Advancing the chemotherapy of tuberculous meningitis: a consensus view.

Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.

Sex Differences in the Risk of Stroke Associated With Traditional and Non-Traditional Factors in a US Cohort of People With HIV Infection.

BACKGROUND AND OBJECTIVES: Although stroke risk associated with HIV may be greater for women than men, little is known about whether the impact of different factors on cerebrovascular risk varies by sex in people with HIV (PWH) and contributes to stroke risk disparities in this population. The primary objective of this study was to examine whether sex modifies the effect of demographics, cardiometabolic factors, health-related behaviors, and HIV-specific variables on stroke risk in PWH from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. METHODS: In this observational cohort study, we analyzed data from clinical encounters for PWH followed at 5 CNICS sites from approximately 2005 to 2020. All potential stroke events were adjudicated by neurologists. Patient-reported outcomes collected at clinic visits, including substance use and depression, were also available. We used Cox proportional hazards models to determine whether sex modified the association of predictors of interest with incident stroke. RESULTS: Among 13,573 PWH (19% female sex at birth, mean age 44 years, mean follow-up 5.6 years), female sex was associated with a higher risk of stroke only among individuals aged 50 years or younger (hazard ratio [HR] 2.01 at age 40 [1.25-3.21] vs HR 0.60 at age 60 [0.34-1.06]; p = 0.001 for the interaction). Younger female participants who developed a stroke were more likely to have treated hypertension, a higher cardiovascular risk score, and detectable HIV than younger male participants whereas these factors were comparable by sex among older participants who developed a stroke. Sex modified the effect of detectable HIV (HR 4.66 for female participants [2.48-8.74] vs HR 1.30 for male participants [0.83-2.03]; p = 0.001 for the interaction), methamphetamine use (HR 4.78 for female participants [1.47-15.56] vs HR 1.19 for male participants [0.62-2.29]; p = 0.04 for the interaction), and treated hypertension (HR 3.44 for female participants [1.74-6.81] vs HR 1.66 for male participants [1.14-2.41]; p = 0.06 for the interaction) on stroke risk. DISCUSSION: Younger female participants with HIV were at elevated cerebrovascular risk compared with younger male participants. Several risk factors had a greater adverse effect on stroke risk in female participants than in male participants, including HIV viremia, methamphetamine use, and treated hypertension. These findings underscore the importance of a personalized approach to predict and prevent cerebrovascular risk among PWH.

Progressive multifocal leukoencephalopathy and spectrum of predisposing conditions: a 20-year retrospective cohort study in a tertiary center in São Paulo, Brazil.

BACKGROUND: Epidemiological studies on predisposing conditions and outcomes of progressive multifocal leukoencephalopathy (PML) cases have been carried out exclusively in high-income countries. We aim to report and compare the main characteristics and outcomes of patients with PML and several underlying diseases in a referral center in a middle-income country. METHODS: We performed a retrospective cohort study of PML cases admitted to a tertiary care hospital in São Paulo, Brazil during 2000-2022. Demographic and PML-specific variables were recorded. One-year case-fatality rate and factors associated with death were identified using a multivariate Cox proportional hazards regression model. RESULTS: Ninety-nine patients with PML were included. HIV infection (84.8%) and malignancy (14.1%) were the most prevalent underlying conditions. Other predisposing diseases were autoimmune/inflammatory diseases (5.1%) and solid organ transplantation (1.0%). One (1.0%) patient had liver cirrhosis and another (1.0%) patient was previously healthy. Focal motor deficits (64.2%) and gait instability (55.1%) were the most common signs. The one-year case-fatality rate was 52.5% (95% CI 42.2-62.7). The one-year case-fatality rate (95% CI) in patients with or without malignancy (85.7%, 95% CI 57.2-98.2% and 47.1%, 95% CI 36.1-58.2%, respectively) were statistically different (P = 0.009). Crude and adjusted Cox regression models identified malignancy as independently associated with death (adjusted HR = 3.92, 95% CI 1.76-8.73, P = 0.001). CONCLUSIONS: HIV/AIDS was the predisposing condition in 84.8% of PML cases. The one-year case-fatality rate was 52.5% and having a malignancy was independently associated with death. This study reports emerging data on the epidemiology and outcome of PML in a middle-income country.

A teenage girl with altered mental status and paraparesis.

