Insights into neurosteroids and their role in women with epilepsy.

Epilepsy, is a serious neurological condition, characterized by recurring, unprovoked seizures and affects over 50 million people worldwide. Epilepsy has an equal prevalence in males and females, and occurs throughout the life span. Women with epilepsy (WWE) present with unique challenges due to the cyclical fluctuation of sex steroid hormone concentrations during their life course. These shifts in sex steroid hormones and their metabolites are intricately intertwined with seizure susceptibility and affect epilepsy during the life course of women in a complex manner. Here we present a review encompassing neurosteroids-steroids that act on the brain regardless of their site of synthesis in the body; the role of neurosteroids in women with epilepsy through their life-course; exogenous neurosteroid trials; and future research directions. The focus of this review is on progesterone and its derived neurosteroids, given the extensive basic research that supports their role in modulating neuronal excitability.

Lacosamide and pregnancy: Data from spontaneous and solicited reports.

OBJECTIVE: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. METHODS: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. RESULTS: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. SIGNIFICANCE: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.

Initiation and Duration of Breastfeeding in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study.

BACKGROUND AND OBJECTIVES: Breastfeeding has important health benefits for both mother and child. We characterize breastfeeding initiation and duration in mothers with epilepsy relative to control mothers in a large prospective cohort. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a prospective, multicenter observational, US cohort study. Pregnant individuals with and without epilepsy, aged 14-45 years, were enrolled between December 19, 2012, and February 11, 2016. Exclusion criteria included intelligence quotient (IQ) <70, and gestational age >20 weeks at enrollment. Breastfeeding was assessed through electronic diary and at study visits until 2 years postpartum. Odds of initiating breastfeeding was compared between cohorts using unadjusted and adjusted logistic regression models. Duration of breastfeeding was compared between cohorts using the log-rank test. RESULTS: Three hundred fifty-one pregnant individuals with epilepsy and 105 pregnant controls were enrolled. Breastfeeding data were available for 325 mothers with epilepsy and 98 controls. Study cohorts were similar demographically except race (p = 0.008); 84.9% of mothers with epilepsy and 71.4% of controls were White. The mean IQ was lower in mothers with epilepsy compared with that in controls (97.7 vs 104.2, p < 0.001). Breastfeeding was initiated by 74.8% mothers with epilepsy and 88.8% controls; this difference was significant in unadjusted logistic regression (odds ratio [OR] 0.4 [95% CI 0.2, 0.7], p = 0.004), but not in adjusted model (OR 0.5 [95% CI 0.2, 1.0], p = 0.051). Factors associated with breastfeeding were higher maternal education and IQ. There was no difference in duration of breastfeeding between mothers with and without epilepsy (median duration 8.5 months vs 9.9 months, p = 0.793). Among mothers with epilepsy, both convulsive seizures and all seizures that impair awareness during pregnancy were associated with lower breastfeeding initiation (OR 0.4 [95% CI 0.2, 0.8], p = 0.013) and (OR 0.4 [95% CI 0.2, 0.8], p = 0.003, respectively). Any peripartum seizures were associated with shorter breastfeeding duration (median 6 months vs 9.7 months, [p = 0.040]). DISCUSSION: Mothers with epilepsy were less likely to initiate breastfeeding compared with controls; however, this difference was not significant when controlling for maternal IQ and education level. Continuation of breastfeeding once initiated was not different between mothers with and without epilepsy. Seizure control was associated with breastfeeding initiation and duration in mothers with epilepsy. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier NCT01730170.

Catamenial epilepsy occurrence and patterns in a mixed population of women with epilepsy.

We evaluated the occurrence and distribution of patterns of catamenial epilepsy in a heterogenous cohort of women with epilepsy on no hormonal therapies, enrolled in a prospective, observational study. The primary aim of the study was pregnancy rate in women with epilepsy with no prior reproductive problems. In this analysis, we included women who recorded one or more menstrual cycles with one or more seizures. We measured progesterone concentrations for one to three cycles. We defined catamenial patterns as twofold or greater average daily seizure frequency around menstruation (C1), ovulation (C2), and for anovulatory cycles, from midcycle through menstruation (C3). Twenty-three of the 89 enrolled women with epilepsy were eligible for this analysis; 12 of 23 met criteria for catamenial epilepsy; five of 23 demonstrated only a C1 pattern, two of 23 only a C2 pattern, five of 23 a combined C1/C2 pattern, and the one woman with anovulatory cycles did not demonstrate a C3 pattern. There were no differences in likelihood of demonstrating a catamenial pattern between those who reported a prior catamenial pattern and those who did not (p = .855). This analysis demonstrates the utility of app-based tracking to determine a catamenial pattern. Larger prospective studies could confirm these findings and inform potential therapeutic trial designs for catamenial epilepsy.

