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Clinical Laboratory Nov 2023Alterations in zinc and copper homeostasis may contribute to seizure susceptibility, development, termination, and response to antiepileptic medications. The current...
BACKGROUND
Alterations in zinc and copper homeostasis may contribute to seizure susceptibility, development, termination, and response to antiepileptic medications. The current study examined the profile of zinc, copper, and their ratio in childhood epilepsy and its pharmacological variants (pharmacoresistant and pharmacoresponsive).
METHODS
The study included 100 epileptic children (50 pharmacoresistant and 50 pharmacoresponsive) and 50 healthy, age- and gender-matched controls. History, clinical examination, and assays of serum zinc and copper were performed. Zinc/copper ratio was calculated.
RESULTS
Serum zinc and the zinc/copper ratio were significantly lower in epileptic children than in controls (p < 0.001). Significantly lower zinc and zinc/copper ratio and higher copper levels were found in children treated with levetiracetam/sodium valproate/oxcarbazepine than those treated with levetiracetam alone or combined with sodium valproate (p < 0.05 for all). Epileptic children, particularly pharmacoresistant, exhibited significant negative correlations between the serum levels of zinc and copper (r = -0.279, p = 0.005, and r = -0.363 and p = 0.010, respectively). At cutoff value of zinc/copper ratio < 1.118 in diagnosing children with epilepsy, it gives a sensitivity of 64% and a specificity of 85% with the AUC = 0.8092. At cutoff value of zinc/copper ratio ≤ 0.7826 in distinguishing pharmacoresistant epilepsy, it produced 52% sensitivity, 64% specificity with AUC = 0.576 Conclusions: Low zinc and high copper levels were associated with childhood epilepsy especially those with pharmacoresistant type and treated with Oxcarbazepine. Zinc/copper ratio might be a potential biomarker in diagnosing childhood epilepsy and to some extent in predicting pharmacoresistant type.
Topics: Child; Humans; Valproic Acid; Copper; Oxcarbazepine; Levetiracetam; Zinc; Anticonvulsants; Epilepsy; Biomarkers
PubMed: 37948472
DOI: 10.7754/Clin.Lab.2023.230540 -
JAMA Network Open Feb 2024Use of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications...
IMPORTANCE
Use of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications for the child.
OBJECTIVE
To examine whether use of valproate and other ASMs in pregnancy among mothers with epilepsy is associated with epilepsy risk in their children.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, population-based register cohort study included singletons born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from October 2022 to December 2023.
EXPOSURE
Redeemed prescription for an ASM from 30 days before pregnancy until birth.
MAIN OUTCOMES AND MEASURES
The main outcome was epilepsy in children, assessed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from hospital care. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression. Secondary analyses included dose-response analyses, analyses using children of mothers who discontinued ASM prior to pregnancy as the reference, and sibling analyses.
RESULTS
This cohort study included 38 663 children of mothers with epilepsy (19 854 [51.4%] boys). Children were followed up from birth; the mean length of follow-up was 7.2 years (range 0-22 years). Compared with 22 207 children of mothers not using an ASM in pregnancy, increased risks of epilepsy in children of mothers who used valproate in pregnancy (monotherapy: AHR, 2.18; 95% CI, 1.70-2.79; polytherapy: AHR, 2.10; 95% CI, 1.49-2.96) were observed. However, there was no dose-dependent association, and there was a similar risk of epilepsy in siblings who were exposed and unexposed to valproate (AHR, 0.95; 95% CI, 0.50-1.82). Prenatal exposure to topiramate monotherapy was associated with increased risk of epilepsy (AHR, 2.32; 95% CI, 1.30-4.16), and the risk was greater for higher doses, but the risk attenuated in comparisons with children of mothers who discontinued topiramate before pregnancy (AHR, 1.19; 95% CI, 0.26-5.44). Prenatal exposure to clonazepam monotherapy was also associated with increased epilepsy risk (AHR, 1.90; 95% CI, 1.16-3.12), but limited follow-up and low numbers precluded further analyses. No associations were observed for prenatal exposure to lamotrigine (AHR, 1.18; 95% CI, 0.95-1.47), levetiracetam (AHR, 1.28; 95% CI, 0.77-2.14), carbamazepine (AHR, 1.13; 95% CI, 0.85-1.50), or oxcarbazepine (AHR, 0.68; 95% CI, 0.44-1.05).