A teenage girl presented with fever and altered mental status. MRI showed diffuse leptomeningeal enhancement of the brain and spine. She was diagnosed by a positive cerebrospinal fluid (CSF) culture with tuberculous (TB) meningitis and was started on anti-TB medications and corticosteroids. Her mental status improved, but she was noted to have proximal weakness of the lower extremities. In the course of tapering corticosteroids at week 11 of anti-TB therapy, she became acutely confused and febrile. MRI demonstrated interval development of tuberculomas in the brain and a mass lesion in the thoracic spine causing cord compression. Given the clinical picture was suggestive of a paradoxical reaction, the dose of corticosteroids was increased. Infliximab was added when repeat MRI revealed enlargement of the mass lesion in the spine with worsening cord compression. She was successfully tapered off of corticosteroids. Over several months, the patient's motor function recovered fully, and she returned to ambulating without assistance.

Outcome and Sequelae of Autoimmune Encephalitis.

Autoimmune etiologies are a common cause for encephalitis. The clinical syndromes consistent with autoimmune encephalitis are both distinct and increasingly recognized, but less is known about persisting sequelae or outcomes. We searched PubMed for reports on outcomes after autoimmune encephalitis. Studies assessing validated, quantitative outcomes were included. We performed a narrative review of the published literature of outcomes after autoimmune encephalitis. We found 146 studies that produced outcomes data. The mortality rates were 6%-19% and the relapse risks were 10%-62%. Most patients achieved a good outcome based on a score on the modified Rankin Scale (mRS) of ≤2. Forty-nine studies evaluated outcomes beyond mRS; these studies investigated cognitive outcome, psychiatric sequelae, neurological deficits, global function, and quality-of-life/patient-reported outcomes using various tools at varying time points after the index hospital discharge. These more-detailed assessments revealed that most patients had persistent impairments, with frequent deficits in cognitive function, especially memory and attention. Depression and anxiety were also common. Many of these sequelae continued to improve over months or even years after the acute illness. While we found that lasting impairments were common among survivors of autoimmune encephalitis, additional research is needed to better understand the nature and impact of these sequelae. Standardized evaluation protocols are needed to improve the ability to compare outcomes across studies, guide rehabilitation strategies, and inform outcomes of interest in treatment trials as the field advances.

Outcome and Sequelae of Infectious Encephalitis.

Acute infectious encephalitis is a widely studied clinical syndrome. Although identified almost 100 years ago, its immediate and delayed consequences are still neglected despite their high frequency and possible severity. We reviewed the available data on sequelae and persisting symptoms following infectious encephalitis with the aim of characterizing the clinical picture of these patients at months to years after hospitalization. We searched PubMed for case series involving sequelae after infectious encephalitis. We carried out a narrative review of the literature on encephalitis caused by members of the Herpesviridae family (herpes simplex virus, varicella zoster virus, and human herpesvirus-6), members of the Flaviviridae family (West Nile virus, tick-borne encephalitis virus, and Japanese encephalitis virus), alphaviruses, and Nipah virus. We retrieved 41 studies that yielded original data involving 3,072 adult patients evaluated after infectious encephalitis. At least one of the five domains of cognitive outcome, psychiatric disorders, neurological deficits, global functioning, and quality of life was investigated in the reviewed studies. Various tests were used in the 41 studies and the investigation took place at different times after hospital discharge. The results showed that most patients are discharged with impairments, with frequent deficits in cognitive function such as memory loss or attention disorders. Sequelae tend to improve within several years following flavivirus or Nipah virus infection, but long-term data are scarce for other pathogens. Further research is needed to better understand the extent of sequelae after infectious encephalitis, and to propose a standardized assessment method and assess the rehabilitation efficacy in these patients.

Advancing Diagnosis and Treatment in People Living with HIV and Tuberculosis Meningitis.

PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Inadequate diagnostic testing and treatment regimens adapted from pulmonary tuberculosis without consideration of the unique nature of TBM are among the potential drivers. This review focuses on the progress being made in relation to both diagnosis and treatment of TBM, emphasizing promising future directions. RECENT FINDINGS: The molecular assay GeneXpert MTB/Rif Ultra has improved sensitivity but has inadequate negative predictive value to "rule-out" TBM. Evaluations of tests focused on the host response and bacterial components are ongoing. Clinical trials are in progress to explore the roles of rifampin, fluoroquinolones, linezolid, and adjunctive aspirin. Though diagnosis has improved, novel modalities are being explored to improve the rapid diagnosis of TBM. Multiple ongoing clinical trials may change current therapies for TBM in the near future.

Psychological stress is associated with arterial inflammation in people living with treated HIV infection.

