Retinal structure and function in vigabatrin-treated adult patients with refractory complex partial seizures
Evaluate visual-field and retinal-structure changes following adjunctive vigabatrin treatment in vigabatrin-naive adults with refractory complex partial seizures (rCPS).Methods
Prospective, longitudinal, single-arm, open-label study (NCT01278173). Eligible patients (≥2 seizures/month who failed ≥3 therapies) who could reliably perform perimetry (Humphrey automated static) and retinal-structure assessment (spectral-domain optical coherence tomography) prior to vigabatrin exposure. Following vigabatrin initiation, testing occurred within 1 month (reference) and 3, 6, 9, and 12 months. End points included mean change from reference in mean deviation (dB) and average retinal nerve fiber layer (RNFL) thickness, visual-acuity changes from baseline, and number of patients who met predefined vision-parameter changes at two (confirmed) or three (persistent) consecutive visits.Results
Sixty-five of 91 screened patients received ≥1 vigabatrin dose (all-patients-treated set [APTS]); 55 had valid reference and ≥1 post–reference assessments (full-analysis set [FAS]). Thirty-six APTS patients with valid pre–/post–reference values completed all planned visits (per-protocol set [PPS]). Thirty-eight (59%) APTS patients completed the study; 27 (42%) withdrew (none for visual-field changes); 32% and 15% had abnormally thin RNFL and abnormal visual acuity at baseline, respectively; 20% had abnormal central 30 degree visual fields in the reference period. No significant mean near visual-field changes were observed (PPS); mean change in average RNFL thickness increased significantly (1-year data: Left-eye: 6.37 μm, confidence interval (CI) 4.66–8.09; right-eye: 7.24 μm CI 5.47–9.01; PPS). No confirmed three-line decreases in visual acuity (FAS) were observed; five patients had predefined confirmed/persistent visual-field changes (FAS). All vision-related adverse events were nonserious; the most common was vision blurred (9%).Significance
Prior to vigabatrin initiation, rCPS patients may already exhibit vision deficits. Up to 1 year of adjunctive vigabatrin treatment did not significantly change population near visual fields. Five patients met predefined visual-field-change criteria. RNFL thickening of unknown clinical significance was observed. Limitations include single-arm, open-label design; patients’ inability to perform ophthalmic/visual-field examinations; and limited vigabatrin-exposure duration.
An Epilepsy Research UK-funded study has shown that taking the antiepileptic drugs (AEDs) levetiracetam or topiramate during pregnancy may not have a negative impact on the baby’s IQ and thinking skills. The research, which also confirms the risks associated with valproate (another AED), is published in Neurology® online.
There is accumulating evidence that exposure to valproate before birth is linked to a significantly increased chance of birth defects, developmental problems and lower IQ, especially at higher dosages. However, valproate is an effective and widely-prescribed AED, so it is important to establish what the alternatives are for women with epilepsy during pregnancy (they need to be effective at controlling seizures and safe for the baby). Levetiracetam and topiramate are newer drugs, and to date few studies have looked at their effects on child development and thinking.
Lead Researcher, Dr Rebecca Bromley, at the University of Manchester, comments: “As doctors move away from prescribing valproate, we need to know about the alternatives for pregnant women with epilepsy. Lower IQs early on can harm a child’s educational success for years to come and so it is important that we gain a full understanding about any impact on development these medications may have.”
During the study, the researchers used data from the UK Epilepsy and Pregnancy Register to identify 171 women with epilepsy who had a child between the ages of five and nine years. Forty-two of the women had taken levetiracetam during pregnancy; 27 had taken topiramate; and 47 had taken valproate. A control group of 55 women who did not take AEDs during pregnancy was also included. The team carried out assessments of the children to measure their IQ, verbal and non-verbal comprehension, and the speed at which they could process visual information.
The results showed that the children of women who took levetiracetam or topiramate did not have reduced IQs, or other thinking skills, compared to the control group, regardless of the dosage of medication their mother took. Children whose mothers had taken valproate were found to have the lowest IQs; scoring an average of 11 points lower on the IQ test (which has an average of 100 points). Nine of the 47 children whose mothers took valproate (19%) were shown to be below the average range on the IQ score, compared to three of the 55 children whose mothers did not take any epilepsy drugs during pregnancy ((6%).
