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Cephalalgia : An International Journal... Jun 2023This narrative review aims to discuss several common neurological and psychiatric disorders that show comorbidity with migraine. Not only can we gain pathophysiological... (Review)
Review
BACKGROUND
This narrative review aims to discuss several common neurological and psychiatric disorders that show comorbidity with migraine. Not only can we gain pathophysiological insights by studying these disorders, comorbidities also have important implications for treating migraine patients in clinical practice.
METHODS
A literature search on PubMed and Embase was conducted with the keywords "comorbidity", "migraine disorders", "migraine with aura", "migraine without aura", "depression", "depressive disorders", "epilepsy", "stroke", "patent foramen ovale", "sleep wake disorders", "restless legs syndrome", "genetics", "therapeutics".
RESULTS
Several common neurological and psychiatric disorders show comorbidity with migraine. Major depression and migraine show bidirectional causality and have shared genetic factors. Dysregulation of both hypothalamic and thalamic pathways have been implicated as a possibly cause. The increased risk of ischaemic stroke in migraine likely involves spreading depolarizations. Epilepsy is not only bidirectionally related to migraine, but is also co-occurring in monogenic migraine syndromes. Neuronal hyperexcitability is an important overlapping mechanism between these conditions. Hypothalamic dysfunction is suggested as the underlying mechanism for comorbidity between sleep disorders and migraine and might explain altered circadian timing in migraine.
CONCLUSION
These comorbid conditions in migraine with distinct pathophysiological mechanisms have important implications for best treatment choices and may provide clues for future approaches.
Topics: Humans; Stroke; Brain Ischemia; Comorbidity; Migraine Disorders; Epilepsy; Sleep Wake Disorders
PubMed: 37293935
DOI: 10.1177/03331024231180564 -
The Journal of Headache and Pain Jan 2023Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific... (Review)
Review
BACKGROUND
Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate.
OBJECTIVE
In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification.
DISCUSSION
Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood-brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack.
CONCLUSIONS
Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on.
VIDEO LINK
Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 .
Topics: Humans; Prodromal Symptoms; Migraine Disorders; Migraine with Aura; Trigeminal Nerve; Epilepsy
PubMed: 36627561
DOI: 10.1186/s10194-022-01538-1 -
The Journal of International Medical... Aug 2020Autoimmune epilepsy (AE) refers to epilepsy mediated by autoantibodies or immune cells, and a large proportion of drug-resistant epilepsy cases are classified as AE. AE... (Review)
Review
Autoimmune epilepsy (AE) refers to epilepsy mediated by autoantibodies or immune cells, and a large proportion of drug-resistant epilepsy cases are classified as AE. AE lacks standardized management guidelines. At present, little research has been conducted on the effectiveness of surgical treatment of AE. This paper reports a patient whose surgical treatment was ineffective before AE was diagnosed and who improved after immunotherapy. A literature review was conducted to examine the progress of surgical treatment of epilepsy, the relationship of temporal lobe epilepsy to neuronal antibodies, surgical and prognostic factors, research progress on the anti-Hu antibody, and treatment of autoimmune encephalitis to provide a clinical reference.
Topics: Anticonvulsants; Autoantibodies; Drug Resistant Epilepsy; Encephalitis; Epilepsy; Epilepsy, Temporal Lobe; Humans
PubMed: 32851899
DOI: 10.1177/0300060520947914 -
Cell Stress & Chaperones Nov 2023Epilepsy is a group of neurological diseases which requires significant economic costs for the treatment and care of patients. The central point of epileptogenesis stems... (Review)
Review
Epilepsy is a group of neurological diseases which requires significant economic costs for the treatment and care of patients. The central point of epileptogenesis stems from the failure of synaptic signal transmission mechanisms, leading to excessive synchronous excitation of neurons and characteristic epileptic electroencephalogram activity, in typical cases being manifested as seizures and loss of consciousness. The causes of epilepsy are extremely diverse, which is one of the reasons for the complexity of selecting a treatment regimen for each individual case and the high frequency of pharmacoresistant cases. Therefore, the search for new drugs and methods of epilepsy treatment requires an advanced study of the molecular mechanisms of epileptogenesis. In this regard, the investigation of molecular chaperones as potential mediators of epileptogenesis seems promising because the chaperones are involved in the processing and regulation of the activity of many key proteins directly responsible for the generation of abnormal neuronal excitation in epilepsy. In this review, we try to systematize current data on the role of molecular chaperones in epileptogenesis and discuss the prospects for the use of chemical modulators of various chaperone groups' activity as promising antiepileptic drugs.
