Manna Jose

Malformation risk of antiepileptic drug exposure during pregnancy in women with epilepsy: Results from a pregnancy registry in South India

Kerala Registry of Epilepsy and Pregnancy had been prospectively evaluating the reproductive issues of women with epilepsy since April 1998. This analysis aimed to estimate the relative risk of major congenital malformations (MCM) to the registrants.

Role of multidrug transporters in neurotherapeutics

Acquired resistance to antibiotics and other chemotherapeutic agents is a major problem in the practice of neurology and other branches of medicine. There are several mechanisms by which drug resistance is acquired. Multidrug transporters are important glycoproteins located in the cell membrane that actively transport small lipophilic molecules from one side of the cell membrane to the other, most often from the inside to the outside of a cell. They have important protective role yet may prove inconvenient in chemotherapy. In epilepsy and other disorders this mechanism augments the elimination of drugs from their target cells and leads to drug resistance. In this review, we have discussed the biochemical characteristics of multidrug transporters and the mechanisms by which these membrane bound proteins transport their target molecules from one side to the other side of the cell membrane. We have also briefly discussed the application of this knowledge in the understanding of drug resistance in various clinical situations with particular reference to neurological disorders. These proteins located in the placenta have important role in preventing the transplacental movement of drugs in to the fetus which may result in congenital malformations or other defects. The molecular genetic mechanisms that govern the expression of these important proteins are discussed briefly. The potential scope to develop targeted chemotherapeutic agents is also discussed.

Risk of major congenital malformations in the offsprings of women with epilepsy is not related to family history

UNLABELLED We aimed to ascertain whether family history of major congenital malformations (MCMs) was increased in women with epilepsy (WWE) compared to controls (spouses) and whether family history of MCM was associated with occurrence of MCM in the offspring. PATIENTS AND METHODS Women enrolled in the Kerala Registry of Epilepsy and Pregnancy were probands of this study. The control group comprised of unaffected spouses and their families. We interviewed the probands and spouses to construct detailed pedigree charts with information on MCM. All live born infants of WWE underwent clinical examination, echocardiography and ultrasonography. RESULTS Data were collected for 11,777 family members of probands (n=573) and 10,832 family members of controls (n=550). Family history of MCM was positive for 84 probands (0.71%) and 64 controls (0.59%). Corresponding figures for first degree relatives were 32 out of 2717 for probands (1.18%) and 27 out of 2992 for controls (0.90%). Among the second degree relatives 52 out of 9060 for probands (0.71%) and 64 out of 10,832 for the controls (0.50%) had history of MCM. These differences were not statistically significant (p value=0.29, 0.37 and 0.42, respectively). There was no significant difference in the frequency of MCM between probands with generalized epilepsy and localization related epilepsy. Out of the 426 live born infants of the probands, 44 had MCM; two with family history and 42 without family history (OR 0.74; 95% CI 0.19-3.26). CONCLUSIONS WWE of Asian Indian origin have no familial tendency for MCM and the offsprings with family history have no increased risk of MCM.

Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy

Aim: Pregnancy in women with epilepsy (WWE) who are on anti-epileptic drugs (AEDs) has two- to three-fold increased risk of fetal malformations. AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1. Patients on AED therapy can have folate deficiency. We hypothesize that the polymorphisms in ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase (MTHFR) might result in differential expression resulting in differential drug transport, drug metabolism and folate metabolism, which in turn may contribute to the teratogenic impact of AEDs. Materials and Methods: The ABCB1, Cyp2C9, Cyp2C19 and MTHFR polymorphisms were genotyped for their role in teratogenic potential and the nature of teratogenecity in response to AED treatment in WWE. The allelic, genotypic associations were tested in 266 WWE comprising of 143 WWE who had given birth to babies with WWE-malformation (WWE-M) and 123 WWE who had normal offsprings (WWE-N). Results: In WWE-M, CC genotype of Ex07 + 139C/T was overrepresented (P = 0.0032) whereas the poor metabolizer allele *2 and *2 *2 genotype of CYP2C219 was significantly higher in comparison to WWE-N group (P = 0.007 and P = 0.005, respectively). All these observations were independent of the nature of malformation (cardiac vs. non cardiac malformations). Conclusion: Our study indicates the possibility that ABCB1 and Cyp2C19 may play a pivotal role in the AED induced teratogenesis, which is independent of nature of malformation. This is one of the first reports indicating the pharmacogenetic role of Cyp2C19 and ABCB1 in teratogenesis of AED in pregnant WWE.

