INTRODUCTION — Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system that occurs almost exclusively in immunosuppressed individuals. This disease is caused by the polyomavirus JC (JCV). (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
PML is most likely to be found in patients with lymphoproliferative and myeloproliferative diseases, solid organ malignancies, HIV (human immunodeficiency virus) infection, autoimmune diseases, and in patients on antirejection immunosuppressive drugs after organ transplantation or patients treated with immunomodulatory therapies such as natalizumab. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Underlying conditions'.)
This topic will review the various approaches that have been employed to treat PML. Other aspects of JCV infection and PML are discussed elsewhere. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
APPROACH TO TREATMENT
Immune reconstitution — There is no specific treatment for PML, which has a high mortality rate. Therefore, the main approach is restoring the host adaptive immune response, a strategy that appears to prolong survival [1-4]. Implementation of this strategy differs according to the clinical setting:
●Initiating or optimizing effective antiretroviral therapy (ART) for patients with HIV infection
●Withdrawing immunosuppressive drugs (when possible) for patients without HIV infection
●Discontinuing natalizumab, a medication used to treat multiple sclerosis, and starting plasma exchange for patients with natalizumab-associated PML
Successful restoration of immunity is often accompanied by the immune reconstitution inflammatory syndrome (IRIS), which can be treated with glucocorticoids when there is neurologic deterioration associated with evidence of brain swelling and risk of herniation. (See 'PML-IRIS' below.)
With HIV infection — In patients with HIV infection who have PML, optimization or initiation of effective ART is the best therapeutic option . PML may improve or stabilize with ART [6-8], leading to prolonged survival . Patients receiving ART have a one-year survival rate of approximately 50 percent, compared with approximately 10 percent in those not on ART .
Note that initiating ART for PML may precipitate PML-IRIS, the inflammatory form of PML, which may require glucocorticoid therapy if accompanied by marked neurologic deterioration and clinical or radiologic evidence of brain swelling. (See 'PML-IRIS' below.)
The treatment of HIV infection with ART is discussed in detail separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Without HIV infection — In patients without HIV infection who have PML, we generally discontinue or reduce any potential sources of immunosuppression (when feasible), such as glucocorticoids or calcineurin inhibitors in transplant recipients.
The benefit of this intervention is unproven and is obviously associated with an increased risk of rejection in patients with organ transplants, or relapse in patients with inflammatory diseases. However, possible benefit is suggested by the case reports of renal, liver, and heart transplant recipients who survived PML after immunosuppression was reduced or discontinued [11-14]. Another report described two patients with dermatomyositis who developed PML while on immunosuppressive therapy and showed clinical and radiologic improvement after partial taper or cessation of immunosuppressive treatment .
However, immune reconstitution may not be possible for some patients with hematologic malignancies, even after withdrawal of immunosuppressive therapy, due to long-term immune cell depletion or depressed bone marrow .
Natalizumab-associated PML — Natalizumab treatment for multiple sclerosis is a risk factor for developing PML (see "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Natalizumab'). Therefore, natalizumab should be immediately discontinued in patients who develop PML. Although benefit is uncertain as discussed below, we suggest a course of plasma exchange (eg, every other day for a total of five treatments) for patients with natalizumab-associated PML. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
In addition, we suggest high-dose glucocorticoid therapy for patients who develop PML-IRIS associated with neurologic deterioration and evidence (clinical and/or radiologic) of brain swelling. (See 'PML-IRIS' below.)
Empiric treatment with plasma exchange or immunoadsorption or both has been used to treat natalizumab-associated PML [16-21]. The rationale is to eliminate circulating natalizumab, which has a long duration of action that might delay immune reconstitution. However, the evidence is limited to small, retrospective observational studies, and benefit is unproven. In a review of natalizumab-associated PML cases that compared patients who received plasmapheresis (n = 184) with patients who did not (n = 35), there was no evidence of benefit with plasmapheresis for mortality risk or likelihood of poor versus favorable outcome .
