Refractory Focal Seizures Research Articles

Brivaracetam: How Well Does It Fare as an Anti-Epileptic? A Review.

Epilepsy is a common neurological ailment contributing to significant disability. About one-third of all epilepsy patients would be refractory to two or more medications. Brivaracetam (BRV) is one of the newer anti-seizure medications on which extensive data is available, but its efficacy as an early add-on agent (first/second adjuvant) is unclear. The principal objective of this review is to assess the efficacy of BRV as an early add-on agent in refractory Focal Onset Seizures (FOS) and its pharmacology and usage in various clinical situations associated with seizures. We searched two databases, Medline and Cochrane Central, for papers on BRV and FOS, and selected six studies with randomized parallel control design to extract the data for a meta-analysis. We also did a comprehensive review of the available literature on its pharmacology and usage in various clinical scenarios associated with seizures. For the meta-analysis, we extracted 145 articles; six studies fulfilled the selection criteria that gave us data on 1938 patients who received Brivaracetam as an early add-on agent in FOS. The Risk Ratio (RR) (95% CI) for 50% responders across the trials was 1.88 (1.55-2.29). Similarly, the overall RR (95% CI) was 5.82 (2.15-15.70) for seizure freedom. Our analysis provides moderate evidence for Brivaracetam as an effective agent as an early adjuvant in FOS. Its efficacy for several other indications needs further clinical trials and evaluation.

Epilepsy Brain Responds to Nerve Stimulations

Controlled clinical trials in adults with medically refractory focal seizures treated with the RNS® system have shown that closed-loop nerve stimulation that responds to epileptic foci can reduce the frequency of disabling seizures, is well tolerated, and It is acceptable security. The reduction in seizures begins at the beginning of treatment and continues over time, reaching a median reduction of 75 to 9 years of treatment. Treatment with sensitive cortical stimulation is also related to an improvement in the quality of life and cognitive function related to the functional area being treated. In addition, the chronic dynamic cortical EEG monitoring of the RNS system provides unprecedented insights for the disease management of each patient and the research of epilepsy itself, which can improve the treatment of epilepsy in the future.

Effectiveness of dose-escalated topiramate monotherapy and add-on therapy in neurosurgery-related epilepsy: A prospective study.

Background:Lesional and symptomatic causes of epilepsy are the most common neurological disorders of the brain. Topiramate effectively controls newly diagnosed epilepsy and refractory focal seizures, but high-dose topiramate does not improve seizure control. This study aimed to evaluate the clinical efficacy and safety of dose-escalated topiramate as first-line monotherapy and add-on therapy in patients with neurosurgery-related epilepsy.Material and Methods:A total of 55 neurosurgical patients with epilepsy were divided into monotherapy and add-on therapy groups and both groups received topiramate via the dose-escalation method. The primary efficacy outcomes were seizure-free rate and seizure response rate. Adverse events and seizure frequency were recorded.Results:The seizure response rate in the first month of monotherapy was significantly better than that of add-on therapy (89% vs 65%, P < .05), but no significant differences were found in seizure response rates between the 2 groups after 2 months of treatment. Both monotherapy and add-on therapy were effective in controlling seizures, with mean seizure frequency of 0.725 vs 0.536 and seizure-free rate of 88% vs 78.6%. Both treatments showed good improvement of seizure frequency in patients without tumor. The efficacy of monotherapy was better than that of add-on therapy (80% vs 29.2%) in patients with body mass index (BMI) ≤24. However, add-on therapy was better than monotherapy (76.7% vs 21.4%) in patients with BMI > 24. Dizziness (25.5%) and headache (16.4%) were the most common adverse events. No severe adverse event such as cognitive impairment was observed.Conclusions:Dose-escalated topiramate monotherapy and add-on therapy demonstrate good efficacy and safety, with fewer adverse events in seizure control in neurosurgical patients.

Surgical decision-making among patients with uncontrolled epilepsy: “Making important decisions about my brain, which I happen to love”

To explore decision-making from patients' perceptions of risks and benefits of epilepsy surgery for refractory focal seizures. Using constructivist grounded theory, in-person interviews were conducted with 35 adults with refractory focal epilepsy who were undergoing a pre-surgical evaluation or who had consented for surgery. For this sample of participants decision-making about surgery was complex, centering on the meaning of illness for the self and the impact of epilepsy and its treatment for significant others. Two interrelated categories crystalized from our data: the unique context of brain surgery and how the decisional counterweights of risks and benefits were considered. Exploring components of decision-making from the patients' perspective afforded an opportunity to describe thought processes intrinsic to how people with drug-resistant epilepsy weighed their treatment options. Tensions were evident in how decisions were made. We use the analogy of an imaginary tightrope-walker to create a visual image of what patients face as they consider the illness experience (past and present), their hopes for the future, and the simultaneous uncertainty centered around balancing the counterweights of treatment risks and benefits.