Prospective Cohort Study of Depression During Pregnancy and the Postpartum Period in Women With Epilepsy vs Control Groups.

BACKGROUND AND OBJECTIVES: Assess the incidence and factors associated with major depressive episodes (MDEs) and symptoms of depression and anxiety during pregnancy and postpartum periods in pregnant women with epilepsy (PWWE) compared with healthy pregnant women (HPW) and nonpregnant women with epilepsy (NPWWE) in comparable timeframes. Previous studies have reported higher rates of postpartum depression in women with epilepsy compared with women without epilepsy. However, the incidence of MDE using a structured interview during pregnancy and postpartum has not been directly compared with control groups, and the comparison of depression and anxiety symptoms and the role of associated factors remain ambiguous. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational parallel group cohort study of PWWE and their children. This report examines mood disorders. Unlike previous epilepsy pregnancy studies, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV (SCID) provided lifetime diagnoses, and repeated SCID mood modules assessed for MDE, the a priori primary outcome. Symptoms of depression (Beck Depression Inventory [BDI] and Edinburg Postnatal Depression Scale [EPDS]) and anxiety (Beck Anxiety Inventory [BAI]) were also assessed along with multiple clinical factors. RESULTS: This study included PWWE (n = 331) and HPW (n = 102) during pregnancy and postpartum and NPWWE (n = 102) at comparable times. No difference in SCID-diagnosed MDE incidence was found across groups, but BDI depressive symptoms were worse during pregnancy in PWWE vs NPWWE and during postpartum vs HPW and NPWWE. BAI anxiety symptoms were worse during pregnancy in PWWE vs HPW and NPWWE and during postpartum vs HPW. Factors associated with MDE during pregnancy/postpartum for PWWE included >1 seizure/90 days, anticonvulsant polytherapy, unplanned pregnancy, and lifetime history of mood disorder. Suicidal ideation from BDI or EPDS was related to BAI anxiety symptoms. DISCUSSION: Although SCID-based MDE did not differ across groups, this prospective study confirms higher rates of psychiatric symptoms in patients with epilepsy during pregnancy and postpartum, provides new data on associated factors, and underscores the importance of anxiety in risk for depression and thoughts of death/dying or suicide. Given the risks, PWWE should be routinely assessed and symptomatic patients should be offered treatment. TRIAL REGISTRATION INFORMATION: This study is registered at ClinicalTrials.gov as NCT01730170.

A replicable, open-source, data integration method to support national practice-based research & quality improvement systems.

OBJECTIVES: The Epilepsy Learning Healthcare System (ELHS) was created in 2018 to address measurable improvements in outcomes for people with epilepsy. However, fragmentation of data systems has been a major barrier for reporting and participation. In this study, we aimed to test the feasibility of an open-source Data Integration (DI) method that connects real-life clinical data to national research and quality improvement (QI) systems. METHODS: The ELHS case report forms were programmed as EPIC SmartPhrases at Mass General Brigham (MGB) in December 2018 and subsequently as EPIC SmartForms in June 2021 to collect actionable, standardized, structured epilepsy data in the electronic health record (EHR) for subsequent pull into the external national registry of the ELHS. Following the QI methodology in the Chronic Care Model, 39 providers, epileptologists and neurologists, incorporated the ELHS SmartPhrase into their clinical workflow, focusing on collecting diagnosis of epilepsy, seizure type according to the International League Against Epilepsy, seizure frequency, date of last seizure, medication adherence and side effects. The collected data was stored in the Enterprise Data Warehouse (EDW) without integration with external systems. We developed and validated a DI method that extracted the data from EDW using structured query language and later preprocessed using text mining. We used the ELHS data dictionary to match fields in the preprocessed notes to obtain the final structured dataset with seizure control information. For illustration, we described the data curated from the care period of 12/2018-12/2021. RESULTS: The cohort comprised a total of 1806 patients with a mean age of 43 years old (SD: 17.0), where 57% were female, 80% were white, and 84% were non-Hispanic/Latino. Using our DI method, we automated the data mining, preprocessing, and exporting of the structured dataset into a local database, to be weekly accessible to clinicians and quality improvers. During the period of SmartPhrase implementation, there were 5168 clinic visits logged by providers documenting each patient's seizure type and frequency. During this period, providers documented 59% patients having focal seizures, 35% having generalized seizures and 6% patients having another type. Of the cohort, 45% patients had private insurance. The resulting structured dataset was bulk uploaded via web interface into the external national registry of the ELHS. CONCLUSIONS: Structured data can be feasibly extracted from text notes of epilepsy patients for weekly reporting to a national learning healthcare system.

