Relevance of NR1I2 variants on carbamazepine therapy in Mexican Mestizos with epilepsy at a tertiary-care hospital

Aim: We evaluated the potential influence of genetic ( CYP3A5, EPHX1, NR1I2, HNF4A, ABCC2, RALBP1, SCN1A, SCN2A and GABRA1) and nongenetic factors on carbamazepine (CBZ) response, adverse drug reactions and CBZ plasma concentrations in 126 Mexican Mestizos (MM) with epilepsy. Subjects & methods: Patients were genotyped for 27 variants using TaqMan® assays. Results: CBZ response was associated with NR1I2 variants and lamotrigine cotreatment. CBZ-induced adverse drug reactions were related to antiepileptic polytherapy and SCN1A rs2298771/rs3812718 haplotype. CBZ plasma concentrations were influenced by NR1I2-rs2276707 and -rs3814058, and by phenytoin cotreatment. CBZ daily dose was also influenced by NR1I2-rs3814055 and EPHX1-rs1051740. Conclusion: Interindividual variability in CBZ treatment was partly explained by NR1I2, EPHX1 and SCN1A variants, as well as antiepileptic cotreatment in MM with epilepsy.

A Novel Real-Time PCR Assay for Detection of HLA-A*31:01 in Individuals Being Considered for Carbamazepine Therapy

BackgroundCarbamazepine, an anticonvulsant also used as a mood stabilizer and for trigeminal neuralgia, is associated with serious, sometimes fatal cutaneous adverse drug reactions, including Stevens Johnson Syndrome and toxic epidermal necrolysis1. Current literature demonstrates a genetic predisposition linked to specific class I and II human leukocyte antigen (HLA) types in various ethnic populations2. HLA-A*31:01 is one such HLA type, and is routinely identified by the tag SNP rs1061235. However, rs1061235 has poor specificity for HLA*31:01 due to interference of HLA-A*33 types3. We investigated the false positive rate in our population and developed a novel real-time PCR assay that distinguishes HLA-A*31:01 from other HLA-A types including HLA-A*33.Methods120 unique samples were tested in triplicate during the validation of this assay and were sent to a reference lab for HLA next generation sequencing (NGS) typing, including 89 in-house samples and 31 Coriell samples with documented HLA typing results. The results from our real-time PCR assay were compared to the HLA typing results. HLA typing results were also compared to the tag SNP rs1061235 results to calculate the false positive rate.ResultsThere was 100% concordance between our real-time PCR results and expected results based on HLA typing. 89 sample results for tag SNP rs1061235 were compared to HLA typing results. 75/89 samples had a rs1061235 variant, but 31/75 (41%) samples did not have the HLA-A*31:01 type, thus defining the false positive rate of the tag SNP for our population. We theorized there would be a small subset of rare HLA-A types that would interfere with the assay and we tested the three types available to us. We confirmed that 3 of the HLA types (HLA-A*31:04, 31:12, and 31:16) result falsely positive due to sequence homology with 31:01. There is no known literature indicating whether these rare HLA-A*31 subtypes are associated with cutaneous adverse reactions. These 3 HLA types and the other suspected interfering HLA types have limited frequency data sets and are expected to occur rarely in our patient population; we expect these HLA types make up less than 0.003% of the our population. Our assay specificity for the validation is >99%.ConclusionsOur custom real-time PCR assay for detection of HLA-A*31:01 is significantly more specific than the commonly used tag SNP rs1061235. Clinicians considering carbamazepine therapy for their patients will have a better understanding of cutaneous adverse reaction risk and can make improved personalized treatment decisions. This quick, cost effective assay allows more patients in need of carbamazepine treatment to benefit from its use.FundingGenomind, Inc.