Teratogenicity of antiepileptic dual therapy: Dose-dependent, drug-specific, or both?

Objective To determine the relative risk (RR) of major congenital malformations (MCMs) in infants with antenatal exposure to antiepileptic drug (AED) dual therapy and to explore the influence of specific AEDs vs dose. Methods All completed pregnancies prospectively enrolled in the Kerala Registry of Epilepsy and Pregnancy from 1998 until December 2013 on AED dual therapy exposure during the first trimester were analyzed for the outcome, MCMs. Dose was expressed as ratio of prescribed to daily defined dose (PDD/DDD), and the RR for malformation was referenced to lamotrigine monotherapy. Results Of 1,688 completed pregnancies, 368 women were on dual therapy. The risk of MCM with dual therapy was 1.6 times more than with monotherapy (p = 0.0015). The frequency of renal, alimentary, and skeletal malformations was higher with dual therapy, while cardiac malformations were more common with monotherapy. The risk of MCM was highest with topiramate dual therapy (14.82, 95% confidence interval [CI] 1.88–113.83). No MCMs were seen with levetiracetam or lamotrigine dual therapy. There was a marked reduction in the risk of MCM when dual therapies involving topiramate or valproate were excluded (RR 1.78, 95% CI 1.00–3.15). The risk of MCM with dual therapy was higher even at lower doses (8.2%, PDD/DDD 0.5–1), and the subsequent dose-dependent increment was less profound than with monotherapy. Conclusions Our data indicate that the excess risk of dual therapy over monotherapy is contributed largely by topiramate or valproate. The complex pharmacokinetic and pharmacodynamic effects of dual therapy adversely influence MCM risk.

Spontaneous fetal loss in women with epilepsy: prospective data from pregnancy registry in India

OBJECTIVE To ascertain the risk of spontaneous fetal loss (SPFL) in women with epilepsy (WWE) on antiepileptic drugs (AED), and explore the association between specific AED usage and risk of SPFL. METHODS We identified all SPFL (including stillbirths) among pregnancies registered at Kerala Registry for Epilepsy and Pregnancy between 1998 and 2015. Rates of SPFL were compared between the AED exposed and unexposed groups. RESULTS There were 139 SPFL out of 1987 eligible pregnancies. The AED exposed had excess SPFL (7.4%, 134 out of 1809, Odds Ratio [OR] 2.77, 95% Confidence Interval [CI] 1.17-6.39) than AED unexposed (2.8%, 5 out of 178). The adjusted OR (95% CI) for SPFL for monotherapies with levetiracetam, phenobarbitone and clobazam were comparable to unexposed, while it was significantly higher for topiramate (OR 38.86, CI 5.02-301.19), lamotrigine (OR 13.33, CI 1.41-125.78), oxcarbazepine (OR 7.53, CI 1.54-36.89), valproate (OR 6.92, CI 1.70-28.18), phenytoin (OR 5.82, CI 1.43-23.73) and carbamazepine (OR 3.53, CI 1.15-10.90). With reference to levetiracetam, only topiramate had significantly higher SPFL (OR 11.14, CI 1.56-79.55). CONCLUSION SPFL risk is increased in pregnancies with AED exposure, being least with levetiracetam and highest with topiramate.

Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome?