CONCLUSIONS AND RELEVANCE
In this cohort study of children born to mothers with epilepsy, the associations found between prenatal exposure to certain ASMs and the child's risk of epilepsy did not persist in sensitivity analyses, suggesting that maternal ASM use in pregnancy may not increase epilepsy risk in children beyond that associated with the maternal epilepsy itself. These findings are reassuring for women in need of treatment with ASM in pregnancy.
Topics: Male; Child; Pregnancy; Humans; Female; Valproic Acid; Topiramate; Cohort Studies; Prenatal Exposure Delayed Effects; Prospective Studies; Epilepsy; Vitamins; Mothers
PubMed: 38407908
DOI: 10.1001/jamanetworkopen.2023.56425 -
International Journal of Molecular... Jun 2024The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and...
The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.
Topics: Animals; Oxcarbazepine; Mice; Anticonvulsants; Electroshock; Male; Disease Models, Animal; Seizures; Brain; Memory, Long-Term; Carbamazepine; Avoidance Learning
PubMed: 38928457
DOI: 10.3390/ijms25126751 -
Ear and HearingTypewriter tinnitus refers to a special kind of staccato tinnitus, which is mostly described by patients as Morse code, popcorn, or machine-gun. It has been accepted...
INTRODUCTION
Typewriter tinnitus refers to a special kind of staccato tinnitus, which is mostly described by patients as Morse code, popcorn, or machine-gun. It has been accepted that the mechanism of typewriter tinnitus is caused by the neurovascular compression of the cochleovestibular nerve. Patients who suffered from typewriter tinnitus have exhibited a good response to carbamazepine or oxcarbazepine, but there is a risk of recurrence after treatment cessation. The present study aims to determine the value of auditory brainstem response (ABR) in diagnosing typewriter tinnitus and predicting relapse after drug withdrawal.
METHODS
Patients who presented with typewriter tinnitus from March 2019 to March 2022 were included for the present retrospective study. The auditory and vestibular test results and drug treatment effects were collected and analyzed. Patients with idiopathic unilateral subjective tinnitus, who were matched by age to patients with typewriter tinnitus at a ratio of 2:1, were consecutively recruited for the control group.
RESULTS
Eighteen patients with typewriter tinnitus and 38 controls were included. Ears with typewriter tinnitus had longer interpeak latency (IPL) I-III, and wave III and V latencies, and a higher ratio of IPL I-III ≥2.3 ms based on ABR, when compared to the unaffected side and controls ( p <0.05). Seventeen patients with typewriter tinnitus responded positively to medication. Among these patients, seven patients had a relapse after drug cessation, while 10 patients did not have a relapse. The relapse group had significantly longer IPL I-III and wave V latency, older age, and poorer hearing, when compared to the nonrelapse group ( p < 0.05). Furthermore, IPL I-III had the largest area under the receiver operating characteristic curve, and the optimal cutoff was 2.4 ms (sensitivity, 100.0%; specificity, 66.7%). There were no significant differences in other demography or other clinical test results between the relapse and nonrelapse groups ( p > 0.05). Ramsay Hunt syndrome and neuromyelitis optica spectrum disorders were identified in two cases.
CONCLUSION
Prolonged IPL I-III based on ABR can help in the diagnosis of typewriter tinnitus and its prognosis after treatment cessation. Patients with IPL I-III greater than 2.4 ms, older age and poorer hearing are more likely to relapse. In addition to the neurovascular conflict of the cochleovestibular nerve, the etiologies of neuroinflammation and demyelinating diseases are also possible for typewriter tinnitus.
Topics: Humans; Tinnitus; Retrospective Studies; Prognosis; Evoked Potentials, Auditory, Brain Stem; Recurrence
PubMed: 37171375
DOI: 10.1097/AUD.0000000000001382 -
Expert Opinion on Drug Safety Jan 2024Recently, case reports of priapism associated with the use of some anti-seizure medications began to emerge in the literature. We aimed to investigate if there is a... (Review)
Review
BACKGROUND
Recently, case reports of priapism associated with the use of some anti-seizure medications began to emerge in the literature. We aimed to investigate if there is a potential safety signal of priapism among individual anti-seizure medications and to search the literature for relevant published cases.
