Tolerability, safety, and efficacy of adjunctive brivaracetam for focal seizures in older patients: A pooled analysis from three phase III studies
Brain atrophy, or wasting, and re-organisation of neurons occur in the brains of people with super-refractory status epilepticus (SRSE), according to a study published in JAMA Neurology. The research also shows that the severity of brain atrophy is related to the duration of SRSE.
This is the first study to show that brain atrophy occurs even after difficult-to-treat status epilepticus is controlled with anaesthetic drugs.
Dr Sara Hocker, from the Mayo Clinic in Rochester, Minnesota, and co-authors, reported: “In the hours, days, and weeks after prolonged seizures, long-term changes in gene expression” occur. This is accompanied by the chronic rupture of small blood vessels and “results in seizure-induced neuronal death and neuronal reorganization.”
During the study, Dr Hocker and her colleagues reviewed the medical records of people with SRSE who were admitted to Mayo Clinic Hospital between 2001 and 2014.
A total of 42 people with SRSE were admitted during this time period, 19 of whom met the study criteria: to have had an MRI scan within two weeks of the onset of the SRSE and another MRI within six months of the SRSE resolution, with a minimum of one week between scans. All 19 subjects had received anaesthetic agents to control their seizures.
The researchers analysed the participants’ MRI scans, paying particular attention to the area of the ventricles (fluid cavities) compared with the total area of the brain. A ratio of these (ventricular area/total brain area), known as the ventricular-brain ratio, is a common measure of cerebral atrophy or wasting, and a larger ratio suggests a higher degree of wasting.
Looking at the scans in two groups (initial MRI and follow-up MRI), the team found that the average ventricular-brain ratio amongst the follow-up scans was significantly larger than the average ventricular area amongst the initial scans. This suggests that wasting of brain matter had occurred.
The scientists also discovered that the longer people stayed in hospital and were treated with anaesthetic agents, the more wasting they had in their brain.
Finally, they found that the difference in ventricular-brain ratio was smaller in older people with SRSE, but this was probably due to the fact that the older people already had a larger ventricular-brain ratio at the initial MRI due to their age.
The study was not able to tell whether cerebral atrophy was caused by complications associated with SRSE or the effect of antiepileptic drugs (AEDs).
According to the authors, future studies should focus on which areas of the brain are most affected in SRSE, the association of atrophy with clinical variables, and the influence of atrophy on long-term cognitive function in survivors of SRSE.
SRSE is defined as status epilepticus (or a seizure, or series of seizures lasting for five minutes or more) that continues or recurs 24 hours or more after the onset of anaesthetic therapy.
Author: Dr Özge Özkaya
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To examine if mice with focal cortical dysplasia (FCD) develop spontaneous epileptic seizures and, if so, determine the key electroencephalography (EEG) features.Methods
Unilateral single freeze lesions to the S1 region (SFLS1R) were made in postnatal day 0–1 pups to induce a neocortical microgyrus in the right cortical hemisphere. Continuous 24-h recordings with intracranial EEG electrodes and behavioral tests were performed in adult SFLS1R and sham-control mice to assess neurologic status.Results
A high percentage of adult SFLS1R animals (89%, 40/45) exhibited at least one or more spontaneous nonconvulsive seizure events over the course of 24 h. Of these animals, 60% (27/45) presented with a chronic seizure state that was persistent throughout the recording session, consisting of bursts of rhythmic high-amplitude spike-wave activities and primarily occurring during periods of slow-wave sleep. In comparison, none of the control, age-matched, mice (0/12) developed seizures. The epileptic discharge pattern closely resembled a pattern of continuous spike-waves during slow-wave sleep (CSWS) of the human syndrome described as an electrical status epilepticus during slow-wave sleep (ESES). Key findings in the SFLS1R model indicated that the observed CSWS (1) were more prevalent in female (18/23) versus male (9/22, p < 0.05), (2) were strongest in the right S1 region although generalized to other brain regions, (3) were associated with significant cognitive and behavioral deficits, (4) were temporarily alleviated by ethosuximide treatment or optogenetic activation of cortical γ-aminobutyric acid (GABA)ergic neurons, and (5) theta and alpha band rhythms may play a key role in the generalization of spike-wave activities.Significance
This is the first report of an in vivo animal FCD model that induces chronic spontaneous electrographic brain seizures. Further characterization of the abnormal oscillations in this mouse model may lead to a better understanding of the mechanisms of CSWS/ESES.
