RARE DISEASE
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Synonyms: PML, Progressive multifocal leukoencephalitis
Synonyms: PML, Progressive multifocal leukoencephalitis
Synonyms: PML, Progressive multifocal leukoencephalitis
Drug discovery
6
drugs
With orphan designations
Overview
Progressive multifocal leukoencephalopathy (PML) is a rare, lethal demyelinating CNS infection caused by JC virus reactivation in immunocompromised individuals. It manifests with progressive neurological deficits (e.g., motor impairment, cognitive decline, vision/speech changes) and is diagnosed via MRI white matter lesions and CSF JC virus PCR [1][5][11]. Prognosis remains poor despite immune restoration therapies [1][7].
Therapies
Immune reconstitution: ART for HIV-PML [10], immunosuppressant withdrawal +/- plasma exchange (e.g., natalizumab-associated PML) [3][6].
Experimental agents: PD-1 inhibitors (pembrolizumab), JCV-specific T-cell therapy, and IL-7 immunotherapy under investigation [13][18].
Supportive care: Corticosteroids for immune reconstitution inflammatory syndrome (IRIS) [6][8].
Categories: rare infectious diseases, rare neurological diseases
Research Papers
791 drug discovery papers about Progressive multifocal leukoencephalopathy, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
791 drug discovery papers about Progressive multifocal leukoencephalopathy, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-08-25 | Pembrolizumab in people with HIV-associated progressive multifocal leukoencephalopathy: a retrospective case series.
Progressive multifocal leukoencephalopathy (PML) in people with HIV (PWH) carries high mortality, and no specific antiviral treatment is available. In this retrospective single-centre case series of six patients treated with pembrolizumab, four showed clinical improvement or stabilisation. Pembrolizumab might represent a salvage option in this population.
2026-08-24 | Progressive multifocal leukoencephalopathy in a 15-year-old boy with X-linked hyper-IgM syndrome: a case report
Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal infection caused by JC polyomavirus, primarily affecting individuals with impaired cellular immunity. We report a 15-year-old boy with genetically confirmed X-linked hyper-IgM syndrome due to a pathogenic CD40LG variant. Despite regular intravenous immunoglobulin replacement therapy and antimicrobial prophylaxis, he developed concurrent Pneumocystis jirovecii pneumonia and COVID-19. Approximately 2 months after recovery from the pulmonary infections, he developed progressive visual impairment, diplopia, impaired concentration, and mild generalized weakness. Brain magnetic resonance imaging revealed extensive bilateral temporo-parieto-occipital white-matter lesions. Cerebrospinal fluid polymerase chain reaction was positive for JC polyomavirus DNA, confirming the diagnosis of PML; HIV testing was negative. In the absence of an established antiviral therapy, a single intravenous dose of pembrolizumab (80 mg) was administered as an experimental immune-based intervention. Three weeks later, the patient developed rapidly progressive generalized muscle weakness and respiratory failure requiring intensive care and mechanical ventilation. Despite intensive supportive treatment, he subsequently died. The precise cause of this deterioration could not be conclusively established, and a multifactorial process involving progression of PML and treatment-related or critical-illness complications could not be excluded. PML should be considered in patients with X-linked hyper-IgM syndrome who develop new neurological manifestations. Pembrolizumab remains an experimental intervention in this setting, with uncertain efficacy and safety in primary immunodeficiency.
2026-07-03 | Efficacy and safety of extended-interval dosing of natalizumab in multiple sclerosis: a systematic review and meta-analysis with subgroup evaluation.
Natalizumab is effective for relapsing-remitting multiple sclerosis (RRMS) but increases the risk of progressive multifocal leukoencephalopathy (PML). Extended-interval dosing (EID) may lessen this risk by reducing drug exposure, though its efficacy and safety compared with standard-interval dosing (SID) remain unclear. This review and meta-analysis evaluates both regimens across clinical and MRI outcomes. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Web of Science, Cochrane Library, and ScienceDirect from inception to July 2025. Eligible studies compared extended- (5-12 weeks) and standard-interval (4 weeks) natalizumab dosing in MS. Meta-analyses used random- or fixed-effects models with results as RR or MD based on heterogeneity (I²). Twenty-five studies were included. Analysis showed no significant differences between EID and SID in disability progression (MD -0.09, 95% CI: -0.46 to 0.29), or the risk of new T2 lesions (RR 1.24, 95% CI: 0.96 to 1.61). For PML incidence (RR 1.03, 95% CI: 0.29-3.60), the analysis was severely underpowered due to rare events; the wide confidence interval precludes any firm conclusion about comparative safety. However, EID was associated with a significantly higher risk of gadolinium-enhancing lesions (RR 1.35, 95% CI: 1.03-1.77). EID was associated with a borderline reduction in the risk of clinical relapse (RR 0.91, 95% CI: 0.83 to 1.00), but this finding is likely influenced by selection bias and should be considered hypothesis-generating rather than confirmatory. Subgroup analysis suggested a possible difference between intervals (P = 0.0323 for T2 lesions), but this finding is based on very sparse data, with only one subgroup (Q5-8 W) containing multiple studies and all other subgroups relying on single studies. Therefore, no definitive conclusion about optimal interval length can be drawn; the result is hypothesis-generating only. Extended-interval dosing of natalizumab shows efficacy and safety comparable to standard dosing. Although relapse reduction was noted, this may reflect selection bias. Shorter EID intervals (5-8 weeks) appear to maintain better radiologic control, supporting EID up to 6-8 weeks as a viable option pending long-term and biomarker-guided validation.
2026-06-11 | Brain Immune Cell Composition in Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy After Natalizumab: An Immunohistochemical Cohort Study.
Natalizumab therapy in multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML) and may alter lymphocyte distribution within the CNS. Tissue-resident memory CD8+ T cells (TRM CD8+), which rely on activation through CD4+ T cells, are essential for antiviral defense and may contribute to JC virus (JCV) control. We, therefore, investigated lymphoid infiltrates in patients with MS after natalizumab treatment and in patients with natalizumab-associated PML to assess antiviral immunity and clinical outcomes. Fluorescence immunohistochemistry was performed on brain biopsies and autopsies from patients with MS (n = 34) and those with PML (n = 27) with and without prior natalizumab exposure and from healthy controls (n = 11). The analysis included CD103+ (TRM) CD8+, total CD8+, and CD4+ T cells; CD209+ dendritic cells; and JCV-infected cells. Cell densities were correlated with clinical outcomes using the modified Rankin Scale and Expanded Disability Status Scale. TRM CD8+ T-cell numbers remained stable in the normal-appearing white matter of patients with MS previously treated with natalizumab and matched levels in healthy controls. By contrast, CD4+ and CD8+ T cells were elevated in MS irrespective of natalizumab exposure and increased further beyond 35 days after treatment cessation, suggesting immune restoration that may reduce PML risk, particularly under extended-interval dosing. In PML lesions, TRM CD8+ T cells were abundant, and natalizumab-associated PML demonstrated infiltrates comparable to inflammatory PML lesions (>500 T cells/mm2), indicating strong local immune activation. Approximately 4 months after natalizumab withdrawal, marked viral clearance was observed and higher densities of TRM CD8+ and total CD8+ T cells were associated with better clinical outcomes. TRM CD8+ T cells appear central to CNS antiviral defense and remain largely preserved during natalizumab therapy. Although natalizumab restricts T-cell trafficking, the postwithdrawal rise in CD4+ and CD8+ T cells indicates immune reconstitution that may enhance TRM CD8+ activation. In natalizumab-associated PML, the presence of strong T-cell infiltrates and declining viral loads after treatment cessation underscore the importance of restored local immunity for effective JCV control. Higher densities of TRM CD8+ and total CD8+ T cells were linked to better clinical outcomes, highlighting their contribution to viral clearance and recovery.