OBJECTIVE The management of Women With Epilepsy (WWE) in pregnancy is a challenge that demands balancing the risks of Major Congenital Malformation (MCM) on one hand with adequate seizure control on the other. While most studies have analysed the risks of Anti-Epileptic Drugs (AED) exposure in the first trimester, AED changes during the second and third trimester and their effects on fetal outcome has not been studied adequately. MATERIALS AND METHODS Data of WWE who were prospectively followed up and completed pregnancy with live birth under the Kerala registry of epilepsy and pregnancy (KREP) between 1998 and 2014 were analysed. The AED addition, dose escalation, unchanged continuation, dose reduction or stoppage during the second or third trimester in comparison to the first trimester was tabulated for each drug. The outcome measures evaluated were malformation status and Developmental Quotient (DQ) at one year as extracted from the clinical records of the registry. RESULTS The first trimester AED exposure was nil for 231, monotherapy for 925 and polytherapy for 391 WWE. WWE on monotherapy in first trimester were more likely to remain on the same number of AEDs in second or third trimester than those who were on polytherapy (OR 3.1, 95% CI 2.2 - 4.46). AED naïve women had a higher likelihood (OR 16.7; 95% CI 10.9-25.8) of being started on AED than women on monotherapy being switched to polytherapy. At least one AED was reduced or stopped during second or third trimester more often in women on polytherapy (15.1%) than in women on monotherapy (3.7%) (OR 4.7; 95% CI 2.9-7.2). Malformation rates for the infants of women whose AED dosage was increased or added were not significantly different from those of others. There was no statistically significant change in DQ with increase in dose or addition of drugs in the second or third trimester. CONCLUSION AEDs were reduced in a significant proportion of patients on polytherapy while more than a third of women who were not on AEDs in the first trimester were subsequently started on AEDs. Increase in dose or addition of AEDs after the first trimester is unlikely to influence malformation outcome but the potential adverse effect on the DQ needs to be explored on a larger set of data.

Epileptiform discharges in EEG and seizure risk in adolescent children of women with epilepsy

We aimed to study the epileptiform discharges (ED) and seizure risk in EEG of 12-18-year-old children of women with epilepsy (WWE). Children of WWE who were prospectively followed up in the Kerala registry of epilepsy and pregnancy (KREP), aged 12-16years (n=92; males 48, females 44) underwent clinical evaluation and a 30-min digital 18-channel EEG. The EEG showed epileptiform discharges in 13 children (5 males and 8 females). The EDs were generalized in 9 and focal in 4 (occipital 2, frontal 1, and centroparietal 1). They had significantly higher risk of ED (odds ratio 4.02, 95% CI 1.04-15.51) when compared to published prevalence of ED in healthy children. There were 2 children with epilepsy (one with localization-related epilepsy and the other generalized epilepsy). The children under study had a trend towards higher prevalence of epilepsy (odds ratio 3.39, 95% CI 0.82-13.77) when compared to age specific prevalence of epilepsy from community surveys in same region. Children of WWE showed increased risk of ED in EEG and trend towards increased seizure risk when compared to healthy children.

Teratogenic effects of carbamazepine in mice

Objectives: The aim of this study was to determine the teratogenic effects of carbamazepine (CBZ) in BALB/c mice. Materials and Methods: Mature female and male BALB/c mice (25–30 g) were used for all experiments. After standardization of administration and dose of CBZ, animals in the CBZ-treated groups (CBZ 450 mg/kg and 600 mg/kg) were fed on medicinal diet. The dams in the control group were mated on the same day as that of the CBZ-treated dams. After cesarean section (CS), fetal viability status and weights were recorded. Gross histopathological examination of fetuses was conducted to identify alterations in morphology and external or internal organs due to in utero exposure of CBZ. Results: Out of the nine female animals (three treated on CBZ 450 mg/kg, three treated on CBZ 600 mg/kg and three controls), seven were pregnant, and two (one each from the two CBZ-treated groups) were nonpregnant. All fetuses of the control group (n = 31) and CBZ 450 mg/kg treated group (n = 24) were live, but eight out of the twenty fetuses (40%) of CBZ 600 mg/kg treated group were dead at CS. The birth weight of the fetuses antenatally exposed to CBZ was drastically reduced (0.71 ± 0.06) when compared to control fetuses (1.67 ± 0.12) (P < 0.0001). All the fetuses of the CBZ-treated groups showed stunted physical development. Conclusion: Although oral administration of CBZ to mice is a convenient model to study the effect of CBZ to pregnancy, higher oral dose was associated with increased fetal loss. Some of the fetuses exposed to CBZ demonstrated structural abnormalities and low body weight.