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).
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).
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.
ABCB1; anti-epileptic drugs; Cyp2C19; Cyp2C9; epilepsy; methylene tetrahydrofolate reductase; pharmacogenomics; South India; teratogenic
Clinicians during their training period and practice are often called upon to conduct studies to explore the association between certain exposures and disease states or interventions and outcomes. More often they need to interpret the results of research data published in the medical literature. Case-control studies are one of the most frequently used study designs for these purposes. This paper explains basic features of case control studies, rationality behind applying case control design with appropriate examples and limitations of this design. Analysis of sensitivity and specificity along with template to calculate various ratios are explained with user friendly tables and calculations in this article. The interpretation of some of the laboratory results requires sound knowledge of the various risk ratios and positive or negative predictive values for correct identification for unbiased analysis. A major advantage of case-control study is that they are small and retrospective and so they are economical than cohort studies and randomized controlled trials.
Analysis; case-control study; design
One-third of women with epilepsy (WWE) may experience infertility (failure to conceive after 12 months of regular unprotected intercourse). We aimed to compare the hormone profile of WWE and infertility (WWE-I) with that of WWE who had conceived earlier (WWE-F).
Materials and Methods:
In the Kerala Registry of Epilepsy and Pregnancy, we compared the clinical and hormone profile of 50 WWE-I and 40 age-matched WWE-F. Subjects were examined and blood samples were drawn in follicular phase (1-14 days) for 21 WWE-I and 18 WWE-F, in luteal phase (15-30 days) for 23 WWE-I and 15 WWE-F and beyond 30 days for 6 WWE-I and WWE-F who had irregular cycles.
The two groups were comparable regarding physical, epilepsy syndrome, duration of epilepsy, body mass index, and serum cholesterol levels. Menstrual periods were irregular for 6 WWE-I and 5 WWE-F. The WWE-I group (compared to the WWE-F group) had significantly (P < 0.01) higher levels of dehydroepiandrostenedione (2.0 ± 1.7 ug/mL vs. 1.0 ± 0.7 ug/mL) and luteinizing hormone-LH (26.4 ± 37.3 mIU/mL vs. 9.9 ± 14.5 mIU/mL) and lower levels of progesterone (5.2 ± 9.2 ng/mL vs. 10.4 ± 13.4 ng/mL). There was no significant difference in the levels of FT3, FT4, thyroid stimulating hormone, prolactin, follicle-stimulating hormone (FSH), progesterone, testosterone, or androstenedione levels. The WWE-I had 8.5 times higher risk (95% confidence interval 1.2-59.9) of abnormal LH/FSH ratio. WWE who were on antiepileptic drugs (AEDs) (compared to WWE who were not on AEDs) had higher risk of elevated LH/FSH ratio.
The hormone profile of WWE-I is significantly different from that of WWE-F. These variations need to be interpreted with caution as a causal relationship to epilepsy or use of antiepileptic drugs need to be established through further studies.
Antiepileptic drug; infertility; pregnancy; reproductive endocrine
Oxidative stress can be a final common pathway for AED-induced teratogenesis.
To compare the oxidative stress of women with epilepsy (WWE) and unfavorable pregnancy outcome (fetal malformation or spontaneous abortion - group EM) with that of WWE with normal pregnancy outcome (group ENM) and healthy women with normal pregnancy outcome (group C).
Materials and Methods:
We identified WWE under group EM (n = 43) and group ENM (n = 22) from the Kerala Registry of Epilepsy and Pregnancy (KREP). Group C was constituted of healthy volunteers (N = 20). Oxidative stress was assessed by estimating serum levels of malondialdehyde (MDA) and isoprostane (ISP). The antioxidant profile was evaluated as activity of superoxide dismutase (SOD), glutathione reductase (GR), catalase (CAT), total antioxidant status (TAO), and glutathione (GSH) content.
The MDA and ISP levels for group EM (3.46 + 0.82 and 17.77 + 3.0) were higher than that of group ENM (3.07 + 1.02 and 14.0 + 5.3), and both were significantly higher than that of group C (2.42 + 0.51 and 10.77 + 4.1). Their levels of SOD (146.82 + 42.64 vs. 175.81 + 42.61) and GSH (0.98 + 0.98 vs. 1.55 + 1.3) were significantly lower than those of controls. No significant changes were seen in TAO and GR. WWE on polytherapy showed significant increase in MDA when compared to monotherapy group.
