Global synergistic actions to improve brain health for human development.

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization's new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022-2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a 'neurological revolution' across four key pillars - surveillance, prevention, acute care and rehabilitation - termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course.

Characterization of adult patients with Guillain-Barré syndrome during the arboviral infection outbreaks in Honduras.

Arbovirus infections have been associated with a wide spectrum of neurological manifestations. Among these, Guillain-Barré syndrome (GBS) is one of the most common. This study describes the characteristics of GBS associated with arbovirus infections during the outbreak which occurred in Honduras from January 2016 to February 2019. This was an observational retrospective study of adult patients who were diagnosed with GBS during that time. The diagnosis of GBS was based upon the criteria first published by Asbury, et al. and subsequently revised as the Brighton Criteria. A total of 91 patients with GBS constituted the study population. RT-PCR tests for ZIKV, CHIKV, and DENV arboviruses were performed in 47 (52%) of the patients. Of the tested population, 8/47 were positive for one of the arboviruses (5/8 for ZIKV, 3/8 for CHIKV; 0/8 for DENV). The clinical profile of the eight cases with GBS and arboviral infection did not differ significantly from the GBS patients who tested negative for ZIKV and CHIKV. In the cases with GBS and ZIKV, a parainfectious onset of the disease was suggested. Although not a strikingly large number of patients with GBS and arbovirus infection were seen, the close temporal relationship in these eight cases suggests an arbovirus (ZIKV and CHIKV) etiology.

Hydroxychloroquine/ chloroquine as a treatment choice or prophylaxis for Covid-19 at the primary care level in developing countries: A Primum non Nocere dilemma.

The Food and Drug Administration (FDA) warned against the use of Hydroxychloroquine or chloroquine for Covid-19 outside of a hospital or a clinical trial setting due to the risk of QT interval prolongation, ventricular tachycardia and the increased risk of these complications when combined with some antibiotics such as azithromycin. Several studies have reported no benefit of Hydroxychloroquine or chloroquine, when used alone or with a macrolide in COVID-19 hospitalized patients. Despite these warnings, in several developing countries the official guidelines for treatment of Covid-19 patients at the primary care level recommend Hydroxychloroquine and azithromycin, among other treatments, as the first-choice for mild symptomatic Covid-19 patients, asymptomatic contacts or for prophylaxis. In our opinion there is a primum non nocere dilemma during this Covid-19 pandemic. In order to solve this bioethical problem, we strongly recommend that a randomized controlled trial in a primary care setting be carried out as a matter of urgency in these areas of the world.

A trauma registry experience from the main referral center of Honduras: A call for action.

BACKGROUND: Honduras is one of the most violent countries in the world and it has limited epidemiological data that describes the extent of intentional and unintentional injuries. This research is needed to develop and inform prevention programs in Honduras, as well as to spread international awareness. METHODS: A cross-sectional study was carried out on a paper-based injury surveillance system (InSS) with the help of Honduras' University Medical School Hospital (UMSH), the main referral medical center in Tegucigalpa-Honduras. Descriptive statistics and bivariate analysis were carried out using data from all registered injuries in 2013. RESULTS: Of the 17,971 injuries reported, intentional injuries made up 18.14% of all injuries. Interpersonal violence from gun violence, robberies, and physical altercations accounted for 14.68%. Self-inflicted injuries made up 3.46% of injuries, with suicide falls and poison intoxications being the most frequent (1.9% and 1.2%, respectively). Sexual harassment was minimally reported (0.27%, n = 48). Unintentional injuries made up 81.79% of the total injuries. The most common causes of unintentional injuries were falls (38.01%) and road traffic injuries (16.65%). Motorocyclists made up 35.4% of those injured by road traffic accidents. In general, injuries occured during the weekend and mainly affected men during the ages when they would be most likely to work and maintain jobs. The modified Kampala trauma score (M-KTS) showed that most of the injuries were mild (range 3-11), with 59.59% of the patients with a M-KTS of 9, and an overall mortality rate of 0.65% (n = 117). CONCLUSION: The description of injuries provides the basis for prevention. The disproportionate number of unintentional injuries (4:1) seen in Honduras' referral hospital calls for further research in: 1) trauma care logistics and emergency systems, 2) mortality and lethality of intentional injuries, and 3) analysis of the types of unintentional injuries. Further research is necessary to evaluate interventions and identify the socioeconomic effects of injuries in the region.

Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy.

BACKGROUND: In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS: Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS: A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS: Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).

New spectrum of the neurologic consequences of Zika.

Zika virus infection represents a new neuropathological agent with association to a wide spectrum of neurological complications: a) Congenital Zika Syndrome by affecting the neural stem cells of the human fetal brain; b) Guillain-Barré Syndrome by an autoimmune response against peripheral myelin and/or axonal components or probable direct inflammatory reaction; c) Encephalitis/meningoencephalitis and myelitis by a direct viral inflammatory process on the central nervous system; d) Sensory neuropathy by infecting directly the peripheral neurons and causing substantial cell death and pathogenic transcriptional dysregulation; e) Acute Disseminated Encephalomyelitis and optic neuropathy; f) Seizures and Epilepsy and g) childhood arterial ischemic stroke by probable inflammatory reaction and endothelial injury.

Clinical Features and Neurologic Complications of Children Hospitalized With Chikungunya Virus in Honduras.

The first case of Chikungunya virus in Honduras was identified in 2014. The virus has spread widely across Honduras via the Aedes aegypti mosquito, leading to an outbreak of Chikungunya virus (CHIKV) in 2015 that significantly impacted children. A retrospective chart review of 235 children diagnosed with CHIKV and admitted to the National Autonomous University of Honduras Hospital Escuela (Hospital Escuela) in Tegucigalpa, Honduras, was accomplished with patients who were assessed for clinical features and neurologic complications. Of 235 children admitted to Hospital Escuela with CHIKV, the majority had symptoms of fever, generalized erythematous rash, and irritability. Fourteen percent had clinical arthritis. Ten percent of patients had seizures. Six percent had meningoencephalitis. There were 2 childhood deaths during the course of this study, one from meningoencephalitis and another from myocarditis. Chikungunya virus can cause severe complications in children, the majority of which impact the central nervous system.

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality.

PURPOSE: EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. METHODS: We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. RESULTS: Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. CONCLUSIONS: NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.

Estimating and mapping the incidence of dengue and chikungunya in Honduras during 2015 using Geographic Information Systems (GIS).

Geographical information systems (GIS) use for development of epidemiological maps in dengue has been extensively used, however not in other emerging arboviral diseases, nor in Central America. Surveillance cases data (2015) were used to estimate annual incidence rates of dengue and chikungunya (cases/100,000 pop) to develop the first maps in the departments and municipalities of Honduras. The GIS software used was Kosmo Desktop 3.0RC1®. Four thematic maps were developed according departments, municipalities, diseases incidence rates. A total of 19,289 cases of dengue and 85,386 of chikungunya were reported (median, 726 cases/week for dengue and 1460 for chikungunya). Highest peaks were observed at weeks 25th and 27th, respectively. There was association between progression by weeks (p<0.0001). The cumulated crude national rate was estimated in 224.9 cases/100,000 pop for dengue and 995.6 for chikungunya. The incidence rates ratio between chikungunya and dengue is 4.42 (ranging in municipalities from 0.0 up to 893.0 [San Vicente Centenario]). Burden of both arboviral diseases is concentrated in capital Central District (>37%, both). Use of GIS-based epidemiological maps allow to guide decisions-taking for prevention and control of diseases that still represents significant issues in the region and the country, but also in emerging conditions.

The Pan-American Federation of Neurological Societies (PAFNS): A New Regional Organization.

The Pan-American Federation of Neurological Societies (PAFNS) was created on 15 November 2011 during the 20th World Congress of Neurology in Marrakech by virtue of the "Declaration of Morocco" signed by the WFN Latin American delegates and ratified on 5 March 2012 by delegates attending the 13th Pan-American Congress of Neurology in La Paz, Bolivia. On 20 March 2013 delegates attending the 65th Annual Meeting of the American Academy of Neurology in San Diego, California, USA, gave formal approval to the PAFNS Constitution. The neurological societies from the following countries have approved and signed the constitution as founding members and active ordinary members: Argentina, Brazil, Bolivia, Chile, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Puerto Rico, Uruguay, and Venezuela. The Ibero-American Stroke Society (SIECV), the Commission on Latin American Affairs of the International League Against Epilepsy (ILAE) and the World Sleep Society have requested the status of Associate Members. The WFN and the American Academy of Neurology provided seed grants for the creation of the Pan-American Federation of Neurological Societies. PAFNS represents a major step for the improvement of regional neurological care, education and research.