Favorable response to carbamazepine therapy in genetically proven myoclonus-dystonia child

Background Myoclonus dystonia (MDS) is a dominantly inherited genetic disorder caused by loss-of-function mutations in the epsilon sarcoglycan gene (SGCE). Case presentation We here in report a twenty months old Saudi boy who presented to us with a concern that the child is unable to walk properly. On assessment, he was flexing his left arm and left leg that usually followed by a back-ward fall. Diagnosis of dystonia induced with initiation of movement was suggested that later on proven genetically to be pathogenic mutation of sarcoglycan gene. Carbamazepine therapy was initiated with dramatic response. Response was maintained at 4 years follow up. Conclusions Our patient and the other previously reported cases might highlight the response of SGCE mutations to carbamazepine therapy.

Effect of carbamazepine on emotional intelligence and mindfulness in patients with partial epilepsy

Objective: To assess the effectiveness of carbamazepine on emotional intelligence and mindfulness in patients with epilepsy. Method: The repeated-measure case-control study was conducted at the Nishter Hospital, Multan, Bahawal Victoria Hospital, Bahawalpur, and Civil Hospital, Bahawalpur, Pakistan, from April 2017 to March 2018, and comprised patients with partial epilepsy and healthy controls. Baseline data was collected using BarOn Emotional Quotient Inventory and Cognitive and Affective Mindfulness Scale-Revised. Subsequent data was collected twice in titration and maintenance phases during carbamazepine therapy for patients, while the controls were on no medication. . Data was analysed using SPSS 20. Results: Of the 80 subjects, 40(50%) were cases with a mean age of 37.92±9.09 years, and 40(50%) were controls with a mean age of 37.80±9.00 years. The patients had significantly lower emotional intelligence and mindfulness compared to the controls (p<0.001). Patients showed improved emotional intelligence and mindfulness after the therapy compared to their baseline scores (p<0.05). Conclusion: Carbamazepine was found to be effective in improving emotional intelligence and mindfulness in patients with epilepsy. Key Words: Epilepsy, Carbamazepine, Mindfulness, Cognition, Continuous...

Association of Dyslipidemia and Hyperhomocysteinemia in epileptic patients on carbamazepine monotherapy.

Objectives: To observe the association between dyslipidemia and homocysteine level in epileptic patients; especially on carbamazepine monotherapy. Study Design: Cross sectional study. Setting: Neurology Department and Epilepsy Centre of Jinnah Post Graduate Medical Centre, Karachi. Period: From January 2015 – January 2016. Material & Methods: Total 300 subjects, aged more than 15 years were included and divided into three groups. Group A (100 healthy individuals) was control group, Group B (100 newly diagnosed epileptic patients without antiepileptic therapy), Group C (100 epileptic patients on Carbamazepine therapy, which was further subdivided into C-I (n=33) had epileptic patients on Carbamazepine therapy less than 1 year, C-II (n=33) comprised of epileptic patients on Carbamazepine therapy 1-2 years and C-III (n=33) had epileptic patients on Carbamazepine therapy more than 2 years. Serum lipid profile and homocysteine levels were measured. Results: In patients with different durations of carbamazepine monotherapy; a noteworthy incremental trend in the levels of homocysteine, total cholesterol, triglyceride, low density lipoprotein cholesterol, very low density lipoprotein cholesterol was observed. Homocysteine was found positively correlated with total cholesterol, triglyceride, low density lipoprotein cholesterol, very low density lipoprotein cholesterol. Conclusion: In our study dyslipidemia was associated with hyperhomocysteinemia, which in turn was correlated with atherosclerosis in CBZ treated epileptic patients.

Association of Dyslipidemia and Hyperhomocysteinemia in epileptic patients on carbamazepine monotherapy.

