HLA-B*53:01 Is a Significant Risk Factor of Liver Injury due to Phenytoin and Other Antiepileptic Drugs in African Americans.

INTRODUCTION: To investigate human leukocyte antigen alleles associated with liver injury due to antiepileptic drugs (AEDs) in African Americans (AA). METHODS: In this study, 21 AA with AED drug-induced liver injury (DILI), 176 AA with DILI due to non-AEDs, and 5816 AA population controls were included. RESULTS: HLA-B*53:01 was significantly associated with aromatic AED-DILI (odds ratio: 4.52, 95% confidence interval: 2.42-8.44, P = 1.46 × 10 -5 ). Phenytoin DILI showed the strongest association with HLA-B*53:01 (odds ratio: 9.17; 95% confidence interval: 3.61-23.28, P = 1.1 × 10 -5 ). The HLA-B*53:01 allele was carried by 8 of 9 AA phenytoin DILI cases. DISCUSSION: HLA-B*53:01 is a significant risk factor of liver injury due to antiepileptics, particularly phenytoin, in AA.

Facial dysmorphology in children exposed in pregnancy to anticonvulsant medications correlates with deficits in IQ.

Some children exposed at conception to the antiepileptic drugs (AEDs) phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) have changes in their midface and fingers. It has been suggested that the anticonvulsant-exposed child with these subtle changes in facial features (the "anticonvulsant face") has a greater likelihood of having deficits in IQ in comparison with children exposed to the same anticonvulsants who do not have these features. 115 AED-exposed children (40, PHT; 34, PB; and 41, CBZ) between 6.5 and 16 years of age and 111 unexposed children matched by sex, race, and year in school were evaluated. The evaluations were (WISC-III), physical examination with measurements of facial features and digits and photographs. The AED-exposed children had cephalometric radiographs, but not the unexposed. Each parent had a similar examination of face and hands plus tests of intelligence. These AED-exposed children showed an increased frequency of a short nose and anteverted nares, features of the "anticonvulsant face." Lateral skull radiographs showed a decrease in the angle between the anterior cranial base and nasal bone, which produces anteverted nares. Mean IQs were significantly lower on one or more IQ measures for the children with these facial features. Shortening of the distal phalanges and small fingernails correlated with the presence of a short nose in that child. The findings in 115 children exposed at conception to either phenytoin, phenobarbital, or carbamazepine, as monotherapy, confirmed the hypothesis that those with a short nose and anteverted nares had a lower IQ than exposed children without those features.

Phenytoin is associated with increased risk of osteoporosis and fragility fractures in adult epileptic patients.

INTRODUCTION: Osteoporotic fractures lead to significant decreases in the quality of life with increases in morbidity, mortality, and disability. Treatment with a variety of anti-epileptic drugs, such as phenytoin, has been understood to cause a decrease in bone mineral density. MATERIALS AND METHODS: Cohort A was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures that were also prescribed phenytoin. Cohort B was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures but were not prescribed phenytoin or other anti-epileptic medications. Cohorts were matched for relevant confounding pathologies and demographic factors. Outcomes were evaluated from 1 day to 5 years after the indexed event. RESULTS: A total of 35,936 patients with epilepsy that were prescribed phenytoin were matched with 109,335 patients with epilepsy that were not prescribed phenytoin. Patients on phenytoin therapy were at significantly higher risk for osteoporosis without pathological fracture, fracture of metatarsal bone, fracture of shoulder and upper arm, fracture of distal radius, fracture of thoracic vertebra, fracture of cervical vertebra, fracture of lumbar vertebra, fracture of femoral head or neck, pertrochanteric fracture, femoral shaft fracture, and distal tibia fracture (all outcomes p < 0.001). CONCLUSION: Epileptic patients on phenytoin therapy that were 18-55 years old exhibited higher associated risk of osteoporosis and osteoporotic-fragility fractures of various regions. Patients that undergo phenytoin therapy for epilepsy treatment should be educated on the increased risk of bone fractures and have appropriate lifestyle and diet modifications.

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial.

OBJECTIVE: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE. METHODS: We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug. RESULTS: A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061). CONCLUSION: The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT. TRIAL REGISTRATION NUMBER: jRCTs031190160.

