Clinical Metagenomic Next-Generation Sequencing for Diagnosis of Central Nervous System Infections: Advances and Challenges.

Central nervous system (CNS) infections carry a substantial burden of morbidity and mortality worldwide, and accurate and timely diagnosis is required to optimize management. Metagenomic next-generation sequencing (mNGS) has proven to be a valuable tool in detecting pathogens in patients with suspected CNS infection. By sequencing microbial nucleic acids present in a patient's cerebrospinal fluid, brain tissue, or samples collected outside of the CNS, such as plasma, mNGS can detect a wide range of pathogens, including rare, unexpected, and/or fastidious organisms. Furthermore, its target-agnostic approach allows for the identification of both known and novel pathogens. This is particularly useful in cases where conventional diagnostic methods fail to provide an answer. In addition, mNGS can detect multiple microorganisms simultaneously, which is crucial in cases of mixed infections without a clear predominant pathogen. Overall, clinical mNGS testing can help expedite the diagnostic process for CNS infections, guide appropriate management decisions, and ultimately improve clinical outcomes. However, there are key challenges surrounding its use that need to be considered to fully leverage its clinical impact. For example, only a few specialized laboratories offer clinical mNGS due to the complexity of both the laboratory methods and analysis pipelines. Clinicians interpreting mNGS results must be aware of both false negatives-as mNGS is a direct detection modality and requires a sufficient amount of microbial nucleic acid to be present in the sample tested-and false positives-as mNGS detects environmental microbes and their nucleic acids, despite best practices to minimize contamination. Additionally, current costs and turnaround times limit broader implementation of clinical mNGS. Finally, there is uncertainty regarding the best practices for clinical utilization of mNGS, and further work is needed to define the optimal patient population(s), syndrome(s), and time of testing to implement clinical mNGS.

Time to Confirmed Neuroinfectious Diagnoses: Diagnostic Testing and Resource Allocation.

Background and Objectives: In a retrospective study evaluating the diagnostic approach of definitive neurological infections at a tertiary referral center, we assessed the time to diagnosis from presentation, number of diagnostic tests ordered, and modality of etiologic diagnosis. Methods: A total of 111 confirmed clinical cases of neurological infections from 2010-2018 were reviewed. Definitive neuroinfectious diagnoses were defined by positive cerebrospinal (CSF) polymerase chain reaction (PCR)/antigen, CSF culture, CSF antibody, serology, or pathology tests. Results: An etiologic diagnosis was determined at an average (SD) of 3.1 (5.9) days after presentation with an average (SD) of 27.7 (15.6) diagnostic tests ordered per workup.Viral neuro-infections were associated with lower intensive care unit (ICU) admission rates, shorter length of hospitalization, and fewer diagnostic tests ordered, as well as shorter time to definitive diagnosis (P < .05). Longer hospitalizations were associated with immunosuppression status regardless of infectious etiology (P < .001). Discussion: Given the high morbidity and mortality of neuroinfectious disease, specifically meningitis and encephalitis, efficient diagnostic testing is imperative to facilitate the most appropriate clinical course of action with special attention to the specific patient population.

Chemokine-mediated cell migration into the central nervous system in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4. Single-cell transcriptomics of CSF cells suggests an enrichment of distinct CD4+ and CD8+ T cells expressing chemokine receptors CCR2, CCR5, and CXCR3, in addition to ITGA4 and the genetic PML risk genes STXBP2 and LY9. This suggests that specific immune cell subpopulations migrate into the central nervous system to mitigate PML, and their absence might coincide with PML development. Monitoring them might hold clues for PML risk, and boosting their recruitment or function before therapeutic immune reconstitution might improve its risk-benefit ratio.

Clinical and Diagnostic Features of West Nile Virus Neuroinvasive Disease in New York City.

