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Intensive Care Medicine Jan 2024Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Management that follows published guidelines is best suited to... (Review)
Review
Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Management that follows published guidelines is best suited to improve outcomes, with the most severe cases frequently being managed in the intensive care unit (ICU). Diagnosis of convulsive SE can be made without electroencephalography (EEG), but EEG is required to reliably diagnose nonconvulsive SE. Rapidly narrowing down underlying causes for SE is crucial, as this may guide additional management steps. Causes may range from underlying epilepsy to acute brain injuries such as trauma, cardiac arrest, stroke, and infections. Initial management consists of rapid administration of benzodiazepines and one of the following non-sedating intravenous antiseizure medications (ASM): (fos-)phenytoin, levetiracetam, or valproate; other ASM are increasingly used, such as lacosamide or brivaracetam. SE that continues despite these medications is called refractory, and most commonly treated with continuous infusions of midazolam or propofol. Alternatives include further non-sedating ASM and non-pharmacologic approaches. SE that reemerges after weaning or continues despite management with propofol or midazolam is labeled super-refractory SE. At this step, management may include non-sedating or sedating compounds including ketamine and barbiturates. Continuous video EEG is necessary for the management of refractory and super-refractory SE, as these are almost always nonconvulsive. If possible, management of the underlying cause of seizures is crucial particularly for patients with autoimmune encephalitis. Short-term mortality ranges from 10 to 15% after SE and is primarily related to increasing age, underlying etiology, and medical comorbidities. Refractoriness of treatment is clearly related to outcome with mortality rising from 10% in responsive cases, to 25% in refractory, and nearly 40% in super-refractory SE.
Topics: Humans; Anticonvulsants; Midazolam; Propofol; Status Epilepticus; Intensive Care Units
PubMed: 38117319
DOI: 10.1007/s00134-023-07263-w -
The Lancet. Neurology Aug 2023Drug resistance is estimated to affect about a third of individuals with epilepsy, but its prevalence differs in relation to the epilepsy syndrome, the cause of... (Review)
Review
Drug resistance is estimated to affect about a third of individuals with epilepsy, but its prevalence differs in relation to the epilepsy syndrome, the cause of epilepsy, and other factors such as age of seizure onset and presence of associated neurological deficits. Although drug-resistant epilepsy is not synonymous with unresponsiveness to any drug treatment, the probability of achieving seizure freedom on a newly tried medication decreases with increasing number of previously failed treatments. After two appropriately used antiseizure medications have failed to control seizures, individuals should be referred whenever possible to a comprehensive epilepsy centre for diagnostic re-evaluation and targeted management. The feasibility of epilepsy surgery and other treatments, including those targeting the cause of epilepsy, should be considered early after diagnosis. Substantial evidence indicates that a delay in identifying an effective treatment can adversely affect ultimate outcome and carry an increased risk of cognitive disability, other comorbidities, and premature mortality. Research on mechanisms of drug resistance and novel therapeutics is progressing rapidly, and potentially improved treatments, including those targeting disease modification, are on the horizon.
Topics: Humans; Anticonvulsants; Epilepsy; Seizures; Treatment Outcome; Drug Resistant Epilepsy; Drug Resistance
PubMed: 37352888
DOI: 10.1016/S1474-4422(23)00151-5 -
Epilepsia Open Sep 2023This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded... (Observational Study)
Observational Study
OBJECTIVE
This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded Access Program (EAP).
METHOD
This was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3-, 6-, and 12-month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation.
RESULTS
The study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness.
SIGNIFICANCE
In this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild-to-moderate, and few led to discontinuation.