Phenytoin Intoxication in a Patient Receiving a Therapeutic Dose for Postoperative Seizure Prophylaxis: A Case Study.

OBJECTIVE: Phenytoin is commonly prescribed to prevent postoperative seizures. Despite the rarity of the CYP2C9 genetic polymorphism, which may result in poor phenytoin metabolism, in the Thai population, the authors report a case of phenytoin toxicity in a patient with poor metabolism administered with a standard dose of phenytoin. CASE REPORT: A 58-year-old Thai woman presented to the outpatient clinic with a 2-day history of nausea, vomiting, and dizziness. She underwent craniotomy for tumor removal 2 weeks after being diagnosed with tuberculum sellae meningioma. After the surgery, she was prescribed 300 mg of phenytoin daily to prevent seizures. During the physical examination, ataxia, horizontal nystagmus, and cerebellar abnormalities were observed, with an initial serum phenytoin concentration of 58.85 mg/L. The brain imaging results were unremarkable. Omeprazole was the only recognized drug interaction; however, it is highly unlikely to account for this condition. Pharmacogenetic investigation of CYP2C9 revealed a homozygous CYP2C9*3/*3 mutation, which is indicative of suboptimal drug metabolism and can reduce phenytoin metabolism by 50%. This patient was administered repeated dosages of activated charcoal over the course of 2 days. Her symptoms eventually subsided, with the phenytoin levels dropping to 29.51 mg/L. CONCLUSIONS: In the absence of an overdose history or drug-drug interaction, CYP2C9 polymorphism should be suspected in patients with phenytoin toxicity. In such situations, the phenytoin dosage must be decreased and monitored closely.

Enhancement of receptor-mediated calcium responses by phenytoin through the suppression of calcium excretion in human gingival fibroblasts.

BACKGROUND AND OBJECTIVES: Gingival overgrowth caused by phenytoin is proposed to be associated with Ca2+ signaling; however, the mechanisms that increase the intracellular Ca2+ concentration ([Ca2+ ]i ) are controversial. The current study aimed to elucidate the mechanism underlying the phenytoin-induced increase in [Ca2+ ]i in human gingival fibroblasts (HGFs). METHODS: Effects of 100 µM phenytoin on [Ca2+ ]i in HGFs were examined at the single-cell level using fluorescence images of fura-2 captured by an imaging system consisting of an EM-CCD camera coupled to an inverted fluorescence microscope at room temperature. RESULTS: Exposure of HGFs to 100 µM phenytoin induced a transient increase in [Ca2+ ]i in the absence of extracellular Ca2+ , indicating that the phenytoin-induced increase in [Ca2+ ]i does not require an influx of extracellular Ca2+ . In addition, phenytoin increased [Ca2+ ]i in HGFs depleted of intracellular Ca2+ stores by thapsigargin, indicating that neither Ca2+ release from stores nor inhibition of Ca2+ uptake is involved. Furthermore, the phenytoin-induced [Ca2+ ]i elevation was reduced to 18.8% in the absence of extracellular Na+ , and [Ca2+ ]i elevation upon removal of extracellular Na+ was reduced to 25.9% in the presence of phenytoin. These results imply that phenytoin increases [Ca2+ ]i of HGFs by suppressing the Na+ /Ca2+ exchanger. Suppression of intracellular Ca2+ excretion is thought to enhance the Ca2+ responses induced by various stimuli. Analysis at the single-cell level showed that stimulation with 1 µM ATP or 3 µM histamine increased [Ca2+ ]i in 20-50% of cells, and [Ca2+ ]i increased in many unresponsive cells in the presence of phenytoin. CONCLUSION: Our findings demonstrate that phenytoin induced increase in [Ca2+ ]i by the inhibition of Ca2+ efflux in HGFs. It was also found that phenytoin strongly enhanced small Ca2+ responses induced by stimulation with a low concentration of ATP or histamine by inhibiting Ca2+ efflux. These findings suggest a possibility that phenytoin causes drug-induced gingival overgrowth by interacting with inflammatory bioactive substances in the gingiva.

Valproate-related hyperammonemic encephalopathy with generalized suppression EEG: a case report.

