Cognitive impairment in people living with HIV: consensus recommendations for a new approach.

Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury - including active or pretreatment legacy damage - from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies.

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.

Associations of the COVID-19 pandemic with quality of life: A cross-sectional study of older-age people with and without HIV in rural Uganda.

Background: COVID-19-related lockdowns and other public health measures may have differentially affected the quality of life (QOL) of older people with and without human immunodeficiency virus (HIV) in rural Uganda. Methods: The Quality of Life and Aging with HIV in Rural Uganda study enrolled people with and without HIV aged over 49 from October 2020 to October 2021. We collected data on COVID-19-related stressors (behavior changes, concerns, interruptions in health care, income, and food) and the participants' QOL. We used linear regression to estimate the associations between COVID-19-related stressors and QOL, adjusting for demographic characteristics, mental and physical health, and time before vs after the lockdown during the second COVID-19 wave in Uganda. Interaction between HIV and COVID-19-related stressors evaluated effect modification. Results: We analyzed complete data from 562 participants. Mean age was 58 (standard deviation (SD) = 7); 265 (47%) participants were female, 386 (69%) were married, 279 (50%) had HIV, and 400 (71%) were farmers. Those making ≥5 COVID-19-related behavior changes compared to those making ≤2 had worse general QOL (estimated linear regression coefficient (b) = - 4.77; 95% confidence interval (CI) = -6.61, -2.94) and health-related QOL (b = -4.60; 95% CI = -8.69, -0.51). Having access to sufficient food after the start of the COVID-19 pandemic (b = 3.10, 95% CI = 1.54, 4.66) and being interviewed after the start of the second lockdown (b = 2.79, 95% CI = 1.30, 4.28) were associated with better general QOL. Having HIV was associated with better health-related QOL (b = 5.67, 95% CI = 2.91,8.42). HIV was not associated with, nor did it modify the association of COVID-19-related stressors with general QOL. Conclusions: In the context of the COVID-19 pandemic in an HIV-endemic, low-resource setting, there was reduced QOL among older Ugandans making multiple COVID-19 related behavioral changes. Nonetheless, good QOL during the second COVID-19 wave may suggest resilience among older Ugandans.

Gender Disparities in the Career of Neurology Researchers.

BACKGROUND AND OBJECTIVES: To assess gender disparities in neurology researcher careers in the United States. METHODS: A 34-question survey was distributed to 4,644 US-based American Academy of Neurology members who self-identified as researchers in 2020 addressing the following domains: research and funding, scholarly activities, coronavirus disease 2019 (COVID-19) effect, and local institutional climate. RESULTS: A total of 700 (15%) individuals completed the survey (women, n = 231; men, n = 426), with 71% White and >80% conducting research. Women respondents were significantly younger than men, more likely to be assistant professors (32% vs 21%), and less likely to be full professors (18% vs 39%). Compared with men, women received equivalent grants and research support and had comparable or additional formal research training and mentorship. Women had less middle author publications (mean 5.8 [SD 9.2] vs mean 8.2 [SD 11.8], p = 0.03) compared with men but similar first or last author publications (mean 4.3[5.4] vs 6.1 [9.8], p = 0.05). A lower proportion of women presented research at grand rounds or at a national/international conference compared with men (58% vs 69%, p = 0.01). Women spent more time in nonprofessional responsibilities, were less satisfied with their work-life balance, and were less likely to agree with statements addressing equity/diversity and institutional climate. Respondents shared their concerns regarding how the pandemic was affecting neurology research careers, with a higher proportion of women reporting that family responsibilities affected research activities and lead to delayed submission of non-COVID-19-related manuscripts. DISCUSSION: Our survey of US-based neurology researchers demonstrated continued gender-based disparities in academic rank, manuscript authorship, and invited speaking engagements, although funding opportunities and access to additional training were equivalent. Women were less likely than men to agree that neurology departments support diversity and equity and that the institutional climate was inclusive and transparent. The pandemic had affected both genders in research, but areas were different for women related to family responsibilities. This article also highlights additional areas of research and areas for intervention to improve and reduce gender disparities among neurology researchers.

Need to Revise Frascati Criteria for HIV-Associated Neurocognitive Disorders to Improve Relevance for Diverse Global Populations.

