Antiepileptic drugs and pregnancy. Population based pharmaco-epidemiological study on prescription patterns, pregnancy outcome and foetal health

Aims of the study: To assess the prevalence of Antiepileptic Drug (AED) exposure in pregnant women with or without epilepsy and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirth, major congenital malformations (MCMs) and foetal growth retardation (FGR) following intrauterine AED exposure in the Emilia Romagna region (RER), Northern Italy (4 million inhabitants). Methods: Data were obtained from official regional registries: Certificate of Delivery Assistance, Hospital Discharge Card, reimbursed prescription databases and Registry of Congenital Malformations. We identified all the deliveries, hospitalized abortions and MCMs occurred between January 2009 and December 2011. Results: We identified 145,243 pregnancies: 111,284 deliveries (112,845 live births and 279 stillbirths), 16408 spontaneous abortions and 17551 TOPs. Six hundred and eleven pregnancies (0.42% 95% Cl: 0.39-0.46) were exposed to AEDs. Twenty-one per cent of pregnancies ended in TOP in the AED group vs 12% in the non-exposed (OR:2.24; CI 1.41-3.56). The rate of spontaneous abortions and stillbirth was comparable in the two groups. Three hundred fifty-three babies (0.31%, 95% CI: 0.28-0.35) were exposed to AEDs during the first trimester. The rate of MCMs was 2.3% in the AED group (2.2% in babies exposed to monotherapy and 3.1% in babies exposed to polytherapy) vs 2.0% in the non-exposed. The risk of FGR was 12.7 % in the exposed group compared to 10% in the non-exposed. Discussion and Conclusion: The prevalence of AED exposure in pregnancy in the RER was 0.42%. The rate of MCMs in children exposed to AEDs in utero was almost superimposable to the one of the non-exposed, however polytherapy carried a slightly increased risk . The rate of TOPs was significantly higher in the exposed women. Further studies are needed to clarify whether this high rate reflects a higher rate of MCMs detected prenatally or other more elusive reasons

Sleep-related hypermotor epilepsy: Long-term outcome in a large cohort

To assess the long-term outcome of sleep-related hypermotor epilepsy (SHE)

Emilia-Romagna Study on Pregnancy and Exposure to Antiepileptic drugs (ESPEA): a population-based study on prescription patterns, pregnancy outcomes and fetal health

Objectives To assess the prevalence of antiepileptic drug (AED) exposure in pregnant women and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirths, major birth defects (MBDs), neonatal distress and small for gestational age (SGA) infants following intrauterine AED exposure in the Emilia Romagna region, Italy (4 459 246 inhabitants on 31 December 2011). Methods We identified all deliveries and hospitalised abortions in Emilia Romagna in the period 2009-2011 from the certificate of delivery assistance registry (Certificato di Assistenza al Parto -CedAP) and the hospital discharge card registry, exposure to AEDs from the reimbursed drug prescription registries, MBDs from the regional registry of congenital malformations, and Apgar scores and cases of SGA from the CedAP. Records from different registries were linked. Results We identified 145 243 pregnancies: 111 284 deliveries, 16 408 spontaneous abortions and 17 551 TOPs. Six hundred and eleven pregnancies (0.42%; 95% Cl 0.39 to 0.46) were exposed to AEDs. In the AED-exposed group 21% of pregnancies ended in TOPs vs 12% in the non-exposed women (OR: 2.24; 95% CI 1.41 to 3.56). Rates of spontaneous abortions, stillbirths, neonatal distress and SGA were comparable. Three hundred and fifty-three babies (0.31%; 95% CI 0.28 to 0.35) were exposed to AEDs during the first trimester. MBD rates were 2.3% in the exposed vs 2.0% in the non-exposed pregnancies (OR: 1.12, 95% CI 0.55 to 2.55). Conclusion The Emilia Romagna prevalence of AED exposure in pregnancy was 0.42%, comparable with previous European studies. Rates of spontaneous abortions, stillbirths, neonatal distress, SGA and MBDs following AED exposure were not significantly increased. The rate of TOPs was significantly higher in the AED-exposed women

Treatment with metformin in twelve patients with Lafora disease

Background: Lafora disease (LD) is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. Studies on a mouse model of LD showed a good response to metformin, a drug with a well known neuroprotective effect. For this reason, in 2016, the European Medicines Agency granted orphan designation to metformin for the treatment of LD. However, no clinical data is available thus far. Methods: We retrospectively collected data on LD patients treated with metformin referred to three Italian epilepsy centres. Results: Twelve patients with genetically confirmed LD (6 EPM2A, 6 NHLRC1) at middle/late stages of disease were treated with add-on metformin for a mean period of 18 months (range: 6-36). Metformin was titrated to a mean maintenance dose of 1167 mg/day (range: 500-2000 mg). In four patients dosing was limited by gastrointestinal side-effects. No serious adverse events occurred. Three patients had a clinical response, which was temporary in two, characterized by a reduction of seizure frequency and global clinical improvement. Conclusions: Metformin was overall safe in our small cohort of LD patients. Even though the clinical outcome was poor, this may be related to the advanced stage of disease in our cases and we cannot exclude a role of metformin in slowing down LD progression. Therefore, on the grounds of the preclinical data, we believe that treatment with metformin may be attempted as early as possible in the course of LD