BACKGROUND: Valproic acid (VPA) is a prevalent antiseizure medication (ASM) used to treat epilepsy. Valproate-related hyperammonemic encephalopathy (VHE) is a type of encephalopathy that can occur during neurocritical situations. In VHE, the electroencephalogram (EEG) displays diffuse slow waves or periodic waves, and there is no generalized suppression pattern. CASE PRESENTATION: We present a case of a 29-year-old female with a history of epilepsy who was admitted for convulsive status epilepticus (CSE), which was controlled by intravenous VPA, as well as oral VPA and phenytoin. The patient did not experience further convulsions but instead developed impaired consciousness. Continuous EEG monitoring revealed a generalized suppression pattern, and the patient was unresponsive. The patient's blood ammonia level was significantly elevated at 386.8 µmol/L, indicating VHE. Additionally, the patient's serum VPA level was 58.37 µg/ml (normal range: 50-100 µg/ml). After stopping VPA and phenytoin and transitioning to oxcarbazepine for anti-seizure and symptomatic treatment, the patient's EEG gradually returned to normal, and her consciousness was fully restored. DISCUSSION: VHE can cause the EEG to display a generalized suppression pattern. It is crucial to recognize this specific situation and not to infer a poor prognosis based on this EEG pattern.

Clinical characteristics of antiepileptic-induced liver injury in patients from the DILIN prospective study.

BACKGROUND & AIMS: Antiepileptic drugs (AEDs) are a common cause of drug-induced liver injury (DILI). Over the last few decades, several newer AEDs were approved for marketing in the United States, and they are increasingly prescribed for indications other than seizures. Contemporaneous data related to trends and characteristics of AED-related liver injury are sparse. METHODS: We report the trends, characteristics, and outcomes of patients with AED-related DILI enrolled into the DILIN Prospective Study between 2004 and 2020. RESULTS: Among 1,711 participants with definite, highly likely, or probable DILI, 66 (3.9%) had AED-related DILI (lamotrigine [n = 18], phenytoin [n = 16], carbamazepine [n = 11], valproate [n = 10], gabapentin [n = 4], and others [n = 7]). The frequency of AED-related liver injury significantly decreased during the study period (from 8.5% of cases during 2004-2007 to 2.6% during 2015-2020, p = 0.01). AEDs other than phenytoin were commonly prescribed for non-seizure indications. Compared to non-AEDs, patients with AED-related liver injury were younger (mean age 38.5 vs. 50.1 years-old, p <0.001) and more likely African American (27% vs. 12%, p = 0.008). DRESS was common with liver injury caused by lamotrigine, phenytoin, and carbamazepine, but not valproate or gabapentin. Liver injury severity was moderate to severe in the majority: 5 died, and 3 underwent orthotopic liver transplantation (OLT). No patient with lamotrigine-related DILI, including 13 with hepatocellular jaundice, died or needed OLT, while 3 out of 16 patients (19%) with phenytoin-related DILI either died or required OLT. CONCLUSION: The frequency of AED-related liver injury significantly decreased over the last 2 decades in our experience. AED-related liver injury has several distinctive features, including a preponderance in African American patients and those with immunoallergic skin reactions, with outcomes depending on the type of AED involved. LAY SUMMARY: Medications used to treat epilepsy may sometimes cause severe liver injury. However, several new medications have been approved over the last 2 decades and they may not be as toxic to the liver as older antiepileptic medications (AEDs). This study shows that overall liver injury due to AEDs is decreasing, likely due to decreasing use of older AEDs. Liver injury due to AEDs appears to be more common in African Americans and is commonly associated with allergic skin reactions.

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus.

BACKGROUND: The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. METHODS: In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death. RESULTS: A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant. CONCLUSIONS: In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

Pseudotumour cerebri due to phenytoin in a child.

Pseudotumour cerebri is a manifestation of intracranial hypertension in an otherwise normal individual. We hereby report phenytoin-induced pseudotumour cerebri in a 9-year-old boy who received phenytoin as a prophylactic anticonvulsant following surgical removal of unifocal Langerhans cell histiocytosis involving the right frontal bone. The child was evaluated for headache and diplopia after starting phenytoin and on evaluation was found to have bilateral sixth nerve palsy. The only abnormality detected was an elevated cerebrospinal fluid pressure. Withdrawal of phenytoin resulted in complete resolution of symptoms. Despite meticulous literature search, we found only 1 other report of phenytoin induced pseudotumour cerebri. We report this case to highlight the need to consider this entity whenever a patient presents with new onset or persistent headache and visual symptoms soon after starting a medication since a high degree of suspicion is needed to arrive at the diagnosis and to take appropriate steps before it progresses to harmful complications such as vision loss.