2026-06-09 | Progressive Multifocal Leukoencephalopathy in an Immunocompetent Host Treated with Pembrolizumab (P9-3.003)
To describe a rare case of biopsy-proven progressive multifocal leukoencephalopathy (PML) in an immunocompetent patient and the clinical–radiological response to pembrolizumab treatment.
gene therapies
2026-08-25 | Reply: Age confounding in HIV-associated progressive multifocal leukoencephalopathy prognosis
Nicolas Lambert, Adèle Le Guilloux, Agnès Sommet, Guillaume Martin-Blondel; Reply: Age confounding in HIV-associated progressive multifocal leukoencephalop
2026-08-14 | Guideline of the German Society of Neurology (DGN): "diagnosis and therapy of HIV-1-associated neurological disorders".
Epidemiology and treatment of HIV changed substantially within the last three decades. However, HIV-associated neurological disorders such as mild forms of HIV-associated neurocognitive disorder (HAND) as well as HIV-associated distal symmetrical sensory polyneuropathy are amongst the most frequent complications in patients with longstanding HIV infection. Opportunistic infections occur less frequently compared to former years, but especially in patients with late presentation of HIV progressive multifocal leukoencephalopathy (PML) (0.7 per 1,000 patient-years), toxoplasma encephalitis (0.4 per 1,000 patient-years) and cryptococcal meningitis (0.2 per 1,000 patient-years) remain the most common opportunistic infections. The guidelines for diagnosis and treatment of HIV-associated neurological disorders of the German Society of Neurology were revised addressing recent changes in treatment opportunities of HAND, HIV associated complications of the peripheral nervous system and muscles and opportunistic infections of the central nervous system (CNS).
2026-06-25 | Progressive Multifocal Leukoencephalopathy or Lymphoma? A Massive Unilateral Hemispheric Mimicker in a Patient Undergoing Lymphoma Treatment.
An 81-year-old woman with follicular lymphoma treated with obinutuzumab and bendamustine developed cognitive impairment and dysarthria. Three months before death, neurological exams showed dysarthria, right hemiparesis, and gait disturbance. Blood tests showed lymphocytopenia (lymphocyte 10.4%). Cerebrospinal fluid (CSF) findings were unremarkable, including with respect to cytology. Brain MRI demonstrated a mass-like hyperintense lesion in the left parietal lobe and band-like abnormalities in the left fronto-temporal white matter that lacked contrast enhancement. Symptoms progressed to hemiplegia and mutism; severe dysphagia eventually necessitated intravenous fluid management. Follow-up MRI one month before death revealed a lesion encompassing nearly the entire left hemisphere, with hyperperfusion observed during arterial spin labeling (ASL). JC virus was detected in CSF (221 copy/mL), confirming that the patient had progressive multifocal leukoencephalopathy (PML). Subsequently, she exhibited poor arousal, followed by death. Here, lymphoma recurrence or PML was suspected due to a post-chemotherapy unilateral expanding brain lesion. These conditions are usually differentiated by contrast-enhancement patterns, but PML can also enhance during immune reconstitution. Moreover, lesions rarely cause a mass effect and more often exhibit hyperperfusion, which may aid in diagnosis. While unilateral PML has been reported, especially in the early stage, such an extensive lesion involving nearly an entire single hemisphere, as seen in our case, is rare.
2026-06-09 | Progressive Multifocal Leukoencephalopathy with Immune Reconstitution Inflammatory Syndrome and Good Outcome in an Immunocompetent Patient: Case Report and Literature Review (P9-3.004)
To report a case of progressive multifocal leukoencephalopathy (PML) with immune reconstitution inflammatory syndrome (IRIS) in an immunocompetent patient with a favorable outcome.
2026-05-22 | Human Polyomaviruses of Clinical Relevance: Modes of Transmission and Associated Pathologies.
Polyomaviruses are non-enveloped viruses with double-stranded circular DNA genome. Currently, 13 members of the Polyomaviridae family have been classified as human polyomavirus (HPyVs). Despite high seroprevalence values have been reported for the majority of the HPyVs worldwide, the main mode of transmission remains to be elucidated, and simple and common routes, such as faecal-oral and respiratory have been suggested. In general, HPyVs are responsible for asymptomatic primary infection, followed by asymptomatic lifelong persistent infection. In situations of severe immunosuppression, viral reactivation of some HPyVs may occur and result in the development of associated clinical manifestations. JCPyV is the causative agent of Progressive Multifocal Leukoencephalopathy, BKPyV is associated with nephropathy among kidney transplant recipients, MCPyV with Merkel Cell Carcinoma and TSPyV with Trichodysplasia spinulosa. The association of certain HPyVs with severe diseases, in addition to the high seroprevalence of the majority of HPyVs, emphasises the need to address various knowledge gaps that still exists in the natural history of these viruses, including the transmission routes and the pathogenic mechanisms. The present review summarises current information on HPyV transmission routes and associated diseases, including diagnosis and available treatment options, highlighting the need for further studies.
small molecules
2026-09-09 | Tenofovir in Progressive Multifocal Leukoencephalopathy: Virus Suppression Without Clinical Benefit in 2 Cases.
Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the CNS caused by reactivation of the JC polyomavirus (JCV), typically in immunocompromised individuals. As no specific therapy against JCV exists, current management focuses on immune reconstitution. Recently, a potential therapeutic effect of tenofovir was reported. We report 2 patients with PML who received tenofovir under a compassionate use protocol. Treatment was accompanied by MRI, clinical, and virologic monitoring. In both patients (serum and CSF), viral load was markedly reduced. In 1 patient, this was accompanied by temporary clinical stabilization and reduction in MRI lesion burden. The other patient further declined clinically, accompanied by progression of MRI lesion size and contrast enhancement. Dense lymphocytic infiltration on biopsy suggested predominant effects of alleviated immunosuppression rather than the direct antiviral drug effect. Both patients ultimately died of the disease. Despite virus reduction in both cases, sustained clinical improvement was not achieved. This suggests that viral load reduction alone is insufficient, and pathogenesis may be largely driven by the immune response to the infection. A combination of tenofovir with low-dose anti-inflammatory drugs may be a useful addition to PML therapy.
