Summary The burden of comorbidity in people with epilepsy is high. Several diseases, including depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis are up to eight ...times more common in people with epilepsy than in the general population. Several mechanisms explain how epilepsy and comorbidities are associated, including shared risk factors and bidirectional relations. There is a pressing need for new and validated screening instruments and guidelines to help with the early detection and treatment of comorbid conditions. Preliminary evidence suggests that some conditions, such as depression and migraine, negatively affect seizure outcome and quality of life. Further investigation is needed to explore these relations and the effects of targeted interventions. Future advances in the investigation of the comorbidities of epilepsy will strengthen our understanding of epilepsy and could play an important part in stratification for genetic studies.
Precision medicine in the epilepsies has gathered much attention, especially with gene discovery pushing forward new understanding of disease biology. Several targeted treatments are emerging, some ...with considerable sophistication and individual‐level tailoring. There have been rare achievements in improving short‐term outcomes in a few very select patients with epilepsy. The prospects for further targeted, repurposed, or novel treatments seem promising. Along with much‐needed success, difficulties are also arising. Precision treatments do not always work, and sometimes are inaccessible or do not yet exist. Failures of precision medicine may not find their way to broader scrutiny. Precision medicine is not a new concept: It has been boosted by genetics and is often focused on genetically determined epilepsies, typically considered to be driven in an individual by a single genetic variant. Often the mechanisms generating the full clinical phenotype from such a perceived single cause are incompletely understood. The impact of additional genetic variation and other factors that might influence the clinical presentation represent complexities that are not usually considered. Precision success and precision failure are usually equally incompletely explained. There is a need for more comprehensive evaluation and a more rigorous framework, bringing together information that is both necessary and sufficient to explain clinical presentation and clinical responses to precision treatment in a precision approach that considers the full picture not only of the effects of a single variant, but also of its genomic and other measurable environment, within the context of the whole person. As we may be on the brink of a treatment revolution, progress must be considered and reasoned: One possible framework is proposed for the evaluation of precision treatments.
The Lancet Countdown has already reported on the serious current and projected consequences of climate change on population health, as related at the meeting by executive director of the project ...Marina Romanello (UCL), but it has not systematically considered individual disease areas. Neurologist Angel Aledo-Serrano (Vithas Madrid La Milagrosa University Hospital, Madrid, Spain) and paediatric neurologist Bernadette Macrohon (Zamboanga City Medical Center, Zamboanga City, Philippines) reported their experience of practising in a warming climate. ...heat-related illnesses (eg, hyperthermia and heat stroke) are often marked by acute or permanent neurological impairments. Health-care systems embody the weighty paradox that, while they will increasingly need to manage climate-related health effects, they are also significant producers of greenhouse gases.
Pharmacogenomics in epilepsy Balestrini, Simona; Sisodiya, Sanjay M.
Neuroscience letters,
02/2018, Volume:
667
Journal Article
Peer reviewed
Open access
•Genetic variation can influence response to antiepileptic drug (AED) treatment through various effector processes.•Metabolism of many AEDs is mediated by the cytochrome P450 (CYP) family; some of ...the CYPs have allelic variants that may affect serum AED concentrations.•‘Precision medicine’ focuses on the identification of an underlying genetic aetiology allowing personalised therapeutic choices.•Certain human leukocyte antigen, HLA, alleles are associated with an increased risk of idiosyncratic adverse drug reactions.•New results are emerging from large-scale multinational efforts, likely imminently to add knowledge of value from a pharmacogenetic perspective.
There is high variability in the response to antiepileptic treatment across people with epilepsy. Genetic factors significantly contribute to such variability. Recent advances in the genetics and neurobiology of the epilepsies are establishing the basis for a new era in the treatment of epilepsy, focused on each individual and their specific epilepsy. Variation in response to antiepileptic drug treatment may arise from genetic variation in a range of gene categories, including genes affecting drug pharmacokinetics, and drug pharmacodynamics, but also genes held to actually cause the epilepsy itself.
From a purely pharmacogenetic perspective, there are few robust genetic findings with established evidence in epilepsy. Many findings are still controversial with anecdotal or less secure evidence and need further validation, e.g. variation in genes for transporter systems and antiepileptic drug targets. The increasing use of genetic sequencing and the results of large-scale collaborative projects may soon expand the established evidence.
