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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.
Journal Article
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
Journal Article
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.
Summary
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.
Journal Article
Progressive Multifocal Leukoencephalopathy and Newer Biological Agents
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the brain due to a polyoma virus, JC virus. Despite the ubiquity of this virus, PML is rare and almost always seen in association with an underlying immunosuppressive condition. In the last 30 years, AIDS has been the most common predisposing factor. The observation of PML attending the use of certain monoclonal antibody therapies and other pharmacological agents has raised concerns about the safety profile of these agents, but has also provided a window into the pathogenesis of PML. Certain agents, such as the monoclonal antibodies natalizumab, an [alpha]4 [beta]1 and [alpha]4 [beta]7 integrin inhibitor, and efalizumab, an antibody directed against CD11a, appear to uniquely predispose to PML. Prior to their introduction for multiple sclerosis and Crohn's disease with respect to natalizumab, and psoriasis with respect to efalizumab, PML had never been observed with these disorders. PML occurring with other agents that currently carry US FDA-mandated 'blackbox' warnings, such as rituximab, an antibody directed to CD20, or mycophenolate mofetil, a drug that inhibits T- and B-cell proliferation, typically occur in the background of underlying disorders that have already been identified as risks for PML. This review will focus on the available data regarding the risk for PML with monoclonal antibodies and other drugs. A biologically plausible explanation for the increased risk of PML will be proposed, as well as potential strategies for mitigating disease risk.
Journal Article
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.
Journal Article
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.
Journal Article
Guilty by association: Epstein–Barr virus in multiple sclerosis
Two new studies provide robust epidemiological evidence and a mechanistic link, with potential implications for strategies that target Epstein–Barr virus.
Journal Article
Diagnosis and Treatment of Progressive Multifocal Leukoencephalopathy Associated with Multiple Sclerosis Therapies
Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease-modifying therapies (DMTs) utilized in treating multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system—typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied.
Journal Article
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.
Journal Article