These findings are encouraging; however Dr Bromley adds a note of caution: “While our findings represent a promising start, larger studies need to be done ensure that these drugs will not change the thinking abilities of children.”
She notes that one limitation of the study is that the pregnancy registry represents only a small proportion of women with epilepsy, and that therefore the results may not be representative of all women with epilepsy. She also observes that topiramate has been associated with an increased risk of birth defects such as cleft lip and palate. Due to the fact that few children exposed to topiramate were included in the study, the results should be interpreted carefully.
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Evaluation of a simplified modified Atkins diet for use by parents with low levels of literacy in children with refractory epilepsy: a randomized controlled trial.
Results from the US and China may help to explain why some children with epilepsy outgrow their condition in adolescence.
At the heart of these findings is ‘GABA’; a brain chemical that acts via structures called receptors to dampen down electrical activity in neurons (and prevent them from becoming hyperexcitable). Recent evidence shows that there is a specific type of GABA receptor, called α4βδ, that is only made in the brain during puberty.
In the current study, the team, led by Dr Sheryl Smith, at SUNY Downstate, New York, wanted to explore the role of α4βδ receptors in regulating seizure activity. To do this they used animal brain tissue, from before puberty and during puberty, and induced seizure-like activity in it using approved methods.
The researchers found that when they tried to induce seizure-like activity in the pre-pubertal tissue, they were successful in 60% of cases. However, when they used the same techniques in the ‘pubertal’ tissue, only 7% developed seizure-activity.
To make sure that it was the α4βδ receptor that accounted for this difference at not another factor, the team repeated their experiment using tissue from pubertal animals that had been bred to lack the gene that encodes α4βδ (instead of pubertal animals with normal α4βδ).
Here they found no reduction in seizure-like activity in the pubertal tissue compared with pre-pubertal tissue. This suggests that the α4βδ receptor does indeed play a role in reducing seizure-like activity at puberty, in this model of epilepsy.
Interestingly, the administration of drugs that selectively enhance inhibitory activity mediated by this receptor further decreased seizure-like activity in the brain of the animals. If the findings from this study are translatable to humans, a brand new avenue for epilepsy treatment will open.
Dr Smith and colleagues concluded: “These findings suggest a mechanism for remission of epilepsy in adolescence and also suggest potential new therapies for childhood epilepsy.”
The study was published in the leading journal Scientific Reports.
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Dynamics of sensorimotor cortex activation during absence and myoclonic seizures in a mouse model of juvenile myoclonic epilepsy
Generalized epilepsy syndromes often confer multiple types of seizures, but it is not known if these seizures activate separate or overlapping brain networks. Recently, we reported that mice with a juvenile myoclonic epilepsy mutation (Gabra1[A322D]) exhibited both absence and myoclonic generalized seizures. Here, we determined the time course of sensorimotor cortex activation and the spatial distribution of spike voltage during these two seizures.Methods
We implanted Gabra1+/A322D mice with multiple electroencephalography (EEG) electrodes over bilateral somatosensory cortex barrel fields (S1) and anterior (aM1) and posterior (pM1) motor cortices and recorded absence seizures/spike-wave discharges (SWDs) and myoclonic seizures. We used nonlinear-association analyses and cross-correlation calculations to determine the strength, leading regions, and time delays of cortical coupling from the preictal to ictal states and within the spike and interspike periods. The distribution of spike voltage was also measured in SWDs and myoclonic seizures.Results
EEG connectivity among all electrode pairs increased at the onset of both SWDs and myoclonic seizures. Surprisingly, during spikes of both seizure types, S1 led M1 with similar delay times. Myoclonic seizure spikes started more focally than SWD spikes, with a significant majority appearing first only in S1 electrodes, whereas a substantial fraction of SWD spikes were detected first in S1 and at least one M1 electrode. The absolute voltage of myoclonic seizure spikes was significantly higher than that of SWD spikes, and there was a greater relative voltage over M1 during myoclonic seizure spikes than in the first one to two SWD spikes.Significance
The leading sites in S1 and similar delay times suggest both SWDs and myoclonic seizures activate overlapping networks in sensorimotor cortex and thus, therapeutically targeting of this network could potentially treat both seizures. Spike focality, absolute voltage, and voltage distribution provide insight into neuronal activation during these two seizure types.