West Nile virus (WNV) neuroinvasive disease (WNND) occurs in approximately 1 percent of WNV-infected patients and typically presents as encephalitis, meningitis, or acute flaccid paralysis (AFP). WNND remains a difficult inpatient diagnosis, creating significant challenges for prognostication and therapy selection. We characterized the clinical and diagnostic features of WNND cases at two major academic medical centers in New York City in routine clinical practice. We retrospectively reviewed the charts of thirty-six patients with WNND, including twenty-six encephalitis, four meningitis, and six AFP cases. The most common presenting symptoms were fever (86.1%) and gastrointestinal symptoms (38.9%) in addition to altered mental status (72.2%), lethargy (63.9%), gait disturbances (46.2%), and headache (44.4%). Fourteen (48.3%) patients displayed acute magnetic resonance imaging (MRI) findings, particularly T2 hyperintensities in the bilateral thalami, brainstem, and deep white matter. New York State Department of Health WNV CSF IgM testing was utilized for diagnosis in 58.3% of patients; however, just 38.1% had the result by discharge, compared to 85.6% of those who underwent serum IgM testing. The median length of stay was 13.5 days, 38.9% were intubated, and three patients (8.9%) died during acute hospitalization. Our findings underscore the morbidity, mortality, and diagnostic challenges of WNND, suggesting the potential utility of serum IgM testing in combination with confirmatory CSF testing to expedite diagnosis in the acute setting.

Autoimmune and inflammatory neurological disorders in the intensive care unit.

PURPOSE OF REVIEW: The present review summarizes the diagnostic approach to autoimmune encephalitis (AE) in the intensive care unit (ICU) and provides practical guidance on therapeutic management. RECENT FINDINGS: Autoimmune encephalitis represents a group of immune-mediated brain diseases associated with antibodies that are pathogenic against central nervous system proteins. Recent findings suggests that the diagnosis of AE requires a multidisciplinary approach including appropriate recognition of common clinical syndromes, brain imaging and electroencephalography to confirm focal pathology, and cerebrospinal fluid and serum tests to rule out common brain infections, and to detect autoantibodies. ICU admission may be necessary at AE onset because of altered mental status, refractory seizures, and/or dysautonomia. Early management in ICU includes prompt initiation of immunotherapy, detection and treatment of seizures, and supportive care with neuromonitoring. In parallel, screening for neoplasm should be systematically performed. Despite severe presentation, epidemiological studies suggest that functional recovery is likely under appropriate therapy, even after prolonged ICU stays. CONCLUSION: AE and related disorders are increasingly recognized in the ICU population. Critical care physicians should be aware of these conditions and consider them early in the differential diagnosis of patients presenting with unexplained encephalopathy. A multidisciplinary approach is mandatory for diagnosis, ICU management, specific therapy, and prognostication.

Building Equitable Neuroscience Research Collaborations in Resource-limited Settings.

The burden of noncommunicable neurological disorders, such as stroke, dementia, and headache disorders, are on the rise in low- to middle-income countries (LMICs), while neuroinfectious diseases remain a major concern. The development of neuroscience research aimed at defining the burden of neurological diseases across the lifespan, as well as optimizing diagnosis and treatment strategies, is fundamental to improving neurological health in resource-limited settings. One of the key factors to advancing neuroscience research in LMICs is the establishment of effective collaborations based on responsible and trustworthy partnerships between local scientists in LMICs and international collaborators. LMIC researchers face many logistical, institutional, and individual level challenges as they embark on their neuroscience research journey. Despite these challenges, there are opportunities for improving LMIC investigator-led research that should focus on human and institutional infrastructure development. With regard to human capacity building, potential areas for offering support include enhancing research methodology training, offering instruction in manuscript and grant-writing, institutionalizing mentorship programs, and providing opportunities to conduct funded, mentored research to disseminate in high-impact journals. The foundational elements required for implementing and optimizing neuroscience research within an institution include an institutional review board, mentorship programs, data management, research administration, and laboratory facilities. This institutional capacity varies significantly across and within countries, and many rely on collaborations with better-resourced institutions to initiate research. Successful equitable collaborations ensure the engagement of all local and international stakeholders, as well as implementation of a self-sustaining long-term program. Building research capacity in LMICs is an essential endeavor that requires ongoing commitment to training independent scientists. As research capacity increases, LMIC institutions and governments should consider developing competitive research grant programs to support innovative studies led by local researchers, foster regional collaborations, and hence create a sustainable and independent neuroscience research environment.

Accuracy of automated analyzers for the estimation of CSF cell counts: A systematic review and meta-analysis.