Stress and depression are increasingly recognized as cerebrovascular risk factors, including among high stress populations such as people living with HIV infection (PLWH). Stress may contribute to stroke risk through activation of neural inflammatory pathways. In this cross-sectional study, we examined the relationships between stress, systemic and arterial inflammation, and metabolic activity in stress-related brain regions on 18F-fluorodeoxyglucose (FDG)-PET in PLWH. Participants were recruited from a parent trial evaluating the impact of alirocumab on radiologic markers of cardiovascular risk in people with treated HIV infection. We administered a stress battery to assess different forms of psychological stress, specifying the Perceived Stress Scale as the primary stress measure, and quantified plasma markers of inflammation and immune activation. Participants underwent FDG-PET of the brain, neck, and chest. Age- and sex-matched control participants without HIV infection were selected for brain FDG-PET comparisons. Among PLWH, we used nonparametric pairwise correlations, partial correlations, and linear regression to investigate the association between stress and 1) systemic inflammation; 2) atherosclerotic inflammation on FDG-PET; and metabolic activity in 3) brain regions in which glucose metabolism differed significantly by HIV serostatus; and 4) in a priori defined stress-responsive regions of interest (ROI) and stress-related neural network activity (i.e., ratio of amygdala to ventromedial prefrontal cortex or temporal lobe activity). We studied 37 PLWH (mean age 60 years, 97% men) and 29 control participants without HIV (mean age 62 years, 97% men). Among PLWH, stress was significantly correlated with systemic inflammation (r = 0.33, p = 0.041) and arterial inflammation in the carotid (r = 0.41, p = 0.023) independent of age, race/ethnicity, traditional vascular risk factors and health-related behaviors. In voxel-wise analyses, metabolic activity in a cluster corresponding to the anterior medial temporal lobes, including the bilateral amygdalae, was significantly lower in PLWH compared with controls. However, we did not find a significant positive relationship between stress and this cluster of decreased metabolic activity in PLWH, a priori defined stress-responsive ROI, or stress-related neural network activity. In conclusion, psychological stress was associated with systemic and carotid arterial inflammation in this group of PLWH with treated infection. These data provide preliminary evidence for a link between psychological stress, inflammation, and atherosclerosis as potential drivers of excess cerebrovascular risk among PLWH.

Consensus Competencies for Postgraduate Fellowship Training in Global Neurology.

BACKGROUND AND OBJECTIVES: Use a modified Delphi approach to develop competencies for neurologists completing ≥1 year of advanced global neurology training. METHODS: An expert panel of 19 United States-based neurologists involved in global health was recruited from the American Academy of Neurology Global Health Section and the American Neurological Association International Outreach Committee. An extensive list of global health competencies was generated from review of global health curricula and adapted for global neurology training. Using a modified Delphi method, United States-based neurologists participated in 3 rounds of voting on a survey with potential competencies rated on a 4-point Likert scale. A final group discussion was held to reach consensus. Proposed competencies were then subjected to a formal review from a group of 7 neurologists from low- and middle-income countries (LMICs) with experience working with neurology trainees from high-income countries (HICs) who commented on potential gaps, feasibility, and local implementation challenges of the proposed competencies. This feedback was used to modify and finalize competencies. RESULTS: Three rounds of surveys, a conference call with United States-based experts, and a semistructured questionnaire and focus group discussion with LMIC experts were used to discuss and reach consensus on the final competencies. This resulted in a competency framework consisting of 47 competencies across 8 domains: (1) cultural context, social determinants of health and access to care; (2) clinical and teaching skills and neurologic medical knowledge; (3) team-based practice; (4) developing global neurology partnerships; (5) ethics; (6) approach to clinical care; (7) community neurologic health; (8) health care systems and multinational health care organizations. DISCUSSION: These proposed competencies can serve as a foundation on which future global neurology training programs can be built and trainees evaluated. It may also serve as a model for global health training programs in other medical specialties as well as a framework to expand the number of neurologists from HICs trained in global neurology.

Brief Report: Sex Differences in the Association Between Cerebrovascular Function and Cognitive Health in People Living With HIV in Urban China.

