Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC virus (JCV), which belongs to the Polyomaviridae family. JCV is latent in 50–70% of the population, but the development of PML usually requires an immunosuppressed state.
The prevalence of PML in the general population is 0.22 per 100,000 people, and the incidence is 0.11 per 100,000. The risk of developing PML is significantly increased in HIV-infected individuals, especially those with CD4-positive T-lymphocyte counts below 200 cells/µL. The mortality rate of HIV-associated PML reaches up to 30% at 1 year and 50–60% at 2 years 1). With the introduction of antiretroviral therapy (ART), the median survival time improved from 0.4 years to 1.8 years 1).
The incidence of PML in patients with autoimmune diseases is 0.4 to 4.0 per 100,000 people, and drugs such as rituximab and natalizumab can also induce PML. The incidence of natalizumab-associated PML is highest at 3.94 per 1,000 patients overall 4). In rituximab-associated PML, an incidence of 2.89 per 1,000 patient-years has been reported in patients with non-Hodgkin lymphoma 4).
Neuro-ophthalmologic findings in PML provide important diagnostic clues. The most common findings are as follows.
The prevalence in the general population is extremely rare at 0.22 per 100,000 people. However, the frequency is significantly higher in HIV-positive individuals, and even in the ARV era, the one-year mortality rate reaches up to 30% 1). In natalizumab users, the incidence is relatively high at approximately 4 cases per 1,000 patients 4).
The neurological symptoms of PML vary depending on the location of demyelinating lesions. Onset is subacute, which helps differentiate it from acute relapses of multiple sclerosis.
During the use of immunomodulatory drugs for multiple sclerosis (MS), it is necessary to differentiate between PML and MS relapse. The distinguishing points between the two are shown below.
| Feature | MS relapse | PML |
|---|---|---|
| Onset pattern | Acute | Subacute |
| Main symptoms | Optic neuropathy, pyramidal tract signs | Mental status changes, hemiparesis |
| MRI lesion location | Periventricular | Subcortical |
| Clinical course | Recovery present | Recovery difficult |
Homonymous hemianopia due to occipital lobe lesions is most common. Bilateral occipital lobe involvement leads to cortical blindness. Brainstem lesions cause nystagmus and horizontal diplopia due to abducens nerve palsy 6). Balint syndrome and hemispatial neglect have also been reported with parietotemporal lesions 4).
JC virus (JCV) is a DNA virus belonging to the Polyomaviridae family. It has an icosahedral capsid without an envelope and contains double-stranded circular DNA. Primary infection usually occurs in childhood, with the tonsils and gastrointestinal tract considered initial infection sites. After infection, it remains latent in the kidneys, lymphoid tissues, and peripheral blood leukocytes. JCV DNA has also been detected in oligodendrocytes and astrocytes, suggesting the brain may be one of the latent sites.
Infectious Diseases
HIV infection: The greatest risk factor. The risk of developing PML increases markedly when CD4-positive T lymphocyte counts fall below 200 cells/µL1).
Marked decrease in CD4/CD8 ratio: This serves as an immunological predisposition for PML development1).
Autoimmune diseases and medications
Rheumatoid arthritis, SLE, IBD, etc.: Both the underlying disease and immunosuppressive treatment are risk factors.
Natalizumab: Highest risk with PML incidence of 3.94 per 1,000 patients 4).
Rituximab: 57 cases of HIV-negative PML reported with a mortality rate of 90% 2). In RA patients, 92% of biologic-associated PML occurred during rituximab or TNF inhibitor use 5).
Epcoritamab: CD3xCD20 bispecific antibody. First report of PML complication 4).
Hematologic malignancies
Lymphoproliferative disorders: Estimated frequency 0.07%. 1-year mortality 39.2%5).
Chronic lymphocytic leukemia: Lymphopenia after chemotherapy is a trigger8).
Follicular lymphoma: Persistent lymphopenia due to repeated chemotherapy is a risk4).
PML in immunocompetent individuals is rare but has been reported9). Age-related immune decline or undetected latent immunosuppression may be involved.
Natalizumab carries the highest risk (incidence 3.94 per 1,000 people)4). Biologics such as rituximab, TNF inhibitors, and epratuzumab also increase risk2)4)5). Lymphopenia caused by cytotoxic chemotherapy is also an important risk factor.
The diagnosis of PML is based on diagnostic criteria from the American Academy of Neurology (AAN) Neuroinfectious Disease Section.
Definitive Diagnosis
Brain biopsy confirms all three of the following findings:
Demyelination: Extensive destruction of myelin sheaths in the white matter.
Bizarre astrocytes: Abnormal morphology of reactive astrocytes.
Oligodendrocytes with intranuclear inclusions: Cells infected by JCV.
In addition, detection of JCV DNA or protein is required.
Probable
When both of the following are met.
Positive JCV PCR in CSF: Detection of JCV DNA in cerebrospinal fluid.