Associations between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life in patients with focal seizures treated with adjunctive eslicarbazepine acetate: Post hoc analyses of clinical trial results

The relationships between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life (HRQoL) may be important for determining the overall impact of medication therapy on patients with epilepsy. The objectives of these post hoc analyses of the global Phase III 093-0304 trial (NCT00988429, Study 304) of adjunctive eslicarbazepine acetate (ESL) in patients with refractory focal (partial-onset) seizures (FS) were to evaluate associations between seizure severity change, measured by the Seizure Severity Questionnaire (SSQ), and 1) patient characteristics, 2) seizure frequency change, standardized as the seizure frequency (SSF) per 28-day period, and 3) change in HRQoL, evaluated by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) and the Montgomery–Åsberg Depression Rating Scale (MADRS).The analyses were conducted on the per-protocol population (PPP) of patients who were randomized to a placebo arm (n = 188) or an ESL-active group that included treatment with adjunctive ESL 800 mg once daily (QD; n = 184) or adjunctive ESL 1200 mg QD (n = 175). General linear models (GLM) were used to measure the association between SSQ change and patient baseline characteristics or percentage change in the SSF from baseline. Associations between changes in the SSQ and changes in the QOLIE-31 and MADRS were examined using GLM with patient baseline characteristics as covariates. Subgroup analyses were performed for patients in the ESL-active group and those treated with ESL 800 mg or ESL 1200 mg. Minimal clinically important difference (MCIDs) thresholds were used to assess improvements in SSQ scores.The analyses included 547 per-protocol patients. Patients using 1 antiepileptic drug (AED) at baseline had greater improvements in the SSQ compared with those receiving 2 AEDs (P = 0.0606). Treatment with ESL 1200 mg was significantly associated with clinically meaningful improvements in the SSQ (P = 0.0005). The SSQ improvements were significantly associated with an SSF reduction of ≥75%, compared with no reduction (P < 0.0001). In the PPP and the ESL-active group, SSQ improvements were significantly associated with improvements in QOLIE-31 Total Score (TS; P < 0.0001) and the Seizure Worry (SW; P < 0.0001) and Social Functioning (SF; P = 0.0030) subscales. In the ESL 1200 mg subgroup, SSQ improvements were significantly associated with improvements in QOLIE-31 TS (P < 0.0001) and the SW (P < 0.0001) and Energy/Fatigue (EF; P = 0.0007) subscales. In the ESL 800 mg subgroup, improvements in the SSQ were significantly associated with improvements in QOLIE-31 TS (P = 0.0362) and the SW (P = 0.0241) subscale. There was no significant association between changes in the SSQ and changes in the MADRS in patients treated with ESL.These findings demonstrated that in this clinical trial population, adding ESL to baseline AED therapy had utility for decreasing seizure severity and improving HRQoL. There were no significant associations between changes in seizure severity and changes in depressive symptoms in patients with FS.

Subthalamic Nucleus Stimulation Modulates Motor Epileptic Activity in Humans.

Pharmaco-refractory focal motor epileptic seizures pose a significant challenge. Deep brain stimulation (DBS) is a recently recognized therapeutic option for the treatment of refractory epilepsy. To identify the specific target for focal motor seizures, we evaluate the modulatory effects of the subthalamic nucleus (STN) stimulation because of the critical role of STN in cortico-subcortical motor processing. Seven patients with epilepsy with refractory seizures who underwent chronic stereoelectroencephalography (SEEG) monitoring were studied in presurgical evaluation. Seizure onset zone was hypothesized to be partially involved in the motor areas in 6 patients. For each patient, one electrode was temporally implanted into the STN that was ipsilateral to the seizure onset zone. The cortical-subcortical seizure propagation was systemically evaluated. The simultaneously electrophysiological responses over distributed cortical areas to STN stimulation at varied frequencies were quantitatively assessed. We observed the consistent downstream propagation of seizures from the motor cortex toward the ipsilateral STN and remarkable cortical responses on motor cortex to single-pulse STN stimulation. Furthermore, we showed frequency-dependent upstream modulatory effect of STN stimulation on motor cortex specifically. In contrast to the enhanced effects of low frequency stimulation, high-frequency stimulation of the STN can significantly reduce interictal spikes, high-frequency oscillations over motor cortex disclosing effective connections to the STN. This result showed that the STN is not only engaged in as a propagation network of focal motor seizures but STN stimulation can profoundly modulate the epileptic activity of motor cortex in humans, suggesting a mechanism-based alternative for patients suffering from refractory focal motor seizures. ANN NEUROL 2020;88:283-296.