BACKGROUND: Cardiometabolic and cerebrovascular disease are strong independent contributors to cognitive impairment in people living with HIV. Data suggest that cardiovascular risk may play a greater role in cognitive health in women than in men with HIV. METHODS: We performed a cross-sectional study of 104 participants with virologically suppressed HIV from 2 clinics in urban China. Participants underwent neuropsychological testing from which we calculated T scores globally and in 5 cognitive domains. We assessed cerebral vasoreactivity of the middle cerebral arteries in response to breath holding. We constructed linear regression models to determine associations between cerebrovascular and cognitive function overall and stratified by sex. RESULTS: Women were younger than men (48 versus 51 years, P = 0.053), had fewer years of education (9 years versus 12 years, P = 0.004), and fewer cardiometabolic risk factors (0 versus 1 factor, P = 0.008). In a model with all participants, cerebrovascular function was significantly associated with global cognition (2.74 higher T score per 1-point higher cerebral vasoreactivity [SE 1.30], P = 0.037). Cerebrovascular function remained significantly associated with global cognition among women (4.15 higher T score [SE 1.78], P = 0.028) but not men (1.70 higher T score [SE 1.74], P = 0.33). The relationships between cerebrovascular function and specific cognitive domains followed a similar pattern, with significant associations present among women but not men. CONCLUSIONS: Women with well-controlled HIV may be more vulnerable to the effect of cerebrovascular injury on cognitive health than men. Studies evaluating strategies to protect against cognitive impairment in people living with HIV should include adequate representation of women and stratification of analyses by sex.

HIV Infection and 90-Day Stroke Outcomes in Uganda: A Prospective Observational Cohort Study.

Background and Objectives: Little is known about the impact of HIV infection on the clinical presentation and outcomes after stroke in the modern antiretroviral therapy (ART) era. We aimed to compare stroke characteristics and outcomes between persons with HIV (PWH) and without HIV (PWOH) presenting with stroke in Uganda. Methods: We conducted a matched cohort study at Mulago National Referral Hospital and Mbarara Regional Referral Hospital between January 2018 and November 2020. We enrolled consecutive PWH presenting with CT-confirmed acute or subacute stroke (symptom onset ≤14 days) and matched them by sex and stroke type to 2 consecutive available PWOH admitted to the same hospital. We obtained baseline clinical data and followed participants for 90 days from the day of clinical presentation. We compared stroke severity (defined by the NIH stroke scale [NIHSS]) and 90-day all-cause mortality and morbidity (using the modified Rankin Scale [mRS]) by HIV serostatus with and without adjustment for confounders. Results: We enrolled 105 PWH and 157 PWOH with stroke. PWH were younger (mean [SD] age 49 [14] vs 59 [16] years, p < 0.001), and nearly 80% (82/105) were on ART for a median of 5 years and a median CD4 count of 214 cells/uL (interquartile range 140, 337). Compared with PWOH, PWH presented with a 3-point lower median NIHSS (16 vs 19, p = 0.011), a 20% lower proportion of all-cause mortality at 90 days (p = 0.001), and had less disability at 90 days (median mRS 4 vs 5, p = 0.004). Age and NIHSS-adjusted odds ratio of 90-day all-cause mortality in PWH compared with PWOH was 0.45 (95% CI 0.22-0.96, p = 0.037). Discussion: In the modern ART era, PWH with acute stroke in Uganda present with modest stroke and are significantly less likely to die within 90 days than PWOH. This potentially reflects the protective effects of ART, enhanced health care access, and their younger age at stroke presentation.

Glucocorticoid Receptor Function and Cognitive Performance in Women With HIV.

OBJECTIVE: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women. METHODS: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates. RESULTS: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation. CONCLUSIONS: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes.

Prevalence and Characteristics of HIV-Associated Stroke in a Tertiary Hospital Setting in South Africa.

BACKGROUND AND OBJECTIVES: Antiretroviral treatment (ART) era HIV-associated stroke data from sub-Saharan Africa are limited. We determined the prevalence of HIV in patients presenting with acute symptomatic stroke and compared risk factors, clinical characteristics, and brain imaging with age-matched stroke patients without HIV. METHODS: We conducted a retrospective study of adults presenting with any type of stroke to Tygerberg Hospital in a 12-month period. Patients living with HIV (PLWH) and HIV-uninfected (HIV-) patients were matched based on age group (1:2 ratio). Patients were identified by keyword search, while HIV status was ascertained from laboratory data. Clinical and imaging data were extracted from medical records. RESULTS: Among 884 patients presenting with acute strokes, the minimum prevalence of HIV infection was 9.3% (95% CI: 7.4%-11.2%), with 496 patients (56.1%) with negative HIV status and 306 patients with unknown HIV status (34.6%). The mean age at presentation in PLWH was 46 (±11) years compared with 55 (±14) years in HIV- patients (p < 0.001). Smoking was less prevalent in PLWH with an adjusted relative risk ratio of RR = 0.58 (95% CI: 0.39-0.86). Concurrent infection was more prevalent in PLWH (25.6% vs 4.9%, p ≤ 0.001) with an adjusted relative risk ratio of RR = 2.07 (95% CI: 1.49-2.84), largely in patients with a CD4 count <200 cells/µL. PLWH with higher CD4 counts (≥200 cells/µL, 51.3%) had more traditional risk factors and less concurrent infection. Among PLWH, 68.3% were on ART, and 39.3% of them had been started or restarted on ART within the past 6 months. Basal ganglia infarcts (35.6% vs 18.3%, p = 0.014) and multiple vascular territory involvement (25.4% vs 7.7%, p = 0.002) were more common in PLWH. Clinical presentation, ischemic stroke type, and in-hospital outcomes did not differ between the groups. DISCUSSION: Stroke patients with HIV were younger, had less traditional cardiovascular risk factors, and more concurrent infections than patients without HIV, especially those with a lower CD4 count. Recent ART initiation or reinitiation rates were high. Significant differences in CT brain imaging findings were seen. Understanding the multifactorial mechanisms underlying increased stroke risk, including associated infections and potential ART-associated immune reconstitution, is crucial and needs further study.

