The interplay of epilepsy with impaired mitophagy and autophagy linked dementia (MAD): A review of therapeutic approaches.

The duration and, age of dementia have been linked to a higher risk of seizures. The exact mechanism that drives epileptogenesis in impaired mitophagy and autophagy linked dementia (MAD) is fully defined after reviewing the Scopus, Publon, and Pubmed databases. The epileptogenesis in patients with Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) is due to involvement of amyloid plaques (Aß), phosphorylated tau (pTau), Parkin, NF-kB and NLRP3 inflammasome. Microglia, the prime protective and inflammatory cells in the brain exert crosstalk between mitophagy and inflammation. Several researchers believed that the inflammatory brain cells microglia could be a therapeutic target for the treatment of a MAD associated epilepsy. There are conventional antiepileptic drugs such as gabapentin, lamotrigine, phenytoin sodium, carbamazepine, oxcarbazepine, felbamate, lamotrigine, valproate sodium, and topiramate are prescribed by a psychiatrist to suppress seizure frequency. Also, the conventional drugs generate serious adverse effects and synergises dementia characteristics. The adverse effect of carbamazepine is neurotoxic and also, damages haemopoietic system and respiratory tract. The phenytoin treatment causes cerebellar defect and anemia. Dementia and epilepsy have a complicated relationship, thus targeting mitophagy for cure of epileptic dementia makes sense. Complementary and alternative medicine (CAM) is one of the rising strategies by many patients of the world, not only to suppress seizure frequency but also to mitigate dementia characteristics of patients. Therefore our present review focus on the interplay between epilepsy and MAD and their treatment with CAM approaches.

Bilateral calcaneal insufficiency fractures due to chronic carbamazepine use for trigeminal neuralgia: A case report.

Stress fractures of calcaneus are uncommon cause of heel pain. Stress fractures could be seen in risc groups such as metabolic diseases/medications causing poor bone quality and exposing repetitive microtrauma. Anti-epileptic drug (AED) use is related with poor bone quality and increased fracture risc. Although carbamazepine-induced stress fracture is a well-known entity and there are case reports in other bones such as the femoral neck, bilateral calcaneal insufficiency fractures is an extraordinary location. To the best of our knowledge, this is the first case reporting an insufficiency fracture involving calcaneus in the relevant literature. Due to the rarity of both conditions, we decided to present and discuss this patient. When patients receiving AED treatment present with heel pain without previous plantar fasciitis history or traumatic event, insufficiency fractures should be kept in mind. This case highlights the importance of screening adverse effect of CBZ on bone metabolism in patients with long CBZ use. We report here a 41-year-old lady suffering from bilateral heel pain without trauma history. Her complaining did not respond to analgesics and stretching exercises of plantar fascia. In her past medical history she reported ongoing carbamazepine (CBZ) use over 8 years for trigeminal neuralgia. She had had low bone mineral density; defined as osteopenia. Both calcaneus MRI revealed bilateral stress fractures of calcaneum. She had been advised immobilization for 6 weeks, vitamin D and calcium supplements. CBZ has been stopped by neurology specialist and she had undergone microvascular decompression surgery for intractable pain of trigeminal neuralgia. She is doing well with full recovery from heel pain and trigeminal neuralgia at the end of one year. CBZ use causes poor bone quality through vitamin D metabolism. Heel pain without traumatic event, objective findings of plantar fasciitis and calcaneal spur syndrome in an CBZ using patient insufficiency fracture of calcaneus should be remembered and evaluated rigorously.

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero - the Norwegian Mother and Child Cohort Study.

