The anti-epileptic drug Valproic Acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro

Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC

Source-level EEG and graph theory reveal widespread functional network alterations in focal epilepsy

Objective: The hypersynchronous neuronal activity associated with epilepsy causes widespread functional network disruptions extending beyond the epileptogenic zone. This altered network topology is considered a mediator for non-seizure symptoms, such as cognitive impairment. The aim of this study was to investigate functional network alterations in focal epilepsy patients with good seizure control and high quality of life. Methods: We compared twenty-two focal epilepsy patients and sixteen healthy controls on graph metrics derived from functional connectivity of source-level resting-state EEG. Graph metrics were calculated over a range of network densities in five frequency bands. Results: We observed a significantly increased small world index in patients relative to controls. On the local level, two left-hemisphere regions displayed a shift towards greater alpha band "hubness". The findings were not mediated by age, sex or education, nor by age of epilepsy onset, duration or focus lateralisation. Conclusions: Widespread functional network alterations are evident in focal epilepsy, even in a cohort characterised by successful anti-seizure medication therapy and high quality of life. These findings might support the position that functional network analysis could hold clinical relevance for epilepsy. Significance: Focal epilepsy is accompanied by global and local functional network aberrancies which might be implied in the sustenance of non-seizure symptoms. (c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Antiepileptic drugs and quality of life in the elderly: results from a randomized double-blind trial of carbamazepine and lamotrigine in patients with onset of epilepsy in old age.

During an international double-blind trial evaluating the efficacy and tolerability of lamotrigine and carbamazepine in patients aged >or=65 with newly diagnosed epilepsy, the comparative effects of the drugs on health-related quality of life were investigated based on screening and 12-, 28-, and 40-week data, using the modified Side Effect and Life Satisfaction (SEALS) Inventory and the Liverpool Adverse Event Profile. Of 167 patients, 29 discontinued before first follow-up, and data were incomplete for 13. In 125 eligible subjects (62 taking carbamazepine, 63 taking lamotrigine), comparable baseline data did not change significantly during medication, within or across treatments. A borderline difference in the SEALS Dysphoria subscores favored lamotrigine. No difference between completers and noncompleters was identified. Twelve-week data for noncompleters were comparable across treatments. Changes in the inventories up to 40 weeks correlated moderately. Neither lamotrigine nor carbamazepine seems likely to cause significant changes in health-related quality of life measures after 40 weeks at therapeutic doses

Source-level EEG and graph theory reveal widespread functional network alterations in focal epilepsy

Objective: The hypersynchronous neuronal activity associated with epilepsy causes widespread functional network disruptions extending beyond the epileptogenic zone. This altered network topology is considered a mediator for non-seizure symptoms, such as cognitive impairment. The aim of this study was to investigate functional network alterations in focal epilepsy patients with good seizure control and high quality of life. Methods: We compared twenty-two focal epilepsy patients and sixteen healthy controls on graph metrics derived from functional connectivity of source-level resting-state EEG. Graph metrics were calculated over a range of network densities in five frequency bands. Results: We observed a significantly increased small world index in patients relative to controls. On the local level, two left-hemisphere regions displayed a shift towards greater alpha band “hubness”. The findings were not mediated by age, sex or education, nor by age of epilepsy onset, duration or focus lateralisation. Conclusions: Widespread functional network alterations are evident in focal epilepsy, even in a cohort characterised by successful anti-seizure medication therapy and high quality of life. These findings might support the position that functional network analysis could hold clinical relevance for epilepsy. Significance: Focal epilepsy is accompanied by global and local functional network aberrancies which might be implied in the sustenance of non-seizure symptoms