Quantitative dried blood spot microsampling for therapeutic drug monitoring of -antiseizure medications by design of experiment and UHPLC-MS/MS

Background Therapeutic drug monitoring (TDM) of Antiseizure Medications (ASMs) is an essential tool for persons with epilepsy (PwE). Compared to traditional venipuncture, microsampling requires lower blood volume through less painful and invasive fingerprick offering a sampling methodology potentially performed at-home. This study aimed to validate the extraction method of ASMs from Capitainer®-qDBS microsampling. Five ASMs were considered. According to EMA guidelines, through technical and clinical validation, ASMs’ quantification from qDBS device was performed by UHPLC-MS/MS. Extraction parameters were optimized by Design of Experiment. Clinical validation was performed to compare ASMs concentrations in Capitainer®-qDBS with those in plasma in 30 PwE. Results The method used in the chosen extraction procedure was proven to be accurate and precise. Intra and inter-assay reproducibility analyses showed accuracy and precision ≤15 % across the calibration range. Recovery was >75 %, and matrix effect >75 %, for most of the ASMs analyzed. Stability was tested at 7, 15, and 30 days of storage, showing mutual robustness at 30 days at room temperature. No hematocrit effect was observed over a range of 20–70 %. Linear regression and Bland-Altman analysis indicated a good correlation for the ASMs considered. Significance A UHPLC-MS/MS assay was developed and validated according to EMA guidelines for quantifying ASMs from qDBS devices. This validation has the advantage of allowing the potential to utilize the new microsampling qDBS device, providing a patient-friendly approach to blood sampling eventually even at-home

The Effect of Curcumin on Idiopathic Parkinson Disease: A Clinical and Skin Biopsy Study

There are currently no standardized therapies for Parkinson disease (PD). Curcumin shows anti-amyloidogenic properties in vitro and may be a promising treatment for PD. We evaluated the effects of curcumin supplementation on clinical scales and misfolded, phosphorylated α-synuclein (p-syn) accumulation in skin biopsies in 19 PD patients who received curcumin supplementation for 12 months and 14 PD patients to treated with curcumin. The patients underwent autonomic (COMPASS-31), motor (MDS-UPDRS and H&Y) and nonmotor (NMSS) questionnaires and skin biopsies to evaluate clinical involvement and p-syn load in skin nerves at the beginning and the end of study. Curcumin and curcuminoid levels were assayed in plasma and CSF. Supplemented patients showed detectable CSF curcuminoid levels that were lower than those in plasma. They showed a decrease of COMPASS-31 and NMSS scores, and a slight p-syn load decrease versus untreated patients who displayed a worsening of these parameters despite increased levodopa doses. Multiple regression models showed a significant effect of curcumin supplementation in decreasing the worsening of the clinical parameters and p-syn load at after curcumin treatment. These data suggest that curcumin can cross the blood-brain barrier, that it is effective in ameliorating clinical parameters and that it shows a tendency to decrease skin p-syn accumulation in PD patients

Definition of miRNAs expression profile in glioblastoma samples: the relevance of non-neoplastic brain reference.

Glioblastoma is the most aggressive brain tumor that may occur in adults. Regardless of the huge improvements in surgery and molecular therapy, the outcome of neoplasia remains poor. MicroRNAs are small molecules involved in several cellular processes, and their expression is altered in the vast majority of tumors. Several studies reported the expression of different miRNAs in glioblastoma, but one of the most critical point in understanding glioblastoma miRNAs profile is the comparison of these studies. In this paper, we focused our attention on the non-neoplastic references used for determining miRNAs expression. The aim of this study was to investigate if using three different non-neoplastic brain references (normal adjacent the tumor, commercial total RNA, and epileptic specimens) could provide discrepant results. The analysis of 19 miRNAs was performed using Real-Time PCR, starting from the set of samples described above and the expression values compared. Moreover, the three different normal RNAs were used to determine the miRNAs profile in 30 glioblastomas. The data showed that different non-neoplastic controls could lead to different results and emphasize the importance of comparing miRNAs profiles obtained using the same experimental condition

Early nasal microbiota and subsequent respiratory tract infections in infants with cystic fibrosis