2026-04-01 | E043 Progressive multifocal leukoencephalopathy: a rare neurological complication of mycophenolate therapy in antisynthetase syndrome
Abstract Background/Aims Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating infection of the central nervous system caused by reactivation of the John Cunningham (JC) virus in immunocompromised individuals. The incidence density of PML among mycophenolate mofetil (MMF) users is estimated at 14.4 cases per 100,000 person-years. While monoclonal antibody therapies such as natalizumab and efalizumab are the most frequent culprits, PML has also been reported in patients receiving conventional immunosuppressants, including MMF. The disease carries a poor prognosis, with mortality rates reaching 50-65 % within the first year despite cessation of immunosuppressive therapy. Mirtazapine, a 5-HT2A receptor antagonist, has been explored as a potential adjunct as it may inhibit JC virus entry into glial cells. Methods We report the case of a 57-year-old woman with antisynthetase syndrome (Jo-1 and Ro-52 antibody positive) who presented to the stroke unit at Maidstone Hospital with a two-week history of progressive neurological symptoms, including memory impairment, motor dysphasia, left-sided weakness, and intermittent kaleidoscopic visual disturbance. She had interstitial lung involvement but was otherwise amyopathic and functionally independent. She was on MMF and a low maintenance dose of prednisolone, with no prior rituximab exposure. On examination, she was cognitively intact with normal gait and subtle left pronator drift. Power was 4-/5 in the left upper limb and 5/5 elsewhere, with preserved sensation. Inflammatory markers were mildly elevated (CRP 14 mg/L, ESR 6 mm/h). MRI brain showed extensive multifocal right-sided subcortical white-matter lesions. The stroke team referred her to rheumatology to evaluate for cerebral involvement of antisynthetase syndrome. However, neuroradiology review suggested an infective aetiology, raising suspicion for PML. Results HIV testing was negative. Cerebrospinal fluid JC-virus PCR was initially negative, recognising that false negatives occur in up to 30% of early cases. As symptoms progressed, she was referred to a tertiary centre in London, where a stereotactic brain biopsy revealed focal macrophage-rich inflammation with enlarged oligodendroglial nuclei displaying a ground-glass appearance. Luxol-fast blue staining highlighted multifocal demyelination, and immunohistochemistry for SV40 confirmed oligodendroglial intranuclear viral inclusions, consistent with PML. Following multidisciplinary discussion, all immunosuppressive therapy was withdrawn. She was commenced on intravenous immunoglobulin (IVIG) for her antisynthetase syndrome. Mirtazapine was considered but declined. Her neurological status improved after discontinuation of immunosuppression, and she remains clinically stable on IVIG alone. Conclusion This case underscores the diagnostic challenge of PML in autoimmune disease treated with MMF. Even in the absence of monoclonal antibody therapy, clinicians should maintain a high index of suspicion for PML when new focal or cognitive deficits occur. Early neuroimaging, CSF analysis, and tissue confirmation are essential to guide management. Given the high mortality rate, prompt discontinuation of immunosuppression, multidisciplinary collaboration, and patient education on PML risk before initiating MMF therapy are vital. Disclosure A. Vijayan: None. A. Nur: None. A. Waller: None. M. Szeto: None. A. Keough: None. P. Sengupta: None.
2026-01-19 | Progressive multifocal leukoencephalopathy in the modern therapeutic era: A critical synthesis of epidemiology, diagnostics, and policy implications with regional context from Korea
This review aims to synthesize contemporary evidence on progressive multifocal leukoencephalopathy (PML), a rare, demyelinating disease of the central nervous system caused by reactivation of the John Cunningham virus (JCV) in immunocompromised individuals. Since its initial description in 1958, PML has evolved from being predominantly associated with hematological malignancies to a multifaceted opportunistic infection seen in HIV/AIDS, autoimmune disorders, transplantation medicine, and in patients receiving monoclonal antibody therapies such as natalizumab. The global epidemiology of PML reflects both improved survival in immunocompromised populations and expanded iatrogenic risk due to modern immunomodulatory agents. This review synthesizes contemporary evidence on the epidemiology, pathogenesis, diagnostic strategies, and therapeutic approaches to PML, with an emphasis on comparing international patterns to emerging data from Korea. Although Korean reports remain limited, recent case studies reveal unique patterns of presentation, delayed diagnosis, and frequent misattribution to alternative neurological disorders, underscoring the need for heightened clinical vigilance. The review critically examines diagnostic limitations, including the imperfect sensitivity of cerebrospinal fluid JCV PCR, and highlights emerging biomarkers and neuroimaging signatures that may improve early detection. Therapeutic options remain largely supportive, with immune reconstitution representing the most effective strategy; however, novel antiviral and immunomodulatory approaches are under investigation. The review concludes with an agenda for future research, calling for international registry development, standardized diagnostic protocols, and cross-disciplinary collaborations to address the persistently high morbidity and mortality associated with PML. By integrating global and Korean perspectives, this paper aims to advance a more nuanced, regionally informed understanding of PML’s evolving clinical landscape.
2025-11-25 | Successful Treatment of Progressive Multifocal Leukoencephalopathy With Tenofovir Alafenamide Fumarate.
Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal CNS infection caused by reactivation of JC virus, typically in immunocompromised patients. No effective antiviral therapy has been established. We report a case of PML in a patient with multiple sclerosis (MS) treated with fingolimod, who received oral tenofovir alafenamide fumarate (TAF). This is a single-patient case report from Stavanger University Hospital, Norway. A 67-year-old woman with secondary progressive MS developed progressive neurologic symptoms during fingolimod treatment. MRI and CSF analyses confirmed PML with detectable JCV DNA. Fingolimod was discontinued, and oral TAF 50 mg/d was initiated. Clinical course, MRI changes, and CSF biomarkers were monitored over 6 months. At baseline, JCV DNA was 4,940 international units [IU]/mL in CSF and the Expanded Disability Status Scale (EDSS) score was 8.5. Four days after TAF initiation, partial radiologic improvement was observed. After 3 and 6 months, JCV DNA was undetectable (<1,000 IU/mL). The patient remained clinically stable with unchanged EDSS score and tolerated TAF without adverse effects. MRI showed regression of PML lesions but development of new MS activity after fingolimod withdrawal. This case demonstrates temporal association between TAF initiation and virologic clearance of JCV, suggesting potential antiviral activity. As a single case without controls, this report provides Class IV evidence that oral TAF might stabilize the clinical course in patients with PML.
2025-11-13 | A Case of Cerebellar-Onset Progressive Multifocal Leukoencephalopathy (PML) Associated with Hepatitis B-related Liver Cirrhosis.
We herein report a case of progressive multifocal leukoencephalopathy (PML) in a woman in her 70s with hepatitis B-related liver cirrhosis. She presented with cerebellar onset symptoms, including ataxia and dysarthria. The diagnosis was delayed despite the initial magnetic resonance imaging (MRI) findings of an asymmetric cerebellar white matter lesion. PML was ultimately diagnosed based on a re-evaluation of a brain biopsy specimen and a retrospective JC virus (JCV) PCR analysis of the cerebrospinal fluid. Treatment with mefloquine and mirtazapine resulted in viral clearance from the cerebrospinal fluid (CSF) and clinical stabilization. This case highlights that crescent-shaped cerebellar lesions should raise suspicion of PML, even in patients without severe immunodeficiency.
cell therapies
2026-08-07 | Adoptive T-cell therapies in neuroinfectious and neuroinflammatory diseases.
Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
2026-07-06 | Treatment of Progressive Multifocal Leukoencephalopathy with Third-Party Allogeneic BK Virus T Cells.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by JC polyomavirus (JCV) that affects immunosuppressed individuals and has no approved therapy. Here we evaluate the safety and efficacy of third-party, off-the-shelf, partially HLA-matched BK virus-specific T cells (BK-VST) in patients with PML. We conducted a single-center phase 2 study where 37 patients received most closely HLA-matched BK-VST at 2.0 x 105 T cells/kg, with additional infusions permitted for subjects who did not achieve a complete response. Twenty-three patients had an underlying diagnosis of hematologic malignancy. Each patient received a median of 2 doses (range, 1-12; IQR 2). Overall response (OR) was defined as virologic clearance with neurologic stabilization or improvement. During 12 months of follow-up, 21 patients (56.8%) achieved an OR, including 16 (43.2%) with a complete response. Responses were rapid (median 23 days) and durable, with no loss of response observed despite limited HLA matching. The 1-year overall survival was 61.1% (95% CI, 41.9-77.4). Patients achieving an OR after the first infusion had markedly improved 1-year survival compared with non-responders (93.3% vs 0%; p<0.001). Higher donor IL-2 and IFN-γ-producing T-cell frequencies and greater HLA matching correlated with clinical benefit. These data demonstrate that third-party BK-VST infusions are safe and potentially effective, supporting a scalable immunotherapeutic approach for this otherwise fatal disease. (ClinicalTrials.gov NCT02479698).
2026-05-27 | Resolution of PML after Treatment with Virus-Specific T Cells and HCT
Two patients with inborn errors of immunity and progressive multifocal leukoencephalopathy received polyomavirus-specific T cells, followed by allogeneic hematopoietic transplantation with good neurologic outcomes.
