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.
Click here for more articles about anti-epileptic drugs and pregnancy risks.
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.
Incidence and outcome of epilepsy syndromes with onset in the first year of life: A retrospective population-based study
Population-based studies on infantile epilepsy syndromes are scarce. Our aim was to provide syndrome-specific data on the incidence and outcome of epilepsy in a population-based cohort of infants with epilepsy onset in the first year.Methods
Included were all infants born in 1997 through 2006 whose epileptic seizures started before 12 months of age and who were residents of the Helsinki University Hospital district at the time of seizure onset. Patients were ascertained from hospital statistics, and all patient charts were reviewed. A reevaluation of the epilepsy syndromes, age at onset, etiology, and outcome at 24 months of age was based on data abstracted from the patient files.Results
Inclusion criteria were fulfilled by 158 infants, of whom 92% were followed until age 24 months or death. The incidence of epilepsy in the first year was 124 of 100,000. An epilepsy syndrome recognized by the revised organization of epilepsies by ILAE was identified in 58% of the patients. The most common syndromes were West syndrome (41/100,000) and benign familial or nonfamilial infantile epilepsy (22/100,000). Etiology was structural-metabolic in 35%, genetic in 17%, and unknown in 48%. Early age at onset was associated with structural-metabolic etiology. Seven infants (4.4%) died before age 2 years. One infant with an SCN2A mutation died of sudden unexplained death in epilepsy (SUDEP). At 24 months, 58% of all children included in the cohort were seizure-free, and 46% had both seizure freedom and age-appropriate cognitive development. Age at onset was not associated with outcome when etiology was controlled for.Significance
Benign familial and nonfamilial infantile epilepsy appears to be more common than previously suggested, second only to West syndrome. Early age at onset is not an independent risk factor for poor outcome.
When left-hemisphere reading is compromised: Comparing reading ability in participants after left cerebral hemispherectomy and participants with developmental dyslexia
We investigated reading skills in individuals who have undergone left cerebral hemispherectomy and in readers with developmental dyslexia to understand diverse characteristics contributing to reading difficulty. Although dyslexia is a developmental disorder, left hemispherectomy requires that patients (re)establish the language process needed to perform the language-based tasks in the nondominant (right) hemisphere to become readers.Methods
Participants with developmental dyslexia (DD; n = 11) and participants who had undergone left hemispherectomy (HEMI; n = 11) were matched on age and gender, and were compared on timed and untimed measures of single word and pseudo-word reading. The hemispherectomy group was subdivided into prenatal (in utero) and postnatal (>3 years) insult groups, indicating the timing of the primary lesion that ultimately required surgical intervention.Results
On an untimed reading measure, the readers with DD were comparable to individuals who had undergone left hemispherectomy due to prenatal insult, but both scored higher than the postnatal hemispherectomy group. Timed word reading differed across groups. The hemispherectomy prenatal subgroup had low average scores on both timed and untimed tests. The group with dyslexia had average scores on untimed measures and below average scores on timed reading. The hemispherectomy postnatal group had the lowest scores among the groups by a significant margin, and the most pronounced reading difficulty.Significance
Patients with prenatal lesions leading to an isolated right hemisphere (RH) have the potential to develop reading to a degree comparable to that in persons with dyslexia for single word reading. This potential sharply diminishes in individuals who undergo hemispherectomy due to postnatal insult. The higher scores of the prenatal hemispherectomy group on timed reading suggest that under these conditions, individuals with an isolated RH can compensate to a significant degree.
Hippocampal malrotation is an anatomic variant and has no clinical significance in MRI-negative temporal lobe epilepsy
There is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)–negative temporal lobe epilepsy (TLE).Methods
We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE.Results
We found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippocampi—14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippocampi—12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe.Significance
HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making.
A prospective study contrasting the psychiatric outcome in drug-resistant epilepsy between patients who underwent surgery and a control group
Psychiatric morbidity in drug-resistant epilepsy is frequent and has a negative influence on quality of life. Surgery is proven to be the best therapeutic alternative for treating seizures. However, it is inconclusive with the current evidence whether surgery, per se, is a risk factor or promotes amelioration of psychiatric disorders. Until now, most studies have been cross-sectional with small or heterogeneous groups. In addition, the few prospective studies did not have an identical control group. The present study aims to clarify the role of surgery in psychopathologic alterations.Methods
We analyzed, through a prospective case-control study, the psychopathologic outcomes of patients with drug-resistant epilepsy, comparing those who underwent surgery and those who continued with pharmacologic treatment due to not being suitable for surgery. The assessments were performed during presurgical evaluation and 6 months after surgery. We studied psychiatric changes for each group, compared differences between groups, and also analyzed de novo and remission cases. Finally, we determined associated factors for postsurgical psychiatric disturbances.Results
The surgical group experienced a significant decrease in psychopathologic alterations in comparison with the control group. In addition, distress perception of surgical patients also improved, whereas it did not decrease in the control group. Patients who underwent surgery presented a decrease in depressive and anxiety symptoms, whereas the nonsurgical group increased its anxiety levels. De novo disturbances that appeared after surgery were less frequent than in nonsurgical patients. We observed significant favorable outcomes considering de novo versus remission cases for anxiety, depression, and total symptoms only in the surgical group. The two main predictors for psychiatric disorders after surgery were presurgical psychiatric functioning and surgery.Significance
Provides evidence that surgery improves psychiatric functioning in drug-resistant epilepsy through a prospective controlled study.
Pathologic increases in excitability levels of cortical tissue commonly underlie the initiation and spread of seizure activity in patients with epilepsy. By reducing the excitability levels in neural tissue, antiepileptic drug (AED) pharmacotherapy aims to reduce seizure severity and frequency. However, AEDs may also bring about adverse effects, which have been reported to increase with higher AED load. Measures that monitor the dose-dependent effects of AEDs on cortical tissue and quantify its excitability level are therefore of prime importance for efficient clinical care and treatment but have been difficult to identify. Here, we systematically analyze continuous multiday electrocorticography (ECoG) data from 10 patients under different levels of AED load and derive the recently proposed intrinsic excitability measures (IEMs) from different brain regions and across different frequency bands. We find that IEMs are significantly negatively correlated with AED load (prescribed daily dose/defined daily dose). Furthermore, we demonstrate that IEMs derived from different brain regions can robustly capture global changes in the degree of excitability. These results provide a step toward the ultimate goal of developing a reliable quantitative measure of central physiologic effects of AEDs in patients with epilepsy.