Long-term exposure and safety of lacosamide monotherapy for the treatment of partial-onset (focal) seizures: Results from a multicenter, open-label trial
To assess long-term use and safety of lacosamide (LCM) ≤800 mg/day monotherapy in patients with partial-onset seizures (POS) enrolled previously in a historical-controlled, conversion-to-monotherapy study (SP902; NCT00520741).Methods
Patients completing or exiting SP902 with LCM as monotherapy or as adjunctive therapy were eligible to enter this 2-year open-label extension (OLE) trial (SP904; NCT00530855) at a starting dose ±100 mg/day of their final SP902 dose. Investigators could adjust the LCM dose to 100–800 mg/day and add up to two antiepileptic drugs to optimize tolerability and seizure reduction.Results
Three hundred twenty-two patients received LCM: 210 patients (65.2%) completed and 112 (34.8%) discontinued, most commonly owing to withdrawal of consent (9.3%). Two hundred fifty-eight patients (80.1%) had ≥1 year of and 216 (67.1%) had ≥2 years of LCM exposure, of whom 179/258 (69.4%) achieved LCM monotherapy lasting for any 12-month period, and 126/216 (58.3%) patients exposed for ≥24 months achieved LCM monotherapy for any 24-month period. Total exposure = 525.5 patient-years. The median modal dose was 500 mg/day. Two hundred ninety-two patients (90.7%) achieved LCM monotherapy at some point during the study. Sixty-five of 87 patients who exited and 193/235 who completed SP902 were exposed for ≥12 months, and 43.1% and 78.2%, respectively, achieved LCM monotherapy for ≥12 months. Median LCM monotherapy duration was 587.0 days (2–791 days); 91.0% of patients reported treatment-emergent adverse events, of which the most common were dizziness (27.3%), headache (17.1%), and nausea (14.3%). Compared with the SP902 study baseline, 74.2% of patients had a ≥50% seizure reduction and 5.6% were seizure-free at 24 months.Significance
The majority of patients were receiving LCM monotherapy at 0, 12, and 24 months in this OLE. Lacosamide monotherapy (median dose of 500 mg/day) had a safety profile similar to that of adjunctive therapy studies. These results support the use of lacosamide as long-term monotherapy treatment for adults with POS.
Genetic risk factors for antiepileptic drug–induced hypersensitivity reactions in Israeli populations
The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)– and toxic epidermal necrolysis (TEN)–related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug–induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.
Disclaimer: Epilepsy Research UK is completely neutral and is not affiliated with any commercial company, or any particular device/product.
The medical company, MMJ PhytoTech Limited, has recently announced that it will begin a new phase two clinical trial by the end of this year to test the effectiveness of its new drug compound, PTL101, in treating children with drug-resistant epilepsy.
During the trial, PTL101 will be administered in the form of capsules containing organically-derived, highly purified cannabidiol – one of more than 100 active ‘cannabinoids’ identified in cannabis.
In a press release, Andreas Gedeon, Managing Director of MMJ PhytoTech said: “We are very pleased to be commencing the Phase 2 clinical trial of our PTL101 capsules, as it marks another critical milestone in the company’s evolution.”
The trial will take place at a centre in Israel and, at present, there has been no indication from the company as to whether it will extend to other sites across the world. We will keep you informed as and when any information regarding this becomes available.
According to the company, the success of the phase 2 trial will be a major step towards the licensing of PTL101 capsules as a prescription therapy that could benefit children with drug resistant epilepsy around the world.
Approximately one third of people with epilepsy do not respond to existing antiepileptic drugs (AEDs) designed to reduce seizures. Some current AEDs are also very difficult to tolerate, because they cause unwanted side effects such as tiredness and slowed thinking.
Author: Dr Özge Özkaya
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Pregnant women and new mothers with epilepsy have reduced life satisfaction, even in societies with high levels of welfare, according to a study published in the scientific journal Epilepsy & Behavior.
The authors therefore suggest: “mothers with epilepsy and their partners should be examined for emotional complaints and partnership satisfaction during and after pregnancy.”
The team of researchers, led by Dr Nils Erik Gilhus, at the University of Bergen, in Norway, analysed more than 100,000 women with and without epilepsy from the Norwegian Mother and Child Cohort Study, during weeks 15-19 of pregnancy and at six and 18 months after birth.
They found that 0.6-0.8% of the women had epilepsy at all three assessment points, and that, compared with those without epilepsy, these women had lower life satisfaction and self-esteem both during and after pregnancy. They also reported lower satisfaction in their relationships and higher levels of work strain during pregnancy, and less general well being and belief in their own abilities 18 months after the birth of their baby.
The authors found that divorce and separation were more common in mothers with epilepsy compared with those without, and that fewer women with epilepsy had a paid job 18 months after giving birth.
Previous work has shown that anxiety about birth and post-natal depression are seen more frequently in women with epilepsy that in those without. Such emotional distresses in pregnant women may have a negative effect on birth outcome. Therefore it is important that women with epilepsy are offered adequate support in order to achieve good emotional health.
Author: Dr Özge Özkaya
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