Precision medicine treatments represent a growing area of interest, focussing on reversing or circumventing the pathophysiological effects of specific gene mutations. This could lead to a dramatic improvement of the effectiveness and safety of epilepsy treatments, by targeting the biological mechanisms responsible for epilepsy in each specific individual.
Whilst much has been written about epilepsy pharmacogenetics, there does now seem to be building momentum that promises to deliver results of use in clinic.
Heatwaves are becoming more common as a result of climate change. Sanjay Sisodiya discusses some of the potential impacts of climate change on the nervous system, particularly in individuals with ...neurological disorders, and emphasizes the need to take action now to help mitigate these effects.
Treatment failure might have occurred because of variant selection, genomic background, modifier variants in other genes, gene expression dynamics, or irreversible compensatory or secondary ...pathophysiology. Precision medicine for genetic epilepsies might require the same multidisciplinary planning; for example, rendering an adult patient with severe intellectual disability seizure-free, could lead to unmanageable challenging behaviour, which might preclude any benefit from seizure control. Involvement of patients and families should form the cornerstone of decision-making in precision medicine.5 Genetic diagnoses can have not only medical effects, but also psychological.6 Genetic discoveries and diagnosis nowadays often lead to the emergence of gene-based support groups, which can contribute to research, and their engagement is amongst the most rewarding facets of precision medicine.
'We are called to be architects of the future, not its victims'-Buckminster Fuller People with chronic neurological conditions may be vulnerable to change and less able to manage its demands: ...neurological diseases are among the most burdensome. Whether climate change has particular effects on specific neurological diseases or not, the known impaired resilience to change affecting people with neurological diseases requires neurologists to have awareness of potential climate impacts and their management. Preparedness should include understanding of general national and local alerts and action systems, and the ability to advise patients about managing extreme weather events, particularly heatwaves, but also floods and cold snaps. At the same time, we need more research into the particular consequences of climate change on specific neurological diseases. Climate change is a serious healthcare issue, requiring the neurological community to respond as it would, or did, to other serious challenges, such as COVID-19. As disease experts, we all have a role to play.
Summary Over 50 million people worldwide have epilepsy. In nearly 30% of these cases, epilepsy remains unsatisfactorily controlled despite the availability of over 20 antiepileptic drugs. Moreover, ...no treatments exist to prevent the development of epilepsy in those at risk, despite an increasing understanding of the underlying molecular and cellular pathways. One of the major factors that have impeded rapid progress in these areas is the complex and multifactorial nature of epilepsy, and its heterogeneity. Therefore, the vision of developing targeted treatments for epilepsy relies upon the development of biomarkers that allow individually tailored treatment. Biomarkers for epilepsy typically fall into two broad categories: diagnostic biomarkers, which provide information on the clinical status of, and potentially the sensitivity to, specific treatments, and prognostic biomarkers, which allow prediction of future clinical features, such as the speed of progression, severity of epilepsy, development of comorbidities, or prediction of remission or cure. Prognostic biomarkers are of particular importance because they could be used to identify which patients will develop epilepsy and which might benefit from preventive treatments. Biomarker research faces several challenges; however, biomarkers could substantially improve the management of people with epilepsy and could lead to prevention in the right person at the right time, rather than just symptomatic treatment.
Summary
A range of medical and neurologic disorders occurs more frequently in people with epilepsy than in the general population and constitutes its somatic comorbidity. Common examples include ...cardiac, gastrointestinal, and respiratory disorders; stroke; dementia; and migraine. Alzheimer’s disease and migraine are not only more common in epilepsy but are also risk factors for the development of seizures, suggesting a bidirectional association and shared disease mechanisms. Less well‐appreciated associations with epilepsy include Parkinson’s disease and obstructive sleep apnea. The association between epilepsy and other conditions can be due to a variety of interacting genetic, biologic, and environmental factors. We propose an etiologic classification of comorbidity into uncertain (coincidence or unknown), causal (cause), shared risk factors (common disease mechanisms or shared predisposing risk factors), and resultant (consequence). Co‐occurrence of other conditions in a person with epilepsy can complicate diagnosis or have adverse prognostic implications. Management of these conditions may facilitate the treatment of epilepsy, as in the case of obstructive sleep apnea. The presence of somatic disorders in epilepsy is associated with increased health care needs, poorer health‐related quality of life, and premature mortality. Prevention, identification, and adequate treatment of comorbid disorders in epilepsy should be an important part of epilepsy management at all levels of care.
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