RESEARCH DESIGN AND METHODS
We conducted a disproportionality analysis using OpenVigil 2.1 to query the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database. Literature search was conducted in PubMed/MEDLINE, Scopus and Web of Science up to 12 July 2023.
RESULTS
We identified positive signal of priapism for valproic acid and its derivatives ( = 23, chi-squared = 59.943, PRR = 4.566), gabapentin ( = 20, chi-squared = 9.790, PRR = 2.060), lamotrigine ( = 16, chi-squared = 8.318, PRR = 2.120), levetiracetam ( = 16, chi-squared = 10.766, PRR = 2.329), topiramate ( = 14, chi-squared = 28.067, PRR = 3.972) and carbamazepine ( = 8, chi-squared = 6.147, PRR = 2.568), as well as published cases of priapism associated with these drugs. We also found published cases of priapism for pregabalin and phenytoin in the literature and FAERS, and at least one reported adverse event of priapism in FAERS for clonazepam, lacosamide, ethosuximide, oxcarbazepine, and vigabatrin in which they were considered primary suspect.
CONCLUSIONS
Our study identified signals for priapism for several anti-seizure medications, but these results need to be confirmed in well-designed pharmacoepidemiological studies.
Topics: Male; Humans; United States; Pharmacovigilance; Priapism; Anticonvulsants; Gabapentin; Levetiracetam; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration
PubMed: 38062555
DOI: 10.1080/14740338.2023.2293208 -
Medicine Nov 2023Posterior reversible encephalopathy syndrome (PRES) is a rare complication commonly associated with headache and acute changes in blood pressure that results from a...
RATIONALE
Posterior reversible encephalopathy syndrome (PRES) is a rare complication commonly associated with headache and acute changes in blood pressure that results from a variety of causes, culminating in vasogenic cerebral edema in the occipital and parietal lobes of the brain.
PATIENT CONCERNS
We report here a woman who suffered from headache, generalized tonic-clonic seizures, and cortical blindness in the late postpartum period.
DIAGNOSES
Posterior reversible encephalopathy syndrome.
INTERVENTIONS
The patient was treated with amlodipine besylate tablets for hypertension, dehydration with mannitol and glycerin fructose, and antispasmodic treatment with sodium valproate and oxcarbazepine.
OUTCOMES
On day 2, the patient became conscious, headache and vision improved. One week later, symptoms and signs disappeared, blood pressure returned to normal, and brain MRI lesions disappeared in re-examination.
LESSONS
Eclampsia associated with PRES is reversible in most cases, but it is a serious and potentially life-threatening obstetric emergency. If adequate treatment is provided in a timely manner, most women will make a full recovery. Attention needs to be paid to timely and adequate treatment, as well as appropriate follow-up and support for patients with PRES.
Topics: Pregnancy; Humans; Female; Eclampsia; Posterior Leukoencephalopathy Syndrome; Postpartum Period; Brain Diseases; Puerperal Disorders; Headache
PubMed: 37960797
DOI: 10.1097/MD.0000000000035867 -
Journal of Pharmacy Practice Jun 2024Phenytoin (PHT) has been approved for the treatment of epilepsy. It belongs to the category of medications with a limited therapeutic window and requires therapeutic...