Topics: Humans; Epilepsy; Neurons; Molecular Chaperones
PubMed: 37755620
DOI: 10.1007/s12192-023-01378-1 -
Epilepsia May 2023"How many epilepsy genes are there?" is a frequently asked question. We sought to (1) provide a curated list of genes that cause monogenic epilepsies, and (2) compare...
OBJECTIVE
"How many epilepsy genes are there?" is a frequently asked question. We sought to (1) provide a curated list of genes that cause monogenic epilepsies, and (2) compare and contrast epilepsy gene panels from multiple sources.
METHODS
We compared genes included on the epilepsy panels (as of July 29, 2022) of four clinical diagnostic providers: Invitae, GeneDx, Fulgent Genetics, and Blueprint Genetics; and two research resources: PanelApp Australia and ClinGen. A master list of all unique genes was supplemented by additional genes identified via PubMed searches up until August 15, 2022, using the search terms "genetics" AND/OR "epilepsy" AND/OR "seizures". Evidence supporting a monogenic role for all genes was manually reviewed; those with limited or disputed evidence were excluded. All genes were annotated according to inheritance pattern and broad epilepsy phenotype.
RESULTS
The comparison of genes included on epilepsy clinical panels revealed high heterogeneity in both number of genes (range: 144-511) and content. Just 111 genes (15.5%) were included on all four clinical panels. Subsequent manual curation of all "epilepsy genes" identified >900 monogenic etiologies. Almost 90% of genes were associated with developmental and epileptic encephalopathies. By comparison only 5% of genes were associated with monogenic causes of "common epilepsies" (i.e., generalized and focal epilepsy syndromes). Autosomal recessive genes were most frequent (56% of genes); however, this varied according to the associated epilepsy phenotype(s). Genes associated with common epilepsy syndromes were more likely to be dominantly inherited and associated with multiple epilepsy types.
SIGNIFICANCE
Our curated list of monogenic epilepsy genes is publicly available: github.com/bahlolab/genes4epilepsy and will be regularly updated. This gene resource can be utilized to target genes beyond those included on clinical gene panels, for gene enrichment methods and candidate gene prioritization. We invite ongoing feedback and contributions from the scientific community via [email protected].
Topics: Humans; Epilepsy; Epileptic Syndromes; Epilepsies, Partial; Epilepsy, Generalized; Australia
PubMed: 36808730
DOI: 10.1111/epi.17547 -
Seizure May 2021The coexistence of epilepsy in familial hemiplegic migraine (FHM) has not been reviewed systematically. We investigated the associations of epilepsy in patients with FHM... (Review)
Review
OBJECTIVE
The coexistence of epilepsy in familial hemiplegic migraine (FHM) has not been reviewed systematically. We investigated the associations of epilepsy in patients with FHM with CACNA1A, ATP1A2, SCN1A or PRRT2 mutations along with clinical and genetic data.
MATERIALS AND METHODS
We performed a search in the PubMed bibliographic database and the Cochrane Library was screened for eligible studies, from April 1997 to December 2020. Additionally, Online Mendelian Inheritance in Man (OMIM) was searched for mutations in the CACNA1A, ATP1A2, SCN1A and PRRT2 genes. Brief reports, letters, and original articles about FHM and epilepsy were included in the review if their mutations and clinical course of diseases were identified.