An earlier series reported 15 patients with natalizumab-associated PML who were treated with plasma exchange; the regimen also included mirtazapine and mefloquine for all 15 patients, and high-dose glucocorticoids for 14 who developed IRIS . At a median follow-up of 22 months from PML diagnosis, the survival rate was 100 percent, while disability was rated as mild, moderate, or severe in 20, 60, and 20 percent, respectively. During the acute phase of PML, eight patients developed seizures, and focal epilepsy persisted in four patients at one year despite antiepileptic therapy. Of note, the results of an underpowered randomized trial suggest that mefloquine is not beneficial for PML, and evidence for mirtazapine is quite limited (see 'Pharmacologic agents' below). Therefore, we do not suggest the use of mefloquine or mirtazapine in natalizumab-associated PML.
PML-IRIS — Some patients with a reversible cause of immunosuppression develop an inflammatory reaction in PML lesions known as the IRIS, which is associated with new onset or clinical worsening of PML and with contrast enhancement of PML lesions (image 1) on brain magnetic resonance imaging (MRI). The enhancement may have a "starry sky" appearance.
●Occurrence – PML-IRIS occurs mainly in two categories of patients, those with HIV infection and PML who are started on ART, and patients with multiple sclerosis who develop natalizumab-associated PML leading to withdrawal of natalizumab therapy.
•Although ART has improved the survival of patients with HIV infection who have PML, it has also been associated with new onset (unmasking) or clinical worsening of PML. PML-IRIS is characterized by a marked increase in CD4-positive T-cell counts and a decrease in HIV plasma viral load, indicating a recovery of the immune system . This paradoxical development of PML is usually accompanied by an inflammatory reaction in PML lesions and demonstrated by contrast enhancement on brain MRI. (See "Immune reconstitution inflammatory syndrome".)
•Most patients with natalizumab-associated PML develop some degree of PML-IRIS approximately three to six weeks after treatment with plasma exchange or immunoadsorption. Furthermore, IRIS can occur in patients with PML weeks to months after discontinuation of natalizumab even when plasma exchange or immunoadsorption are not employed [24,25]. In one report of 35 patients of natalizumab-associated PML, IRIS developed in approximately 90 percent, usually within weeks after stopping natalizumab and starting treatment with plasma exchange or immunoadsorption [18,19]. IRIS usually presented with subacute onset of new symptoms or with worsening of symptoms attributed to PML. The mean time from initiation of plasma exchange or immunoadsorption to the onset of IRIS was just over 30 days . Most of the reported patients who developed IRIS in this setting had severe cases and were treated with high-dose glucocorticoids [18,19]. IRIS also developed several months after stopping natalizumab in a patient who was not treated with plasma exchange or immunoadsorption .
●Management – We suggest high-dose glucocorticoid therapy for patients who develop PML-IRIS when there is both marked neurologic deterioration and clinical or radiologic evidence of brain swelling, which can lead to mass effect, brain herniation, and death. Reasonable regimens include either intravenous dexamethasone (32 mg daily given in four divided doses) for two weeks, or intravenous methylprednisolone (1 g daily for five days), both followed by a slow glucocorticoid taper. High-dose glucocorticoids can be given without temporary interruption of ART.
In the absence of neurologic deterioration with brain swelling, we suggest not treating with glucocorticoids.
Weak retrospective evidence supports the use of glucocorticoid therapy for patients PML-IRIS and neurologic deterioration with brain swelling [23,26]. In a review of 54 patients with HIV infection and PML-IRIS, 12 patients were treated with glucocorticoids, most often for catastrophic deterioration or for evidence of brain inflammation on neuroimaging . The overall mortality was 35 percent. Comparing the groups treated (n = 12) and not treated (n = 42) with glucocorticoids, there were no statistically significant differences on any baseline or outcome measure, including duration of survival or mortality. Of the 12 patients treated with glucocorticoids, 7 survived with good neurologic recovery, and 5 died. Survivors received glucocorticoids earlier after the recognition of IRIS (mean 3 versus 12 weeks), received longer courses of glucocorticoids (mean 13 versus 3 weeks), and were tapered off glucocorticoids more slowly. However, these differences were not statistically significant. Survivors were more likely to have contrast enhancement of PML-IRIS on brain MRI scan (six of seven versus one of five), but the differences were also not statistically significant.