This systematic review evaluates the evidence for accuracy of automated analyzers that estimate cerebrospinal fluid (CSF) white blood cell counts (WBC) compared to manual microscopy. Inclusion criteria of original research articles included human subjects, English language, and manual microscopy comparator. PUBMED, EMBASE and Cochrane Review databases were searched through 2019 and QUADAS-2 Tool was used for assessment of bias. Data were pooled and analyzed by comparison method, using random effects estimation. Among 652 titles, 554 abstracts screened, 104 full-text review, 111 comparisons from 41 studies were included. Pooled estimates of sensitivity and specificity (n = 7) were 95% (95%-CI 93%-97%) and 84% (95%-CI: 64%-96%), respectively. Pooled R2 estimates (n = 29) were 0.95 (95%-CI: 0.95-0.96); Pooled spearman rho correlation (n = 27) estimates were 0.95 (95% CI 0.95-0.96). Among those comparisons using Bland-Altman analysis (n = 11) pooled mean difference was estimated at 0.98 (95% CI-0.54-2.5). Among comparisons using Passing-Bablok regressions (n = 14) the pooled slope was estimated to be 1.05 (95% CI 1.03-1.07). Q tests of homogeneity were all significant with the exception of the Bland-Altman comparisons (I2 10%, p value 0.35). There is good overall accuracy for CSF WBC by automated hematologic analyzers. These findings are limited by the small sample sizes and inconsistent validation methodology in the reviewed studies.

Pre-existing neurological conditions and COVID-19 co-infection: Data from systematic reviews, meta-analyses, and scoping reviews.

BACKGROUND: Pre-existing neurological diseases have been identified as risk factors for severe COVID-19 infection and death. There is a lack of comprehensive literature review assessing the relationship between pre-existing neurological conditions and COVID-19 outcomes. Identification of high risk groups is critical for optimal treatment and care. METHODS: A literature review was conducted for systematic reviews, meta-analyses, and scoping reviews published between January 1, 2020 and January 1, 2023. Literature assessing individuals with pre-existing neurological diseases and COVID-19 infection was included. Information regarding infection severity was extracted, and potential limitations were identified. RESULTS: Thirty-nine articles met inclusion criteria, with data assessing >3 million patients from 51 countries. 26/51 (50.9%) of countries analyzed were classified as high income, while the remaining represented middle-low income countries (25/51; 49.0%). A majority of evidence focused on the impact of cerebrovascular disease (17/39; 43.5%) and dementia (5/39; 12.8%) on COVID-19 severity and mortality. 92.3% of the articles (36/39) suggested a significant association between neurological conditions and increased risk of severe COVID-19 and mortality. Cerebrovascular disease, dementia, Parkinson's disease, and epilepsy were associated with increased COVID severity and mortality. CONCLUSION: Pre-existing neurological diseases including cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, and Parkinson's disease are significant risk factors for severity of COVID-19 infection and mortality in the acute infectious period. Given that 61.5% (24/39) of the current evidence only includes data from 2020, further updated literature is crucial to identify the relationship between chronic neurological conditions and clinical characteristics of COVID-19 variants.

Application of VirCapSeq-VERT and BacCapSeq in the diagnosis of presumed and definitive neuroinfectious diseases.

Unbiased high-throughput sequencing (HTS) has enabled new insights into the diversity of agents implicated in central nervous system (CNS) infections. The addition of positive selection capture methods to HTS has enhanced the sensitivity while reducing sequencing costs and the complexity of bioinformatic analysis. Here we report the use of virus capture-based sequencing for vertebrate viruses (VirCapSeq-VERT) and bacterial capture sequencing (BacCapSeq) in investigating CNS infections. Thirty-four samples were categorized: (1) patients with definitive CNS infection by routine testing; (2) patients meeting clinically the Brighton criteria (BC) for meningoencephalitis; (3) patients with presumptive infectious etiology highest on the differential. RNA extracts from cerebrospinal fluid (CSF) were used for VirCapSeq-VERT, and DNA extracts were used for BacCapSeq analysis. Among 8 samples from known CNS infections in group 1, VirCapSeq and BacCapSeq confirmed 3 expected diagnoses (42.8%), were negative in 2 (25%), yielded an alternative result in 1 (11.1%), and did not detect 2 expected negative pathogens. The confirmed cases identified HHV-6, HSV-2, and VZV while the negative samples included JCV and HSV-2. In groups 2 and 3, 11/26 samples (42%) were positive for at least one pathogen; however, 27% of the total samples (7/26) were positive for commensal organisms. No microbial nucleic acids were detected in negative control samples. HTS showed limited promise for pathogen identification in presumed CNS infectious diseases in our small sample. Before conducting larger-scale prospective studies to assess the clinical value of this novel technique, clinicians should understand the benefits and limitations of using this modality.

A structured evaluation of cryopreservation in generating single-cell transcriptomes from cerebrospinal fluid.