Long-Term Effects of Antiseizure Medications.

Most patients with epilepsy will benefit from seizure control with one of an array of chronic antiseizure medications. Knowledge of the potential long-term effects of these medications is critical to prevent adverse consequences on overall health. Antiseizure medications vary in their capacities to affect the brain and peripheral nerves, hormones, bone mineralization, cardiovascular risk, renal health, hepatic, hematological, and dermatological systems. Understanding of pathophysiology and population risk has evolved, although most of the data available are still on older generation antiseizure medications such as phenytoin, carbamazepine, and valproic acid. The enzyme-inducing properties of some antiseizure medications make their effects on cardiovascular risk and bone health detrimental. Few clear guidelines exist for monitoring long-term effects of medication therapy for epilepsy. When selecting an antiseizure medication, consideration should be given to the individual patient's risks of adverse consequences on other organ systems. During monitoring of patients on chronic therapy, screening tools such as metabolic panels and bone density measurements can help stratify risk and guide management.

Phenytoin induces connective tissue growth factor (CTGF/CCN2) production through NADPH oxidase 4-mediated latent TGFß1 activation in human gingiva fibroblasts: Suppression by curcumin.

OBJECTIVE AND BACKGROUND: Gingival overgrowth (GO) is a common side effect of some drugs such as anticonvulsants, immunosuppressant, and calcium channel blockers. Among them, the antiepileptic agent phenytoin is the most common agent related to this condition due to its high incidence. Transforming growth factor ß (TGFß) importantly contributes to the pathogenesis of GO. Connective tissue growth factor (CTGF or CCN2) is a key mediator of tissue fibrosis and is positively associated with the degree of fibrosis in GO. We previously showed that Src, c-jun N-terminal kinase, and Smad3 mediate TGFß1-induced CCN2 protein expression in human gingival fibroblasts (HGFs). This study investigates whether phenytoin can induce CCN2 synthesis through activated latent TGFß in HGFs and its mechanisms. METHODS: CCN2 synthesis, latent TGFß1 activation, and cellular reactive oxygen species (ROS) generation in HGFs were studied using western blot analysis, a TGFß1 Emax® ImmunoAssay System, and 2',7'-dichlorodihydrofluorescein diacetate (an oxidation-sensitive fluorescent probe), respectively. RESULTS: Phenytoin significantly stimulated CCN2 synthesis, latent TGFß1 activation, and ROS generation in HGFs. Addition of an TGFß-neutralizing antibody, TGFß receptor kinase inhibitor SB431542, and Smad3 inhibitor SIS3 completely inhibited phenytoin-induced CCN2 synthesis. General antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor diphenylene iodonium, and specific NOX4 inhibitor plumbagin almost completely suppressed phenytoin-induced total cellular ROS and latent TGFß1 activation. Curcumin dose-dependently decreased phenytoin-induced TGFß1 activation and CCN2 synthesis in HGFs. CONCLUSIONS: Our findings indicated that NOX4-derived ROS play pivotal roles in phenytoin-induced latent TGFß1 activation. Molecular targeting the phenytoin/NOX4/ROS/TGFß1 pathway may provide promising strategies for the prevention and treatment of GO. Curcumin-inhibited phenytoin-induced CCN2 synthesis is caused by the suppression of latent TGFß1 activation.

Neuropsychological effects in children exposed to anticonvulsant monotherapy during gestation: Phenobarbital, carbamazepine, and phenytoin.

