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Epilepsy Research Mar 2024Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients...
Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.
Topics: Humans; Adolescent; Topiramate; Levetiracetam; Phenytoin; Retrospective Studies; Epilepsy; Insurance
PubMed: 38417192
DOI: 10.1016/j.eplepsyres.2024.107313 -
Epilepsia Apr 2024The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric...
OBJECTIVE
The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group.
METHODS
A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness.
RESULTS
Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (d = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (d = .47), crus I/II (d = .39), VIIIA (d = .45), and VIIIB (d = .40). Earlier age at seizure onset ( = .05) and longer epilepsy duration ( = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls.
SIGNIFICANCE
We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.
Topics: Adult; Humans; Epilepsy, Temporal Lobe; Phenytoin; Cross-Sectional Studies; Epileptic Syndromes; Cerebellum; Seizures; Magnetic Resonance Imaging; Atrophy
PubMed: 38411286
DOI: 10.1111/epi.17881 -
Journal of Ayub Medical College,... 2023Status Epilepticus (SE) is a life-threatening neurological emergency requiring appropriate therapy to terminate seizure activity. SE is managed with supportive measures... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Status Epilepticus (SE) is a life-threatening neurological emergency requiring appropriate therapy to terminate seizure activity. SE is managed with supportive measures and ultra-short-acting benzodiazepines. However, limited data is available in the paediatric population regarding the next best option when this fails. This study aimed at finding new data to recommend levetiracetam or phenytoin as the second-line option.
METHODS
One hundred and thirty-seven patients with status epilepticus were randomized into two groups; group-I was given IV Levetiracetam (LEV) at 20 mg/kg/dose over 5 minutes followed by a maintenance dose of 20mg/kg/dose BID, whereas Group II received phenytoin at 20mg/kg IV loading dose followed by a maintenance dose of 5-8 mg/kg/day divided BID. The primary outcome was seizure cessation, defined as the termination of the apparent convulsion 30 min after the administration of phenytoin or levetiracetam. Secondary outcomes were the use of different anti-convulsants for continued management, admittance to critical treatment, and severe adverse events (including mortality, Stevens-Johnson syndrome, rash, airway problems, cardiovascular instability, extravasation, and severe agitation). Data was recorded via a clinical proforma and was analyzed by SPSS software version 25. All numerical data were expressed in mean±SD forms, and frequency was determined for qualitative baseline data. Secondary outcomes were tested through the χ2 test, A p-value of ≤0.05 was considered statistical significance.
RESULTS
Levetiracetam terminated seizures in 94% of children compared to 77% in those treated with phenytoin. The mean time to seizure termination was 19.94±3.76 minutes for the LEV Group as compared to 23.791±9.1 min for the PHT group. (p=0.046). Regarding safety, a profile study shows LEV has fewer and less severe side effects compared to Phenytoin.
CONCLUSIONS
Levetiracetam is a safe, well-tolerated, and effective treatment as a second-line antiepileptic drug in the management of status epilepticus.
Topics: Child; Humans; Anticonvulsants; Phenytoin; Levetiracetam; Benzodiazepines; Piracetam; Status Epilepticus; Seizures
PubMed: 38404082
DOI: 10.55519/JAMC-03-11897 -
ACS Chemical Neuroscience Mar 2024Voltage-gated sodium channel (Na) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal...
