Neuropsychological endpoints for clinical trials in methylmalonic acidemia and propionic acidemia: A pilot study.

Introduction: This pilot study assessed instruments measuring relatively discrete neuropsychological domains to inform the selection of clinical outcome assessments that may be considered for interventional trials in methylmalonic acidemia (MMA) and propionic acidemia (PA). Methods: Tests and questionnaires were selected for their possible relevance to MMA and PA and potential sensitivity to modest changes in functioning and behavior. Results: Twenty-one patients (<18 years, n = 10;>18 years, n = 11) and/or their caregivers responded to video interviews and paper tests. Language deficits and significant motor deficits in some participants impacted scoring, especially in the verbal and processing speed sections of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) and the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV). However, all participants ≥12 years of age were able to complete the Cookie Theft Picture Task. Thus, verbal discourse remains a potentially useful endpoint for participants in this age group. The Vineland Adaptive Behavior Scales (VABS-3) Adaptive Behavior Composite and Communication Scores confirmed delayed or immature functioning in day-to-day activities in these participants. Significant motor deficits prevented completion of some tests. Computerized processing speed tasks, which require pressing a button or tapping a computer screen, may be easier than writing or checking off boxes on paper in this cohort. Sleep characteristics among MMA participants were within normative ranges of the Child and Adolescent Sleep Checklist (CASC), indicating that this measurement would not provide valuable data in a clinical trial. Despite their challenges, responses to the Metabolic Quality of Life Questionnaire indicated these patients and their caregivers perceive an overall high quality of life. Conclusion: Overall, test and questionnaire results were notably different between participants with MMA and participants with PA. The study demonstrates that pilot studies can detect instruments that may not be appropriate for individuals with language or motor deficits and that may not provide a broad range of scores reflecting disease severity. It also provides a rationale for focusing on discrete neuropsychological domains since some aspects of functioning were less affected than others and some were more closely related to disease severity. When global measures are used, overall scores may mask specific deficits. A pilot study like this one cannot ensure that scores will change over time in response to a specific treatment in a clinical trial. However, it can avert the selection of instruments that do not show associations with severity or biomedical parameters likely to be the target of a clinical trial. A pilot study can also identify when differences in diagnoses and baseline functioning need to be addressed prior to developing the analytical plan for the trial.

Differential risks of changes in seizure frequency with transitions between hormonal and non-hormonal contraception in women with epilepsy: A prospective cohort study.

This prospective, observational, cohort study of 101 women with epilepsy (WWE) assesses the seizure safety of systemic hormonal contraception (HC) versus non-HC (NHC). It reports risks of changes in seizure frequency associated with transition from NHC to HC relative to HC to NHC for (1) proportions of WWE with ≥50% increase and decrease in seizure frequency, (2) changes in seizure frequency, (3) changes in seizure severity, and 4) changes in AED regimen during the study. In comparing NHC to HC versus HC to NHC, NHC to HC had greater risk of ≥50% increase in seizure frequency: RR = 1.98 (1.07-3.64), p = 0.03 and lower risk of ≥50% decrease in seizure frequency: RR = 0.42 (0.22 = 0.83), p = 0.01. These risks were particularly notable for oral contraceptive pill: RR = 2.91 (1.26-6.72), p = 0.01 and RR = 0.54 (0.30-0.97), p = 0.04, respectively. Median monthly seizure frequency (MMSF) increased 302.0% (p = 0.0019) with transition from NHC to HC. MMSF decreased 81.9% with change from HC to NHC (p = 0.001). RR for change in seizure type from milder to more severe type was greater for NHC to HC: RR = 3.32 (1.07-10.27), p = 0.04. Change in AED regimen was not a significant factor. The findings suggest further prospective study to assess whether HC, especially oral contraceptive pill, poses a greater risk of increased seizures than NHC.

Infertility, impaired fecundity, and live birth/pregnancy ratio in women with epilepsy in the USA: Findings of the Epilepsy Birth Control Registry.