Pharmacologic agents — Several medications have been used to treat PML based upon earlier anecdotal evidence of efficacy (eg, cytarabine and cidofovir), or hypothetical mechanisms impeding the JCV (eg, topotecan, mirtazapine, mefloquine) or the immune reconstitution inflammatory syndrome (eg, maraviroc). However, among those tested in randomized trials or prospective studies (ie, cytarabine , cidofovir , and mefloquine ), none has shown clinical benefit. Evidence for the remainder comes from only small numbers of patients with PML. Therefore, these drugs are not considered effective treatment for PML .
●Checkpoint inhibitors – The immune checkpoint inhibitors nivolumab and pembrolizumab are monoclonal antibodies that target programmed cell death protein 1 (PD-1), an inhibitory T-cell surface receptor that promotes self-tolerance and is a marker of immune exhaustion. Upon binding with its ligand, PD-1 inhibits T-cell proliferation and cytokine production. Pembrolizumab and nivolumab block this inhibitory reaction and have been used to reinvigorate antitumoral T-cell activity.
In small reports involving a total of 10 patients with PML, treatment with nivolumab or pembrolizumab was associated with clinical improvement in 7 [30-32]. In the largest of these, eight adults with PML received pembrolizumab 2 mg/kg every four to six weeks for a total of one to three doses; clinical improvement or stabilization was observed in five patients .
These encouraging data are tempered by studies reporting poor outcomes. In a retrospective multicenter survey compiling follow-up data from 79 patients with PML with various predispositions who were treated with immune checkpoint inhibitors, mortality at one year was approximately 48 percent . Other studies noted cases where PML developed after treatment with nivolumab , where PML worsened despite treatment with pembrolizumab [35,36], and where neurologic progression led to death of three kidney transplant recipients within eight weeks of PML presentation despite treatment with nivolumab . Interestingly, only a few patients treated with immune checkpoint inhibitors had HIV/AIDS (acquired immunodeficiency syndrome) . These negative studies did not involve patients with natalizumab-associated PML, where the prognosis is better than in other situations (see 'Prognosis' below).
Further studies are needed to determine whether immune checkpoint inhibitors have a role in the treatment of PML . Of note, these medications would only be effective against PML in patients who have JCV-specific T cells at baseline.
●Cytarabine (cytosine arabinoside) – In a randomized controlled trial involving 57 patients with HIV infection and biopsy-confirmed PML, cytarabine administered either intravenously or intrathecally did not improve prognosis compared with antiretroviral therapy alone .
●Filgrastim – Findings from a 2019 retrospective report of 17 patients with multiple sclerosis and natalizumab-associated PML suggested that adjunct treatment with filgrastim, a recombinant granulocyte colony stimulating factor, was associated with a higher survival rate (100 percent) at two years after PML onset than reported in most earlier studies . There was no apparent worsening of multiple sclerosis associated with filgrastim treatment. Larger prospective studies are needed to determine if filgrastim is beneficial for natalizumab-associated PML.
●Interleukin 7 – In a few case reports of patients with idiopathic CD4+ lymphocytopenia who developed slowly progressive PML, treatment with the cytokine interleukin 7 was associated with some degree of clinical improvement or disease stabilization [42-44]. The actual benefit of interleukin 7 in these cases is speculative. In an observational study of 64 patients with PML treated with interleukin 7, survival for patients with HIV/AIDS was similar to that expected for patients with PML and HIV/AIDS who were not treated with interleukin 7, while survival was longer than expected for patients with hematologic malignances, primary immunodeficiencies, and those with organ transplantation . Nevertheless, benefit is unproven given the small sample size and the retrospective, nonrandomized nature of the study.