Objectives: To observe the association between dyslipidemia and homocysteine level in epileptic patients; especially on carbamazepine monotherapy. Study Design: Cross sectional study. Setting: Neurology Department and Epilepsy Centre of Jinnah Post Graduate Medical Centre, Karachi. Period: From January 2015 – January 2016. Material & Methods: Total 300 subjects, aged more than 15 years were included and divided into three groups. Group A (100 healthy individuals) was control group, Group B (100 newly diagnosed epileptic patients without antiepileptic therapy), Group C (100 epileptic patients on Carbamazepine therapy, which was further subdivided into C-I (n=33) had epileptic patients on Carbamazepine therapy less than 1 year, C-II (n=33) comprised of epileptic patients on Carbamazepine therapy 1-2 years and C-III (n=33) had epileptic patients on Carbamazepine therapy more than 2 years. Serum lipid profile and homocysteine levels were measured. Results: In patients with different durations of carbamazepine monotherapy; a noteworthy incremental trend in the levels of homocysteine, total cholesterol, triglyceride, low density lipoprotein cholesterol, very low density lipoprotein cholesterol was observed. Homocysteine was found positively correlated with total cholesterol, triglyceride, low density lipoprotein cholesterol, very low density lipoprotein cholesterol. Conclusion: In our study dyslipidemia was associated with hyperhomocysteinemia, which in turn was correlated with atherosclerosis in CBZ treated epileptic patients.

Infrequent Monitoring of the Effects of Valproate and Carbamazepine Therapy in Patients With Epilepsy in Nigeria

Background: Carbamazepine and valproate are widely used in the treatment of epileptic seizures. However, these agents exhibit certain adverse effects including hematopoietic disorders (carbamazepine) and severe hepatotoxicity (valproate). Purpose: To determine the extent of monitoring of the hematologic effects of carbamazepine as well as the extent of monitoring of the hepatic effects of valproate in patients with epilepsy receiving treatment with these agents. Method: A cross-sectional antiepileptic drug use study using case notes of patients with epilepsy managed at the neurologic clinics of 2 tertiary medical facilities in Nigeria between January and December 2017. Results: Carbamazepine was the most frequently prescribed antiepileptic drug (48.24%), followed by valproate (29.34%) and levetiracetam (9.24%). Pretreatment monitoring of hematologic effect was carried out in only 61.11% of patients placed on carbamazepine therapy while follow-up monitoring was done in 3.7% of these patients. Also, in patients placed on valproate therapy, pretreatment and follow-up monitoring of the hepatic effect was done in only 33.71% and 19.0% of the patients, respectively. Conclusions: The extent of monitoring of the hematologic effects of carbamazepine, as well as the hepatic effects of valproate in the cohort studied, is poor.

DRESS Syndrome Secondary to Carbamazepine Therapy Presenting with Bilateral Acute Anterior Uveitis and Angle Closure Glaucoma

Purpose: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, lifethreatening multi-system adverse drug reaction characterized by febrile skin rash, hematologic abnormalities, and involvement of internal organs. We report a case of DRESS syndrome in a child presenting with primary ophthalmic manifestations. Case Report: An 11-year-old boy presented with severe pain and diminished vision in both eyes six weeks after starting carbamazepine therapy for seizure disorder. Ocular examination revealed features of bilateral acute anterior uveitis, acute onset myopia, and angle closure glaucoma secondary to uveal effusion. Additionally, the patient was febrile with a generalized maculopapular rash, and blood investigations revealed eosinophilic leukocytosis. A diagnosis of carbamazepine-induced DRESS syndrome was made, and carbamazepine therapy was discontinued. Treatment with cycloplegics, topical, and systemic steroids resulted in prompt clinical recovery. Conclusion: Ophthalmologists should be aware that hypersensitivity to anticonvulsants, such as carbamazepine, can present with bilateral uveitis and uveal effusion along with systemic symptoms. Prompt diagnosis and treatment can prevent vision loss and life-threatening complications. Patients should be counselled about potential adverse effects of anticonvulsants before therapy.

Carbamazepine-Induced Pure Red Cell Aplasia

Antiepileptic therapy is associated with various hematologic disorders. Pure red cell aplasia (PRCA) is a rare disease that may be congenital or acquired. Severe normocytic anemia, reticulocytopenia, and absence of erythroblasts from an otherwise normal bone marrow should raise the suspicion of PRCA. A 32-year-old unmarried woman was admitted with fatigue for 4 months. She had been on carbamazepine therapy for 4 years (200 mg twice daily) for seizure disorder. On evaluation, she was diagnosed to have PRCA secondary to carbamazepine. We describe a patient with carbamazepine-induced PRCA that improved after discontinuation of the drug.