Climate change and disorders of the nervous system.

Anthropogenic climate change is affecting people's health, including those with neurological and psychiatric diseases. Currently, making inferences about the effect of climate change on neurological and psychiatric diseases is challenging because of an overall sparsity of data, differing study methods, paucity of detail regarding disease subtypes, little consideration of the effect of individual and population genetics, and widely differing geographical locations with the potential for regional influences. However, evidence suggests that the incidence, prevalence, and severity of many nervous system conditions (eg, stroke, neurological infections, and some mental health disorders) can be affected by climate change. The data show broad and complex adverse effects, especially of temperature extremes to which people are unaccustomed and wide diurnal temperature fluctuations. Protective measures might be possible through local forecasting. Few studies project the future effects of climate change on brain health, hindering policy developments. Robust studies on the threats from changing climate for people who have, or are at risk of developing, disorders of the nervous system are urgently needed.

Risk-conferring HLA variants in an epilepsy cohort: benefits of multifaceted use of whole genome sequencing in clinical practice.

BACKGROUND: Whole genome sequencing is increasingly used in healthcare, particularly for diagnostics. However, its clinically multifaceted potential for individually customised diagnostic and therapeutic care remains largely unexploited. We used existing whole genome sequencing data to screen for pharmacogenomic risk factors related to antiseizure medication-induced cutaneous adverse drug reactions (cADRs), such as human leucocyte antigen HLA-B*15:02, HLA-A*31:01 variants. METHODS: Genotyping results, generated from the Genomics England UK 100 000 Genomes Project primarily for identification of disease-causing variants, were used to additionally screen for relevant HLA variants and other pharmacogenomic variants. Medical records were retrospectively reviewed for clinical and cADR phenotypes for HLA variant carriers. Descriptive statistics and the χ2 test were used to analyse phenotype/genotype data for HLA carriers and compare frequencies of additional pharmacogenomic variants between HLA carriers with and without cADRs, respectively. RESULTS: 1043 people with epilepsy were included. Four HLA-B*15:02 and 86 HLA-A*31:01 carriers were identified. One out of the four identified HLA-B*15:02 carriers had suffered antiseizure medication-induced cADRs; the point prevalence of cADRs was 16.9% for HLA-A*31:01 carriers of European origin (n=46) and 14.4% for HLA-A*31:01 carriers irrespective of ancestry (n=83). CONCLUSIONS: Comprehensive utilisation of genetic data spreads beyond the search for causal variants alone and can be extended to additional clinical benefits such as identifying pharmacogenomic biomarkers, which can guide pharmacotherapy for genetically-susceptible individuals.

Taking action on climate change: Testimonials and position statement from the International League Against Epilepsy Climate Change Commission.

The release of the 2021 Intergovernmental Panel on Climate Change (IPCC) report makes clear that human activities have resulted in significant alterations in global climate. There is no doubt that climate change is upon us; chronic global warming has been punctuated by more frequent extreme weather events. Humanity will have to mitigate climate change and adapt to these changing conditions or face dire consequences. One under-appreciated aspect of this global crisis is its impact on healthcare, particularly people with epilepsy and temperature-sensitive seizures. As members of the inaugural International League Against Epilepsy (ILAE) Climate Change Commission, we recount the personal motivations that have led each team member to decide to take action, in the hope that our journeys as ordinary clinicians and scientists will help persuade others that they too can act to foster change within their spheres of influence.

Climate change and epilepsy: Insights from clinical and basic science studies.

Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.

The effect of serum levetiracetam concentrations on therapeutic response and IL1-beta concentration in patients with epilepsy.