OBJECTIVE: Usage during pregnancy of the antiseizure medication (ASM), phenobarbital (PB), carbamazepine (CBZ), and phenytoin (PHT), has been associated with adverse pregnancy outcomes. While morphological effects on offspring are well-documented, inconsistent findings have been reported on neuropsychological development, possibly due to differences in attention to maternal demographics, and other design characteristics. Herein, we report the results of a carefully designed protocol used to examine the effects of gestational monotherapy with PB, CBZ, or PHT upon children's general mental abilities, when compared to age- and gender- matched children born to unexposed women of similar age, education, and socioeconomic status. METHODS: For each ASM, we selected qualifying cases from children born to PB, CBZ, or PHT monotherapy-exposed and unexposed women. Following the application of inclusion, exclusion, and matching criteria, our sample included 34 PB-exposed, 40 PHT-exposed, and 41 CBZ-exposed children along with matched unexposed children for each drug group. Criteria were applied through examination of maternal medical and educational histories, parental socioeconomic characteristics, and child's age and gender. Each child's physical and neuropsychological characteristics were examined, using standardized protocols. We report on the cognitive performance of the children as assessed by the Wechsler Intelligence Scale for Children - III (WISC-III), the leading measure of mental ability in the U.S. RESULTS: An overall mixed model ANOVA of the adjusted performance of the children across all groups controlling for maternal IQ revealed significant effects on verbal IQ, but not full-scale IQ or performance IQ. In the individual drug and unexposed group comparisons, only reduced verbal and full-scale IQ scores in PB-exposed versus matched unexposed children were found. Comparisons between drug groups revealed a significant reduction in verbal IQ and full-scale IQ in PB-exposed versus PHT-exposed children, but not in other drug-drug comparisons. SIGNIFICANCE: These results demonstrate effects on children's mental ability due to prenatal PB exposure, such that analyses adjusted for maternal IQ scores, revealed reduced verbal mental abilities and reduced full-scale IQ scores when scores in exposed children were compared to scores from children of the same age and sex born to demographically similar, healthy unexposed women. When comparisons were made between drug groups, children exposed prenatally to PB performed significantly worse than prenatally PHT-exposed children, but CBZ-exposed children's scores were not significantly different from those of PB or PHT-exposed groups. In light of shared effects on structural teratogenicity, these findings suggest that use of PB monotherapy for the management of seizures during pregnancy may be associated with increased risk in comparison to PHT when neurobehavioral functioning is considered, and that only PB-exposed children have reduced performance compared to matched controls. Attention to these effects is critical in the developing world where use of these older medications remains predominant, and prudent choices can be made to reduce impact on cognitive development.

Side effects of long-term oral anti-seizure drugs on thyroid hormones in patients with epilepsy: a systematic review and network meta-analysis.

INTRODUCTION: Anti-seizure drugs have long been known to affect thyroid hormone levels in epilepsy patients. The current study is a network meta-analysis designed to produce a systematic review and comprehensive evaluation of thyroid hormone changes to inform future research and clinical treatment. METHOD: A systematic search of databases, PubMed, EMBASE, Web of Science, and the Cochrane Library, was conducted and all observational studies reporting thyroid hormone levels in epilepsy patients receiving monotherapy and controls were included. Stata MP.14 was used for analysis. RESULTS: A total of 35 studies, including 4135 participants and 8 anti-seizure drugs, were analyzed. TSH levels were elevated following use of topiramate [mean = 1.86; 95%CI: 0.83 to 2.90], levetiracetam [mean = 1.08; 95%CI: 0.07 to 2.09], and valproic acid [mean = 1.54; 95%CI: 0.58 to 2.50]. FT4 levels may be lowered by oxcarbazepine [mean = - 6.13; 95%CI: - 8.25 to - 4.02] and T4 was lowered by carbamazepine [mean = - 1.55; 95%CI: - 2.05 to - 1.05] and phenytoin [mean = - 1.33; 95%CI: - 1.80 to - 0.85]. No significant changes were reported for FT3, although use of phenobarbital resulted in a non-significant decrease [mean = - 0.31; 95%CI: - 0.99 to 0.37]. T3 levels were lowered by carbamazepine [mean = - 0.52; 95%CI: - 0.81 to - 0.24]. Lamotrigine had no significant effect on thyroid hormone levels. CONCLUSION: Carbamazepine and phenytoin were the drugs most strongly associated with decreases in T4 and T3 levels while topiramate had the greatest elevating effect on TSH. Oxcarbazepine may lead to decreased serum FT4 and FT3, an effect relevant to central hypothyroidism. Phenobarbital appeared to significantly lower FT3. Use of levetiracetam and valproic acid may result in subclinical hypothyroidism. The anti-seizure drug with the least disruptive effect on thyroid hormone levels was found to be lamotrigine.