Single-cell transcriptomics allows characterization of cerebrospinal fluid (CSF) cells at an unprecedented level. Here, we report a robust cryopreservation protocol adapted for the characterization of fragile CSF cells by single-cell RNA sequencing (RNA-seq) in moderate- to large-scale studies. Fresh CSF was collected from twenty-one participants at two independent sites. Each CSF sample was split into two fractions: one was processed fresh, while the second was cryopreserved for months and profiled after thawing. B and T cell receptor sequencing was also performed. Our comparison of fresh and cryopreserved data from the same individuals demonstrates highly efficient recovery of all known CSF cell types. We find no significant difference in cell type proportions and cellular transcriptomes between fresh and cryopreserved cells. Results were comparable at both sites and with different single-cell sequencing chemistries. Cryopreservation did not affect recovery of T and B cell clonotype diversity. Our CSF cell cryopreservation protocol provides an important alternative to fresh processing of fragile CSF cells.

Application of VirCapSeq-VERT and BacCapSeq In the Diagnosis of Presumed and Definitive Neuroinfectious Diseases.

Background: Unbiased high-throughput sequencing (HTS) has enabled new insights into the diversity of agents implicated in central nervous system (CNS) infections. The addition of positive selection capture methods to HTS has enhanced the sensitivity while reducing sequencing costs and complexity of bioinformatic analysis. Here we report the use of virus capture based sequencing for vertebrate viruses (VirCapSeq-VERT) and bacterial capture sequencing (BacCapSeq) in investigating CNS infections. Design/Methods: Thirty-four samples were categorized: (1) Patients with definitive CNS infection by routine testing; (2) Patients meeting clinically Brighton Criteria (BC) for meningoencephalitis (3) Patients with presumptive infectious etiology highest on the differential. RNA extracts from cerebrospinal fluid (CSF) were used for VirCapSeq-VERT and DNA extracts were used for BacCapSeq analysis. Results: Among 8 samples from known CNS infections in group 1, VirCapSeq and BacCapSeq confirmed 3 expected diagnoses (42.8%), were negative in 2 (25%), yielded an alternative result in 1 (11.1%), and did not detect 2 expected negative pathogens. The confirmed cases identified HHV-6, HSV-2, and VZV while the negative samples included JCV and HSV-2. In groups 2 and 3,11/26 samples (42%) were positive for at least one pathogen, however 27% of the total samples (7/26) were positive for commensal organisms. No microbial nucleic acids were detected in negative control samples. Conclusions: HTS showed limited promise for pathogen identification in presumed CNS infectious diseases in our small sample. Before conducting larger-scale prospective studies to assess clinical value of this novel technique, clinicians should understand benefits and limitations of using this modality.

Neurological diagnoses in hospitalized COVID-19 patients during the B.1.1.529 surge.

OBJECTIVE: Emerging variants and sublineages of SARS-CoV-2 have differing disease severity, transmissibility, and immune evasion. The neurological conditions associated with the original strain of SARS-CoV-2 are well established. Our study assessed the neurological presentations specific to hospitalized patients during the B.1.1.529 (Omicron) variant surge in New York City. METHODS: A total of 178 cases with positive RT-PCR result within 6 weeks before admission, and subsequent development of select neurological conditions during the SARS-CoV-2 B.1.1.529 (Omicron) surge between December 1, 2021 and February 28, 2022, were included from 12,800 SARS-CoV-2-positive hospital admissions. Clinical data from acute hospitalizations were compared to findings of inpatient neurological cases with COVID-19 infections from the initial surge in NYC in the same hospital system. RESULTS: Compared to SARS-CoV-2 infections of the original strain, COVID-19 cases hospitalized during the Omicron surge (B.1.1.529) were associated with incidental and/or asymptomatic COVID-19 cases (96, 53.9%) and an increased incidence of pre-existing neurological and immunocompromising conditions. Encephalopathy, seizures, and stroke remained the most prevalent neurological conditions identified in hospitalized COVID-19 cases during the study period, reflecting a similar distribution of neurological presentations associated with the original strain. INTERPRETATION: In our cohort of 178 admitted SARS-CoV-2-positive patients with select neurological conditions during the Omicron B.1.1.529 surge, 54% of COVID-19 cases were considered incidental and/or asymptomatic, and the identified neurological conditions resembled those associated with the original SARS-CoV-2 strain. Further studies characterizing neurological presentation in Omicron sublineages and other variants are warranted in an ongoing COVID-19 pandemic.

