Revisiting JC virus and progressive multifocal leukoencephalopathy.

Since its definition 65 years ago, progressive multifocal leukoencephalopathy (PML) has continued to devastate a growing population of immunosuppressed patients despite major advances in our understanding of the causative JC virus (JCV). Unless contained by the immune system, JCV lyses host oligodendrocytes collateral to its life cycle, leading to demyelination, neurodegeneration, and death. Novel treatments have stagnated in the absence of an animal model while current antiviral agents fail to address the now ubiquitous polyomavirus. In this review, we highlight the established pathogenesis by which JCV infection progresses to PML, highlighting major challenges that must be overcome to eliminate the underlying virus and, therefore, the debilitating disease.

Management approach including pembrolizumab for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing-remitting multiple sclerosis.

A 62-year-old man with relapsing-remitting multiple sclerosis developed progressive multifocal leukencephalopathy (PML) after 6 years on fingolimod. The fingolimod was immediately discontinued and preexisting mirtazepine increased. Three weeks later, with brain magnetic resonance imaging (MRI) appearances worsening and cerebrospinal fluid (CSF) JC virus (JCV) titres increasing, maraviroc was introduced. At 6 weeks, subtle punctate contrast enhancement raised the possibility of immune reconstitution inflammatory syndrome (IRIS), followed by a single focal-to-generalised tonic clonic seizure and a further deterioration in clinical disability. Mefloquine was commenced alongside three doses of pembrolizumab administered a month apart. Serial CSF examinations and several imaging modalities including spectroscopy and fused FDG-PET-MRI (18F-fluoro-deoxy-glucose-positron emission tomography-magnetic resonance imaging) were used to help distinguish between PML, PML-IRIS and rebound MS activity and guide optimal management at each stage. A handful of small, enhancing ovoid lesions developed between the first two doses of pembrolizumab, probably representative of a mild rebound phenomenon. A sustained improvement became obvious thereafter with CSF JCV-DNA undetectable 16 weeks following fingolimod withdrawal. To our knowledge, this is the first case of combined therapy and use of pembrolizumab in a fingolimod-associated PML.

Amebic infections of the central nervous system.

The report of death of a person from amebic meningoencephalitis, the proverbial "brain-eating ameba," Naegleria fowleri, acquired in a state park lake in Iowa in July 2022 has once again raised the seasonal alarms about this pathogen. While exceptionally rare, its nearly universal fatality rate has panicked the public and made for good copy for the news media. This review will address free-living ameba that have been identified as causing CNS invasion in man, namely, Naegleria fowleri, Acanthamoeba species, Balamuthia mandrillaris, and Sappinia diploidea (Table 1). Of note, several Acanthamoeba spp. and Balamuthia mandrillaris may also be associated with localized extra-CNS infections in individuals who are immunocompetent and disseminated disease in immunocompromised hosts. These ameba are unique from other protozoa in that they are free-living, have no known insect vector, do not result in a human carrier state, and are typically unassociated with poor sanitation. Table 1 Free-living ameba that have been identified as causing CNS invasion in man, namely, Naegleria fowleri, Acanthamoeba species, Balamuthia mandrillaris, and Sappinia diploidea Entity Pathogenic ameba Predisposing disorders Portal of entry Incubation period Clinical features Radiographic findings CSF finding Diagnostic measures Primary amebic meningoencephalitis Naegleria fowleri; N. australiensis; N. italica Previously healthy children or young adults Olfactory epithelium 2-14 days (average 5 days) Headache, fever, altered mental status, meningeal signs; seizures Brain edema; meningeal enhancement; hydrocephalus; basal ganglia infarctions Increased opening pressure; neutrophilic pleocytosis (~ 1000 cells/cu mm); low glucose Brain biopsy, CSF wet prep, IIF culture or PCR Granulomatous amebic encephalitis Acanthamoeba spp.; Balamuthia mandrillaris; Sappinia diploidea Typically, immunocompromised individual Skin sinuses; olfactory epithelium respiratory tract Weeks to months Headache; altered mental status seizures, focal neurological findings Focal parenchymal lesions with edema; hemorrhagic infarctions; meningeal enhancement Generally, LP contraindicated; when performed lymphocytic pleocytosis; increased protein; low glucose Brain biopsy, CSF culture, wet prep, IIF, or PCR IIF indirect immunofluorescence, LP lumbar puncture, PCR polymerase chain reaction.

COVID-19 and the nervous system.