2026-02-06 | What are the latest available treatments for Progressive Multifocal Leukoencephalopathy and their effectiveness?
Progressive Multifocal Leukoencephalopathy remains challenging to treat, with investigational therapies such as virus-specific T cells, immune checkpoint inhibitors, and antiviral agents presenting potential promise. Current evidence is limited and largely anecdotal, necessitating further research.
2025-07-01 | CXCR4 and CXCR6 dually limit T cell entry into the polyomavirus-infected brain.
T cell responses are vital for controlling viral infection in the central nervous system (CNS), but must be tightly regulated to limit tissue-damaging inflammation. Using mouse polyomavirus (MuPyV) CNS infection, an in vivo model for JCPyV-induced Progressive Multifocal Leukoencephalopathy (PML), we investigated sites of early infection, immune responses, and recruitment of T cells to the brain. Multiplexed error-robust fluorescence in situ hybridization (MERFISH) single-cell spatial transcriptomics was applied to assess the regionality of virus infection and brain-resident cell and infiltrating leukocyte responses. MERFISH, immunofluorescence microscopy, quantitative PCR, and flow cytometry demonstrate that the ependyma is the predominant region of MuPyV CNS infection and localization of T cells, and implicated CXCR4 and CXCR6 in T cell migration to the ependyma and subventricular zone. Using CXCR6 knockout mice and a specific CXCR4 small molecule antagonist, we found that the combined impairment of CXCR6 and CXCR4 signaling resulted in elevated infiltration of T cells in the MuPyV-infected brain. This work demonstrates that CXCR4 and CXCR6 act in a nonredundant fashion to restrict T cell accumulation to the polyomavirus-infected ependyma, with important implications for ongoing efforts to use JCPyV-specific T cell adoptive immunotherapy for PML. The online version contains supplementary material available at 10.1186/s12974-025-03496-2.
other
2025-09-11 | Late-Onset Combined Immunodeficiency presenting with Progressive Multifocal Leukoencephalopathy and associated Immune Reconstitution Inflammatory Syndrome.
Progressive multifocal leukoencephalopathy (PML) can rarely occur in individuals with occult immunosuppression. Here, we describe the case of an adult man who presented with PML, in whom CD4+ lymphocytopenia and hypogammaglobulinemia were subsequently identified, leading to a diagnosis of late-onset combined immunodeficiency. Intravenous immunoglobulin replacement therapy was initiated. His clinical course, though complicated by immune reconstitution inflammatory syndrome, was favorable.
2025-06-19 | Efficacy of filgrastim therapy for patients with progressive multifocal leukoencephalopathy: Two case reports.
Progressive multifocal leukoencephalopathy (PML) is a life-threatening central nervous system condition caused by reactivation of JC virus in individuals with immunosuppression. Although PML typically develops in patients with human immunodeficiency virus (HIV), cases in individuals without HIV have been increasing in recent years. Non-HIV-associated PML has a particularly poor prognosis, high mortality rates, and few therapeutic options. Here, we present the cases of two patients with non-HIV-, nondrug-associated PML who achieved good clinical outcomes after treatment with filgrastim (granulocyte colony-stimulating factor [G-CSF]). One patient had a diagnosis of Good syndrome, a rare primary immunodeficiency disease, whereas the other presented with lymphopenia and a mild decrease in CD4 T cells. After G-CSF administration, both patients showed decreases in CSF JC virus loads and improvements on magnetic resonance images. Given these findings, we propose that, by stimulating innate immunity and activating anti-JC viral immune surveillance, G-CSF may be useful as an immune-enhancing therapy for patients with non-HIV-associated PML.
2024-03-20 | Structural vaccinology, molecular simulation and immune simulation approaches to design multi-epitopes vaccine against John Cunningham virus.
The JCV (John Cunningham Virus) is known to cause progressive multifocal leukoencephalopathy, a condition that results in the formation of tumors. Symptoms of this condition such as sensory defects, cognitive dysfunction, muscle weakness, homonosapobia, difficulties with coordination, and aphasia. To date, there is no specific and effective treatment to completely cure or prevent John Cunningham polyomavirus infections. Since the best way to control the disease is vaccination. In this study, the immunoinformatic tools were used to predict the high immunogenic and non-allergenic B cells, helper T cells (HTL), and cytotoxic T cells (CTL) epitopes from capsid, major capsid, and T antigen proteins of JC virus to design the highly efficient subunit vaccines. The specific immunogenic linkers were used to link together the predicted epitopes and subjected to 3D modeling by using the Robetta server. MD simulation was used to confirm that the newly constructed vaccines are stable and properly fold. Additionally, the molecular docking approach revealed that the vaccines have a strong binding affinity with human TLR-7. The codon adaptation index (CAI) and GC content values verified that the constructed vaccines would be highly expressed in E. coli pET28a (+) plasmid. The immune simulation analysis indicated that the human immune system would have a strong response to the vaccines, with a high titer of IgM and IgG antibodies being produced. In conclusion, this study will provide a pre-clinical concept to construct an effective, highly antigenic, non-allergenic, and thermostable vaccine to combat the infection of the John Cunningham virus.
2023-12-14 | Progressive multifocal leukoencephalopathy associated with systemic lupus erythematosus: longitudinal observation of lymphocytes, JC virus in cerebrospinal fluid, and brain magnetic resonance imaging
Abstract Progressive multifocal leukoencephalopathy (PML) rarely occurs in patients with systemic lupus erythematosus (SLE). This report presents a patient who developed PML due to SLE-associated lymphocytopenia. A 60-year-old woman diagnosed with SLE undergoing multiple immunosuppressive therapies, including azathioprine, presented with cerebral cortical symptoms, lymphocytopenia, and vitamin B12 deficiency and was subsequently diagnosed with SLE-associated PML. We evaluated the cause and disease activity of PML, focusing on the longitudinal assessment of lymphocytopenia, JC virus (JCV) DNA copy number in the cerebrospinal fluid, and magnetic resonance imaging (MRI) findings. Immunosuppressive therapy contributes to lymphocytopenia and PML; discontinuing azathioprine and initiating alternative immunosuppressive treatments (with intramuscular vitamin B12 injections) affected lymphocytopenia and disease management. The large hyperintense and punctate lesions observed on the fluid-attenuated inversion recovery images exhibited varying behaviors, indicating fluctuating PML disease activity. In addition, prominent hypointense signal rims were evident on susceptibility-weighted imaging during the late stages, particularly when JCV DNA copies were low. Clinicians should be meticulous when assessing the underlying pathology of lymphocytopenia owing to the multifactorial causes of PML due to SLE. This case’s time-dependent changes in lymphocytopenia, JCV DNA copy number, and MRI findings could provide clinicians with valuable assessment support.
2023-10-12 | Long-term outcome of progressive multifocal leukoencephalopathy with recombinant interleukin-2 treatment and an associated increase in the number of HPyV-2-specific T-cells: a case report.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by reactivation of the human polyomavirus 2 (HPyV-2). PML is associated with a high morbidity and mortality rate and there is currently no standard curative therapy. We report short-term immunologic response and long-term clinical outcomes in a patient diagnosed with follicular lymphoma (FL) who developed PML. Diagnosis of PML was established conclusively based on findings from a brain biopsy. The patient was treated with recombinant interleukin 2 (IL-2) and showed rapid clinical improvement. HPyV-2-specific T-cells were tracked longitudinally and correlation with clinical status, viral load, and radiographic imaging was documented. After the progression of the patient's FL, which required an allogeneic bone marrow transplant, the patient prophylactically received human leukocyte antigen-matched donor-derived HPyV-2 T-cells to prevent the recurrence of the PML as part of a clinical trial. Twelve years after the initial diagnosis of PML, he did not develop a relapse of his PML, supporting data that therapies that increase HPyV-2-specific T-cells, including IL-2, may be effective in the management of PML.
antibodies
2026-08-25 | Pembrolizumab in people with HIV-associated progressive multifocal leukoencephalopathy: a retrospective case series.
