Nicoline Schiess

Neurological sequelae from acute meningitis are estimated to affect more than 30% of survivors worldwide, though often underreported or undetected due to i

Acute bacterial meningitis (ABM) is a life-threatening condition requiring prompt antibiotic administration to reduce mortality and neurological sequelae.

GJC2 encodes connexin 47 (Cx47), a gap junction protein expressed by oligodendrocytes that forms gap junction channels (GJCs) between adjacent oligodendrocytes (or astrocytes, via heterotypic Cx47–Cx43 GJCs). Autosomal recessive mutations of GJC2 lead to at least three central nervous system phenotypes: Pelizaeus–Merzbacher-like disease 1 (PMLD1), spastic paraparesis 44 (SPG44), and a minimal leukodystrophy. Here, we describe the clinical, functional, and molecular effects of two mutations in GJC2, p.G40S, and p.R244P, identified in two different families with GJC2-related disorders. Expressed exogenously, p.G40S forms GJC plaques like WT but does not functionally couple with WT nor with Cx43. p.R244P also fails to demonstrate functional coupling. Moreover, plaque formation is absent, concomitant with intracellular connexin accumulation. When the two mutants are co-expressed in a compound heterozygous state, plaques form, but no GJC coupling is detected in any configuration. MD simulations demonstrate that p.G40S modifies secondary structure of the pore-lining α-helix, disrupting supersecondary interactions with the N-terminal helix and predicting channel closure. p.R244P simulations are characterized by partial loss of the extracellular β-sheet domains and a marked reduction of electrostatic interactions between the connexin and lipid headgroups of the plasma membrane, suggesting pathways by which p.R244P mutation impairs GJC formation. This combination of in vitro assays and molecular simulations provides mechanistic insight into the pathogenesis of GJC2-related disease.

Objective: Use a modified Delphi approach to develop competencies for neurologists completing >1 year of advanced global neurology training. Methods: An expert panel of 19 US-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, US-based neurologists participated in three 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 seven 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 US-based experts, and a semi-structured questionnaire and focus group discussion with LMIC experts were utilized to discuss and reach consensus on the final competencies. This resulted in a competency framework consisting of 47 competencies across eight domains: (1) Cultural Context, Social Determinants of Health and Access to Care; (2) Clinical and Teaching Skills and Neurological Medical Knowledge; (3) Team-Based Practice; (4) Developing Global Neurology Partnerships; (5) Ethics; (6) Approach to Clinical Care; (7) Community Neurological Health; (8) Health Care Systems and Multinational Health Care Organizations. Conclusions: 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.

The Global Burden of Disease study identified Parkinson disease (PD) as the fastest growing neurological disorder between 1990 and 2016 in terms of death and disability. This calculation was based on a global study with estimates of prevalence, deaths, and disability-adjusted life-years (DALYs) in 195 countries and territories.¹ Current estimates suggest that in 2019, PD resulted in 5.8 million DALYs, increasing by 81% since 2000. Moreover, it is estimated that PD caused 329 000 deaths in 2019, an increase of more than 100% since 2000 (Figure 1).²

Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3–4 weeks before onset of vaccine meningitis may be a risk factor in some cases.

The burden, impact, and social and economic costs of neurological sequelae following meningitis can be devastating to patients, families and communities. An acute inflammation of the brain and spinal cord, meningitis results in high mortality rates, with over 2.5 million new cases of bacterial meningitis and over 236,000 deaths worldwide in 2019 alone. Up to 30% of survivors have some type of neurological or neuro-behavioural sequelae. These include seizures, hearing and vision loss, cognitive impairment, neuromotor disability and memory or behaviour changes. Few studies have documented the long-term (greater than five years) consequences or have parsed out whether the age at time of meningitis contributes to poor outcome. Knowledge of the socioeconomic impact and demand for medical follow-up services among these patients and their caregivers is also lacking, especially in low- and middle-income countries (LMICs). Within resource-limited settings, the costs incurred by patients and their families can be very high. This review summarises the available evidence to better understand the impact and burden of the neurological sequelae and disabling consequences of bacterial meningitis, with particular focus on identifying existing gaps in LMICs.

This article was migrated. The article was marked as recommended. Background: Ample data demonstrates that sleep deprivation leads to impaired functioning including cognitive performance, memory and fine motor skills. Medical students represent a professional sector in which optimizing cognitive performance and functioning is critical from a personal, public health and safety perspective. Aims: To characterize chronotypes of an international cohort of medical students and determine if chronotype is affected by demographics or latitude. Samples: 328 students from medical schools in the United States (US), Malaysia and United Arab Emirates (UAE) were assessed for differences in chronotype and sleep habits. Methods: A cross-sectional, questionnaire-based study from medical schools in the US, Malaysia and UAE between 2013 and 2015. Results: There was a significant difference in mean waking times for Malaysian students who reported awakening earlier than US or UAE students. Malaysian students were most likely to feel their best earlier in the day and consider themselves a "morning type." UAE students were more likely to do "hard physical work" later in the day, followed by US and Malaysian. On average, US students were less likely to shift their bedtime later if they had no commitments the next day. Overall, mean chronotype score was "neither" type for all three groups however the Malaysian group showed a significant preference for morning hours in some individual questions. Conclusion: Medical student sleep patterns vary internationally but chronotype may not. Improving sleep education globally, with awareness of the effects of chronotype, could ultimately result in improved sleep awareness, potentially influencing physician wellbeing, patient care and safety.