A Phenytoin-Induced Ataxia Mimicking a Stroke.

Acute ataxia is commonly the chief complaint among patients visiting the emergency department (ED). It has multiple causes including infection and immunity-related, metabolic, vascular, and organic causes. Therefore, treating physicians should consider the severity and timing of onset in relation to the initial screening tests when making a differential diagnosis, and must be careful not to miss cases that require urgent treatment, such as stroke and drug-induced ataxia. In this report, we describe the case of a 53-year-old woman with recurrent acute ataxia. She had a history of epilepsy but had not had a seizure for over 10 years. She presented to the ED with ataxia that had started the previous evening. She reported two previous episodes of acute ataxia 14 and 4 days previously. She had visited two different hospitals, and undergone two head magnetic resonance imaging (MRI) scans which showed no evidence of a stroke, and had been diagnosed with transient ischemic attacks (TIAs) at both hospitals. She underwent a third head MRI during the ED visit, which again revealed no evidence of a stroke. The plasma levels of phenytoin, carbamazepine, and valproic acid were 21.2 µg/mL (normal range: 7-20 µg/mL), 2.1 µg/mL (normal range: 5-10 µg/mL), and 33.5 µg/mL (normal range: 50-100 µg/mL), respectively. She was finally diagnosed with ataxia due to phenytoin toxicity. Her symptoms improved soon after the phenytoin dose was reduced and did not recur during a year of follow-up.

Efficacy of intravenous levetiracetam versus phenytoin in convulsive status epilepticus and acute repetitive seizures in children.

PURPOSE: Phenytoin is one of the most used antiepileptic drugs (AEDs), but it has serious potential side effects and drug interactions. Although studies have shown levetiracetam to have a much lower side-effect profile, its efficacy when compared with phenytoin is debatable. In our study, we aimed to determine the factors that cause seizure recurrence and to compare the efficacy of levetiracetam and phenytoin in the treatment of convulsive status epilepticus (CSE) and acute repetitive seizures (ARS). METHODS: In this study, 185 patients diagnosed with CSE or ARS and aged between 1 month and 18 years who received intravenous levetiracetam or phenytoin as a second-line AED were retrospectively evaluated. RESULTS: A total of 185 patients were included in the study, 85 (45.9%) girls and 100 (54.1%) boys.While 54.1% (n = 100) of the patients were given phenytoin, levetiracetam was administered to 45.9% (n = 85) of them. The rates of cessation of seizure and prevention of seizure recurrence for 24 h were 84% for phenytoin and 78.8% for levetiracetam, without a significant difference (p > 0.05). Having active seizures on admission to the emergency department and an age of < 36 months were significantly related to seizure recurrence (p < 0.01). CONCLUSIONS: Our results support that the intravenous administration of levetiracetam as the second-line treatment for CSE and ARS in children is as effective as the intravenous administration of phenytoin.

Topical phenytoin administration accelerates the healing of acetic acid-induced colitis in rats: evaluation of transforming growth factor-beta, platelet-derived growth factor, and vascular endothelial growth factor.

Ulcerative colitis (UC), limited to the colon's innermost lining, has become a global health problem. Immunomodulatory and monoclonal antibodies are used to treat UC despite their side effects and limitations. Phenytoin is used to heal wounds owing to its effects on growth factors, collagen, and extracellular matrix synthesis. This study aimed to evaluate the effect of topical phenytoin administration in UC. Phenytoin was administered in two doses during the treatment. Eighty male Wistar rats (230-280 g) were divided randomly into ten groups of sham, control, hydrocortisone, phenytoin 1%, and 3% groups in 6- or 12-day treatment protocols. The UC model was induced by the administration of acetic acid 4% into the colon. Animals were killed on the 7th and 13th postoperative days. The main outcome measures included body weight loss, microscopic score, and ulcer index measured using specific criteria. Growth factors were measured by western blotting. Results illustrated that body weight loss was reversed in the treatment groups. Ulcer index had decreased on 6- and 12-day treatment protocols. Microscopic scores in 6-day enema treatment significantly decreased compared to the control groups. Transforming growth factor-beta (TGFß) significantly increased in a time-dependent manner and platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) significantly increased in a time- and dose-dependent manner in phenytoin 1% and 3% in the 6- and 12-day protocols. Phenytoin dose- and time-dependently reversed weight loss. In addition, histopathological parameters included microscopic scores, and the ulcer index was decreased through the induction of growth factors TGFß, PDGF, and VEGF and consequently accelerated ulcer healing.