WWE (group EM and ENM) had higher oxidative stress and reduced antioxidant activity. The subgroup of WWE with unfavorable pregnancy outcome (group EM) had higher oxidative stress. Excess oxidative stress can be a final common pathway, by which AEDs exert teratogenic effects.
Anti-epileptic drugs; antioxidant; epilepsy; fetal malformation; oxidative stress; teratogenesis
This article is intended to give the reader guidance in evaluating different study designs used in medical research for better scientific quality, reliability and validity of their research. This article explains three main types of study designs with understanding examples. Care and caution with skills and experience needed to design suitable studies and appropriate design coupled with reliable sampling techniques and appropriate statistical analysis, supported by clear objectives with decent communication of the findings, are essential for good research.
Data analysis; study design; trials
Statistical analysis is an essential technique that enables a medical research practitioner to draw meaningful inference from their data analysis. Improper application of study design and data analysis may render insufficient and improper results and conclusion. Converting a medical problem into a statistical hypothesis with appropriate methodological and logical design and then back-translating the statistical results into relevant medical knowledge is a real challenge. This article explains various sampling methods that can be appropriately used in medical research with different scenarios and challenges.
Design; study; sampling
Stigma and resultant psychosocial issues are major hurdles that people with epilepsy confront in their daily life. People with epilepsy, particularly women, living in economically weak countries are often ill equipped to handle the stigma that they experience at multiple levels. This paper offers a systematic review of the research on stigma from sociology and social psychology and details how stigma linked to epilepsy or similar conditions can result in stereotyping, prejudice and discrimination. We also briefly discuss the strategies that are most commonly utilized to mitigate stigma. Neurologists and other health care providers, social workers, support groups and policy makers working with epilepsy need to have a deep understanding of the social and cultural perceptions of epilepsy and the related stigma. It is necessary that societies establish unique determinants of stigma and set up appropriate strategies to mitigate stigma and facilitate the complete inclusion of people with epilepsy as well as mitigating any existing discrimination.
Epilepsy; gender issues; quality of life; stigma; treatment gap
To assess the knowledge of obstetricians about concerns of women with epilepsy.
Materials and Methods:
We surveyed 97 obstetricians (teaching hospitals—43, private hospitals—32, and community health centers–21) using knowledge of women's issues and epilepsy (KOWIE) questionnaire II with additional questions.
The mean duration of practice of the surveyed obstetricians was 12.4 ± 10.7 years and 94% were female doctors. Most of them were well informed about the teratogenic effects of AEDs (91%), need to continue antiepileptic drugs (AEDs) during pregnancy (95%), and the role of folic acid and vitamin K during pregnancy (95%). They agreed AEDs decrease the efficacy of oral contraception and it was safe for the woman to breast-feed the baby while on AEDs. Only 1/3rd of them knew that steroid hormones could alter seizure threshold or that AEDs could predispose to osteomalacia. Fewer doctors knew that WWE could have increased sexual dysfunction (29.9%) or infertility (26.8%). The knowledge did not vary according to years of practice or practice settings.
Obstetricians were well informed about the fetal complications of antenatal AED exposure, but were under informed of other complications such as osteomalacia, sexual dysfunction, and infertility.
Knowledge; obstetricians; survey; women with epilepsy
The cerebrospinal fluid hypovolemia syndrome (CHS) is an under recognized cause of headache. This study was designed to highlight the clinico-radiological and cerebrospinal fluid (CSF) picture of CHS and their long-term outcome from a tertiary referral center.
Materials and Methods:
The CHS was diagnosed on the basis of the criteria proposed by Chung et al. Cases with CSF rhinorrhoea or other CSF leak or head trauma were excluded from the study.
The study included eight consecutive cases of CHS diagnosed over the past 7 years from 2001. The mean age at diagnosis was 40.7 years (range, 34-56 years) and male-to-female ratio was 1:3. All patients presented with orthostatic headache of subacute onset and normal neurological examination. Magnetic resonance imaging studies of all patients showed hyperintensity of pachymeninges in T2W sequences, venous distension sign, and diffuse pachymeningeal gadolinium enhancement. The descent of the brainstem and subdural effusion were noted in two each (25%). CSF study (n = 5) showed low opening pressure in three (60%), and mild pleocytosis with elevated protein in two each (40%). The mean time to complete recovery with conservative treatment alone was 25.6 days. All radiological signs disappeared with clinical improvement in three patients where follow-up imaging was done. On mean follow-up period of 3.6 years, all were asymptomatic without any recurrence of CHS.