A pandemic due to novel coronavirus arose in mid-December 2019 in Wuhan, China, and in 3 months' time swept the world. The disease has been referred to as COVID-19, and the causative agent has been labelled SARS-CoV-2 due to its genetic similarities to the virus (SARS-CoV-1) responsible for the severe acute respiratory syndrome (SARS) epidemic nearly 20 years earlier. The spike proteins of both viruses dictate tissue tropism using the angiotensin-converting enzyme type 2 (ACE-2) receptor to bind to cells. The ACE-2 receptor can be found in nervous system tissue and endothelial cells among the tissues of many other organs.Neurological complications have been observed with COVID-19. Myalgia and headache are relatively common, but serious neurological disease appears to be rare. No part of the neuraxis is spared. The neurological disorders occurring with COVID-19 may have many pathophysiological underpinnings. Some appear to be the consequence of direct viral invasion of the nervous system tissue, others arise as a postviral autoimmune process, and still others are the result of metabolic and systemic complications due to the associated critical illness. This review addresses the preliminary observations regarding the neurological disorders reported with COVID-19 to date and describes some of the disorders that are anticipated from prior experience with similar coronaviruses.

Varicella zoster virus (VZV) oculomeningoencephalomyeloradiculitis: a previously undescribed constellation.

A 53-year-old immunocompromised woman developed acute left eye blindness and paraparesis suspected to be due to neuromyelitis optica (NMO). During treatment for NMO, right eye blindness and progressive multiple cranial neuropathies developed. Cerebrospinal fluid polymerase chain reaction (PCR) revealed Varicella zoster virus (VZV). This case emphasizes the importance of considering VZV in individuals, particularly the immunocompromised, presenting with a constellation of neurological signs and symptoms, even in the absence of rash.

Neurological and Ophthalmological Manifestations of Varicella Zoster Virus.

BACKGROUND: Approximately 1 million new cases of herpes zoster (HZ) occur in the United States annually, including 10%-20% with herpes zoster ophthalmicus (HZO). Postherpetic neuralgia, a debilitating pain syndrome occurs in 30% HZ, whereas 50% HZO develop ophthalmic complications. Diplopia from cranial nerve palsy occurs in less than 30% HZO, whereas optic neuropathy is seen in less than 1% HZO. We reviewed recent developments in the diagnosis, treatment, and prevention of HZ as well as neurological and ophthalmological complications of relevance to the neuro-ophthalmologist. EVIDENCE ACQUISITION: We searched the English language literature on Pubmed and Google scholar for articles relevant to the various sections of this review. RESULTS: Antiviral treatment should be initiated within 48-72 hours of onset of HZ and HZO to decrease pain and reduce complications. We recommend neuroimaging in all patients with neuro-ophthalmic manifestations such as diplopia and acute vision loss. Diagnostic confirmation using polymerase chain reaction and serology on paired serum and cerebrospinal fluid samples should be obtained in those with neurological signs and symptoms or abnormal imaging. Patients with neurological and/or retinal varicella zoster virus (VZV) infection should be treated promptly with intravenous acyclovir. Patients with isolated optic neuropathy or cranial nerve palsy can be managed with oral antivirals. The prognosis for visual recovery is good for patients with isolated optic neuropathy and excellent for patients with isolated ocular motor cranial nerve palsy. CONCLUSIONS: HZ produces a spectrum of potentially blinding and life-threatening complications that adversely affect quality of life and increase health care costs. Individuals at risk for HZ, such as the elderly and immunocompromised, should be encouraged to receive the highly effective VZV vaccine to prevent HZ and its complications.

Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event.

This report assesses the observed risk of PML in patients treated with the anti-CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ≈ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000-50,000 patients). In all cases, patients had ≥ 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time.

Correction to: Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event.

The article "Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event," written by Joseph R. Berger, Vineeta Malik, Stuart Lacey, Paul Brunetta, and Patricia B. Lehane3, was originally published electronically on the publisher's internet portal (currently SpringerLink).

Predictors of severity and functional outcome in natalizumab-associated progressive multifocal leukoencephalopathy.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described. METHODS: We retrospectively analyzed medical records of all patients with natalizumab-PML ( n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman's rho and multivariate regression analysis. RESULTS: In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed. CONCLUSION: This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings.

Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a devastating and often fatal demyelinating disease of the central nervous system for which effective therapies are lacking. It is caused by the replication of polyomavirus JC (JCV) in the oligodendrocytes and astrocytes leading to their cytolytic death and loss of myelin from the subcortical white matter. While the virus is very common in human populations worldwide, the incidence of the disease is very low and confined almost exclusively to individuals with some form of immunological dysfunction. However, the number of people who constitute the at-risk population is growing larger and includes individuals with HIV-1/AIDS and patients receiving immunomodulatory therapies such as multiple sclerosis patients treated with natalizumab. Further adding to the public health significance of this disease are the difficulties encountered in the diagnosis of PML and the lack of useful biomarkers for PML progression. In this review, we examine the diagnostic assays that are available for different aspects of the JCV life cycle, their usefulness and drawbacks, and the prospects for improvements.