Worldwide, cognitive impairment is a frequent complication of HIV, and few treatments are available. Existing diagnostic criteria for cognitive disorders associated with HIV have limited diagnostic accuracy, hampering biomarker and therapeutic development. Furthermore, these criteria are not linked to clinically meaningful outcomes, limiting utility in clinical settings. Limitations in diagnostic accuracy are most pronounced in resource-limited settings where the burden of HIV is greatest, largely because of heavy reliance on neuropsychological testing with limited cross-cultural validity. Accurate and clinically meaningful diagnostic criteria validated in diverse populations will improve research and clinical care for cognitively impaired people living with HIV globally.

Priorities for health and wellbeing for older people with and without HIV in Uganda: a qualitative methods study.

INTRODUCTION: With improved HIV treatment availability in sub-Saharan Africa, the population of older people with HIV (PWH) is growing. In this qualitative study, we intended to understand (1) the lived experiences of ageing people in rural Uganda, with and without HIV, (2) their fears and health priorities as they grow older. METHODS: We conducted 36 semi-structured interviews with individuals with and without HIV in Mbarara, Uganda from October 2019 to February 2020. Interview guide topics included priorities in older age, physical functioning in daily activities, social functioning, HIV-related stigma and the impact of multimorbidity on health and independence. Interviews were conducted in Runyankole, transcribed, translated and inductively coded thematically by two researchers with tests for inter-coder reliability. RESULTS: The respondents were purposively sampled to be evenly divided by sex and HIV serostatus. The median age of respondents was 57 (49-73). Two-thirds were married or cohabitating, 94% had biological children and 75% cited farming as their primary livelihood. Overall, PWH considered themselves as healthy or healthier than people without HIV (PWOH). PWH rarely considered their HIV status a barrier to a healthy life, but some reported a constant sense of anxiety as it relates to their long-term health. Irrespective of HIV status, nearly all respondents noted concerns about memory loss, physical pain, reductions in energy and the effect of these changes on their ability to complete physical tasks like small-scale farming, and activities of daily living important to the quality of life, such as participating in community groups. Increasing reliance on others for social, physical and financial support was also a common theme. The most prevalent health concern among participants involved the threat of non-communicable diseases and perceptions that physical functioning may diminish. CONCLUSIONS: In rural Uganda, we found that PWH consider themselves to be healthy and do not anticipate a different ageing experience from PWOH. Common priorities shared by both groups included the desire for physical and financial independence, health maintenance and social support for daily functioning and social needs. Entities supporting geriatric care in Uganda would benefit from attention to concerns about functional limitations and reported needs as people age with and without HIV.

Neuroimmunology of CNS HIV Infection: A Narrative Review.

This short review provides an overview of the interactions of human immunodeficiency virus type 1 (HIV), immune and inflammatory reactions, and CNS injury over the course of infection. Systemic infection is the overall driver of disease and serves as the "platform" for eventual CNS injury, setting the level of immune dysfunction and providing both the HIV seeding and immune-inflammatory responses to the CNS. These systemic processes determine the timing of and vulnerability to HIV-related neuronal injury which occurs in a separate "compartment" with features that parallel their systemic counterparts but also evolve independently. Direct CNS HIV infection, along with opportunistic infections, can have profound neurological consequences for the infected individual. HIV-related CNS morbidities are of worldwide importance but are enhanced by the particular epidemiological, socioeconomic and environmental factors that heighten the impact of HIV infection in Africa.

Epidemiology, patterns of care and outcomes of traumatic brain injury in deployed military settings: Implications for future military operations.

BACKGROUND: Traumatic brain injury (TBI) is prevalent and highly morbid among Service Members. A better understanding of TBI epidemiology, outcomes, and care patterns in deployed settings could inform potential approaches to improve TBI diagnosis and management. METHODS: A retrospective cohort analysis of Service Members who sustained a TBI in deployed settings between 2001 and 2018 was conducted. Among individuals hospitalized with TBI, we compared the demographic characteristics, mechanism of injury, injury type, and severity between combat and noncombat injuries. We compared diagnostic tests and procedures, evacuation patterns, return to duty rates and days in care between individuals with concussion and those with severe TBI. RESULTS: There were 46,309 service members with TBI and 9,412 who were hospitalized; of those hospitalized, 55% (4,343) had isolated concussion and 9% (796) had severe TBI, of whom 17% (132/796) had multiple injuries. Overall mortality was 2% and ranged from 0.1% for isolated concussion to 18% for severe TBI. The vast majority of TBI were evacuated by rotary wing to role 3 or higher, including those with isolated concussion. As compared with severe TBI, individuals with isolated concussion had fewer diagnostic or surgical procedures performed. Only 6% of service members with severe TBI were able to return to duty as compared with 54% of those with isolated concussion. Traumatic brain injury resulted in 123,677 lost duty days; individuals with isolated concussion spent a median of 2 days in care and those with severe TBI spent a median of 17 days in care and a median of 6 days in the intensive care unit. CONCLUSION: While most TBI in the deployed setting are mild, TBI is frequently associated with hospitalization and multiple injuries. Overtriage of mild TBI is common. Improved TBI capabilities applicable to forward settings will be critical to the success of future multidomain operations with limitations in air superiority. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.