Progressive multifocal leukoencephalopathy (PML) in people with HIV (PWH) carries high mortality, and no specific antiviral treatment is available. In this retrospective single-centre case series of six patients treated with pembrolizumab, four showed clinical improvement or stabilisation. Pembrolizumab might represent a salvage option in this population.
2026-08-24 | Progressive multifocal leukoencephalopathy in a 15-year-old boy with X-linked hyper-IgM syndrome: a case report
Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal infection caused by JC polyomavirus, primarily affecting individuals with impaired cellular immunity. We report a 15-year-old boy with genetically confirmed X-linked hyper-IgM syndrome due to a pathogenic CD40LG variant. Despite regular intravenous immunoglobulin replacement therapy and antimicrobial prophylaxis, he developed concurrent Pneumocystis jirovecii pneumonia and COVID-19. Approximately 2 months after recovery from the pulmonary infections, he developed progressive visual impairment, diplopia, impaired concentration, and mild generalized weakness. Brain magnetic resonance imaging revealed extensive bilateral temporo-parieto-occipital white-matter lesions. Cerebrospinal fluid polymerase chain reaction was positive for JC polyomavirus DNA, confirming the diagnosis of PML; HIV testing was negative. In the absence of an established antiviral therapy, a single intravenous dose of pembrolizumab (80 mg) was administered as an experimental immune-based intervention. Three weeks later, the patient developed rapidly progressive generalized muscle weakness and respiratory failure requiring intensive care and mechanical ventilation. Despite intensive supportive treatment, he subsequently died. The precise cause of this deterioration could not be conclusively established, and a multifactorial process involving progression of PML and treatment-related or critical-illness complications could not be excluded. PML should be considered in patients with X-linked hyper-IgM syndrome who develop new neurological manifestations. Pembrolizumab remains an experimental intervention in this setting, with uncertain efficacy and safety in primary immunodeficiency.
2026-07-03 | Efficacy and safety of extended-interval dosing of natalizumab in multiple sclerosis: a systematic review and meta-analysis with subgroup evaluation.
Natalizumab is effective for relapsing-remitting multiple sclerosis (RRMS) but increases the risk of progressive multifocal leukoencephalopathy (PML). Extended-interval dosing (EID) may lessen this risk by reducing drug exposure, though its efficacy and safety compared with standard-interval dosing (SID) remain unclear. This review and meta-analysis evaluates both regimens across clinical and MRI outcomes. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Web of Science, Cochrane Library, and ScienceDirect from inception to July 2025. Eligible studies compared extended- (5-12 weeks) and standard-interval (4 weeks) natalizumab dosing in MS. Meta-analyses used random- or fixed-effects models with results as RR or MD based on heterogeneity (I²). Twenty-five studies were included. Analysis showed no significant differences between EID and SID in disability progression (MD -0.09, 95% CI: -0.46 to 0.29), or the risk of new T2 lesions (RR 1.24, 95% CI: 0.96 to 1.61). For PML incidence (RR 1.03, 95% CI: 0.29-3.60), the analysis was severely underpowered due to rare events; the wide confidence interval precludes any firm conclusion about comparative safety. However, EID was associated with a significantly higher risk of gadolinium-enhancing lesions (RR 1.35, 95% CI: 1.03-1.77). EID was associated with a borderline reduction in the risk of clinical relapse (RR 0.91, 95% CI: 0.83 to 1.00), but this finding is likely influenced by selection bias and should be considered hypothesis-generating rather than confirmatory. Subgroup analysis suggested a possible difference between intervals (P = 0.0323 for T2 lesions), but this finding is based on very sparse data, with only one subgroup (Q5-8 W) containing multiple studies and all other subgroups relying on single studies. Therefore, no definitive conclusion about optimal interval length can be drawn; the result is hypothesis-generating only. Extended-interval dosing of natalizumab shows efficacy and safety comparable to standard dosing. Although relapse reduction was noted, this may reflect selection bias. Shorter EID intervals (5-8 weeks) appear to maintain better radiologic control, supporting EID up to 6-8 weeks as a viable option pending long-term and biomarker-guided validation.
2026-06-11 | Brain Immune Cell Composition in Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy After Natalizumab: An Immunohistochemical Cohort Study.
Natalizumab therapy in multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML) and may alter lymphocyte distribution within the CNS. Tissue-resident memory CD8+ T cells (TRM CD8+), which rely on activation through CD4+ T cells, are essential for antiviral defense and may contribute to JC virus (JCV) control. We, therefore, investigated lymphoid infiltrates in patients with MS after natalizumab treatment and in patients with natalizumab-associated PML to assess antiviral immunity and clinical outcomes. Fluorescence immunohistochemistry was performed on brain biopsies and autopsies from patients with MS (n = 34) and those with PML (n = 27) with and without prior natalizumab exposure and from healthy controls (n = 11). The analysis included CD103+ (TRM) CD8+, total CD8+, and CD4+ T cells; CD209+ dendritic cells; and JCV-infected cells. Cell densities were correlated with clinical outcomes using the modified Rankin Scale and Expanded Disability Status Scale. TRM CD8+ T-cell numbers remained stable in the normal-appearing white matter of patients with MS previously treated with natalizumab and matched levels in healthy controls. By contrast, CD4+ and CD8+ T cells were elevated in MS irrespective of natalizumab exposure and increased further beyond 35 days after treatment cessation, suggesting immune restoration that may reduce PML risk, particularly under extended-interval dosing. In PML lesions, TRM CD8+ T cells were abundant, and natalizumab-associated PML demonstrated infiltrates comparable to inflammatory PML lesions (>500 T cells/mm2), indicating strong local immune activation. Approximately 4 months after natalizumab withdrawal, marked viral clearance was observed and higher densities of TRM CD8+ and total CD8+ T cells were associated with better clinical outcomes. TRM CD8+ T cells appear central to CNS antiviral defense and remain largely preserved during natalizumab therapy. Although natalizumab restricts T-cell trafficking, the postwithdrawal rise in CD4+ and CD8+ T cells indicates immune reconstitution that may enhance TRM CD8+ activation. In natalizumab-associated PML, the presence of strong T-cell infiltrates and declining viral loads after treatment cessation underscore the importance of restored local immunity for effective JCV control. Higher densities of TRM CD8+ and total CD8+ T cells were linked to better clinical outcomes, highlighting their contribution to viral clearance and recovery.
2026-06-09 | Progressive Multifocal Leukoencephalopathy in an Immunocompetent Host Treated with Pembrolizumab (P9-3.003)
To describe a rare case of biopsy-proven progressive multifocal leukoencephalopathy (PML) in an immunocompetent patient and the clinical–radiological response to pembrolizumab treatment.
gene therapies
2026-08-25 | Reply: Age confounding in HIV-associated progressive multifocal leukoencephalopathy prognosis
Nicolas Lambert, Adèle Le Guilloux, Agnès Sommet, Guillaume Martin-Blondel; Reply: Age confounding in HIV-associated progressive multifocal leukoencephalop
2026-08-14 | Guideline of the German Society of Neurology (DGN): "diagnosis and therapy of HIV-1-associated neurological disorders".