Topics: Humans; Adolescent; Anticonvulsants; Retrospective Studies; Treatment Outcome; Seizures; Epilepsy
PubMed: 37149853
DOI: 10.1002/epi4.12757 -
Journal of Neurology Nov 2023In 2017, one of us reviewed advances in epilepsy (Manford in J Neurol 264:1811-1824, 2017). The current paper brings that review up to date and gives a slight change in... (Review)
Review
In 2017, one of us reviewed advances in epilepsy (Manford in J Neurol 264:1811-1824, 2017). The current paper brings that review up to date and gives a slight change in emphasis. Once again, the story is of evolution rather than revolution. In recognition that most of our current medications act on neurotransmitters or ion channels, and not on the underlying changes in connectivity and pathways, they have been renamed as antiseizure (ASM) medications rather than antiepileptic drugs. Cenobamate is the one newly licensed medication for broader use in focal epilepsy but there have been a number of developments for specific disorders. We review new players and look forward to new developments in the light of evolving underlying science. We look at teratogenicity; old villains and new concerns in which clinicians play a vital role in explaining and balancing the risks. Medical treatment of status epilepticus, long without evidence, has benefitted from high-quality trials to inform practice; like buses, several arriving at once. Surgical treatment continues to be refined with improvements in the pre-surgical evaluation of patients, especially with new imaging techniques. Alternatives including stereotactic radiotherapy have received further focus and targets for palliative stimulation techniques have grown in number. Individuals' autonomy and quality of life continue to be the subject of research with refinement of what clinicians can do to help persons with epilepsy (PWE) achieve control. This includes seizure management but extends to broader considerations of human empowerment, needs and desires, which may be aided by emerging technologies such as seizure detection devices. The role of specialist nurses in improving that quality has been reinforced by specific endorsement from the International League against Epilepsy (ILAE).
Topics: Humans; Quality of Life; Epilepsy; Anticonvulsants; Epilepsies, Partial; Seizures
PubMed: 37458794
DOI: 10.1007/s00415-023-11860-6 -
Drugs Sep 2023Orofacial pain is a category of complex disorders, including musculoskeletal, neuropathic and neurovascular disorders, that greatly affect the quality of life of the... (Review)
Review
Orofacial pain is a category of complex disorders, including musculoskeletal, neuropathic and neurovascular disorders, that greatly affect the quality of life of the patient. These disorders are within the fields of dentistry and medicine and management can be challenging, requiring a referral to an orofacial pain specialist, essential for adequate evaluation, diagnosis, and care. Management is specific to the diagnosis and a treatment plan is developed with diverse pharmacological and non-pharmacological modalities. The pharmacological management of orofacial pain encompasses a vast array of medication classes and approaches. This includes anti-inflammatory drugs, muscle relaxants, anticonvulsants, antidepressants, and anesthetics. In addition, as adjunct therapy, different injections can be integrated into the management plan depending on the diagnosis and needs. These include trigger point injections, temporomandibular joint (TMJ) injections, and neurotoxin injections with botulinum toxin and nerve blocks. Multidisciplinary management is key for optimal care. New and safer therapeutic targets exclusively for the management of orofacial pain disorders are needed to offer better care for this patient population.
Topics: Humans; Quality of Life; Anticonvulsants; Botulinum Toxins; Facial Pain; Nerve Block
PubMed: 37632671
DOI: 10.1007/s40265-023-01927-z -
Handbook of Clinical Neurology 2024Status migrainosus is one of the recognized complications of migraine with or without aura, defined as a persistent debilitating migraine attack lasting for more than... (Review)
Review
Status migrainosus is one of the recognized complications of migraine with or without aura, defined as a persistent debilitating migraine attack lasting for more than 72h with little reprieve, leading to functional disability. The individual impact of status migrainosus and the substantial healthcare burden are highlighted. Current case series which inform our understanding of this condition are examined with two groups emergent, those with classic status migrainosus and those with episodic status migrainosus. The question as to whether status migrainosus is a distinct biological state beyond the established migraine pathophysiology is examined. With the underlying pathophysiology not fully understood, attention is turned to therapeutic considerations and the available evidence informing practice. A practical approach to treatment of status migrainosus is presented. Given the severity and need for emergency care, options detailed are in line with recommendations for acute migraine care: with a staged approach initially combining subcutaneous sumatriptan with parenteral options including dopamine receptor antagonists, nonsteroidal anti-inflammatories and acetaminophen. The place of combination treatment with parenteral magnesium sulfate, dihydroergotamine, antiepileptics, corticosteroids, and anesthetic agents is outlined. With a paucity of high-quality evidence to consolidate current clinical approaches, consideration of future therapies and research questions is raised.