Phenytoin (PHT) has been approved for the treatment of epilepsy. It belongs to the category of medications with a limited therapeutic window and requires therapeutic drug monitoring (TDM). PTH has been observed to induce a variety of Adverse drug reactions (ADRs) including ataxia, dystonia, nystagmus, dyskinesia, etc. Phenytoin-induced ataxia is an uncommonly observed ADR of Phenytoin whose reports are extremely limited. Herein, we present a case report of a 16-year-old Asian patient with a past history of epilepsy that was admitted to a tertiary care hospital due to the development of ataxia, giddiness, and vomiting when taking Phenytoin in addition to Oxcarbazepine, Clobazam, and Levetiracetam to treat seizures. On admission, Magnetic resonance imaging (MRI) findings revealed bilateral variable cerebrospinal fluid (CSF) lesions in the parieto-occipital region of the periventricular area (periventricular leukomalacia). Additionally, serum Phenytoin levels were observed to be in the toxic range (40 μg/mL) due to which physicians confirmed the ADR to be due to Phenytoin toxicity. Thus, the Phenytoin drug was discontinued in the patient gradually and he was continued on clobazam, oxcarbazepine, and brivaracetam which led to reversal of the ADR in the patient. In this case, ataxia resulted from Phenytoin overdose, as confirmed by MRI and serum tests suggesting that TDM of Phenytoin is essential to prevent ADRs. Given the scarcity of ataxia cases caused by Phenytoin, awareness is lacking within the scientific community. Our aim is to provide insights to promote better monitoring and patient-centered treatment outcomes for epileptic patients.
PubMed: 38871356
DOI: 10.1177/08971900241262379 -
Frontiers in Pharmacology 2023Rhabdomyolysis is a potentially fatal adverse reaction mostly triggered by certain medications. Few real-world studies have shown a clear association between...
Rhabdomyolysis is a potentially fatal adverse reaction mostly triggered by certain medications. Few real-world studies have shown a clear association between newer-generation anti-seizure medications (ASMs) and rhabdomyolysis. We sought to quantify the risk and evaluate the clinical features and management of rhabdomyolysis associated with newer-generation ASMs. Data were retrieved from the US FDA Adverse Event Reporting System database (FAERS) from 2018 to 2022 on newer-generation ASMs to identify rhabdomyolysis events, and disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports from 2012 to 31 December 2022 on newer-generation ASMs-induced rhabdomyolysis were retrieved for retrospective analysis. A total of 1,130 rhabdomyolysis reports from the FAERS database were considered. Levetiracetam had the greatest proportion and the highest positive signal values of rhabdomyolysis. The RORs (95% CIs) for newer-generation ASMs were, in descending order, levetiracetam 8.01 (7.26-8.84), lamotrigine 3.78 (3.25-4.40), oxcarbazepine 3.47 (2.53-4.75), pregabalin 2.75 (2.43-3.12), lacosamide 1.85 (1.29-2.65), topiramate 1.64 (1.25-2.15), and gabapentin 1.32 (1.13-1.55). Twenty-six case reports showed evidence of rhabdomyolysis, and levetiracetam (65.4%) was the most frequently reported agent. The median age was 32 years; typical initial symptoms included muscle weakness (34.8%), myalgia (34.8%), backache (17.4%), fatigue (13.0%) and leg pain (8.7%). The median time to onset of rhabdomyolysis was 2 days. All cases had elevated creatine phosphokinase (CPK), and some cases were accompanied by elevated creatinine (57.1%) and myoglobinuria (53.8%). Cessation of ASMs could lead to complete clinical remission. The median time for creatine phosphokinase (CPK) normalization was 8 days. This study identified 7 newer-generation ASMs with significant rhabdomyolysis reporting associations. Prescribers should be more aware of this risk and teach patients to recognize rhabdomyolysis signs/symptoms early.
