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.

Implant-based Breast Reconstruction Infections: The Importance of Recognizing Local Pathogens.

BACKGROUND: Implant-based breast reconstruction (IBR) is the most common method of reconstruction for breast cancer. Bacterial infection is a well-known risk with reported rates ranging from 1% to 43%. The most common pathogens of breast implant infection described in the literature are Staphylococcus aureus, Staphylococcus epidermidis, and coagulase-negative staphylococci. However, the prevalence of other pathogens and their antibiotic sensitivity profile differs profoundly in different parts of the world. OBJECTIVES: To review the current literature and protocols with respect to our region and to determine a more accurate antibiotic protocol aimed at our specific local pathogens. METHODS: A retrospective review was conducted of all cases of clinically infected implant-based breast reconstruction in our institution from June 2013 to June 2019, as well as review of microbiologic data from around the world based on current literature. RESULTS: A total of 28 patients representing 28 clinically infected implant-based breast reconstruction were identified during the studied period. Thirteen patients (46.4%) had a positive bacterial culture growth, with P. aeruginosa being the most common microorganism identified (46.1%). Review of international microbiological data demonstrated significant variation at different places and time periods. CONCLUSIONS: Microbiological data in cases of infected breast reconstructions should be collected and analyzed in every medical center and updated every few years due to the variations observed. These data will help to adjust the optimal empirical antibiotic regimens given to patients presenting with infections after breast reconstruction.

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.

An overview of frailty in kidney transplantation: measurement, management and future considerations.

The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

Disease-Modifying Therapy Adherence and Associated Factors in a National Sample of Medicare Patients With Multiple Sclerosis.

OBJECTIVES: Disease-modifying therapies (DMTs) reduce relapse rates and disability progression for relapsing multiple sclerosis (MS). Although 25% to 30% of all US patients with MS are Medicare beneficiaries, limited information exists on this population. This is the first study using national Medicare data to (1) describe characteristics of patients with MS using DMTs, (2) estimate adherence to DMTs over a 1-year and 3-year follow-up, and (3) examine factors associated with DMT adherence. METHODS: This retrospective claims analysis used 2011-2014 100% Medicare files. Monthly adherence to MS DMTs was defined as the proportion of days covered ≥0.80 with any DMT in each month for 1-year (n = 36 593) and 3-year (n = 17 599) follow-up samples of MS DMT users. Generalized estimating equation logistic regressions were used to estimate factors associated with adherence to DMTs. RESULTS: Over 90% of patients were eligible for Medicare owing to disability, and about three-quarters qualified for low-income subsidies. A downward trend in DMT adherence was observed over time in both samples. Monthly adherence dropped significantly between December of the prior year to January of the following year (from 76% to 65% in the 1-year follow-up sample and similar drops seen across all years in the 3-year follow-up sample). Multivariable regressions indicated characteristics such as being low-income, having a disability, and having high patient out-of-pocket DMT costs associated with poor adherence to DMTs. CONCLUSION: Our study provides important insights into the characteristics and DMT adherence of Medicare patients with MS and highlights the need for interventions and policies mitigating barriers to adherence in this population.

Report from the American Society of Transplantation on frailty in solid organ transplantation.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

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.