BACKGROUND AND PURPOSE: The purpose was to examine the consequences of antiepileptic drug (AED) exposure during pregnancy on language abilities in children aged 5 and 8 years of mothers with epilepsy. METHODS: The study population included children of mothers with and without epilepsy enrolled in the Norwegian Mother and Child Cohort Study 1999-2008. Mothers prospectively provided information on epilepsy diagnosis, AED use during pregnancy and the child's language abilities at age 5 and 8 years, in questionnaires with validated language screening tools. AED concentrations in gestation week 17-19 and in the umbilical cord were measured. RESULTS: The study population included 346 AED-exposed and 388 AED-unexposed children of mothers with epilepsy, and 113 674 children of mothers without epilepsy. Mothers of 117 and 121 AED-exposed children responded to the questionnaires at age 5 and 8 years, respectively. For AED-exposed children, the adjusted odds ratio for language impairment was 1.6 [confidence interval (CI) 1.1-2.5, P = 0.03] at age 5 years and 2.0 (CI 1.4-3.0, P < 0.001) at age 8 years, compared to children of mothers without epilepsy. Children exposed to carbamazepine monotherapy had a significantly increased risk of language impairment compared to control children at age 8 years (adjusted odds ratio 3.8, CI 1.6-9.0, P = 0.002). Higher maternal valproate concentrations correlated with language impairment at age 5 years. Periconceptional folic acid supplement use protected against AED-associated language impairment. CONCLUSION: Foetal AED exposure in utero is associated with an increased risk of language impairment in children aged 5 and 8 years of mothers with epilepsy. Periconceptional folic acid use had a protective effect on AED-associated language impairment.

Valproate decreases vitamin D levels in pediatric patients with epilepsy.

PURPOSE: To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls. METHODS: A meta-analysis performed on articles identified from PubMed and Web of Science online databases evaluated using National Institute of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Subgroup analyses and publication bias assessments were also performed. RESULTS: Eleven publications were eligible based on inclusion/exclusion criteria for the meta-analysis. Results noted a decrease in the mean Vit D level in children with epilepsy on valproate monotherapy compared with healthy children with a Standard Mean Difference = -0.313 [-0.457, -0.169]. Cumulative meta-analysis showed progressive negative effect of valproate therapy on Vit D levels across time. Other antiepileptic medications caused a similar effect on Vit D status. There was no evidence of publication bias in the analyses. Type of study design and country of origin introduced heterogeneities into the meta-analyses. CONCLUSION: This meta-analysis provides evidence that long-term therapy with valproate causes a decrease in Vit D levels in children. Therefore, in children with a seizure disorder on long-term valproate therapy, 25-OH-Vit D levels should be monitored and appropriate supplementation implemented if levels are deficient.

Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary.

PURPOSE/BACKGROUND: High risks of neural tube defects and other teratogenic effects are associated with exposure in early pregnancy to some anticonvulsants, including in women with bipolar disorder. METHODS/PROCEDURES: Based on a semistructured review of recent literature, we summarized findings pertaining to this topic. FINDINGS/RESULTS: Valproate and carbamazepine are commonly used empirically (off-label) for putative long-term mood-stabilizing effects. Both anticonvulsants have high risks of teratogenic effects during pregnancy. Risks of neural tube defects (especially spina bifida) and other major malformations are especially great with valproate and can arise even before pregnancy is diagnosed. Standard supplementation of folic acid during pregnancy can reduce risk of spontaneous spina bifida, but not that associated with valproate or carbamazepine. In contrast, lamotrigine has regulatory approval for long-term use in bipolar disorder and appears not to have teratogenic effects in humans. IMPLICATIONS/CONCLUSIONS: Lack of protective effects against anticonvulsant-associated neural tube defects by folic acid supplements in anticipation of and during pregnancy is not widely recognized. This limitation and high risks of neural tube and other major teratogenic effects, especially of valproate, indicate the need for great caution in the use of valproate and carbamazepine to treat bipolar disorder in women of child-bearing age.

[The decreased level of plasma carnitine in patients with epilepsy]. / Snizhenie kontsentratsii karnitina u patsientov s épilepsiei.