RESULTS
Of the included patients with FHM whose information could be accessed, there were 28 families and 195 individuals, 78 of whom had epilepsy; 30 patients had focal epilepsy and 30 patients had generalized epilepsy. All mutations except ATP1A2, which could not be evaluated due to insufficient data, revealed first epilepsy then HM. In 60 patients for whom the epilepsy prognosis was evaluated, only 3.5% of patients were drug-resistant, and the remainder had a self-limited course or responded to anti-epileptic drug treatment.
CONCLUSION
Mutations in all three and possibly four FHM genes can cause epilepsy. Contrary to our expectations, the well-known epilepsy gene SCN1A mutations are not the leading cause; the highest number of cases associated with epilepsy belongs to the ATP1A2 mutation. Drug-resistant forms of epilepsy are rare in all FHM mutations, and this information is important for counseling patients.
Topics: Epilepsy; Epilepsy, Generalized; Humans; Migraine with Aura; Mutation; Pedigree; Sodium-Potassium-Exchanging ATPase
PubMed: 33839563
DOI: 10.1016/j.seizure.2021.03.028 -
Neurotherapeutics : the Journal of the... Apr 2014The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of... (Review)
Review
The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.
Topics: Epilepsy; Genetic Markers; Humans; Precision Medicine
PubMed: 24566939
DOI: 10.1007/s13311-014-0262-5 -
The Journal of Headache and Pain Jan 2024Migraine and epilepsy are two paroxysmal chronic neurological disorders affecting a high number of individuals and being responsible for a high individual and... (Review)
Review
BACKGROUND
Migraine and epilepsy are two paroxysmal chronic neurological disorders affecting a high number of individuals and being responsible for a high individual and socioeconomic burden. The link between these disorders has been of interest for decades and innovations concerning diagnosing and treatment enable new insights into their relationship.
FINDINGS
Although appearing to be distinct at first glance, both diseases exhibit a noteworthy comorbidity, shared pathophysiological pathways, and significant overlaps in characteristics like clinical manifestation or prophylactic treatment. This review aims to explore the intricate relationship between these two conditions, shedding light on shared pathophysiological foundations, genetic interdependencies, common and distinct clinical features, clinically overlapping syndromes, and therapeutic similarities. There are several shared pathophysiological mechanisms, like CSD, the likely underlying cause of migraine aura, or neurotransmitters, mainly Glutamate and GABA, which represent important roles in triggering migraine attacks and seizures. The genetic interrelations between the two disorders can be observed by taking a closer look at the group of familial hemiplegic migraines, which are caused by mutations in genes like CACNA1A, ATP1A2, or SCN1A. The intricate relationship is further underlined by the high number of shared clinical features, which can be observed over the entire course of migraine attacks and epileptic seizures. While the variety of the clinical manifestation of an epileptic seizure is naturally higher than that of a migraine attack, a distinction can indeed be difficult in some cases, e.g. in occipital lobe epilepsy. Moreover, triggering factors like sleep deprivation or alcohol consumption play an important role in both diseases. In the period after the seizure or migraine attack, symptoms like speech difficulties, tiredness, and yawning occur. While the actual attack of the disease usually lasts for a limited time, research indicates that individuals suffering from migraine and/or epilepsy are highly affected in their daily life, especially regarding cognitive and social aspects, a burden that is even worsened using antiseizure medication. This medication allows us to reveal further connections, as certain antiepileptics are proven to have beneficial effects on the frequency and severity of migraine and have been used as a preventive drug for both diseases over many years.
CONCLUSION
Migraine and epilepsy show a high number of similarities in their mechanisms and clinical presentation. A deeper understanding of the intricate relationship will positively advance patient-oriented research and clinical work.