●Maraviroc – Maraviroc is a CCR5 receptor antagonist that is approved for the treatment of HIV infection. In several cases of patients with PML, the addition of maraviroc was associated with clinical improvement [46-49], but no benefit was found in other cases [50,51]. In a placebo-controlled randomized trial of 276 patients with HIV, maraviroc was not effective for preventing IRIS after ART initiation .
●Mefloquine – The antimalarial drug mefloquine has some anti-JCV activity in vitro . However, a randomized trial evaluating mefloquine for the treatment of PML was stopped prematurely because recruitment was slow and an interim analysis suggested that mefloquine failed to reduce JCV DNA levels in the cerebrospinal fluid .
●Mirtazapine – In vitro studies have provided evidence that JCV may infect cells through the serotonin receptor 5HT2a, suggesting a potential role for mirtazapine, a potent antagonist of 5HT2 and 5HT3 serotonin receptors . Data for mirtazapine in PML are limited to a few cases. In HIV-negative patients, a case report described a woman with biopsy-proven PML who had subsequent clinical and radiologic improvement within a month of initiating mirtazapine . In addition, a patient with PML and dermatomyositis may have benefited from mirtazapine, although the patient also received cytarabine . By contrast, a patient with hepatitis C had a rapid fatal outcome from PML despite mirtazapine and cytarabine .
In patients with HIV infection and PML, a case series reported that treatment with mirtazapine 15 mg daily was associated with objective clinical improvement in three of four patients , and several case reports also noted that mirtazapine treatment was associated with clinical improvement [58,59]. However, ART was also used or initiated for PML treatment in these patients, so it is uncertain whether mirtazapine was responsible for the improvement. A controlled trial would be needed to settle the issue.
●Topotecan – The topoisomerase inhibitor topotecan is a candidate for the treatment of PML based on the knowledge that topoisomerases are required to unwind the double stranded circular viral DNA and thus allow viral replication. In a pilot study, 3 of 11 patients with HIV infection and PML showed a response to treatment with topotecan . However, topotecan was poorly tolerated, and severe anemia, leukopenia, and thrombocytopenia were frequent side effects.
Virus-specific T cell therapy — An investigational treatment for PML involves the use of virus-specific cytotoxic T cells generated from the patient (autologous) or from allogenic third-party donors. This approach has been used to treat BK virus infection after stem cell transplantation . In an early published report of this therapy for PML, three immunosuppressed or immunodeficient patients with PML were treated with cryopreserved, partially human leukocyte antigen (HLA)-matched, BK virus-specific T cells generated from healthy donors . These T cells were chosen because of the genetic and immunogenic similarity between the BK virus and JCV, the cause of PML. In two of the patients, T cell infusion was associated with improvement in the clinical and neuroimaging manifestations of PML along with clearing of JCV in the cerebrospinal fluid (CSF). In the other patient, T cell infusion was followed by stabilization (but not improvement) of symptoms and signs of PML and a reduction in the JCV load in the CSF that persisted until the patient died in hospice eight months after the first infusion.
Although the treatment was well tolerated, any conclusion regarding efficacy appears premature. One problem is that the T cell response against JCV, which is crucial for the containment of PML, was not measured prior to the first infusion . Another is that immune recovery occurred in all three patients after discontinuation of immunosuppression or re-initiation of antiretroviral therapy; one of the patients presented with IRIS prior to the fist infusion of BK virus T-cells. Regardless of therapeutic effect, this paper illustrates the importance of quality-of-life issues in PML, as one patient opted for hospice care despite apparent stabilization of the disease.