Antiepileptic drugs (AEDs) have long been known to affect carnitine metabolism, dropping the plasma free carnitine. Valproate (VPA) was considered to be the strongest carnitine-reducing agent. VPA-induced hyperammonemic encephalopathy and hepatotoxicity are well known, and pre-existing carnitine deficiency can be a predisposing factor, especially in congenital metabolic disorders. Several studies have shown that carnitine supplementation in patients receiving VPA to result in subjective and objective improvements and to prevent VPA-induced hepatotoxicity and encephalopathy, in parallel with increases in carnitine serum concentrations. Level of free plasma carnitine <20 micromol/l (syn. carnitine deficiency) in patients with epilepsy (in 15-30% of cases) may occur not only with administration of VPA but with administration of other AEDs (phenobarbital, phenytoin, carbamazepine) and low nutritional intake of carnitine. Some findings indicate that the number of AEDs used is a risk factor for carnitine deficiency. It was established that body weight, height and multidrug therapy are significantly associated with low level of free plasma in epileptic patients. Carnitine deficiency can have severe consequences; but most epileptic patients suffering from it are asymptomatic. Although carnitine deficiency is not uncommon among patients receiving AEDs, it seems not necessary to routinely monitor carnitine levels in epileptic ambulatory patients, this is reasonable only in groups of risk. L-carnitine supplementation is clearly indicated in case of VPA-induced hepatotoxicity (i.v. administration) VPA overdose (i.v. administration), primary carnitine-transporter defect and is strongly recommended in specific secondary carnitine deficiency syndromes, symptomatic VPA-associated hyperammonemia, infants and young children receiving VPA, especially those younger than 2 years, patients with a complex neurologic disorder, who are receiving multiple AEDs, patients who have risk factors for hepatotoxicity and carnitine insufficiency. In the absence of double blind trials, clinical practice is based on empiric observation, clinical experience, and theory. Well-designed studies of specific and general uses of L-carnitine replacement therapy in patients with epilepsy are needed.

Trends in culprit drugs and clinical entities in cutaneous adverse drug reactions: a retrospective study.

PURPOSE: Morbidity due to cutaneous adverse drug reactions (CADRs) is quite common. The specific culprit drugs change over time and clinicians must be kept informed with updated knowledge, thus preventing potential CADRs. This retrospective study is a survey of CADRs encountered in a hospital-based population in Southern China during three time intervals, from 1984 to 2015. MATERIALS AND METHODS: The clinical records were review of 306 patients with CADRs who were admitted to our hospital from 2011 to 2015. These data were compared with patients visiting our hospital during 1984-1994 and 2003-2010. RESULTS: From 2011 to 2015, the most common CADRs were exanthematous reactions (40.8%) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN; 17.0%). There were eight cases (2.6%) of CADRs related to targeted therapy in oncology. In the 205 CADR cases that were due to single medications, the most common offending drugs were allopurinol (21.5%), cephalosporins (10.7%) and carbamazepine (10.2%). The percentages of CADR cases due to allopurinol, carbamazepine, or epidermal growth factor receptor inhibitors were significantly higher from 2011 to 2015 compared with 1984-1994 or 2003-2010. The rate of SJS/TEN occurrence was significantly higher in the two recent periods compared with 1984-1994. CONCLUSIONS: Changes in drug prescriptions are a major factor that affects the CADRs seen in clinical records. Newer drugs can be culpable for CADRs, and more CADRs are now documented with increased severity at clinical presentation. Reliable screening tests for specific drugs are urgently required to eliminate possible fatalities.

Recurrent venous thrombosis under rivaroxaban and carbamazepine for symptomatic epilepsy.

BACKGROUND: The direct oral anticoagulant (DOAC) rivaroxaban, an oral Factor Xa inhibitor, is increasingly used as an alternative to vitamin-K-antagonists (VKAs). Absorption and elimination of DOACs are dependent on the permeability glycoprotein (P-gp) efflux transporter protein system, and DOACs are substrates of the hepatic cytochrome P 450 3A4 (CYP3A4) enzymes. Therefore, drug-interactions may occur when DOACs are administered with drugs affecting the activity of P-gp or CYP3A4 systems. Several antiepileptic drugs like carbamazepine are known to affect P-gp and CYP3A4-activity. CASE REPORT: A 55-year-old male was admitted because of pain and swelling of his right leg spontaneously since 2 days. He was under a therapy with 20mg rivaroxaban since 4 months because of an unprovoked venous thrombosis of his right leg. He had a history of poliomyelitis at age 6 months, structural epilepsy due to poly-microgyria with complex partial seizures with secondary generalization since age 6 years, why he was treated with carbamazepine (900mg/d). He reported to be highly adherent to his anticoagulant and antiepileptic medication. Anti-Xa activity was <20ng/ml according to a rivaroxaban calibrated anti-factor Xa assay. Therapy with rivaroxaban was stopped, and low-molecular-weight heparin, followed by phenprocoumon, was started. CONCLUSION: The combination of DOACs with carbamazepine, an inducer of P-gp and CYP3A4-activity, should be avoided since the anticoagulant effect is decreased. There is an urgent need to increase our knowledge and physicians' awareness about the potential of drug-drug interactions of DOACs.

Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians.

OBJECTIVE: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). METHODS: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)-induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. RESULTS: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10-10; odds ratio 27.90; 95% confidence interval [CI] 7.84-99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077-0.584). CONCLUSIONS: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

Hyperhomocysteinaemia in children receiving phenytoin and carbamazepine monotherapy: a cross-sectional observational study.

OBJECTIVE: Long-term therapy with phenytoin and carbamazepine is known to cause hyperhomocysteinaemia. We evaluated the prevalence of hyperhomocysteinaemia in North Indian children receiving phenytoin or carbamazepine monotherapy for >6 months duration and the effect of folic acid supplementation on plasma homocysteine. METHODS: In this cross-sectional observational study we enrolled consecutive children aged 2-12 years with epilepsy who had received phenytoin or carbamazepine monotherapy for >6 months. Plasma total homocysteine, folic acid, vitamin B12 and antiepileptic drug concentrations were measured. Healthy age- and sex-matched controls were recruited. Children with homocysteine >10.4 µmol/L received folic acid supplementation for 1 month and homocysteine and folic acid concentrations were measured after 1 month follow-up. RESULTS: A total of 112 children receiving antiepileptic monotherapy for >6 months were enrolled. Hyperhomocysteinaemia was present in 54 children (90%) receiving phenytoin, 45 children (90%) receiving carbamazepine therapy and 17 (34%) controls (p<0.05). Mean plasma homocysteine concentrations were significantly higher (18.9±10.2 vs 9.1±3 µmol/L) and serum folic acid concentrations (10.04±8.5 ng/ml vs 12.6±4.8 p<0.001) and vitamin B12 concentrations (365±155 pg/mL vs 474±332 pg/mL, p=0.02) were significantly lower in the study group compared with the control group. Duration of antiepileptic drug therapy correlated significantly with elevated homocysteine and reduced folic acid concentrations (p<0.05). Supplementation with folic acid for 1 month led to a reduction in plasma homocysteine concentrations in the study group (from 20.9±10.3 µmol/L to 14.2±8.2 µmol/L, p<0.05). CONCLUSIONS: Phenytoin or carbamazepine monotherapy for >6 months duration is associated with hyperhomocysteinaemia in 90% of North Indian children. Elevated homocysteine concentrations were normalised in these children with folic acid supplementation.

Adenosine A1 receptor-mediated suppression of carbamazepine-resistant seizure-like events in human neocortical slices.

OBJECTIVE: The need for alternative pharmacologic strategies in treatment of epilepsies is pressing for about 30% of patients with epilepsy who do not experience satisfactory seizure control with present treatments. In temporal lobe epilepsy (TLE) even up to 80% of patients are pharmacoresistant, and surgical resection of the ictogenic tissue is only possible for a minority of TLE patients. In this study we investigate purinergic modulation of drug-resistant seizure-like events (SLEs) in human temporal cortex slices. METHODS: Layer V/VI field potentials from a total of 77 neocortical slices from 17 pharmacoresistant patients were recorded to monitor SLEs induced by application of 8 mM [K(+) ] and 50 µm bicuculline. RESULTS: Activating A1 receptors with a specific agonist completely suppressed SLEs in 73% of human temporal cortex slices. In the remaining slices, incidence of SLEs was markedly reduced. Because a subportion of slices can be pharmacosensitive, we tested effects of an A1 agonist, in slices insensitive to a high dose of carbamazepine (50 µm). Also in these cases the A1 agonist was equally efficient. Moreover, ATP and adenosine blocked or modulated SLEs, an effect mediated not by P2 receptors but rather by adenosine A1 receptors. SIGNIFICANCE: Selective activation of A1 receptors mediates a strong anticonvulsant action in human neocortical slices from pharmacoresistant patients. We propose that our human slice model of seizure-like activity is a feasible option for future studies investigating new antiepileptic drug (AED) candidates.

Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen.

The development of immune-dependent drug hypersensitivity reactions (IDHR) is likely to involve activation of the innate immune system to stimulate neo-antigen specific T-cells. Previously it has been shown that, upon oral exposure to several drugs with immune-adjuvant capacity, mice developed T-cell-dependent responses to TNP-OVA. These results were indicative of the adjuvant potential of these drugs. The present study set out to evaluate the nature of this adjuvant potential by focusing on early immune changes in the spleen, by testing several drugs in the same experimental model. Mice were exposed to one or multiple oral doses of previously-tested drugs: the non-steroidal-anti-inflammatory drug (NSAID) diclofenac (DF), the analgesic acetaminophen (APAP), the anti-epileptic drug carbamazepine (CMZ) or the antibiotic ofloxacin (OFLX). Within 24 h after the final dosing, early innate and also adaptive immune parameters in the spleen were examined. In addition, liver tissue was also evaluated for damage. Exposure to APAP resulted in severe liver damage, increased levels of serum alanine aminotransferase (ALT) and local MIP-2 expression. DF exposure did not cause visible liver damage, but did increase liver weight. DF also elicited clear effects on splenic innate and adaptive immune cells, i.e. increased levels of NK cells and memory T-cells. Furthermore, an increase in plasma MIP-2 levels combined with an influx of neutrophils into the spleen was observed. OFLX and CMZ exposure resulted in increased liver weights, MIP-2 expression and up-regulation of co-stimulatory molecules on antigen-presenting cells (APC). The data suggested that multiple immune parameters were altered upon exposure to drugs known to elicit immunosensitization and that broad evaluation of immune changes in straightforward short-term animal models is needed to determine whether a drug may harbor the hazard to induce IDHR. The oral exposure approach as used here may be applied in the future as an immunotoxicological research tool in this type of evaluation.

The bone mineral content alterations in pediatric patients medicated with levetiracetam, valproic acid, and carbamazepine.

AIM: The negative effect of antiepileptic drugs on bone health has been previously documented. However, which antiepileptic drug is safer in regard to bone health is still questionable. Our aims were to investigate the bone mineral density alterations in pediatric patients who receive antiepileptic medication for a minimum of two years and to compare the results of these drugs. MATERIALS AND METHODS: Fifty-nine patients (32 males, 27 females; mean age: 8.6±4.6years) and a control group (13 males, 7 females; mean age: 7.6±3.3years) were included in the study. The patients were receiving necessarily the same antiepileptic drugs (AEDs) for at least two years, and none of the patients had mental retardation or cerebral palsy. The patients were divided into three groups: group 1 (patients receiving levetiracetam (LEV), n=20), group 2 (patients receiving carbamazepine (CBZ), n=11), and group 3 (patients receiving valproic acid (VPA), n=28). Plasma calcium (Ca), phosphorus (P), parathyroid hormone (PTH), alkaline phosphatase (ALP), vitamin D levels, and bone mineral density (BMD) values of femur and vertebras (L1-4) and z-scores (comparative results of BMD values of the patients with the age- and gender-matched controls in device database) of the groups were compared. RESULTS: The differences between P, PTH, ALP and age, Ca and BMD results, and vitamin D levels of the patients in all four groups was not statistically significant according to Kruskal-Wallis test (p>0.05). The z-score levels of all the patient and control groups were also not statistically significantly different compared with each other. CONCLUSION: In contrast to previous reports in pediatric patients, our study has documented that there is not a considerable bone loss in patients receiving long-term AED medication. Although levetiracetam has been proposed as bone-protecting medication, we did not observe any difference between AEDs regarding bone mineral density after two years of treatment.

IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.

OBJECTIVE: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. METHODS: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. RESULTS: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85. CONCLUSIONS: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

Vascular function and risk factors in children with epilepsy: associations with sodium valproate and carbamazepine.