Immunosenescence: the Role of Aging in the Predisposition to Neuro-Infectious Complications Arising from the Treatment of Multiple Sclerosis.

PURPOSE OF REVIEW: This review highlights some of the important changes in the immune system that occur in the process of normal aging. Immunosenescence as a concept is directly relevant to the world of neuro-inflammation, as it may be a contributing factor to the risks associated with some of the current immunosuppressive and immunomodulatory therapies used in treating multiple sclerosis (MS) and other inflammatory disorders. RECENT FINDINGS: Profound qualitative and quantitative changes occur in the adaptive and innate immunity compartments during aging. These changes may explain why patients of older age are at an increased risk of infections and infection-associated mortality. Immunosenescence-associated changes may be additive or synergistic with the effects produced by immunomodulatory and immunosuppressive medications. Clinicians should exercise a high level of vigilance in monitoring the risk of infections in older patients on these treatments.

Reassessing the risk of natalizumab-associated PML.

The risk algorithm for natalizumab-associated PML was first established in 2012 using the observations that JC virus antibody status, prolonged duration of natalizumab therapy (>2 years), and prior exposure to immunosuppressive therapy increased the risk for the disease. Prior to the publication of Biogen's algorithm, a risk algorithm was created by Fox and Rudick using an Excel spreadsheet in order to address the concerns of their patients. Applying the most recently available data regarding natalizumab-associated PML, the risk assessments for PML were recalculated. The current numbers indicate substantially higher risks for PML in 2015 than in 2012. Our calculations suggest that an individual having all three risk factors has an approximately 1 in 44 chance of developing PML.

Persistence and pathogenesis of the neurotropic polyomavirus JC.

Many neurological diseases of the central nervous system (CNS) are underpinned by malfunctions of the immune system, including disorders involving opportunistic infections. Progressive multifocal leukoencephalopathy (PML) is a lethal CNS demyelinating disease caused by the human neurotropic polyomavirus JC (JCV) and is found almost exclusively in individuals with immune disruption, including patients with human immunodeficiency virus/acquired immunodeficiency syndrome, patients receiving therapeutic immunomodulatory monoclonal antibodies to treat conditions such as multiple sclerosis, and transplant recipients. Thus, the public health significance of this disease is high, because of the number of individuals constituting the at-risk population. The incidence of PML is very low, whereas seroprevalence for the virus is high, suggesting infection by the virus is very common, and so it is thought that the virus is restrained but it persists in an asymptomatic state that can only occasionally be disrupted to lead to viral reactivation and PML. When JCV actively replicates in oligodendrocytes and astrocytes of the CNS, it produces cytolysis, leading to formation of demyelinated lesions with devastating consequences. Defining the molecular nature of persistence and events leading to reactivation of the virus to cause PML has proved to be elusive. In this review, we examine the current state of knowledge of the JCV life cycle and mechanisms of pathogenesis. We will discuss the normal course of the JCV life cycle including transmission, primary infection, viremia, and establishment of asymptomatic persistence as well as pathogenic events including migration of the virus to the brain, reactivation from persistence, viral infection, and replication in the glial cells of the CNS and escape from immunosurveillance.

Vaccines in Multiple Sclerosis.

Vaccinations help prevent communicable disease. To be valuable, a vaccine's ability to prevent disease must exceed the risk of adverse effects from administration. Many vaccines present no risk of infection as they are comprised of killed or non-infectious components while other vaccines consist of live attenuated microorganisms which carry a potential risk of infection-particularly, in patients with compromised immunity. There are several unique considerations with respect to vaccination in the multiple sclerosis (MS) population. First, there has been concern that vaccination may trigger or aggravate the disease. Second, disease-modifying therapies (DMTs) employed in the treatment of MS may increase the risk of infectious complications from vaccines or alter their efficacy. Lastly, in some cases, vaccination strategies may be part of the treatment paradigm in attempts to avoid complications of therapy.

WEST NILE VIRUS MENINGO-ENCEPHALITIS: POSSIBLE SEXUAL TRANSMISSION.

PURPOSE: We report a previously healthy middle aged woman who developed West Nile virus meningo-encephalitis within two weeks of unprotected vaginal intercourse with her husband. SUBJECT: This patient's husband had serologically confirmed West Nile virus infection manifested by a flu-like illness and rash with the sexual contact one day before the onset of his symptoms. RESULT: This well documented neuroinvasive West Nile virus infection in our patient was within the incubation period of transmission and there was no reported mosquito bite exposure. CONCLUSION: The timeframe of infection raises the possibility that her illness was sexually transmitted.