Epidemiology and treatment of HIV changed substantially within the last three decades. However, HIV-associated neurological disorders such as mild forms of HIV-associated neurocognitive disorder (HAND) as well as HIV-associated distal symmetrical sensory polyneuropathy are amongst the most frequent complications in patients with longstanding HIV infection. Opportunistic infections occur less frequently compared to former years, but especially in patients with late presentation of HIV progressive multifocal leukoencephalopathy (PML) (0.7 per 1,000 patient-years), toxoplasma encephalitis (0.4 per 1,000 patient-years) and cryptococcal meningitis (0.2 per 1,000 patient-years) remain the most common opportunistic infections. The guidelines for diagnosis and treatment of HIV-associated neurological disorders of the German Society of Neurology were revised addressing recent changes in treatment opportunities of HAND, HIV associated complications of the peripheral nervous system and muscles and opportunistic infections of the central nervous system (CNS).
2026-06-25 | Progressive Multifocal Leukoencephalopathy or Lymphoma? A Massive Unilateral Hemispheric Mimicker in a Patient Undergoing Lymphoma Treatment.
An 81-year-old woman with follicular lymphoma treated with obinutuzumab and bendamustine developed cognitive impairment and dysarthria. Three months before death, neurological exams showed dysarthria, right hemiparesis, and gait disturbance. Blood tests showed lymphocytopenia (lymphocyte 10.4%). Cerebrospinal fluid (CSF) findings were unremarkable, including with respect to cytology. Brain MRI demonstrated a mass-like hyperintense lesion in the left parietal lobe and band-like abnormalities in the left fronto-temporal white matter that lacked contrast enhancement. Symptoms progressed to hemiplegia and mutism; severe dysphagia eventually necessitated intravenous fluid management. Follow-up MRI one month before death revealed a lesion encompassing nearly the entire left hemisphere, with hyperperfusion observed during arterial spin labeling (ASL). JC virus was detected in CSF (221 copy/mL), confirming that the patient had progressive multifocal leukoencephalopathy (PML). Subsequently, she exhibited poor arousal, followed by death. Here, lymphoma recurrence or PML was suspected due to a post-chemotherapy unilateral expanding brain lesion. These conditions are usually differentiated by contrast-enhancement patterns, but PML can also enhance during immune reconstitution. Moreover, lesions rarely cause a mass effect and more often exhibit hyperperfusion, which may aid in diagnosis. While unilateral PML has been reported, especially in the early stage, such an extensive lesion involving nearly an entire single hemisphere, as seen in our case, is rare.
2026-06-09 | Progressive Multifocal Leukoencephalopathy with Immune Reconstitution Inflammatory Syndrome and Good Outcome in an Immunocompetent Patient: Case Report and Literature Review (P9-3.004)
To report a case of progressive multifocal leukoencephalopathy (PML) with immune reconstitution inflammatory syndrome (IRIS) in an immunocompetent patient with a favorable outcome.
2026-05-22 | Human Polyomaviruses of Clinical Relevance: Modes of Transmission and Associated Pathologies.
Polyomaviruses are non-enveloped viruses with double-stranded circular DNA genome. Currently, 13 members of the Polyomaviridae family have been classified as human polyomavirus (HPyVs). Despite high seroprevalence values have been reported for the majority of the HPyVs worldwide, the main mode of transmission remains to be elucidated, and simple and common routes, such as faecal-oral and respiratory have been suggested. In general, HPyVs are responsible for asymptomatic primary infection, followed by asymptomatic lifelong persistent infection. In situations of severe immunosuppression, viral reactivation of some HPyVs may occur and result in the development of associated clinical manifestations. JCPyV is the causative agent of Progressive Multifocal Leukoencephalopathy, BKPyV is associated with nephropathy among kidney transplant recipients, MCPyV with Merkel Cell Carcinoma and TSPyV with Trichodysplasia spinulosa. The association of certain HPyVs with severe diseases, in addition to the high seroprevalence of the majority of HPyVs, emphasises the need to address various knowledge gaps that still exists in the natural history of these viruses, including the transmission routes and the pathogenic mechanisms. The present review summarises current information on HPyV transmission routes and associated diseases, including diagnosis and available treatment options, highlighting the need for further studies.
small molecules
2026-09-09 | Tenofovir in Progressive Multifocal Leukoencephalopathy: Virus Suppression Without Clinical Benefit in 2 Cases.
Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the CNS caused by reactivation of the JC polyomavirus (JCV), typically in immunocompromised individuals. As no specific therapy against JCV exists, current management focuses on immune reconstitution. Recently, a potential therapeutic effect of tenofovir was reported. We report 2 patients with PML who received tenofovir under a compassionate use protocol. Treatment was accompanied by MRI, clinical, and virologic monitoring. In both patients (serum and CSF), viral load was markedly reduced. In 1 patient, this was accompanied by temporary clinical stabilization and reduction in MRI lesion burden. The other patient further declined clinically, accompanied by progression of MRI lesion size and contrast enhancement. Dense lymphocytic infiltration on biopsy suggested predominant effects of alleviated immunosuppression rather than the direct antiviral drug effect. Both patients ultimately died of the disease. Despite virus reduction in both cases, sustained clinical improvement was not achieved. This suggests that viral load reduction alone is insufficient, and pathogenesis may be largely driven by the immune response to the infection. A combination of tenofovir with low-dose anti-inflammatory drugs may be a useful addition to PML therapy.
2026-04-01 | E043 Progressive multifocal leukoencephalopathy: a rare neurological complication of mycophenolate therapy in antisynthetase syndrome
Abstract Background/Aims Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating infection of the central nervous system caused by reactivation of the John Cunningham (JC) virus in immunocompromised individuals. The incidence density of PML among mycophenolate mofetil (MMF) users is estimated at 14.4 cases per 100,000 person-years. While monoclonal antibody therapies such as natalizumab and efalizumab are the most frequent culprits, PML has also been reported in patients receiving conventional immunosuppressants, including MMF. The disease carries a poor prognosis, with mortality rates reaching 50-65 % within the first year despite cessation of immunosuppressive therapy. Mirtazapine, a 5-HT2A receptor antagonist, has been explored as a potential adjunct as it may inhibit JC virus entry into glial cells. Methods We report the case of a 57-year-old woman with antisynthetase syndrome (Jo-1 and Ro-52 antibody positive) who presented to the stroke unit at Maidstone Hospital with a two-week history of progressive neurological symptoms, including memory impairment, motor dysphasia, left-sided weakness, and intermittent kaleidoscopic visual disturbance. She had interstitial lung involvement but was otherwise amyopathic and functionally independent. She was on MMF and a low maintenance dose of prednisolone, with no prior rituximab exposure. On examination, she was cognitively intact with normal gait and subtle left pronator drift. Power was 4-/5 in the left upper limb and 5/5 elsewhere, with preserved sensation. Inflammatory markers were mildly elevated (CRP 14 mg/L, ESR 6 mm/h). MRI brain showed extensive multifocal right-sided subcortical white-matter lesions. The stroke team referred her to rheumatology to evaluate for cerebral involvement of antisynthetase syndrome. However, neuroradiology review suggested an infective aetiology, raising suspicion for PML. Results HIV testing was negative. Cerebrospinal fluid JC-virus PCR was initially negative, recognising that false negatives occur in up to 30% of early cases. As symptoms progressed, she was referred to a tertiary centre in London, where a stereotactic brain biopsy revealed focal macrophage-rich inflammation with enlarged oligodendroglial nuclei displaying a ground-glass appearance. Luxol-fast blue staining highlighted multifocal demyelination, and immunohistochemistry for SV40 confirmed oligodendroglial intranuclear viral inclusions, consistent with PML. Following multidisciplinary discussion, all immunosuppressive therapy was withdrawn. She was commenced on intravenous immunoglobulin (IVIG) for her antisynthetase syndrome. Mirtazapine was considered but declined. Her neurological status improved after discontinuation of immunosuppression, and she remains clinically stable on IVIG alone. Conclusion This case underscores the diagnostic challenge of PML in autoimmune disease treated with MMF. Even in the absence of monoclonal antibody therapy, clinicians should maintain a high index of suspicion for PML when new focal or cognitive deficits occur. Early neuroimaging, CSF analysis, and tissue confirmation are essential to guide management. Given the high mortality rate, prompt discontinuation of immunosuppression, multidisciplinary collaboration, and patient education on PML risk before initiating MMF therapy are vital. Disclosure A. Vijayan: None. A. Nur: None. A. Waller: None. M. Szeto: None. A. Keough: None. P. Sengupta: None.