OBJECTIVE: To determine the current risks of infertility and impaired fecundity as well as the live birth/pregnancy ratio among women with epilepsy (WWE) in the USA and whether antiepileptic drug (AED) use is a factor. METHODS: These retrospective survey data come from the 2010-2014 Epilepsy Birth Control Registry (EBCR) Web-based survey of 1000 WWE in the USA, aged 18-47 years, who provided demographic, epilepsy, AED, reproductive, and contraceptive data. We report risks of infertility and impaired fecundity, live birth/pregnancy ratio, and whether outcomes differ by AED use or category versus No AED. RESULTS: A total of 978 of the 1000 USA WWE reported reproductive data; 373 WWE had 724 pregnancies and 445 births. An additional 38 WWE (9.2%, 95% confidence interval [CI] = 6.7-12.4%) tried to conceive but were infertile. A total of 72.5% had a live birth outcome for their first pregnancy, 89.0% had at least one live birth for their first two pregnancies, and 61.6% had two live births for their first two pregnancies. Eighty-four of 406 WWE (20.7%, 95% CI = 17.0-2.9%) had impaired fecundity. The risk of impaired fecundity trended higher on AED polytherapy than on No AED (risk ratio [RR] = 1.79, 95% CI = 0.94-3.11, P = .08). The ratio of live birth/unaborted pregnancy (445/594, 74.9%) was similar among WWE on No AED (71.3%), AED monotherapy (71.8%), and polytherapy (69.7%). None of the AED categories differed significantly from No AED. Note that glucuronidated AED (lamotrigine), which had the highest ratio of live birth/pregnancy (89.1%), compared favorably to enzyme-inhibiting AED (valproate), which had the lowest (63.3%; RR = 1.41, 95% CI = 1.05-1.88, P = .02). SIGNIFICANCE: The EBCR finds 9.2% infertility risk and 20.7% impaired fecundity risk among WWE in the USA. Impaired fecundity trended higher on AED polytherapy than on No AED. Live birth/pregnancy ratio was higher with the use of lamotrigine than valproate. These findings may provide WWE a more objective basis for pregnancy planning.

Prevalence of highly effective contraception use by women with epilepsy.

OBJECTIVE: To determine (1) the proportion of women with epilepsy (WWE) at risk of unintended pregnancy who use highly effective contraception, (2) demographic predictors, and (3) folic acid (FA) use. METHODS: These cross-sectional data come from 311 US WWE, 18-47 years, who participated in the Epilepsy Birth Control Registry (EBCR) web-based survey in 2017. They provided demographic, epilepsy, antiepileptic drug (AED), contraceptive, and FA data. We report frequencies of highly effective contraception use and use logistic regression to determine demographic predictors. We report the proportion who take FA. RESULTS: A total of 186 (59.8%) of the 311 WWE were at risk of unintended pregnancy. A total of 131 (70.4%) used a highly effective contraceptive category; 55 (29.6%) did not. An additional 13 (7.0%) used a combination of generally effective hormonal contraception with an enzyme-inducing AED, which poses increased risk of unintended pregnancy. Overall, 68 (36.6%) of the 186 WWE at risk did not use highly effective contraception. Increasing income (p = 0.004) and having insurance (p = 0.048) were predictors of highly effective contraception. A total of 50.0% took FA supplement. There was no significant difference in relation to the use or lack of use of highly effective contraception. CONCLUSION: A total of 36.6% of WWE in the EBCR did not use highly effective contraception and 50.0% did not take FA in 2017 despite the important negative consequences of unintended pregnancy on pregnancy outcomes. There is a need for more readily available information and counseling on safe and effective contraception and FA use for this community.

Does the age of seizure onset relate to menarche and does it matter?

PURPOSE: To determine whether there is a relationship between the age of seizure onset and the age of menarche. METHODS: 1144 women with epilepsy (WWE) in the community, ages 18-47 years, provided web-based survey data. We compared the frequencies of the individual differences between their ages of seizure onset and menarche to each other and chance. We determined whether the age of menarche is a predictor of the age of seizure onset and the percentage of the variance that menarche explains. We used two-step cluster analysis to auto-identify a cluster of years relative to the age of menarche that showed the greatest predilection for seizure onset. RESULTS: Average age of menarche was 12.55 [95% CI: 12.45-12.65]. It was greater in WWE who developed seizures before versus after menarche (12.70 [12.54-12.86] v 12.42 [12.30-12.54], p = 0.006). More WWE had seizure onset during the year of menarche than during any other year (8.3% v expected 2.1%; p < 0.0001). Menarche, however, explained only 1% of the variance. Seizure onset frequencies were greatest for an auto-identified cluster that spanned 2 years before to 6 years after menarche and subsumed 49.3% of seizure onset. CONCLUSION: Although the results indicate a significant relationship between the age of seizure onset and the age of menarche, the broader auto-identified perimenarchal cluster that subsumes 49.3% of seizure onset suggests that research target the potential role of the great increase in adrenarchal, as well as gonadarchal, neuroactive steroids that modulate neuronal excitability and seizures during that span.

Association of Unintended Pregnancy With Spontaneous Fetal Loss in Women With Epilepsy: Findings of the Epilepsy Birth Control Registry.

