manifestations: paradoxical IRIS, in which symptoms of a previously recognized infection worsen, and unmasked IRIS, in which the inflammatory response against subclinical infection renders it clinically manifest. Estimates suggest that 4-42% of patients with HIV-related PML develop IRIS 84,86,[90][91][92][93] . Clinical manifestations are usually mild, but if the associated inflammatory response is extensive -which most commonly occurs in patients with the sharpest rise in CD4 + T cell counts -IRIS can be life-threatening; mortality is 5-28% 86,[94][95][96] .…”

“…Clinical manifestations are usually mild, but if the associated inflammatory response is extensive -which most commonly occurs in patients with the sharpest rise in CD4 + T cell counts -IRIS can be life-threatening; mortality is 5-28% 86,[94][95][96] . In general, the development of inflammatory features in PML is thought to be associated with higher survival rates 96,97 , although some reports suggest that this is not always the case 92 .…”

Use of Pembrolizumab for Treatment of Progressive Multifocal Leukoencephalopathy in People Living with HIV

“…A separate discussion is deserved for the patient with PML-IRIS, patient 3. IRIS occurs in about 4–42% of HIV/AIDS patients starting cART [ 6 , 18 , 19 ] and is the result of an excessive immune response to either pre-existing or latent opportunistic pathogens [ 20 ]. PML has been reported to occur within the first weeks to months after initiating cART and has been associated with clinical and radiological worsening [ 21 , 22 ].…”

“…Among persons living with HIV (PLWH), the prevalence of PML over time has gradually decreased, suggesting that the immunity restoration induced by an effective combined antiretroviral treatment (cART) is a possible treatment strategy [ 4 , 5 ], in absence of specific anti-JCV therapy. Nevertheless, PML remains a disease burdened by very high morbidity and mortality even in the cART era [ 6 ]. The clinical presentation depends on the localization, the extent of demyelination and the rapidity of progression leading to a wide spectrum of severe associated signs and symptoms, including impaired behaviour and cognitive disorders, motor and language deficits, hemianopsia and seizures [ 7 ].…”

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“…131,132 Thalidomide has been used in HIV-infected patients 133,134 and in an immunocompetent patient experiencing C-IRIS. 135 Innovative, though unproven therapies in other forms of IRIS have been reported, including interleukin 6 (IL-6) inhibitors such as tocilizumab, best known for its role in chimeric antigen receptor T-cell therapyassociated neurological immune response, anakinra (human recombinant IL-1 receptor antagonist), 136 maraviroc (a C-C chemokine receptor 5 (CCR5) inhibitor) 137,138 and other TNF-blockers such as infliximab. 139 CCR2/CCR5 inhibitors such as cenicriviroc (also called CVC) is currently being trialled in COVID-19 treatment studies 140 and may have potential in C-IRIS.…”