Prevalence of Epilepsy, Human Cysticercosis, and Porcine Cysticercosis in Western Kenya.

Cysticercosis is the leading cause of acquired epilepsy worldwide and has been shown to be highly prevalent in pig populations in western Kenya. We conducted a community-based door-to-door survey in a region of western Kenya with a high proportion of pig-keeping households. Persons with epilepsy (PWE) were determined using a screening questionnaire followed by a neurologist evaluation. Cysticercosis serum apDia antigen ELISAs and Western blot for LLGP and rT24h antigen were performed on all PWE and 2% of screen-negative patients. All PWE or people with positive apDia underwent contrast-enhanced brain computed tomography (CT). Of a sample of 810 village residents, 660 (81%) were present in the homestead, of whom 648 (98%) participated. Of these, 17 were confirmed to have lifetime epilepsy, an estimated crude prevalence of 2.6%. No humans with (N = 17) or without (N = 12) epilepsy had serological evidence of cysticercosis infection. Fourteen PWE and one individual with borderline positive apDia antigen ELISA underwent brain CT; none had radiographic findings consistent with neurocysticercosis. Nearly 30% of households kept pigs, with 69% always tethered in both wet and dry seasons. More than 8% (6/72) of pigs had palpable lingual cysts; these pigs all originated from homesteads with latrines, one-third of which were free-ranging at least some of the time. Epilepsy prevalence in our study was greater than the national prevalence, but we found no individuals with epilepsy attributable to cysticercosis. Additional studies are required to identify causes of epilepsy, human and porcine cysticercosis, the role of spatial clustering, and protective factors like host-pathogen immunity.

Epidemiology of non-traumatic spinal cord injury in Uganda: a single center, prospective study with MRI evaluation.

BACKGROUND: A few reliable national data concerning the etiology of non-traumatic spinal cord injury (SCI) in sub-Sahara Africa exists, mainly because of the limitations of diagnostic imaging. These are both expensive and mostly unavailable in several resource-limited settings. Only a few studies have employed the magnetic resonance imaging (MRI) in documenting non-traumatic SCI and most of these studies are from South Africa. We sought to describe the clinical presentation, MRI radiological patterns, and one-year survival among subjects with non-traumatic SCI in Uganda. METHODS: We enrolled a prospective cohort of 103 participants with non-traumatic SCI at Mulago National Referral Hospital Kampala, Uganda in 2013-2015. Participants received standard of care management, with surgical intervention as needed, with one-year follow up. Data were analyzed using Descriptive statistics. RESULTS: In 103 participants with non-traumatic SCI, the median (IQR) age was 37 (18, 85) years and 25% of the participants were HIV-infected. Paraplegia/paraparesis was the most common clinical presentation in 70% (n = 72). Severe disease was present in 82% (n = 85) as per American Spinal Injury Association (ASIA) scale A-C. On MRI, 50% had extradural lesions. However, bone lesions accounted for only 75% of all the extradural lesions. More than 60% of the patients had lesions that could only be diagnosed on MRI. Deaths occurred in 42% (n = 44) of participants, with the highest mortality among those with extradural lesions (60%). CONCLUSION: The mortality following non-traumatic spinal cord injuries in Uganda is high. We demonstrated an equal distribution between extradural and intradural lesions, which differs from the historical predominance of extradural lesions. Increased utilization of MRI particularly among young age groups is needed to make a diagnosis.

A Systematic Review of Non-Traumatic Spinal Cord Injuries in Sub-Saharan Africa and a Proposed Diagnostic Algorithm for Resource-Limited Settings.