Background Respiratory tract infections (RTIs) drive lung function decline in children with cystic fibrosis (CF). While the respiratory microbiota is clearly associated with RTI pathogenesis in infants without CF, data on infants with CF is scarce. We compared nasal microbiota development between infants with CF and controls and assessed associations between early-life nasal microbiota, RTIs, and antibiotic treatment in infants with CF. Methods We included 50 infants with CF and 30 controls from two prospective birth cohorts followed throughout the first year of life. We collected 1511 biweekly nasal swabs and analyzed the microbiota after amplifying the V3-V4 region of the 16S rRNA gene. We conducted structured weekly interviews to assess respiratory symptoms and antibiotic treatment. We calculated generalized additive mixed models and permutational analysis of variance. Results Here, we show that the nasal microbiota is already altered before the first RTI or antibiotic treatment in infants with CF. Microbiota diversity differs between infants with CF and controls following RTIs and/or antibiotic treatment. CF infants with lower α-diversity have a higher number of subsequent RTIs. Conclusions Early nasal microbiota alterations may reflect predisposition or predispose to RTIs in infants with CF, and further change after RTIs and antibiotic treatment. This highlights the potential of targeting the nasal microbiota in CF-related RTI management, while also questioning current practices in the era of novel modulator therapies

Valproate discontinuation in girls and women of childbearing age with epilepsy: An Italian multicenter retrospective study on prescribing patterns and outcomes

Objective: This study aimed to identify prescribing behaviors in women of childbearing potential (WOCP) with epilepsy already taking valproate (VPA), and to investigate the relationship between VPA maintenance, substitution, reduction, or withdrawal as part of polytherapy, and seizure worsening or relapse. Methods: We retrospectively reviewed the prescription behaviors and seizure outcomes in WOCP (16-50 years of age) with epilepsy, referred to eight Italian epilepsy centers, who were taking VPA for at least 1 year between 2014 and 2019. Results: Among 750 women (~12% of all WOCP), 528 (70.4%) maintained VPA unchanged throughout the observation period, 103 (13.7%) replaced VPA with another antiseizure medication (ASM), 90 (12%) reduced VPA, and 29 (3.9%) discontinued VPA in polytherapy. Focal epilepsy was most strongly associated with VPA withdrawal (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.38-6.38), whereas generalized epilepsy was most associated with its non-withdrawal (reduction/switch/maintenance) (OR .31, 95% CI .14-.68). Intellectual disability, higher seizure frequency, and higher VPA doses were linked to VPA continuation. VPA withdrawal from polytherapy was associated with a higher risk of tonic-clonic seizure worsening (OR 2.91, 95% CI 1.09-7.77) compared to non-withdrawal. Significance: VPA was rarely withdrawn or substituted in WOCP with epilepsy, in secondary and tertiary care settings following European regulatory restrictions. This likely reflects a population with severe epilepsies where VPA is difficult to replace; whereas women with milder epilepsies likely discontinued VPA earlier, as evidenced by its low overall prescription frequency. Withdrawal of VPA from a polytherapy regimen was associated with a threefold increased risk of seizure exacerbation

Second-Line Medications for Women Aged 10 to 50 Years With Idiopathic Generalized Epilepsy

Importance: Women with idiopathic generalized epilepsy (IGE) face challenges in treatment due to limited options that are both effective and safe. Objective: To evaluate the effectiveness and safety of substitution monotherapy vs add-on therapy as second-line options for women who might become pregnant with IGE after failure of first-line antiseizure medications (ASMs) other than valproic acid. Design, setting, and participants: Multicenter retrospective comparative effectiveness cohort study at 18 primary, secondary, and tertiary adult and children epilepsy centers across 4 countries, analyzing data from 1995 to 2023. Participants were women aged 10 to 50 years diagnosed with IGE who were prescribed a second line of ASM. Main outcomes and measures: Treatment failure (TF), defined as the replacement or addition of a second ASM due to ineffectiveness, was compared between patients receiving ASM add-on or substitution monotherapy using inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards regression. Exploratory analyses were also conducted to assess the effectiveness of individual ASMs and various ASM combinations. Results: This study included 249 women with a median (IQR) age of 18.0 (15.5-22.0) years. Among them, 146 (58.6%) received an add-on regimen, and 103 (41.4%) received substitution monotherapy. During follow-up, TF occurred in 48 patients (32.9%) receiving add-on therapy and 36 (35.0%) using substitution monotherapy, with no significant differences between groups (IPTW-adjusted hazard ratio [HR], 0.89; 95% CI, 0.53-1.51; P = .69). ASM discontinuation due to ineffectiveness or adverse effects occurred in 36 patients (24.7%) receiving add-on therapy and 29 (28.2%) receiving substitution monotherapy, showing no significant differences (IPTW-adjusted HR, 0.97; 95% CI, 0.57-1.65; P = .92). Rates of ASM discontinuation due to adverse effects only were low in both groups, occurring in 13 patients (9.0%) receiving add-on therapy and 9 (8.7%) receiving a substitution monotherapy. Among add-on regimens other than valproic acid, the combination of levetiracetam and lamotrigine demonstrated a lower risk of TF compared with other combinations with levetiracetam plus other ASM (adjusted HR, 2.41; 95% CI, 1.12-5.17; P = .02) and lamotrigine plus other ASM (adjusted HR, 4.03; 95% CI, 1.73-9.39; P = .001). However, valproic acid remained the most effective second-line ASM when considering individual agents. Conclusions and relevance: In this comparative effectiveness study of second-line treatment strategies for women with IGE, no significant differences were observed between substitution monotherapy and add-on therapy