Animal Models for Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the CNS caused by the human polyomavirus JC (JCV). JCV replication occurs only in human cells and investigation of PML has been severely hampered by the lack of an animal model. The common feature of PML is impairment of the immune system. The key to understanding PML is working out the complex mechanisms that underlie viral entry and replication within the CNS and the immunosurveillance that suppresses the virus or allows it to reactivate. Early models involved the simple inoculation of JCV into animals such as monkeys, hamsters, and mice. More recently, mouse models transgenic for the gene encoding the JCV early protein, T-antigen, a protein thought to be involved in the disruption of myelin seen in PML, have been employed. These animal models resulted in tumorigenesis rather than demyelination. Another approach is to use animal polyomaviruses that are closely related to JCV but able to replicate in the animal such as mouse polyomavirus and SV40. More recently, novel models have been developed that involve the engraftment of human cells into the animal. Here, we review progress that has been made to establish an animal model for PML, the advances and limitations of different models and weigh future prospects.

A risk classification for immunosuppressive treatment-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare, complex opportunistic infection of the central nervous system caused by the JC virus. This past decade, PML was increasingly recognized to be associated with the use of immunosuppressive and biologic agents. The risk for PML differs among these agents and remains difficult to quantify because of the complex pathogenesis of PML and the presence of confounding factors. This paper explores and updates the association of PML with different biologic and immunosuppressive agents and proposes an expanded classification system for the risk of PML. We identify three classes of drug that vary by PML risk, latency to infection, and underlying illness. We also review some of the most common agents with known associations to PML and explore risk mitigation strategies that aim to inform the decision-making process for clinicians and patients in the face of the changing incidence of PML and the growing landscape of immunologic agents.

Progressive Multifocal Leukoencephalopathy: Recent Advances and a Neuro-Ophthalmological Review.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a severe often fatal opportunistic infection of the central nervous system caused by reactivation of a ubiquitous polyoma virus, JC virus. Although typically characterized by multifocal asymmetric subcortical white matter lesions, it may be monofocal and affect the cortical gray matter. Among the broad spectrum of clinical manifestations that occurs with PML, visual complaints are common. EVIDENCE ACQUISITION: Combination of representative personally observed cases of PML and comprehensive review of case series of PML from 1958 through 2014. RESULTS: Neuro-ophthalmic signs and symptoms were reported in approximately 20%-50% of patients with PML and can be the presenting manifestation in half of these. A majority of these presentations occur from damage to cerebral visual pathways resulting in visual field defects, cortical blindness, and other disorders of visual association. Given the decreased frequency of infratentorial and cerebellar involvement, ocular motility disorders are less common. CONCLUSIONS: Visual complaints occur in patients with PML and are often the presenting sign. Awareness of this condition is helpful in avoiding unnecessary delays in the diagnosis of PML and management of the underlying condition. Recent guidelines have established criteria for diagnosis of PML in the high-risk patient population and strategies to mitigate the risk in these populations.

JC virus antibody status underestimates infection rates.

OBJECTIVE: JC virus (JCV) seropositivity is a risk factor for progressive multifocal leukoencephalopathy (PML) in patients on natalizumab. Accordingly, the JCV serological antibody test is of paramount importance in determining disease risk. METHODS: We tested the accuracy of the JCV serum antibody test by comparing the results of JCV serology to JCV viruria and viremia in 67 patients enrolled in a single-center, retrospective cohort study. Bodily fluids (urine and blood) were assessed for JCV DNA by real time quantitative polymerase chain reaction 6 to 47 months (mean = 26.1 months) before JCV antibody testing. In 10 individuals, blood and urine samples were obtained on 2 separate occasions at 6-month intervals. RESULTS: Forty (59.7%) of the 67 patients were JCV seropositive. Of 27 JCV seronegative patients, 10 (37%) had JCV viruria. Urine JCV DNA copy numbers were significantly higher in the seropositive group (mean log copy number = 5.93, range = 1.85-9.21) than the seronegative group (mean log copy number = 2.41, range = 1.85-5.43; p = 0.0026). Considering all body fluid test results, 50 (74.6%) of the 67 patients were previously infected with JCV. INTERPRETATION: The false-negative rate of the JCV serology in this study was 37%; therefore, JCV serostatus does not appear to identify all patients infected with JCV. Thus, a negative JCV antibody result should not be conflated with absence of JCV infection. This discordance may be important in understanding JCV biology, risk for PML, and PML pathogenesis.