Another study reported nine HIV-negative patients with immune suppression due to hematologic malignancies or congenital immune deficiencies who developed PML . Most had additional risk factors for PML such as chemotherapy, treatment with B cell-depleting monoclonal antibodies, or hematopoietic stem cell transplantation. T cell response against JCV was not detectable prior to treatment. Seven patients were treated with JCV-specific T cells generated ex vivo, and two were treated with banked JCV-specific T cells. Over the course of the study (median follow-up 39 months from PML diagnosis), four of the nine patients had neurologic improvement and survived with mild or minimal residual disability, one survived with severe disability, and four died. All survivors developed punctate contrast enhancement in or near PML lesions, but none were considered to have an immune reconstitution inflammatory syndrome (IRIS). There were no treatment-related adverse events.
A third study, the first prospective report of virus-specific T cells for PML, excluded patients with HIV infection or a readily reversible immunosuppressed state . Virus-specific T cells were generated by collecting T cells from first-degree relative donors (to maximize HLA matching) and stimulating the cells ex vivo with BK virus peptide libraries that exhibited high sequence homology to the JC virus, a process that required four to six weeks. During this delay, six eligible patients died from rapid progression of PML before they could be treated. Twelve patients were treated with infusions of virus-specific T cells, with a median follow-up of 110 days (range 23 to 699); five treated patients died from PML in the first three months of the study, while seven treated patients survived for more than one year after the first infusion.
Further studies involving larger groups of patients are necessary to determine the efficacy of this novel treatment for PML.
Morbidity and mortality — The disease course of PML is usually progressive and is often fatal but varies according to the underlying condition and treatment. In a cohort of 584 patients diagnosed with PML from a French national health care database, the overall one-year mortality rate was 38 percent, and the median time from PML diagnosis to death was 63 days .
●With HIV infection – Before effective antiretroviral therapy (ART), only 10 percent of patients with HIV infection and PML survived longer than one year . With ART, several reports suggest that the one-year survival rate has increased to 50 percent or more [10,65,67,68]. In a nationwide Danish cohort study of all patients ≥16 years of age with HIV infection, the median survival time increased from 0.4 years (95% CI 0.0-0.7) in those diagnosed with PML before 1997 (ie, pre-ART) to 1.8 years (95% CI 0.9-2.6) in those diagnosed with PML from 1997 to 2006, when ART became more common . Nevertheless, PML remains a devastating disease despite widespread access to ART, and survival varies widely among different studies. As an example, a single-center case series from Atlanta, Georgia identified patients with HIV infection who tested positive by PCR for cerebrospinal fluid JCV between 2013 and 2017 . The median survival with PML (n = 15) and PML-IRIS (n = 11) was only 266 days and 109 days, respectively. By contrast, a review of patients diagnosed with PML between 1994 and 2019 at two centers in Boston, Massachusetts, identified 45 patients with PML and underlying HIV infection, a group with a median survival of 1992 days (approximately 5.4 years), including 13 patients who survived more than 10 years after PML onset .
While survival in the ART era is longer, remyelination does not occur in affected areas of the brain, and 55 to 80 percent of PML survivors are left with severe neurologic sequelae . Brain magnetic resonance imaging (MRI) in long-term survivors shows volume loss as a sequelae of previous PML lesions (image 2) .
●Without HIV infection or natalizumab-associated PML – The overall median survival of patients without HIV infection or natalizumab-associated PML is estimated to be approximately three months [70,71]. Within this category, consisting mainly of patients with hematologic malignancies, the type of immunosuppressive treatment likely affects outcome from PML. A retrospective review identified 107 PML cases associated with hematologic malignancies from 1995 to 2017, including patients who received hematopoietic stem cell transplantation (HSCT group; 40 percent of cases) and patients who received chemotherapy or immunotherapy (CIT group; 40 percent of cases) . Patients who received HSCT had a lower mortality rate (56 percent, versus 88 percent with CIT) and a longer median survival (8 months, versus 2 months with CIT). The better survival associated with HSCT may be related to immune reconstitution.
●Natalizumab-associated PML – In patients with multiple sclerosis who develop natalizumab-associated PML, the available evidence suggests that survival is ≥80 percent at one year after PML diagnosis, but most survivors have moderate to severe disability . (See 'Natalizumab-associated PML' above.)