Clinical Reasoning: A Young Man With Daily Episodes of Altered Awareness.

Stretch syncope is a distinct entity characterized by transient alteration in awareness (TAA) induced by neck hyperextension during stretching. Few cases of stretch syncope have been reported in the literature. Nevertheless, this is a highly relevant diagnosis as it can be easily mistaken for epilepsy for a number of reasons. These include stereotypical motor activity associated with the events, development of ictal tachycardia, and the presence of rhythmic/semirhythmic slowing on EEG in the context of transient cerebral hypoperfusion.We present the case of a young man who was referred to our comprehensive epilepsy center for frequent episodes of TAA. After careful evaluation, the episodes were initially considered to be epileptic. Given that he had negligible clinical response to antiseizure medications, he underwent an experimental protocol at a cardiovascular research laboratory that ultimately confirmed the diagnosis of stretch syncope. The present article describes an approach to the evaluation of TAA and illustrates a typical case of stretch syncope. The importance of considering stretch syncope in the differential diagnosis of TAA is exemplified. Finally, our analyses help elucidate the pathophysiology of this rare entity.

Variations in Seizure Frequency During Pregnancy and Postpartum by Epilepsy Type.

BACKGROUND AND OBJECTIVES: To assess whether increased seizure frequency during pregnancy and postpartum is influenced by epilepsy type, seizure location, and antiseizure medications. METHODS: Clinical data were collected in a longitudinal prospective database of pregnant women with epilepsy at Brigham and Women's Hospital. Within each individual participant, baseline seizure frequency was calculated for the 9 months before conception, and whether seizure frequency increased during pregnancy or the postpartum period was determined. Seizure frequency was calculated for each 4-week interval during pregnancy. Generalized estimating equations for logistic regression were applied. RESULTS: Ninety-nine patients contributing 114 pregnancies were included from 2013 to 2018. Increased seizure frequency occurred more often during pregnancies of women with focal vs generalized epilepsy (21.1% vs 5.3%, odds ratio [OR] 4.70, 95% confidence interval [CI] 1.00-22.00; p = 0.0497). Among women with focal epilepsy, increased seizure frequency occurred more often in those with frontal lobe epilepsy (OR 8.00, 95% CI 2.19-29.21; p = 0.0017). There was no difference in seizure worsening in the postpartum period between the focal and generalized (11.1% vs 9.1%; p = 0.4478) or frontal and other focal (18.8% vs 6.0%; p = 0.1478) epilepsy groups. Pregnancies on polytherapy had higher odds of seizure worsening compared to monotherapy (OR 8.36, 95% CI 2.07-33.84; p = 0.0029), regardless of the medication or epilepsy type. A lack of preconception seizure freedom was also associated with increased seizure frequency during pregnancy (OR 6.418; p = 0.0076). DISCUSSION: Women with focal epilepsy have higher likelihood of seizure worsening during pregnancy compared to women with generalized epilepsy; frontal lobe epilepsy poses an especially elevated risk. Polytherapy and lack of preconception seizure freedom are additional predictors for an increased likelihood of seizure worsening.

Pregnant women with more seizures have lower allopregnanolone concentrations.

Neuroactive steroids have rapid, nongenomic effects on neuronal excitability. The effects in humans are less clear. We compared seizure control and concentrations of neuroactive steroids, known to influence neuroexcitability in animal studies, in pregnant women. Participants were prospectively followed throughout pregnancy with seizure-medication diaries and blood samples, assayed for steroid concentrations with gas chromatography-mass spectrometry. Baseline seizure frequency was calculated for the preconception year, and it was determined if seizure frequency was increased in each trimester. The Wilcoxon rank-sum test was used to compare neuroactive steroid concentrations in between the group with increased frequency to the group without, as calculated for the respective trimester, with the Holm-Bonferroni method to correct for multiple comparisons. Among eighty-three pregnancies included, twenty-eight had increased seizure frequency during at least one trimester (15, 18 and 10, respectively) compared to preconception seizure frequency. Allopregnanolone concentrations were lower in the 3rd trimester (p < 0.001), with a similar trend in the 1st (p = 0.08), for pregnancies with increased compared to those with stable seizure frequency. Other neuroactive steroid concentrations were similar. Our findings suggest that lower allopregnanolone concentrations are associated with increased seizure frequency during pregnancy. Validation of these finding in a larger cohort has potential important clinical applications.

Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy.