AIM: To investigate biochemical cardiovascular risk factors and vascular endothelial function and structure in children with epilepsy on antiepileptic drugs (AEDs), particularly sodium valproate (VPA) and carbamazepine (CBZ). BACKGROUND: Individuals with epilepsy have increased risk factors for vascular disease, particularly lipid abnormalities and elevated total plasma homocyst(e)ine (tHcy). AED induced B-vitamin deficiencies have been suggested to contribute to this risk. Vitamin B supplementation has consequently been recommended for children on AEDs. Early vascular endothelial dysfunction and atherosclerosis are detectable by measuring flow-mediated dilation (FMD) and intima-media thickness (IMT). METHODS: Thirty children with epilepsy on AEDs (13.3±2.3 years, 14 male) and 30 controls (13.9±2.9 years, 14 male) were recruited. Fasting tHcy, folate, pyridoxal-5-phosphate (PLP), vitamin B12, glucose and lipids were measured. Vascular function and structure were assessed using FMD (brachial artery) and IMT (carotid/aortic arteries). RESULTS: No differences were found between children with epilepsy and controls for tHcy, folate, PLP, lipids, FMD, carotid or aortic IMT. Vitamin B12 levels were elevated and glucose reduced in children treated with VPA. Elevated total cholesterol, cholesterol/HDL ratio and triglycerides occurred in children treated with CBZ. Aortic IMT correlated with weight (r=0.75, p<0.001), BMI (r=0.54, p=0.01), and HDL cholesterol (r=-0.58, p=0.006). CONCLUSION: We found no early changes in vascular function or structure in children on valproate or carbamazepine. We were also unable to confirm previous reports of tHcy abnormalities in this group. This may be due to higher B-vitamin intake, which compensates for loss of vitamins induced by this AED therapy. Vitamin supplementation in children with epilepsy on valproate and carbamazepine is not required in populations with adequate dietary intake of B vitamins.

Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.

OBJECTIVES: Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine. METHODS: Fifteen-year prospective observational study from 1996 until 2012. The main outcome measure is the MCM rate. RESULTS: Informative outcomes were available for 5206 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy and 2198 to lamotrigine monotherapy. The MCM risk with valproate monotherapy exposure in utero was 6.7% (95% CI 5.5% to 8.3%) compared with 2.6% with carbamazepine (95% CI 1.9% to 3.5%) and 2.3% with lamotrigine (95% CI 1.8% to 3.1%). A significant dose effect was seen with valproate (p=0.0006) and carbamazepine (p=0.03) exposed pregnancies. A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (>400 mg daily) was lower than the MCM rate for pregnancies exposed to <600 mg daily of valproate, but this was not significant (3.4% vs 5.0%, p=0.31). CONCLUSIONS: In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.

Acute effect of carbamazepine on corticothalamic 5-9-Hz and thalamocortical spindle (10-16-Hz) oscillations in the rat.

A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)-thalamocortical (TC) network, more specifically on CT 5-9-Hz and TC spindle (10-16-Hz) oscillations. Two to three successive 5-9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5-9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5-9-Hz depolarizing wave-hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately -70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5-9-Hz waves can trigger TC spindles.

Carbamazepine-induced DRESS syndrome in a child: rapid response to pulsed corticosteroids.

DRESS syndrome is an idiosyncratic reaction to drugs, which can occur in both adults and children. To date there is no agreed upon criteria for its diagnosis; there is even less consensus on its management. We report the case of a 14- year-old boy with carbamazepine induced DRESS syndrome, predominantly involving the liver. He responded rapidly to high dose pulsed intravenous corticosteroids.

Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing.

Human leukocyte antigen B (HLA-B) is a gene that encodes a cell surface protein involved in presenting antigens to the immune system. The variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in response to carbamazepine treatment. We summarize evidence from the published literature supporting this association and provide recommendations for the use of carbamazepine based on HLA-B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this article is to provide information to allow the interpretation of clinical HLA-B*15:02 genotype tests so that the results can be used to guide the use of carbamazepine. The guideline provides recommendations for the use of carbamazepine when HLA-B*15:02 genotype results are available. Detailed guidelines regarding the selection of alternative therapies, the use of phenotypic tests, when to conduct genotype testing, and cost-effectiveness analyses are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on the PharmGKB website at (http://www.pharmgkb.org).