BACKGROUND: Non-traumatic myelopathy is common in Africa and there are geographic differences in etiology. Clinical management is challenging due to the broad differential diagnosis and the lack of diagnostics. The objective of this systematic review is to determine the most common etiologies of non-traumatic myelopathy in sub-Saharan Africa to inform a regionally appropriate diagnostic algorithm. METHODS: We conducted a systemic review searching Medline and Embase databases using the following search terms: "Non traumatic spinal cord injury" or "myelopathy" with limitations to epidemiology or etiologies and Sub-Saharan Africa. We described the frequencies of the different etiologies and proposed a diagnostic algorithm based on the most common diagnoses. RESULTS: We identified 19 studies all performed at tertiary institutions; 15 were retrospective and 13 were published in the era of the HIV epidemic. Compressive bone lesions accounted for more than 48% of the cases; a majority were Pott's disease and metastatic disease. No diagnosis was identified in up to 30% of cases in most studies; in particular, definitive diagnoses of non-compressive lesions were rare and a majority were clinical diagnoses of transverse myelitis and HIV myelopathy. Age and HIV were major determinants of etiology. CONCLUSION: Compressive myelopathies represent a majority of non-traumatic myelopathies in sub-Saharan Africa, and most were due to Pott's disease. Non-compressive myelopathies have not been well defined and need further research in Africa. We recommend a standardized approach to management of non-traumatic myelopathy focused on identifying treatable conditions with tests widely available in low-resource settings.

Nervous system disorders across the life course in resource-limited settings.

The resiliency of the adult nervous system is markedly affected by the environment and the circumstances during infant and child development. As such, adults in resource-limited settings who may have experienced early deprivation are particularly vulnerable to subsequent neurological disorders. Adult populations in countries with relatively recent advances in economic development may still have a higher susceptibility to neurological illness or injury that is reflective of the socioeconomic environment that was present during that population's infancy and childhood. Brain and peripheral nervous system research conducted over the past decade in resource-limited settings has led to an impressive and growing body of knowledge that informs our understanding of neurological function and dysfunction, independent of geography. Neurological conditions feature prominently in the burgeoning epidemic of non-communicable diseases facing low- and middle-income countries. Neurological research in these countries is needed to address this burden of disease. Although the burden of more prevalent and severe neurological disease poses public health and clinical challenges in settings with limited neurological expertise, the same factors, along with genetic heterogeneity and the relative absence of ingrained clinical care practices, offer circumstances well-suited for the conduct of crucial future research that is globally relevant.

Neurology and the Global HIV Epidemic.

The vast majority of people living with human immunodeficiency virus (HIV) infection reside in resource-limited settings. As compared with resource-rich settings, there are important differences in the epidemiology and outcomes of HIV infection in resource-limited settings. Nonetheless, little HIV neurology research occurs in these regions. We will first review clinical, epidemiological, and translational HIV neurology research originating from resource-limited settings. We will then discuss the barriers to conducting neurologic research, such as limited human resources, diagnostics, and access to medications. Finally, we will review existing initiatives to build capacity for research in resource-limited settings. Despite the barriers, there is growing interest in and opportunities for collaborative international neurologic research. Including diverse viral and human populations from across the globe in research opens possibilities for important implementation science, clinically oriented science, and basic science discoveries.

Is it time to rethink how neuropsychological tests are used to diagnose mild forms of HIV-associated neurocognitive disorders? Impact of false-positive rates on prevalence and power.

BACKGROUND: Between 0 and 48% of normal HIV-uninfected individuals score below threshold neuropsychological test scores for HIV-associated neurocognitive disorders (HAND) or are false positives. There has been little effort to understand the effect of varied interpretations of research criteria for HAND on false-positive frequencies, prevalence and analytic estimates. METHODS: The proportion of normal individuals scoring below Z score thresholds drawn from research criteria for HAND, or false-positive frequencies, was estimated in a normal Kenyan population and a simulated normal population using varied interpretations of research criteria for HAND. We calculated the impact of false-positive frequencies on prevalence estimates and statistical power. RESULTS: False-positive frequencies of 2-74% were observed for asymptomatic neurocognitive impairment/mild neurocognitive disorder and 0-8% for HIV-associated dementia. False-positive frequencies depended on the definition of an abnormal cognitive domain, Z score thresholds and neuropsychological battery size. Misclassification led to clinically important overestimation of prevalence and dramatic decreases in power. CONCLUSIONS: Minimizing false-positive frequencies is critical to decrease bias in prevalence estimates and minimize reductions in power in studies of association, particularly for mild forms of HAND. We recommend changing the Z score threshold to ≤-1.5 for mild impairment, limiting analysis to 3-5 cognitive domains and using the average Z score to define an abnormal domain.