Voltage-gated sodium channel (Na) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal action potential firing to reduce excitability in the brain. However, all currently available Na-targeting antiseizure medications nonselectively inhibit the brain channels Na1.1, Na1.2, and Na1.6, which potentially limits the efficacy and therapeutic safety margins of these drugs. Here, we report on XPC-7724 and XPC-5462, which represent a new class of small molecule Na-targeting compounds. These compounds specifically target inhibition of the Na1.6 and Na1.2 channels, which are abundantly expressed in excitatory pyramidal neurons. They have a > 100-fold molecular selectivity against Na1.1 channels, which are predominantly expressed in inhibitory neurons. Sparing Na1.1 preserves the inhibitory activity in the brain. These compounds bind to and stabilize the inactivated state of the channels thereby reducing the activity of excitatory neurons. They have higher potency, with longer residency times and slower off-rates, than the clinically used antiseizure medications carbamazepine and phenytoin. The neuronal selectivity of these compounds is demonstrated in brain slices by inhibition of firing in cortical excitatory pyramidal neurons, without impacting fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model, whereas XPC-7224 does not, suggesting a possible requirement of Nav1.2 inhibition in 0-Mg- or 4-AP-induced brain slice seizure models. The profiles of these compounds will facilitate pharmacological dissection of the physiological roles of Na1.2 and Na1.6 in neurons and help define the role of specific channels in disease states. This unique selectivity profile provides a new approach to potentially treat disorders of neuronal hyperexcitability by selectively downregulating excitatory circuits.
Topics: Humans; Neurons; Voltage-Gated Sodium Channels; Epilepsy; Brain; Seizures; Action Potentials
PubMed: 38359277
DOI: 10.1021/acschemneuro.3c00757 -
Advances in Therapy Apr 2024This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Tolerability of Adjunctive Brivaracetam in Patients with Focal-Onset Seizures on Specific Concomitant Antiseizure Medications: Pooled Analysis of Double-Blind, Placebo-Controlled Trials.
INTRODUCTION
This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen.
METHODS
This was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation.
RESULTS
Nine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups.
CONCLUSION
BRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.
Topics: Adult; Humans; Treatment Outcome; Drug Therapy, Combination; Seizures; Anticonvulsants; Lacosamide; Double-Blind Method; Pyrrolidinones
PubMed: 38356105
DOI: 10.1007/s12325-024-02795-z -
Unplugging lateral fenestrations of NALCN reveals a hidden drug binding site within the pore module.BioRxiv : the Preprint Server For... Jan 2024The sodium (Na ) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium...
UNLABELLED
The sodium (Na ) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (Na s and Ca s, respectively). Unlike Na s and Ca s, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145 and Y1436) that block these openings. Structural data suggest that oc-cluded lateral fenestrations underlie the pharmacological resistance of NALCN to lipophilic compounds, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned resi-dues with alanine (AAAA) and compared the effects of Na , Ca and NALCN block-ers on both wild-type (WT) and AAAA channels. Most compounds behaved in a simi-lar manner on both channels, but phenytoin and 2-aminoethoxydiphenyl borate (2-APB) elicited additional, distinct responses on AAAA channels. Further experiments using single alanine mutants revealed that phenytoin and 2-APB enter the inner cav-ity through distinct fenestrations, implying structural specificity to their modes of ac-cess. Using a combination of computational and functional approaches, we identified amino acid residues critical for 2-APB activity, supporting the existence of drug bind-ing site(s) within the pore region. Intrigued by the activity of 2-APB and its ana-logues, we tested additional compounds containing the diphenylmethane/amine moiety on WT channels. We identified compounds from existing clinically used drugs that exhibited diverse activity, thus expanding the pharmacological toolbox for NALCN. While the low potencies of active compounds reiterate the resistance of NALCN to pharmacological targeting, our findings lay the foundation for rational drug design to develop NALCN modulators with refined properties.
SIGNIFICANCE STATEMENT
The sodium leak channel (NALCN) is essential for survival: mutations cause life-threatening developmental disorders in humans. However, no treatment is currently available due to the resistance of NALCN to pharmacological targeting. One likely reason is that the lateral fenestrations, a common route for clinically used drugs to enter and block related ion channels, are occluded in NALCN. Using a combination of computational and functional approaches, we unplugged the fenestrations of NALCN which led us to the first molecularly defined drug binding site within the pore region. Besides that, we also identified additional NALCN modulators from existing clinically used therapeutics, thus expanding the pharmacological toolbox for this leak channel.