Perspectives on Diagnosis and Management of All-Cause Encephalitis: A National Survey of Adult Infectious Diseases Physicians.

Background: Encephalitis is widely recognized as a challenging condition to diagnose and manage. The care of patients with encephalitis typically involves multiple disciplines, including neurologists and infectious disease (ID) physicians. Our objective was to describe the perspectives and needs of ID physicians regarding encephalitis, using a cross-sectional questionnaire survey. Methods: We performed a survey among physician members of the Infectious Diseases Society of America's (IDSA) Emerging Infections Network (EIN). Results: Response rate was 33% (480 among 1472 active EIN physician members). More than 75% of respondents reported caring for patients with suspected encephalitis. Although one-third were involved in the care of multiple patients with autoimmune encephalitis (AE) annually, comfort in diagnosing and managing encephalitis, and in particular AE, was low. Experience with advanced diagnostic tools was variable, as were approaches toward deployment of such tools. Respondents noted that training could be improved by incorporating a multidisciplinary approach taking advantage of online and virtual platforms. ID physicians report a heavy reliance on the 2008 IDSA guidelines for the management of encephalitis, and indicated strong support for a formal update. Conclusions: ID physicians play an important role in the diagnosis and management of all-cause encephalitis. Despite exposure to AE, few ID physicians are comfortable in recognizing, diagnosing, and treating AE. Moreover, comfort with and use of advanced diagnostic tools for infectious encephalitis was highly variable. Training in encephalitis should include a focus on use and stewardship of advanced diagnostic tools and on collaborative approaches with neurologists and other practitioners on mechanisms and clinical presentations of AE. There is a need for a formal update of 2008 guidelines on the management of encephalitis.

Arthropod-borne encephalitis: an overview for the clinician and emerging considerations.

The rapid spread of arboviral infections in recent years has continually established arthropod-borne encephalitis to be a pressing global health concern. Causing a wide range of clinical presentations ranging from asymptomatic infection to fulminant neurological disease, the hallmark features of arboviral infection are important to clinically recognise. Arboviral infections may cause severe neurological presentations such as meningoencephalitis, epilepsy, acute flaccid paralysis and stroke. While the pathogenesis of arboviral infections is still being investigated, shared neuroanatomical pathways among these viruses may give insight into future therapeutic targets. The shifting infection transmission patterns and evolving distribution of arboviral vectors are heavily influenced by global climate change and human environmental disruption, therefore it is of utmost importance to consider this potential aetiology when assessing patients with encephalitic presentations.

Observational Study of Patients Hospitalized With Neurologic Events After SARS-CoV-2 Vaccination, December 2020-June 2021.

Background and Objectives: The global spread of the COVID-19 pandemic accelerated the vaccine development time line, regulatory approval, and widespread implementation in the population underscoring the importance of postauthorization/postlicensure vaccine safety surveillance. To monitor for vaccine-related adverse events, we prospectively identified patients hospitalized for prespecified neurologic conditions who received mRNA or adenovirus COVID-19 vaccines and assessed cases for potential risk factors and alternative etiologies of the adverse event. Methods: We identified prespecified neurologic conditions in hospitalized individuals within 6 weeks of receipt of a dose of any COVID-19 vaccination between December 11, 2020, and June 22, 2021 (Columbia University Irving Medical Center/New York Presbyterian Hospital, New York City, New York). Clinical data from electronic medical records in these vaccinated patients were reviewed for assessment of contributing risk factors and etiologies for these neurologic conditions by use of a published algorithm. Results: Among 3,830 individuals screened for COVID-19 vaccination status and neurologic conditions, 138 (3.6%) cases were included in this study (126 after mRNA and 6 after Janssen vaccines). The 4 most prevalent neurologic syndromes included ischemic stroke (52, 37.7%), encephalopathy (45, 32.6%), seizure (22, 15.9%), and intracranial hemorrhage (ICH) (13, 9.4%). All 138 cases (100%) had 1 or more risk factors and/or evidence for established causes. Metabolic derangement was the most common etiology for seizures (24, 53.3%) and encephalopathy (5, 22.7%) while hypertension was the most significant risk factor in ischemic stroke (45, 86.5%) and ICH cases (4, 30.8%). Discussion: All cases in this study were determined to have at least 1 risk factor and/or known etiology accounting for their neurologic syndromes. Our comprehensive clinical review of these cases supports the safety of mRNA COVID-19 vaccines.