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5-6.0 Hz polyspike waves.

Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5-6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two-point parametric linkage analyses were performed with 5185 single-nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2-q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage (Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3-q31.2 (Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease-causing genes, favoring the concept of JME as several distinct diseases. Whole-exome sequencing will likely identify a CAE/JME gene in 2q21.2-2q31.1, a JME/pA gene in 13q13.3-q31.2, and a cJME gene in 17q12.

ICD coding for epilepsy: past, present, and future--a report by the International League Against Epilepsy Task Force on ICD codes in epilepsy.

The World Health Organization (WHO) International Classification of Diseases (ICD) has been used to classify causes of morbidity and mortality such as epilepsy for more than 50 years. The aims of this critical commentary are to do the following: (1) Introduce the ICD classification, summarize the ICD-9 and ICD-10 codes for epilepsy and seizures, and discuss the challenges of mapping epilepsy codes between these two versions; (2) discuss how the ICD-9 and ICD-10 relate to the revised International League Against Epilepsy (ILAE) terminology and concepts for classification of seizures and epilepsies; (3) discuss how ICD-coded data have been used for epilepsy care and research and briefly examine the potential impact of the international ICD-10 clinical modifications on research; (4) discuss the upcoming ICD-11 codes and the role of the epilepsy community in their development; and (5) discuss how the ICD-11 will conform more closely to the current ILAE terminology and classification of the epilepsies and seizures and its potential impact on clinical care, surveillance, and public health and research.

In memoriam of Professor Theodore L. Munsat (1930-2013): his outstanding legacy with the WFN.

The World Federation of Neurology (WFN) lost an outstanding leader on November 22, 2013 with the death of Professor Theodore Leon Munsat ("Ted"), in Waltham, Massachusetts, USA. Professor Munsat was Emeritus professor of Neurology at Tufts University School of Medicine and served the WFN in several capacities as trustee, chairman of the WFN Education and research committees, chairman of the WFN ALS Research group and founding director of the WFN Seminars in Clinical Neurology. He was president of the American Academy of Neurology (AAN), 1989-1991, chairman of the Continuing Educational Committee of the AAN and founding director of AAN's premier continuing medical education journal Continuum: Lifelong Learning in Neurology. He left an outstanding legacy with the WFN.

The quest for juvenile myoclonic epilepsy genes.

Introduced into a specific population, a juvenile myoclonic epilepsy (JME) mutation generates linkage disequilibrium (LD). Linkage disequilibrium is strongest when the JME mutation is of recent origin, still "hitchhiking" alleles surrounding it, as a haplotype into the next thousands of generations. Recombinations decay LD over tens of thousands of generations causing JME alleles to produce smaller genetic displacements, requiring other genes or environment to produce an epilepsy phenotype. Family-based linkage analysis captures rare epilepsy alleles and their "hitchhiking" haplotypes, transmitted as Mendelian traits, supporting the common disease/multiple rare allele model. Genome-wide association studies identify JME alleles whose linkage disequilibrium has decayed through thousands of generations and are sorting out the common disease/common allele versus rare allele models. Five Mendelian JME genes have been identified, namely, CACNB4, CASR, GABRa1, GABRD, and Myoclonin1/EFHC1. Three SNP alleles in BRD2, Cx-36, and ME2 and microdeletions in 15q13.3, 15q11.2, and 16p13.11 also contribute risk to JME.

Consensus on diagnosis and management of JME: From founder's observations to current trends.

An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

Revising the ICD-10 codes for epilepsy and seizures.

The World Health Organization is currently revising the International Classification of Disease, 10th Revision (ICD-10). A Neurology Task Force Advisory Group [TAG] has been charged with producing a revision that reflects scientific advances and new concepts of pathophysiology since 1992. The ICD codes are used globally to report mortality and morbidity statistics, and they play a vital role in health care planning, training, and allocation of health care resources in many countries. Although used by physicians and hospitals at all levels, the primary users of the ICD codes are primary health care providers, which, particularly in low income countries, include nurses, clinical assistants, and health officers. The TAG, which consists of representatives of major international subspecialty groups such as the International League Against Epilepsy (ILAE), has published draft codes that are available online for public comment.