Plasma Markers of Neurologic Injury and Inflammation in People With Self-Reported Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: The biologic mechanisms underlying neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are incompletely understood. METHODS: We measured markers of neurologic injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and soluble markers of inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery after the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported CNS PASC symptoms during the late recovery time point. We compared fold changes in marker values between those with and without CNS PASC symptoms using linear mixed-effects models and examined relationships between neurologic and immunologic markers using rank linear correlations. RESULTS: Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p = 0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p = 0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison with those who did not report CNS PASC symptoms (p = 0.041). Those who went on to report CNS PASC also exhibited elevations in interleukin 6 (48% higher during early recovery and 38% higher during late recovery), monocyte chemoattractant protein 1 (19% higher during early recovery), and tumor necrosis factor α (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery. DISCUSSION: Self-reported neurologic symptoms present approximately 4 months after SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at earlier time points. Some inflammatory pathways seem to be involved months after acute infection. Additional work will be needed to better characterize these processes and to identify interventions to prevent or treat this condition.

An Analysis of Stroke Risk Factors by HIV Serostatus in Uganda: Implications for Stroke Prevention in Sub-Saharan Africa.

OBJECTIVE: HIV infection is an important stroke risk factor in sub-Saharan Africa.  However, data on stroke risk factors in the era of antiretroviral therapy (ART) are sparse. We aimed to determine if stroke risk factors differed by HIV serostatus in Uganda. METHODS: We conducted a matched cohort study, enrolling persons living with HIV (PWH) with acute stroke, matched by sex and stroke type to HIV uninfected (HIV-) individuals. We collected data on stroke risk factors and fitted logistic regression models for analysis. RESULTS: We enrolled 262 participants:105 PWH and 157 HIV-. The median ART duration was 5 years, and the median CD4 cell count was 214 cells/uL. PWH with ischemic stroke had higher odds of hypertriglyceridemia (AOR 1.63; 95% CI 1.04, 2.55, p=0.03), alcohol consumption (AOR 2.84; 95% CI 1.32, 6.14, p=0.008), and depression (AOR 5.64; 95%CI 1.32, 24.02, p=0.02) while HIV- persons with ischemic stroke were more likely to be > 55 years of age (AOR 0.43; 95%CI 0.20-0.95, p=0.037), have an irregular heart rhythm (AOR 0.31; 95%CI 0.10-0.98, p=0.047) and report low fruit consumption (AOR 0.39; 95%CI 0.18-0.83, p=0.014).  Among all participants with hemorrhagic stroke (n=78) we found no differences in the prevalence of risk factors between PWH and HIV-. CONCLUSIONS: PWH with ischemic stroke in Uganda present at a younger age, and with a combination of traditional and psychosocial risk factors. By contrast, HIV- persons more commonly present with arrhythmia. A differential approach to stroke prevention might be needed in these populations.

Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report.

Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF (N = 39), HIV CSF (N = 79), or other suspected and confirmed neuroinflammatory CSF cases (N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity.

Infectious Meningitis and Encephalitis.

Infectious meningitis and encephalitis are associated with significant morbidity and mortality worldwide. Acute bacterial meningitis is rapidly fatal and early recognition and institution of therapy are imperative. Viral meningitis is typically a benign self-limited illness. Chronic meningitis (defined as presenting with >4 weeks of symptoms) is most often caused by tuberculosis and fungal infection. Because the diagnostic testing for tuberculous meningitis is insensitive and cultures often take weeks to grow, therapy is often initiated empirically when the diagnosis is suspected. Human simplex virus encephalitis is the most common cause of encephalitis and requires prompt treatment with intravenous acyclovir.