PubMed: 38328210
DOI: 10.1101/2023.04.12.536537 -
Clinical Parkinsonism & Related... 2024Here we report the first case of phenytoin intoxication that was closely associated with hand-foot synkinesis. This case suggests a close association between cerebellar...
Here we report the first case of phenytoin intoxication that was closely associated with hand-foot synkinesis. This case suggests a close association between cerebellar dysfunction and hand-foot synkinesis. In patients with hand-foot synkinesis, lesions of not only the secondary motor areas but also the cerebellum should be considered.
PubMed: 38327515
DOI: 10.1016/j.prdoa.2024.100237 -
Journal of the Neurological Sciences Feb 2024Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or... (Observational Study)
Observational Study
Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or controversial. The objectives of this study were to describe the long-term clinical course and treatment outcomes of individuals suffering from Nodding Syndrome. In addition, we aimed to provide a comprehensive characterization of the epileptological and social features of patients with Nodding Syndrome. From 11/2014 to 4/2015, we conducted a hospital-based, cross-sectional and observational study in Mahenge, Tanzania. Seventy-eight individuals (female:male ratio: 40:38, age at examination: 21.1 ± 6.39 (SD) years) have been enrolled, of whom 38 (49%) had also been examined in 2005 and in 2009. The 10-year clinical course analysis of this revisited subgroup revealed a calculated case fatality of 0.8-2.3%. Progressive physical or cognitive deterioration has not been observed in any of the 78 individuals and more than half of the people studied (38/69; 55%) managed to live and work independently. 14/78 individuals (18%) were seizure-free, (no head nodding, no other seizure types), 13 of whom were taking antiseizure medication. Phenytoin was more effective against head nodding seizures (14/19 (74%)) than monotherapy with other available antiseizure medication (phenobarbitone 12/25 (48%) and carbamazepine 7/22 (32%), p = 0.02, chi-square test). Our ten-year clinical outcome data show that Nodding Syndrome is not a fatal disease, however, the response to treatment is worse than in epilepsy patients in general. Phenytoin may be more effective than carbamazepine and phenobarbitone, but further studies are needed to confirm this observation.
Topics: Humans; Male; Female; Anticonvulsants; Phenytoin; Nodding Syndrome; Cross-Sectional Studies; Epilepsy; Phenobarbital; Carbamazepine; Treatment Outcome; Benzodiazepines; Disease Progression
PubMed: 38278097
DOI: 10.1016/j.jns.2024.122893 -
International Journal of Clinical... Nov 2023Gingival enlargement or gingival overgrowth (GO) is a very common complication of the various classes of drugs and the most common being, the anticonvulsant drug...
BACKGROUND
Gingival enlargement or gingival overgrowth (GO) is a very common complication of the various classes of drugs and the most common being, the anticonvulsant drug phenytoin (PHT). PHT and its metabolites have a direct effect on the periodontal tissues; with poor oral hygiene also contributing to the severity of inflammation in patients with drug-induced gingival overgrowth (DIGO).
CASE DESCRIPTION
Here we present a case of PHT-induced gingival overgrowth (PGO) in a 12-year-old male patient and discuss the management of the condition.
CONCLUSION
Management of drug-induced overgrowth of gingiva includes strict oral hygiene maintenance practice, meticulous professional care with several adjunctive periodontal therapies like photodynamic therapy and Local drug delivery. Surgical treatment is indicated if the overgrown tissue has become fibrotic.
CLINICAL SIGNIFICANCE
The pediatric dentist plays an important role in early identification and proper management of the condition by timely intervention and collaboration with other specialists.
HOW TO CITE THIS ARTICLE
Dalal R, Garg S, Gupta A. Nonsurgical Management of Drug-induced Gingival Overgrowth in a Young Patient. Int J Clin Pediatr Dent 2023;16(S-3):S331-S334.
PubMed: 38268630
DOI: 10.5005/jp-journals-10005-2482