CHS can resolve completely with conservative management and intervention with subdural blood patch or surgical repair would be required only if symptoms persist for more than 1 month.
Headache; spontaneous intracranial hypotension; venous distension sign
Comprehensive instruments to evaluate the child rearing knowledge and practice are not readily available for clinical research.
Materials and Methods:
We have designed in two phases a new instrument to evaluate the child rearing knowledge and practice under the four major domains of child rearing. Twenty-five subject experts from the field of Paediatrics, Obstetrics, Neurology and Nursing elicited the content validity of the instrument. The test retest reliability was evaluated by 25 young mothers who completed the CRKS at an interval of two weeks.
The Content Validity Ratio (CVR) of individual items ranged between 0.6 to 1. The reliability was tested for the 20 individual items of the CRKS using Kappa coefficient. The measurement of agreement Kappa ranged from 0.51 to 1. The total knowledge scores and sub scores data were analysed for correlation using Pearson’s correlation coefficient. A significant Pearson’s correlation indicated that the total scores were consistent over time (r = 0.89). The sub scores on feeding (6 items), Growth and development (4 items), protection (7 items), and infant stimulation (3 items) were found to have reliability of 0.91, 0.76, 0.84, and 0.89 respectively using Pearson’s correlation.
The instrument is found to be valid and reliable and can be used to measure child rearing knowledge and practice in early infancy.
Child rearing knowledge; child rearing practice scale; reliability and validity
To describe the clinical, radiological, and cerebrovascular fluid (CSF) findings and the outcome of microbiologically or histopathologically proven fungal infections of the central nervous system (CNS) in HIV-negative patients.
Methodology and Results:
We identified definite cases of CNS mycosis by screening the medical records of our institute for the period 2000–2008. The clinical and imaging details and the outcome were abstracted from the medical records and entered in a structured proforma. There were 12 patients with CNS mycosis (i.e., 2.7% of all CNS infections treated in this hospital); six (50%) had cryptococcal infection, three (25%) had mucormycosis, and two had unclassified fungal infection. Four (33%) of them had diabetes as a predisposing factor. The common presentations were meningoencephalitis (58%) and polycranial neuritis (41%). Magnetic resonance imaging revealed hydrocephalus in 41% and meningeal enhancement in 25%, as well as some unusual findings such as subdural hematoma in the bulbocervical region, carpeting lesion of the base of the skull, and enhancing lesion in the cerebellopontine angle. The CSF showed pleocytosis (66%), hypoglycorrhachia (83%), and elevated protein levels (100%). The diagnosis was confirmed by meningocortical biopsy (in three cases), paranasal sinus biopsy (in four cases), CSF culture (in three cases), India ink preparation (in four cases), or by cryptococcal polysaccharide antigen test (in three cases). Out of the ten patients for whom follow-up details were available, six patients recovered with antifungal medications (amphotericin B, 1 mg/kg/day for the minimum period of 6 weeks) and/or surgical treatment. Four patients expired (only one of them had received antifungal therapy).
Most patients with CNS mycosis recover with appropriate therapy, but the diagnosis and management of these rare infections remains a challenge to clinicians.
Amphotericin; central nervous system mycosis; outcome
Status epilepticus (SE) is a medical emergency associated with significant morbidity and mortality. SE is defined as a continuous seizure lasting more than 30 min, or two or more seizures without full recovery of consciousness between any of them. Based on recent understanding of the pathophysiology, it is now considered that any seizure that lasts more than 5 min probably needs to be treated as SE. GABAergic mechanisms play a crucial role in terminating seizures. When the seizure persists, GABA-mediated mechanisms become ineffective and several other putative mechanisms of seizure suppression have been recognized. Early treatment of SE with benzodiazepines, followed if necessary by fosphenytoin administration, is the most widely followed strategy. About a third of patients with SE may have persistent seizures refractory to the first-line medications. They require aggressive management with second-line medications such as barbiturates, propofol, or other agents. In developing countries where facilities for assisted ventilation are not readily available, it may be helpful to use nonsedating antiepileptic drugs (such as sodium valproate, levetiracetam, or topiramate) at this stage. It is important to recognize SE and institute treatment as early as possible in order to avoid a refractory state. It is equally important to attend to the general condition of the patient and to ensure that the patient is hemodynamically stable. This article reviews current knowledge regarding the management of convulsive SE in adults.
Anticonvulsants; barbiturates; lorazepam; midazolam; phenytoin; propofol; refractory status epilepticus; status epilepticus