Characteristic clinical and MRI findings: Multifocal demyelination in subcortical white matter.
Suspected
When both of the following are met:
Characteristic clinical and MRI findings present: However, JCV DNA not detected in CSF.
No appropriate alternative diagnosis: Other causes are excluded.
JCV DNA PCR in CSF is the cornerstone of clinical diagnosis. However, PCR sensitivity is approximately 58%, and initial tests may be negative 5). In one case, after an initial negative PCR, a second CSF test was positive for JCV (116 IU/mL), leading to a definitive diagnosis 5). Repeat testing is important when PML is strongly suspected clinically.
Brain MRI is the first-choice imaging test when PML is suspected.
The following characteristic imaging findings have been reported.
Brainstem-limited PML lesions are extremely rare, but 10 cases have been reported in the literature review6). Infratentorial lesions are found in 27.4% of all drug-associated PML cases6).
In patients receiving drugs with PML risk, periodic blood tests for JCV DNA may be performed before starting treatment and every 6 months. In patients using natalizumab, risk stratification is performed using the anti-JCV antibody index 4).
Currently, there is no established specific anti-JCV therapy for PML. The basis of treatment is restoration of immune function.
Prompt initiation of combination antiretroviral therapy (cART) is recommended. With the introduction of ARV, the median survival time for PML improved from 0.4 years to 1.8 years 1). Collaboration with an infectious disease specialist is important.
Immediate discontinuation of immunosuppressive drugs is recommended 2)5). A review of 27 cases of biologic-associated PML in rheumatoid arthritis patients found a mean delay of 2.5 months from onset to diagnosis 5). Early drug discontinuation is essential for improving survival.
Paradoxical clinical worsening may occur after starting cART or discontinuing immunosuppressive drugs. This is called PML-IRIS (PML-immune reconstitution inflammatory syndrome), an excessive immune response to a large antigen load. It is treated with corticosteroid therapy.
Currently, there is no established specific treatment for JCV. In HIV patients, immune recovery with cART, and in non-HIV patients, discontinuation of immunosuppressants are the best strategies. For novel treatments such as immune checkpoint inhibitors, refer to the “Latest Research” section.
JCV typically causes primary infection in childhood. Initial transmission is suspected to occur through close personal contact or fomites. The tonsils are considered a site of latency after initial exposure, and the gastrointestinal tract may also be a major site of primary infection.
In immunocompetent individuals, JCV infection rarely causes disease, but the dormant virus often persists. In this state, JCV DNA is detectable, but protein levels (indicators of active transcription) are not detected. Before reactivation, JCV resides in the kidneys, lymphoid tissues, and peripheral blood leukocytes. JCV DNA has also been confirmed in oligodendrocytes and astrocytes, suggesting the brain is also a site of latency.
The JCV life cycle is characterized by 12 steps.
The pathogenesis of JCV reactivation involves the presence of immunosuppression. The strongest association is with HIV-1 infection, and the HIV-1 Tat regulatory protein is thought to stimulate JCV DNA replication. Oligodendrocytes harboring latent JCV DNA have been suggested to strongly absorb Tat protein.
Lysis of oligodendrocytes by JCV is the essence of demyelination. When myelin sheaths are destroyed, saltatory conduction becomes impossible, leading to nerve conduction deficits. Multiple demyelinated areas coalesce, causing extensive white matter destruction before macrophages phagocytose the breakdown products.
Brain biopsy shows the following characteristic pathological findings.
The pathology of PML involves immune exhaustion via the PD-1 pathway, and reactivation of JCV immunity using immune checkpoint inhibitors (ICIs) is being attempted.
Lambert et al. (2022) administered the anti-PD-L1 antibody atezolizumab (1,200 mg every 3 weeks) to a PML patient (77-year-old female, CD4=280 cells/µL) who developed PML after treatment for chronic lymphocytic leukemia. One week after starting treatment, improvement in aphasia and cognitive function was observed, and CSF JCV load dramatically decreased from 733,845 copies/mL to 945 copies/mL. However, treatment was accompanied by immune reconstitution inflammatory syndrome (IRIS) and severe immune-related adverse events (rash, atrioventricular block, seizures), requiring high-dose methylprednisolone. Suppression of JCV-specific T-cell responses by steroids ultimately led to PML relapse and death 8).
Pembrolizumab (anti-PD-1 antibody) and nivolumab have also been reported to be effective in some cases, but management of IRIS and immune-related adverse events associated with ICI treatment remains a challenge.
Wang et al. (2022) administered combination therapy with mirtazapine (15 mg/day) and mefloquine (250 mg/week) to a 67-year-old immunocompetent female PML patient. Mirtazapine blocks the 5HT2A receptor and inhibits JCV entry into astrocytes. Mefloquine suppresses JCV replication in vitro. The patient maintained clinical stability for over two years 9).
However, the efficacy of mefloquine has not been confirmed in clinical trials, and verification in large-scale studies is needed.