OBJECTIVE: To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency. METHODS: Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1-3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without. RESULTS: AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05). CONCLUSION: AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

Delivery of a Personalized Treatment Approach to Women with Epilepsy.

Personalized treatment for women with epilepsy is essential, and requires thorough weighing of the risks and benefits of the initial diagnostic and therapeutic options chosen, with readjustments of the antiepileptic regimen throughout the patient's life.Approximately one-third of women with epilepsy have a catamenial pattern, and the most common pattern is an increase in seizure frequency in the perimenstrual phase. These women are also more likely to experience a decrease in seizure frequency during pregnancy and menopause. A good treatment option for catamenial epilepsy is still lacking.For contraception, an intrauterine device is currently the preferred choice. Prior to conception, it is advisable to review the known impact of different antiepileptic drugs on the developing fetus and to optimize the patient's treatment regimen. Pregnancy registries and observational studies have provided key data and continue to refine our understanding of the risks to the structural and cognitive development of the fetus of specific antiepileptic drugs, including polytherapies and newer medications. Different studies consistently report that valproic acid has notably high relative risks for congenital malformations, lower IQ, and features of autism. During pregnancy, there is growing evidence that therapeutic dose monitoring is beneficial for seizure control. Counseling about seizure safety and minimizing provoking factors during the peripartum period is important for the patient with epilepsy.Clinical studies continue to investigate the complex relationship between cycling sex steroid hormones, epilepsy, and antiepileptic medications, with hopes to better explain drug clearance changes during pregnancy, changes in seizure frequency, and neuroendocrine abnormalities. Thorough understanding of these key factors and a continuous review of literature for updated data on different treatment options will enable optimal treatment recommendations that will improve the health of women with epilepsy and their children.

Management of epilepsy during pregnancy.

Over a million women with epilepsy are of childbearing age in the USA and require careful consideration of not only type of antiepileptic drug (AED) but also dosage, in the event of a planned or unplanned pregnancy. Careful selection of AEDs can lower the potential adverse effects of AEDs while maintaining seizure control for the health of not only on the patient, the mother, but also the unborn fetus. The number of treatment options has increased significantly in the last 20 years and remarkable progress has been made in characterizing the risks AEDs pose to pregnant women and fetuses. There are now robust data on teratogenesis, a growing body of data on neonatal/obstetrical outcomes and on neurodevelopmental problems associated with each AED, and some data about seizure control during pregnancy. Based on clinical evidence so far, levetiracetam and lamotrigine have emerged as the safest during pregnancy, although others may also be suitable. Despite being a common belief, not all polytherapy combinations may be detrimental, especially when avoiding valproate and topiramate. Here, we review the available clinical research, highlighting recent findings and provide thoughts for future directions in the field.

LKB1 and AMPK regulate synaptic remodeling in old age.

Age-related decreases in neural function result in part from alterations in synapses. To identify molecular defects that lead to such changes, we focused on the outer retina, in which synapses are markedly altered in old rodents and humans. We found that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate this process. In old mice, synaptic remodeling was accompanied by specific decreases in the levels of total LKB1 and active (phosphorylated) AMPK. In the absence of either kinase, young adult mice developed retinal defects similar to those that occurred in old wild-type animals. LKB1 and AMPK function in rod photoreceptors where their loss leads to aberrant axonal retraction, the extension of postsynaptic dendrites and the formation of ectopic synapses. Conversely, increasing AMPK activity genetically or pharmacologically attenuates and may reverse age-related synaptic alterations. Together, these results identify molecular determinants of age-related synaptic remodeling and suggest strategies for attenuating these changes.

Direction-selective retinal ganglion cells arise from molecularly specified multipotential progenitors.

Single progenitors can give rise to any and all of the main retinal cell types: photoreceptors, interneurons (horizontal, bipolar, and amacrine cells), retinal ganglion cells (RGCs), and glia. Many of these types are divisible into multiple functionally, structurally, and molecularly distinct subtypes (e.g., ~25 for RGCs). It remains unknown when and how progenitors become committed to generate such subtypes. Here, we determine the origin of RGCs that respond selectively to vertical motion and express cadherin 6 (cdh6). Using Cre recombinase-based lineage tracing, we show that these RGCs arise from progenitors that themselves express cdh6. These progenitors are capable of generating all major retinal cell types, but the RGCs they generate are predominantly of the single direction-selective subtype. In contrast, cdh6-positive progenitors retain the ability to generate multiple subtypes of amacrine and bipolar cells. Our results demonstrate that type and subtype specification are regulated in different ways and suggest that multipotential but fate-restricted progenitors contribute to subtype specification in retina.