2026-01-19 | Progressive multifocal leukoencephalopathy in the modern therapeutic era: A critical synthesis of epidemiology, diagnostics, and policy implications with regional context from Korea
This review aims to synthesize contemporary evidence on progressive multifocal leukoencephalopathy (PML), a rare, demyelinating disease of the central nervous system caused by reactivation of the John Cunningham virus (JCV) in immunocompromised individuals. Since its initial description in 1958, PML has evolved from being predominantly associated with hematological malignancies to a multifaceted opportunistic infection seen in HIV/AIDS, autoimmune disorders, transplantation medicine, and in patients receiving monoclonal antibody therapies such as natalizumab. The global epidemiology of PML reflects both improved survival in immunocompromised populations and expanded iatrogenic risk due to modern immunomodulatory agents. This review synthesizes contemporary evidence on the epidemiology, pathogenesis, diagnostic strategies, and therapeutic approaches to PML, with an emphasis on comparing international patterns to emerging data from Korea. Although Korean reports remain limited, recent case studies reveal unique patterns of presentation, delayed diagnosis, and frequent misattribution to alternative neurological disorders, underscoring the need for heightened clinical vigilance. The review critically examines diagnostic limitations, including the imperfect sensitivity of cerebrospinal fluid JCV PCR, and highlights emerging biomarkers and neuroimaging signatures that may improve early detection. Therapeutic options remain largely supportive, with immune reconstitution representing the most effective strategy; however, novel antiviral and immunomodulatory approaches are under investigation. The review concludes with an agenda for future research, calling for international registry development, standardized diagnostic protocols, and cross-disciplinary collaborations to address the persistently high morbidity and mortality associated with PML. By integrating global and Korean perspectives, this paper aims to advance a more nuanced, regionally informed understanding of PML’s evolving clinical landscape.
2025-11-25 | Successful Treatment of Progressive Multifocal Leukoencephalopathy With Tenofovir Alafenamide Fumarate.
Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal CNS infection caused by reactivation of JC virus, typically in immunocompromised patients. No effective antiviral therapy has been established. We report a case of PML in a patient with multiple sclerosis (MS) treated with fingolimod, who received oral tenofovir alafenamide fumarate (TAF). This is a single-patient case report from Stavanger University Hospital, Norway. A 67-year-old woman with secondary progressive MS developed progressive neurologic symptoms during fingolimod treatment. MRI and CSF analyses confirmed PML with detectable JCV DNA. Fingolimod was discontinued, and oral TAF 50 mg/d was initiated. Clinical course, MRI changes, and CSF biomarkers were monitored over 6 months. At baseline, JCV DNA was 4,940 international units [IU]/mL in CSF and the Expanded Disability Status Scale (EDSS) score was 8.5. Four days after TAF initiation, partial radiologic improvement was observed. After 3 and 6 months, JCV DNA was undetectable (<1,000 IU/mL). The patient remained clinically stable with unchanged EDSS score and tolerated TAF without adverse effects. MRI showed regression of PML lesions but development of new MS activity after fingolimod withdrawal. This case demonstrates temporal association between TAF initiation and virologic clearance of JCV, suggesting potential antiviral activity. As a single case without controls, this report provides Class IV evidence that oral TAF might stabilize the clinical course in patients with PML.
2025-11-13 | A Case of Cerebellar-Onset Progressive Multifocal Leukoencephalopathy (PML) Associated with Hepatitis B-related Liver Cirrhosis.
We herein report a case of progressive multifocal leukoencephalopathy (PML) in a woman in her 70s with hepatitis B-related liver cirrhosis. She presented with cerebellar onset symptoms, including ataxia and dysarthria. The diagnosis was delayed despite the initial magnetic resonance imaging (MRI) findings of an asymmetric cerebellar white matter lesion. PML was ultimately diagnosed based on a re-evaluation of a brain biopsy specimen and a retrospective JC virus (JCV) PCR analysis of the cerebrospinal fluid. Treatment with mefloquine and mirtazapine resulted in viral clearance from the cerebrospinal fluid (CSF) and clinical stabilization. This case highlights that crescent-shaped cerebellar lesions should raise suspicion of PML, even in patients without severe immunodeficiency.
cell therapies
2026-08-07 | Adoptive T-cell therapies in neuroinfectious and neuroinflammatory diseases.
Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
2026-07-06 | Treatment of Progressive Multifocal Leukoencephalopathy with Third-Party Allogeneic BK Virus T Cells.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by JC polyomavirus (JCV) that affects immunosuppressed individuals and has no approved therapy. Here we evaluate the safety and efficacy of third-party, off-the-shelf, partially HLA-matched BK virus-specific T cells (BK-VST) in patients with PML. We conducted a single-center phase 2 study where 37 patients received most closely HLA-matched BK-VST at 2.0 x 105 T cells/kg, with additional infusions permitted for subjects who did not achieve a complete response. Twenty-three patients had an underlying diagnosis of hematologic malignancy. Each patient received a median of 2 doses (range, 1-12; IQR 2). Overall response (OR) was defined as virologic clearance with neurologic stabilization or improvement. During 12 months of follow-up, 21 patients (56.8%) achieved an OR, including 16 (43.2%) with a complete response. Responses were rapid (median 23 days) and durable, with no loss of response observed despite limited HLA matching. The 1-year overall survival was 61.1% (95% CI, 41.9-77.4). Patients achieving an OR after the first infusion had markedly improved 1-year survival compared with non-responders (93.3% vs 0%; p<0.001). Higher donor IL-2 and IFN-γ-producing T-cell frequencies and greater HLA matching correlated with clinical benefit. These data demonstrate that third-party BK-VST infusions are safe and potentially effective, supporting a scalable immunotherapeutic approach for this otherwise fatal disease. (ClinicalTrials.gov NCT02479698).
2026-05-27 | Resolution of PML after Treatment with Virus-Specific T Cells and HCT
Two patients with inborn errors of immunity and progressive multifocal leukoencephalopathy received polyomavirus-specific T cells, followed by allogeneic hematopoietic transplantation with good neurologic outcomes.
2026-02-06 | What are the latest available treatments for Progressive Multifocal Leukoencephalopathy and their effectiveness?
Progressive Multifocal Leukoencephalopathy remains challenging to treat, with investigational therapies such as virus-specific T cells, immune checkpoint inhibitors, and antiviral agents presenting potential promise. Current evidence is limited and largely anecdotal, necessitating further research.
2025-07-01 | CXCR4 and CXCR6 dually limit T cell entry into the polyomavirus-infected brain.