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.

BACKGROUND: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. METHODS: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. FINDINGS: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. INTERPRETATION: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. FUNDING: National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Investigating the association of Lamotrigine and Phenytoin-induced Stevens-Johnson syndrome/Toxic Epidermal Necrolysis with HLA-B*1502 in Iranian population.

Previous studies have found an association between HLA-B*1502 allele and lamotrigine-induced Stevens-Johnson syndrome (SJS)/ toxic epidermal necrosis (TEN) spectrum in Han Chinese populations. This study aims to investigate the association between HLA-B*1502 and lamotrigine- or phenytoin- induced SJS/TEN in an Iranian population. The medical records of twenty-eight lamotrigine-induced SJS/TEN patients and twenty-five lamotrigine-tolerant controls as well as eight phenytoin-induced SJS/TEN and twelve phenytoin-tolerant controls were extracted between March 2013 and March 2019 from the university hospitals in Mashhad, Iran. The presence of HLA-B*1502 allele was determined using real-time polymerase chain reaction (PCR). Among lamotrigine-induced patients with SJS/TEN, 11 (39.3%) patients tested positive for the HLA-B*1502 while only 3 (12.0%) of the lamotrigine-tolerant controls tested positive for this allele. The risk of lamotrigine-induced SJS/TEN was significantly higher in patients with HLA-B*1502, with an odds ratio (OR) of 4.74 [95% confidence interval (CI) 1.14-19.73, p = 0.032]. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HLA-B*1502 for lamotrigine-induced SJS/TEN was 39.29%, 88.00%, 78.57% and 56.41%, respectively. The HLA-B*1502 allele was present in 2 (25.0%) of phenytoin-induced SJS/TEN cases and 5 (41.7%) of the phenytoin-tolerant controls tested positive for HLA-B*1502 allele. The risk of phenytoin-induced SJS/TEN was not higher in the patients with HLA-B*1502 (OR = 0.467 [95% confidence interval (CI) 0.065-3.34, p = 0.642]). Lamotrigine-induced SJS/TEN is associated with HLA-B*1502 allele in an Iranian population but this is not the case for phenytoin-induced SJS/TEN.

Incidence rates of severe cutaneous adverse reactions due to antiseizure medication: A nationwide study using health claims data in Korea.

OBJECTIVE: Antiseizure medications (ASMs) can rarely result in severe, sometimes fatal, cutaneous adverse reactions. To date, few studies have reported on the incidence rates (IRs) of severe cutaneous adverse reactions (SCARs) due to ASM use. This study aimed to determine the IRs of SCAR resulting from the use of seven commonly prescribed ASMs, carbamazepine (CBZ), phenytoin (PHT), oxcarbazepine (OXC), lamotrigine (LMT), zonisamide (ZNS), levetiracetam (LVT), and topiramate (TPM), and to compare the associated risks among the drugs. METHODS: Using a nationwide health claims database, we selected all the patients prescribed with one of the target ASMs. We defined a SCAR case as the first hospitalization with one of three specific codes provided by the International Classification of Diseases, 10th revision (L511, L512, and L27). We then calculated the IR of SCARs according to each target ASM. RESULTS: The IR of SCARs for each ASM was as follows: 870/1 000 000 person-years (PYs) for CBZ, 5750/1 000 000 PYs for PHT, 1490/1 000 000 PYs for OXC, 3860/1 000 000 PYs for LMT, 1540/1 000 000 PYs for ZNS, 830/1 000 000 PYs for LVT, and 400/1 000 000 PYs for TPM. Concomitant use of antibiotics and nonsteroidal anti-inflammatory drugs significantly increased the risk of SCARs with OXC, LVT, or TPM use. Comorbid skin disease was associated with a significantly higher IR of SCARs from CBZ, PHT, OXC, LMT, or LVT use. SIGNIFICANCE: This is the first study in Asia to determine the IRs of SCARs for various ASMs and compare the rates across drugs using a large dataset. The results from this study should help clinicians select safer ASMs in practice.