Topics: Humans; Migraine Disorders; Epilepsy; Migraine with Aura; Anticonvulsants; Comorbidity
PubMed: 38273253
DOI: 10.1186/s10194-024-01719-0 -
Epilepsy & Behavior : E&B Aug 2014Seizures in some 30% to 40% of patients with epilepsy fail to respond to antiepileptic drugs or other treatments. While much has been made of the risks of new drug... (Review)
Review
Seizures in some 30% to 40% of patients with epilepsy fail to respond to antiepileptic drugs or other treatments. While much has been made of the risks of new drug therapies, not enough attention has been given to the risks of uncontrolled and progressive epilepsy. This critical review summarizes known risks associated with refractory epilepsy, provides practical clinical recommendations, and indicates areas for future research. Eight international epilepsy experts from Europe, the United States, and South America met on May 4, 2013, to present, review, and discuss relevant concepts, data, and literature on the consequences of refractory epilepsy. While patients with refractory epilepsy represent the minority of the population with epilepsy, they require the overwhelming majority of time, effort, and focus from treating physicians. They also represent the greatest economic and psychosocial burdens. Diagnostic procedures and medical/surgical treatments are not without risks. Overlooked, however, is that these risks are usually smaller than the risks of long-term, uncontrolled seizures. Refractory epilepsy may be progressive, carrying risks of structural damage to the brain and nervous system, comorbidities (osteoporosis, fractures), and increased mortality (from suicide, accidents, sudden unexpected death in epilepsy, pneumonia, vascular disease), as well as psychological (depression, anxiety), educational, social (stigma, driving), and vocational consequences. Adding to this burden is neuropsychiatric impairment caused by underlying epileptogenic processes ("essential comorbidities"), which appears to be independent of the effects of ongoing seizures themselves. Tolerating persistent seizures or chronic medicinal adverse effects has risks and consequences that often outweigh risks of seemingly "more aggressive" treatments. Future research should focus not only on controlling seizures but also on preventing these consequences.
Topics: Anticonvulsants; Drug Resistance; Epilepsy; Humans
PubMed: 24980390
DOI: 10.1016/j.yebeh.2014.05.031 -
Neurobiology of Disease Jun 2023Over the past decade, there has been tremendous progress in understanding brain somatic mosaicism in epilepsy in the research setting. Access to resected brain tissue... (Review)
Review
Over the past decade, there has been tremendous progress in understanding brain somatic mosaicism in epilepsy in the research setting. Access to resected brain tissue samples from patients with medically refractory epilepsy undergoing epilepsy surgery has been key to making these discoveries. In this review, we discuss the gap between making discoveries in the research setting and bringing results back to the clinical setting. Current clinical genetic testing mainly uses clinically accessible tissue samples, like blood and saliva, and can detect inherited and de novo germline variants and potentially non-brain-limited mosaic variants that have resulted from post-zygotic mutation (also called "somatic mutations"). Methods developed in the research setting to detect brain-limited mosaic variants using brain tissue samples need to be further translated and validated in the clinical setting, which will allow post-resection brain tissue genetic diagnoses. However, obtaining a genetic diagnosis after surgery for refractory focal epilepsy, when brain tissue samples are available, is arguably "too late" to guide precision management. Emerging methods using cerebrospinal fluid (CSF) and stereoelectroencephalography (SEEG) electrodes hold promise for establishing genetic diagnoses pre-resection without the need for actual brain tissue. In parallel, development of curation rules for interpreting the pathogenicity of mosaic variants, which have unique considerations compared to germline variants, will assist clinically accredited laboratories and epilepsy geneticists in making genetic diagnoses. Returning results of brain-limited mosaic variants to patients and their families will end their diagnostic odyssey and advance epilepsy precision management.
Topics: Humans; Mosaicism; Epilepsy; Brain; Mutation; Epilepsies, Partial; Drug Resistant Epilepsy
PubMed: 36972791
DOI: 10.1016/j.nbd.2023.106104