Prognostic markers — Clinical features associated with survival in a retrospective series of 336 cases of natalizumab-associated PML were younger age at diagnosis, a lower JCV load at diagnosis, less disability prior to PML onset, and localized brain lesions on magnetic resonance imaging (MRI) .
●Biomarkers – JCV levels may be prognostic markers in patients with PML. A small study found that patients with a low JCV burden (50 to 100 copies/mL) in the cerebrospinal fluid (CSF) had a longer survival than patients with high JCV burden . Another study measured JCV DNA levels from sequential CSF samples in 24 patients with PML and HIV infection and found that patients who showed PML stabilization with ART exhibited a progressive decline in JCV DNA levels compared with patients who had progressive fatal PML with or without ART . Other studies have also found that detection of a JCV-specific immune response in blood and CSF is associated with a favorable outcome in PML [76-80].
●IRIS – The development of at least a limited degree inflammatory immune response against JCV in the central nervous system may be instrumental in stabilization of the disease [81,82]. The presence of contrast enhancement of PML lesions, otherwise atypical, is suggestive of development of an inflammatory response with breakdown of the blood brain barrier. Although data are scant, contrast enhancement has been associated with a better prognosis in some reports . An inflammatory immune response in patients with HIV infection and PML may be facilitated with CD4-positive T-cell counts above 300 cells/microL. One study of patients with HIV infection and PML found that only variable associated with outcome was the baseline CD4+ count; higher mortality was associated with a CD4+ count of <100 cells/microL .
SUMMARY AND RECOMMENDATIONS
●There is no specific treatment for progressive multifocal leukoencephalopathy (PML). Therefore, the main approach is restoring the host adaptive immune response, a strategy that appears to prolong survival. (See 'Immune reconstitution' above.)
●In patients with PML and HIV infection, initiation and optimization of effective antiretroviral therapy (ART) therapy is crucial. (See 'With HIV infection' above and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
●For immunosuppressed patients without HIV infection who have PML, we generally stop or reduce immunosuppressive therapy (when feasible) since PML is usually a progressive, fatal disease. (See 'Without HIV infection' above.)
●For patients with multiple sclerosis who develop PML during natalizumab treatment, natalizumab should be immediately discontinued. In addition, we suggest a course of plasma exchange (Grade 2C). In these patients, IRIS is likely to develop approximately three to six weeks after plasma exchange. (See 'Natalizumab-associated PML' above and 'PML-IRIS' above.)
●PML may be associated with the immune reconstitution inflammatory syndrome (IRIS), which is associated with new onset or clinical worsening of PML symptoms and with contrast enhancement of PML lesions on brain magnetic resonance imaging (MRI). PML-IRIS occurs mainly in patients with HIV infection and PML who are started on ART, and in patients with multiple sclerosis who develop natalizumab-associated PML, leading to withdrawal of natalizumab therapy. (See 'PML-IRIS' above.)
•For patients who develop PML-IRIS and have both neurologic deterioration and clinical or radiologic evidence of brain swelling, we suggest high-dose glucocorticoid therapy (Grade 2C). Reasonable regimens include either intravenous dexamethasone (32 mg daily given in four divided doses) for two weeks, or intravenous methylprednisolone (1 g daily for five days), both followed by a slow glucocorticoid taper. In patients with HIV infection, glucocorticoid therapy can be started without interruption of ART. (See 'PML-IRIS' above.)
●PML is often fatal, and the median survival of patients without HIV infection (excluding those with natalizumab-associated PML) is only three months. In patients with HIV infection and PML, the median survival for patients has increased with widespread use of ART, but the increment varies among published series. In patients with natalizumab-associated PML, the available evidence suggests that survival with treatment is ≥80 percent at one year after PML diagnosis. Most survivors have moderate to severe disability. (See 'Prognosis' above.)
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