PubMed: 37849732
DOI: 10.3389/fphar.2023.1197470 -
HLA Sep 2023In this observational case-control study, 107 cutaneous adverse reaction (CAR) cases (CAR+) manifesting up to 12 weeks after the start of treatment with antiseizure... (Observational Study)
Observational Study
In this observational case-control study, 107 cutaneous adverse reaction (CAR) cases (CAR+) manifesting up to 12 weeks after the start of treatment with antiseizure medication (ASM) were identified. Control groups consisted of 98 epilepsy patients without a history of CAR (CAR-) and 3965 healthy individuals in the Brazilian National Registry of Bone Marrow Donors. All participants were HLA typed by high-resolution Next Generation Sequencing for HLA-A, B, C, DQB1 and DRB1; HLA-DPA1, DPB1, DQA1, DRB3, DRB4 and DRB5 were also sequenced in samples from CAR+ and CAR- individuals. The relationship between the carrier frequency of each allele, CAR type and ASM for all participants was investigated. The ASMs most frequently associated with CAR were carbamazepine (48% of CAR+ subjects), lamotrigine (23%), phenytoin (18%), phenobarbital (13%) and oxcarbazepine (5%). The main alleles associated with a risk of CAR were HLA-A*02:05 (OR = 6.28; p = 0.019, carbamazepine or oxcarbazepine); HLA-DPA1*02:02 (OR = 4.16, p = 0.003, carbamazepine); HLA-B*53:01 (OR = 47.9, p = 0.014, oxcarbazepine), HLA-DPA1*03:01/DPB1*105:01 (OR = 25.7, p = 0.005, phenobarbital); HLA-C*02:10 (OR = 25.7, p = 0.005, phenobarbital) and HLA-DRB1*04:02 (OR = 17.22, p = 0.007, phenytoin). HLA-A*03:01 increased the risk for phenytoin-induced maculopapular exanthema 4.71-fold (p = 0.009), and HLA-B*35:02 was associated with a 25.6-fold increase in the risk of carbamazepine-induced Stevens-Johnson syndrome (p = 0.005). None of the 4170 subjects carried the HLA-B*15:02 allele, and HLA-A*31:01 was not associated with CAR. Hence, HLA-A*31:01 and HLA-B*15:02 were not associated with CAR in this population. Although other HLA class I and II alleles tested were associated with a risk of CAR, none of these associations were strong enough to warrant HLA testing before prescribing ASM.
Topics: Humans; Alleles; Brazil; Oxcarbazepine; Phenytoin; Case-Control Studies; HLA-B Antigens; Carbamazepine; HLA-A Antigens; Phenobarbital
PubMed: 37002612
DOI: 10.1111/tan.15045 -
Epilepsia Dec 2023This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially...
OBJECTIVE
This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially started on monotherapy.
METHODS
The data were derived from the Human Epilepsy Project. Differences between the durations of the most commonly first prescribed ASM monotherapies were assessed using a Cox proportional hazards model. Subjects were classified into three groups: monotherapy, sequential monotherapy, and polytherapy.
RESULTS
A total of 443 patients were included in the analysis, with a median age of 32 years (interquartile range [IQR] = 20-44) and median follow-up time of 3.2 years (IQR = 2.4-4.2); 161 (36.3%) patients remained on monotherapy with their initially prescribed ASM at the time of their last follow-up. The mean (SEM) and median (IQR) duration that patients stayed on monotherapy with their initial ASM was 2.1 (2.0-2.2) and 1.9 (.3-3.5) years, respectively. The most commonly prescribed initial ASM was levetiracetam (254, 57.3%), followed by lamotrigine (77, 17.4%), oxcarbazepine (38, 8.6%), and carbamazepine (24, 5.4%). Among those who did not remain on the initial monotherapy, 167 (59.2%) transitioned to another ASM as monotherapy (sequential monotherapy) and 115 (40.8%) ended up on polytherapy. Patients remained significantly longer on lamotrigine (mean = 2.8 years, median = 3.1 years) compared to levetiracetam (mean = 2.0 years, median = 1.5 years) as a first prescribed medication (hazard ratio = 1.5, 95% confidence interval = 1.0-2.2). As the study progressed, the proportion of patients on lamotrigine, carbamazepine, and oxcarbazepine as well as other sodium channel agents increased from a little more than one third (154, 34.8%) of patients to more than two thirds (303, 68.4%) of patients.
SIGNIFICANCE
Slightly more than one third of focal epilepsy patients remain on monotherapy with their first prescribed ASM. Approximately three in five patients transition to monotherapy with another ASM, whereas approximately two in five end up on polytherapy. Patients remain on lamotrigine for a longer duration compared to levetiracetam when it is prescribed as the initial monotherapy.
Topics: Humans; Young Adult; Adult; Lamotrigine; Oxcarbazepine; Levetiracetam; Epilepsy; Anticonvulsants; Epilepsies, Partial; Carbamazepine; Benzodiazepines
PubMed: 37846772
DOI: 10.1111/epi.17802