T cell responses are vital for controlling viral infection in the central nervous system (CNS), but must be tightly regulated to limit tissue-damaging inflammation. Using mouse polyomavirus (MuPyV) CNS infection, an in vivo model for JCPyV-induced Progressive Multifocal Leukoencephalopathy (PML), we investigated sites of early infection, immune responses, and recruitment of T cells to the brain. Multiplexed error-robust fluorescence in situ hybridization (MERFISH) single-cell spatial transcriptomics was applied to assess the regionality of virus infection and brain-resident cell and infiltrating leukocyte responses. MERFISH, immunofluorescence microscopy, quantitative PCR, and flow cytometry demonstrate that the ependyma is the predominant region of MuPyV CNS infection and localization of T cells, and implicated CXCR4 and CXCR6 in T cell migration to the ependyma and subventricular zone. Using CXCR6 knockout mice and a specific CXCR4 small molecule antagonist, we found that the combined impairment of CXCR6 and CXCR4 signaling resulted in elevated infiltration of T cells in the MuPyV-infected brain. This work demonstrates that CXCR4 and CXCR6 act in a nonredundant fashion to restrict T cell accumulation to the polyomavirus-infected ependyma, with important implications for ongoing efforts to use JCPyV-specific T cell adoptive immunotherapy for PML. The online version contains supplementary material available at 10.1186/s12974-025-03496-2.
other
2025-09-11 | Late-Onset Combined Immunodeficiency presenting with Progressive Multifocal Leukoencephalopathy and associated Immune Reconstitution Inflammatory Syndrome.
Progressive multifocal leukoencephalopathy (PML) can rarely occur in individuals with occult immunosuppression. Here, we describe the case of an adult man who presented with PML, in whom CD4+ lymphocytopenia and hypogammaglobulinemia were subsequently identified, leading to a diagnosis of late-onset combined immunodeficiency. Intravenous immunoglobulin replacement therapy was initiated. His clinical course, though complicated by immune reconstitution inflammatory syndrome, was favorable.
2025-06-19 | Efficacy of filgrastim therapy for patients with progressive multifocal leukoencephalopathy: Two case reports.
Progressive multifocal leukoencephalopathy (PML) is a life-threatening central nervous system condition caused by reactivation of JC virus in individuals with immunosuppression. Although PML typically develops in patients with human immunodeficiency virus (HIV), cases in individuals without HIV have been increasing in recent years. Non-HIV-associated PML has a particularly poor prognosis, high mortality rates, and few therapeutic options. Here, we present the cases of two patients with non-HIV-, nondrug-associated PML who achieved good clinical outcomes after treatment with filgrastim (granulocyte colony-stimulating factor [G-CSF]). One patient had a diagnosis of Good syndrome, a rare primary immunodeficiency disease, whereas the other presented with lymphopenia and a mild decrease in CD4 T cells. After G-CSF administration, both patients showed decreases in CSF JC virus loads and improvements on magnetic resonance images. Given these findings, we propose that, by stimulating innate immunity and activating anti-JC viral immune surveillance, G-CSF may be useful as an immune-enhancing therapy for patients with non-HIV-associated PML.
2024-03-20 | Structural vaccinology, molecular simulation and immune simulation approaches to design multi-epitopes vaccine against John Cunningham virus.
The JCV (John Cunningham Virus) is known to cause progressive multifocal leukoencephalopathy, a condition that results in the formation of tumors. Symptoms of this condition such as sensory defects, cognitive dysfunction, muscle weakness, homonosapobia, difficulties with coordination, and aphasia. To date, there is no specific and effective treatment to completely cure or prevent John Cunningham polyomavirus infections. Since the best way to control the disease is vaccination. In this study, the immunoinformatic tools were used to predict the high immunogenic and non-allergenic B cells, helper T cells (HTL), and cytotoxic T cells (CTL) epitopes from capsid, major capsid, and T antigen proteins of JC virus to design the highly efficient subunit vaccines. The specific immunogenic linkers were used to link together the predicted epitopes and subjected to 3D modeling by using the Robetta server. MD simulation was used to confirm that the newly constructed vaccines are stable and properly fold. Additionally, the molecular docking approach revealed that the vaccines have a strong binding affinity with human TLR-7. The codon adaptation index (CAI) and GC content values verified that the constructed vaccines would be highly expressed in E. coli pET28a (+) plasmid. The immune simulation analysis indicated that the human immune system would have a strong response to the vaccines, with a high titer of IgM and IgG antibodies being produced. In conclusion, this study will provide a pre-clinical concept to construct an effective, highly antigenic, non-allergenic, and thermostable vaccine to combat the infection of the John Cunningham virus.
2023-12-14 | Progressive multifocal leukoencephalopathy associated with systemic lupus erythematosus: longitudinal observation of lymphocytes, JC virus in cerebrospinal fluid, and brain magnetic resonance imaging
Abstract Progressive multifocal leukoencephalopathy (PML) rarely occurs in patients with systemic lupus erythematosus (SLE). This report presents a patient who developed PML due to SLE-associated lymphocytopenia. A 60-year-old woman diagnosed with SLE undergoing multiple immunosuppressive therapies, including azathioprine, presented with cerebral cortical symptoms, lymphocytopenia, and vitamin B12 deficiency and was subsequently diagnosed with SLE-associated PML. We evaluated the cause and disease activity of PML, focusing on the longitudinal assessment of lymphocytopenia, JC virus (JCV) DNA copy number in the cerebrospinal fluid, and magnetic resonance imaging (MRI) findings. Immunosuppressive therapy contributes to lymphocytopenia and PML; discontinuing azathioprine and initiating alternative immunosuppressive treatments (with intramuscular vitamin B12 injections) affected lymphocytopenia and disease management. The large hyperintense and punctate lesions observed on the fluid-attenuated inversion recovery images exhibited varying behaviors, indicating fluctuating PML disease activity. In addition, prominent hypointense signal rims were evident on susceptibility-weighted imaging during the late stages, particularly when JCV DNA copies were low. Clinicians should be meticulous when assessing the underlying pathology of lymphocytopenia owing to the multifactorial causes of PML due to SLE. This case’s time-dependent changes in lymphocytopenia, JCV DNA copy number, and MRI findings could provide clinicians with valuable assessment support.
2023-10-12 | Long-term outcome of progressive multifocal leukoencephalopathy with recombinant interleukin-2 treatment and an associated increase in the number of HPyV-2-specific T-cells: a case report.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by reactivation of the human polyomavirus 2 (HPyV-2). PML is associated with a high morbidity and mortality rate and there is currently no standard curative therapy. We report short-term immunologic response and long-term clinical outcomes in a patient diagnosed with follicular lymphoma (FL) who developed PML. Diagnosis of PML was established conclusively based on findings from a brain biopsy. The patient was treated with recombinant interleukin 2 (IL-2) and showed rapid clinical improvement. HPyV-2-specific T-cells were tracked longitudinally and correlation with clinical status, viral load, and radiographic imaging was documented. After the progression of the patient's FL, which required an allogeneic bone marrow transplant, the patient prophylactically received human leukocyte antigen-matched donor-derived HPyV-2 T-cells to prevent the recurrence of the PML as part of a clinical trial. Twelve years after the initial diagnosis of PML, he did not develop a relapse of his PML, supporting data that therapies that increase HPyV-2-specific T-cells, including IL-2, may be effective in the management of PML.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
6 orphan drug designations for Progressive multifocal leukoencephalopathy.
6 orphan drug designations for Progressive multifocal leukoencephalopathy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Human IgG1 monoclonal antibody against JC polyomavirus, major capsid protein VP1 | antibodies | EMA | — | Pomona Ricerca S.r.l. |
Allogeneic JC polyomavirus-specific T-cell therapy | cell therapies | FDA | Cellevolve Bio Inc. | |
Recombinant human interleukin-7 fused to a hybrid crystallizable fragment region of a human antibody (rhIL-7-hyFc). | proteins | FDA | NeoImmuneTech, Inc. | |
imatinib mesylate | small molecules | FDA | — | Inhibikase Therapeutics, Inc. |
glycosylated recombinant human interleukin-7 | proteins | FDA | — | Cytheris, Inc. |
Recombinant human interleukin-7 | proteins | EMA | Inserm-ANRS (Agence Nationale de Recherches sur le Sida et les Hépatites Virales) |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.