Neurological Considerations with COVID-19 Vaccinations.

The benefits of coronavirus disease 2019 (COVID-19) vaccination significantly outweigh its risks on a public health scale, and vaccination has been crucial in controlling the spread of SARS-CoV-2. Nonetheless, several reports of adverse events following vaccination have been published.To summarize reports to date and assess the extent and quality of evidence regarding possible serious adverse neurological events following COVID-19 vaccination, focusing on Food and Drug Administration (FDA)-approved vaccines in the United States (BNT162b2, mRNA-1273, and Ad26.COV2.S).A review of literature from five major electronic databases (PubMed, Medline, Embase, Cochrane Library, and Google Scholar) was conducted between December 1, 2020 and June 5, 2022. Articles included in the review were systematic reviews and meta-analysis, cohort studies, retrospective studies, case-control studies, case series, and reports. Editorials, letters, and animal studies were excluded, since these studies did not include quantitative data regarding adverse side effects of vaccination in human subjects.Of 149 total articles and 97 (65%) were case reports or case series. Three phase 3 trials initially conducted for BNT162b2, MRNA-1273, and Ad26.COV2.S were included in the analysis.The amount and quality of evidence for possible neurological adverse events in the context of FDA-approved COVID-19 vaccinations is overall low tier. The current body of evidence continues to suggest that COVID-19 vaccinations have a high neurological safety profile; however, the risks and benefits of vaccination must continue to be closely monitored.

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression.

Importance: Progressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease. Objective: To describe characteristics of patients with S-PML. Design, Setting, and Participants: For this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023. Exposures: Sarcoidosis without active therapeutic immune suppression. Main Outcomes and Measures: Clinical, laboratory, and radiographic features of patients with S-PML. Results: Twenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/µL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not. Conclusions and Relevance: In this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

Addressing vaccine-preventable encephalitis in vulnerable populations.

PURPOSE OF REVIEW: Vaccinations have been pivotal in lowering the global disease burden of vaccine-preventable encephalitides, including Japanese encephalitis, tick-borne encephalitis, measles encephalitis, and rabies encephalitis, among others. RECENT FINDINGS: Populations vulnerable to vaccine-preventable infections that may lead to encephalitis include those living in endemic and rural areas, military members, migrants, refugees, international travelers, younger and older persons, pregnant women, the immunocompromised, outdoor, healthcare and laboratory workers, and the homeless. There is scope for improving the availability and distribution of vaccinations, vaccine equity, surveillance of vaccine-preventable encephalitides, and public education and information. SUMMARY: Addressing these gaps in vaccination strategies will allow for improved vaccination coverage and lead to better health outcomes for those most at risk for vaccine-preventable encephalitis.

Threat of resurgence or hope for global eradication of poliovirus?

PURPOSE OF REVIEW: Recent outbreaks of poliomyelitis in countries that have been free of cases for decades highlight the challenges of eradicating polio in a globalized interconnected world beset with a novel viral pandemic. We provide an epidemiological update, advancements in vaccines, and amendments in public health strategy of poliomyelitis in this review. RECENT FINDINGS: Last year, new cases of wild poliovirus type 1 (WPV1) were documented in regions previously documented to have eradicated WPV1 and reports of circulating vaccine-derived poliovirus type 2 (cVDPV2) and 3 (cVDPV3) in New York and Jerusalem made international headlines. Sequencing of wastewater samples from environmental surveillance revealed that the WPV1 strains were related to WPV1 lineages from endemic countries and the cVDPV2 strains from New York and Jerusalem were not only related to each other but also to environmental isolates found in London. The evidence of importation of WPV1 cases from endemic countries, and global transmission of cVDPVs justifies renewed efforts in routine vaccination programs and outbreak control measures that were interrupted by the COVID-19 pandemic. After the novel oral poliovirus vaccine type 2 (nOPV2) received emergency authorization for containment of cVDPV2 outbreaks in 2021, subsequent reduced incidence, transmission rates, and vaccine adverse events, alongside increased genetic stability of viral isolates substantiates the safety and efficacy of nOPV2. The nOPV1 and nOPV3 vaccines, against type 1 and 3 cVDPVs, and measures to increase accessibility and efficacy of inactivated poliovirus vaccine (IPV) are in development. SUMMARY: A revised strategy utilizing more genetically stable vaccine formulations, with uninterrupted vaccination programs and continued active surveillance optimizes the prospect of global poliomyelitis eradication.