Topics: Humans; Migraine Disorders; Anticonvulsants; Adrenal Cortex Hormones; Sumatriptan
PubMed: 38307660
DOI: 10.1016/B978-0-12-823357-3.00017-3 -
Molecules (Basel, Switzerland) Apr 2024It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat... (Review)
Review
It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.
Topics: Humans; Cannabidiol; Epilepsy; Anticonvulsants; Randomized Controlled Trials as Topic; Lennox Gastaut Syndrome; Child; Treatment Outcome; Epilepsies, Myoclonic
PubMed: 38731471
DOI: 10.3390/molecules29091981 -
Der Nervenarzt Apr 2024Regarding treatment of women of childbearing potential with epilepsy, several aspects of family planning and desire to have children have to be taken into account. (Review)
Review
BACKGROUND
Regarding treatment of women of childbearing potential with epilepsy, several aspects of family planning and desire to have children have to be taken into account.
OBJECTIVE
Overview of current data on mutual implications of epileptic seizures, antiseizure medication (ASM), pregnancy and child development.
METHOD
Review of the current literature, discussion and presentation of resulting treatment recommendations.
RESULTS
Many ASMs bear the potential for clinically relevant interactions with both contraceptives and altered concentrations of sexual hormones and modified pharmacokinetics during pregnancy. All ASMs show an increased risk for congenital malformations; however, due to seizure-related risks for the mother and child effective ASM treatment during pregnancy is crucial.
CONCLUSION
When considering the special aspects of consultation and treatment of women of childbearing potential with epilepsy most pregnancies are uncomplicated.
Topics: Child; Pregnancy; Female; Humans; Epilepsy; Seizures; Child Development; Mothers; Referral and Consultation; Anticonvulsants
PubMed: 38451327
DOI: 10.1007/s00115-024-01626-4 -
Journal of Veterinary Internal Medicine 2023Approximately 30% of dogs with idiopathic epilepsy (IE) are drug-resistant. Recent studies have suggested cannabidiol (CBD) may be an effective anticonvulsant in dogs...
BACKGROUND
Approximately 30% of dogs with idiopathic epilepsy (IE) are drug-resistant. Recent studies have suggested cannabidiol (CBD) may be an effective anticonvulsant in dogs with IE.
OBJECTIVE
To evaluate the addition of CBD to antiseizure drugs (ASDs) on seizure frequency and to report adverse events in dogs with drug-resistant IE.
ANIMALS
Fifty-one dogs. Dogs having at least 2 seizures per month while receiving at least 1 ASD were included in the trial.
METHODS
Double-blinded placebo-controlled crossover study. The 5 mg/kg/day dosage met futility requirements after 12 dogs, and a dosage of 9 mg/kg/day was used in the next 39 dogs. Dogs were randomly assigned to receive CBD or placebo for 3 months, with a 1-month washout period between oils. Total numbers of seizures and seizure days were recorded. Diagnostic testing was performed periodically throughout the trial.
RESULTS
At the 9 mg/kg/day dose, the decrease in total seizure frequency was significant compared with placebo. A 24.1% decrease in seizure days occurred in dogs receiving CBD and a 5.8% increase occurred in dogs receiving placebo (P ≤ .05). No significant difference was found in the number of responders (≥50% decrease in total seizures or seizure days). Liver enzyme activities increased at both dosages. Decreased appetite and vomiting were more common in the CBD phase (P ≤ .05).
CONCLUSIONS AND CLINICAL IMPORTANCE
Cannabidiol decreased total seizures and seizure days compared to placebo when administered to dogs PO at 9 mg/kg/day. Liver enzymes should be monitored with administration of CBD in dogs.
Topics: Dogs; Animals; Cannabidiol; Cross-Over Studies; Seizures; Anticonvulsants; Double-Blind Method; Dog Diseases
PubMed: 37889215
DOI: 10.1111/jvim.16912 -
Proceedings of the National Academy of... Oct 2023Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the...
Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Na1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Na1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Na channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.
Topics: Humans; Anticonvulsants; Lamotrigine; Cannabidiol; Sodium; Voltage-Gated Sodium Channels
PubMed: 37782796
DOI: 10.1073/pnas.2309773120