Importance: If unintended pregnancy is common among women with epilepsy and is associated with increased risk of spontaneous fetal loss (SFL), it is important to develop guidelines for safe and effective contraception for this community. Objective: To assess whether planned pregnancy is a determinant of SFL in women with epilepsy. Design, Setting, and Participants: The Epilepsy Birth Control Registry conducted this web-based, retrospective survey between 2010 and 2014. It gathered demographic, epilepsy, antiepileptic drug (AED), contraceptive, and reproductive data from 1144 women with epilepsy in the community between ages 18 and 47 years. Data were analyzed between March 2018 and May 2018. Main Outcomes and Measures: The primary outcome was the risk ratio (RR) with 95% confidence intervals for SFL in unplanned vs planned pregnancies. The secondary outcome was the identification of some potentially modifiable variables (maternal age, pregnancy spacing, and AED category) of SFL vs live birth using binary logistic regression. Results: The participants were proportionally younger (mean [SD] age, 28.5 [6.8] years), and 39.8% had household incomes of $25 000 or less. Minority women represented only 8.7% of the participants. There were 530 of 794 unplanned pregnancies (66.8%) and 264 of 794 planned pregnancies (33.2%). The risk for SFL in 653 unaborted pregnancies in women with epilepsy was greater for unplanned (n = 137 of 391; 35.0%) than planned (n = 43 of 262; 16.4%) pregnancies (RR, 2.14; 95% CI, 1.59-2.90; P < .001). Regression analysis found that the risk for SFL was greater when planning was entered alone (odds ratio [OR], 2.75; 95% CI, 1.87-4.05; P < .001) and more so when adjusted for maternal age, interpregnancy interval, and AED category (OR, 3.57; 95% CI, 1.54-8.78; P = .003). Interpregnancy interval (OR, 2.878; 95% CI, 1.8094-4.5801; P = .008) and maternal age (OR, 0.957; 95% CI, 0.928-0.986 for each year from 18 to 47 years; P = .02), but not AED category, were also associated. The risk was greater when interpregnancy interval was less than 1 year (n = 56 of 122; 45.9%) vs greater than 1 year (n = 56 of 246; 22.8%) (RR, 2.02; 95% CI, 1.49-2.72; P < .001). Relative to the younger than 18 years cohort (n = 15 of 29; 51.7%), the risks were lower for the intermediate older cohort aged 18 to 27 years (n = 118 of 400; 29.5%; RR, 0.57; 95% CI, 0.39-0.84; P < .004) and the cohort aged 28 to 37 years (n = 44 of 212; 20.8%; RR, 0.40; 95% CI, 0.26-0.62; P < .001) but not significantly different for the small number of participants in the aged 38 to 47 years cohort (n = 3 of 12; 25.0%). No individual AED category's SFL frequency differed significantly from the no AED category. Conclusions and relevance: The Epilepsy Birth Control Registry retrospective survey finding that unplanned pregnancy in women with epilepsy may double the risk for SFL warrants prospective investigation with outcome verification.

Folic acid use by women with epilepsy: Findings of the Epilepsy Birth Control Registry.

PURPOSE: To determine the prevalence and predictors of folic acid (FA) use by women with epilepsy (WWE) at risk of unintended pregnancy. METHODS: These retrospective data come from the Epilepsy Birth Control Registry (EBCR) web-based survey of 1144 WWE in the community, 18-47years, who provided demographic, epilepsy, AED, contraception, pregnancy, healthcare visits and FA data. We report prevalence and predictors of FA use in relation to risk of pregnancy (not at risk, at risk, seeking pregnancy, pregnant), demographics, seizure types and AED and contraception categories. RESULTS: 368 (47.6%) of the 773 WWE at risk of unintended pregnancy in the EBCR took FA supplement. Being at risk was a significant predictor in comparison to WWE not at risk (OR=1.464 [1.103-1.944], p=0.008). In comparison to WWE at risk, FA use trended greater for WWE actively seeking pregnancy (29/47, 61.7% v 368/773, 47.6%; p=0.0605) and was greater for pregnant WWE (17/19, 89.5% v 368/773, 47.6%; p=0.0007). Demographic predictors for WWE at risk were race (p=0.003), education (p=0.012) and income (0.043) with significantly greater FA use by Caucasians than minorities and direct correlations between FA use and levels of education and household income. Seizure type, AED use, category and dosage, polytherapy and contraceptive category were not predictors. A healthcare provider visit during the year prior to the survey was not a predictor. Prevalence of FA use was similar following visits with gynecologists - 51.7%, neurologists - 48.7% and primary care - 48.6%. FA supplementation by prescription was greater for WWE at risk on AED versus no AED (190/355, 53.5% v 3/13, 23.1%; p=0.045). CONCLUSION: Low prevalence of preconception FA use may reflect a need for more education. In addition, further research is needed to provide definitive evidence that FA reduces congenital malformations in the offspring of WWE.