OBJECTIVE: Assessment of the relevance between serum drug concentration to its therapeutic response is a valid monitoring strategy for the clinical efficacy of antiepileptic drugs (AEDs). Levetiracetam (LEV) is a broad spectrum AED with a possible anti-inflammatory effect. We aimed to determine the relationship between LEV concentrations and its therapeutic response, and the effect of LEV on IL1-beta concentrations in patients with epilepsy. METHODS: Patients on monotherapy (n = 7) or polytherapy (n = 15) with LEV for their seizures management were included. Blood samples of each patient were collected: just before LEV intake, 1 h, 2 h, 4 h and 8 h following the last dose. Serum LEV concentrations were measured by liquid chromatography mass spectrometry and IL1-beta concentrations by chemiluminescent immunometric assay. Concentration to dose (C/D) ratio values was used for analyses. LEV concentrations were compared between responders (≤1 seizure/month) and non-responders (>1 seizure/month) and patients with or without adverse reactions. IL1-beta concentrations before and at 2 h following LEV ingestion were compared in order to detect the effect of the increase in serum LEV concentration on IL1-beta. RESULTS: Although there was no change in LEV (C/D) ratio or LEV maximum concentration (Cmax)/D ratio of the responders and non-responders, the C/D ratio following 1 h of LEV intake (2.17 ± 0.59 kg.day/L) and Cmax/D ratio (2.25 ± 0.56 kg.day/L) in the patients with adverse effects was significantly higher than for the patients without adverse effects (1.09 ± 0.12 kg.day/L and 1.49 ± 0.14 kg.day/L respectively). A statistically significant decrease was found in the IL1-beta concentration to LEV (C/D) ratio with the increase in LEV concentration in patients on LEV monotherapy. CONCLUSION: The possible relationship between LEV Cmax and its therapeutic response or IL1-beta concentrations may be an importance indication of LEV antiepileptic efficacy. Consequently, monitoring LEV Cmax values may enhance LEV adherence because patients would be less likely to develop adverse effects.

The role of the substantia nigra pars reticulata in kindling resistance in rats with genetic absence epilepsy.

OBJECTIVE: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) show a resistance to secondary generalization of focal limbic seizures evoked by kindling. The substantia nigra pars reticulata (SNR) is involved in the propagation and modulation of seizures in kindling. We first examined the role of the SNRanterior and SNRposterior subregions in the resistance to the development of kindling in GAERS. Subsequently, to determine whether kindling resistance relates to differential sensitivity of γ-aminobutyric acid γ-aminobutyric acid (GABA)ergic or dopaminergic SNR neurons to kindling, we studied the effects of kindling-inducing stimulations on parvalbumin (PRV; GABAergic neuron marker) or tyrosine hydroxylase (TH; dopaminergic neuron marker) immunoreactivity (ir), respectively, in GAERS and in nonepileptic control (NEC) Wistar rats that lack kindling resistance. METHODS: Adult male GAERS were implanted with a stimulation electrode in the amygdala, and bilateral injection cannulas for lidocaine or saline injection (30 min before each kindling stimulation until the animals reached three stage 5 seizures or the 22 stimulations) into the SNRanterior or SNRposterior . In another experiment, PRV-ir in SNRanterior and SNRposterior and TH-ir in SNRposterior only were densitometrically compared in GAERS-SHAM, NEC-SHAM GAERS-STIM, and NEC-STIM animals (6 kindling stimulations). RESULTS: Bilateral SNRposterior infusions of lidocaine eliminated the kindling resistance and resulted in stage 5 generalized motor seizures in all kindled rats. Bilateral lidocaine infusions in the SNRanterior failed to alter the kindling resistance in GAERS. PRV-ir in the SNRposterior was unaltered in GAERS-STIM but increased in NEC-STIM group. Cellular TH-ir in the SNRposterior significantly increased by kindling stimulations in both NEC-STIM and GAERS-STIM groups. SIGNIFICANCE: The kindling resistance in GAERS is mediated by the SNRposterior in a lidocaine-sensitive manner. The insensitivity to kindling stimulation of PRV-ir in SNRposterior of GAERS but not NEC rats, implicate GABAergic SNRposterior neurons in kindling resistance. In contrast, the observed stimulation-specific increase in TH-ir in the SNRposterior is unrelated to kindling resistance.