Predictors of focal to bilateral tonic-clonic seizures during long-term video-EEG monitoring.

To determine predictors of focal to bilateral tonic-clonic seizures (FBTCS) during video-electroencephalography (EEG) monitoring (VEM). All adult patients undergoing presurgical VEM from 2014 to 2015 in the department of epileptology were eligible (N=229). Those with refractory focal epilepsy and epileptic seizures recorded during VEM were analyzed (N=188, Group 1). To assess the effects of antiepileptic drug (AED) taper, the total AED load was calculated as the sum of the ratios of prescribed daily dose and defined daily dose of all AEDs per VEM day and was correlated with the occurrence of focal seizures without bilateral tonic-clonic seizures (FwoBTCS) and FBTCS. To validate the findings, data of patients undergoing VEM in 2004 and 2005 (Group 2, eligible N=243, analyzed N=203) were also investigated. In Group 1, 53 patients had FBTCS and 135 patients had exclusively FwoBTCS during VEM. Reduced AED load at seizure onset was the most important modifiable risk factor for FBTCS (receiver-operating characteristic [ROC]: area under the curve [AUC]=0.78). Furthermore, the risk of FBTCS varied with the history and frequency of FBTCS prior to VEM. For instance, patients had a 50% risk of FBTCS by reducing the AED load to ~20% when no information about history of FBTCS was taken into account, to ~30% when a positive history of FBTCS was taken into account, and to ~50% when a high frequency of FBTCS prior to VEM was taken into account. These findings were largely replicated in Group 2 (59 patients with FBTCS and 144 exclusively with FwoBTCS). The risk of FTBCS during VEM depends on the history and frequency of FTBCS prior to VEM and is particularly associated with the extent of AED reduction. Our data underscore the need for appropriate tapering regimens in VEM units.

Neural processes of auditory perception in Heschl’s gyrus for upcoming acoustic stimuli in humans

In the natural environment, attended sounds tend to be perceived much better than unattended sounds. However, the physiological mechanism of how our neural systems direct the state of perceptual attention to prepare for the detection of upcoming acoustic stimuli before auditory stream segregation remains elusive. In this study, based on the direct intracerebral recordings from the auditory cortex in eight epileptic patients with refractory focal seizures, we investigated the neural processing of auditory attention by comparing the local field potentials before ‘attentional’ and ‘distracted’ conditions. Here we first showed a distinct build-up of slow, negative cortical potential in Heschl’s gyrus. The amplitude increased steadily, starting from 600 to 800 ms before presentation of the tone until the onset of the evoked component P/N 60–80 when the patients were in the attentional condition. Because of their specific topographical distribution and modality-specific properties, we named these ‘auditory preparatory potentials’, which are also associated with increased gamma oscillations (30–150 Hz) and desynchronized low frequency activity (below 30 Hz). Thus, our findings suggest that the auditory cortex is pre-activated to facilitate the perception of forthcoming sound events, and contribute to the understanding of the neurophysiological mechanisms of auditory perception from a new perspective.

Progesterone in Treatment of Catamenial Epilepsy

Catamenial epilepsy refers to the temporal correlation of seizure exacerbations with the menstrual cycle. Changes in the serum estradiol and progesterone are implicated in this phenomenon, which makes management of epilepsy in women more challenging. This is a case of a 24-year-old nulligravid who was referred to a reproductive medicine specialist due to refractory focal seizures despite antiepileptic pharmacotherapy. EEG confirmed neurologic dysfunction but clinical history, physical examination, cranial CT and MRI ruled out structural, vascular, traumatic, and infectious causes of seizure. Adjunctive hormonal treatment was given, which improved patient symptoms. This report aims to discuss catamenial epilepsy as to its pathophysiology, diagnosis, and management. Better understanding of this disease entity will help address treatment difficulties in epilepsy in female patients and the associated management issues.

Long-term safety and efficacy following conversion to eslicarbazepine acetate monotherapy in adults with focal seizures

ObjectiveTo assess the long-term safety and efficacy of eslicarbazepine acetate (ESL) monotherapy in adults with focal seizures (FS). MethodsStudy 050 was a long-term, multicenter, open-label (OL) safety extension of two conversion-to-ESL monotherapy studies in adults with refractory FS. After participating in Study 045 or 046, patients started on ESL 1600 mg once daily (QD) (or 1200 mg if they previously had a dose reduction), and could adjust the dose 400 mg/week to a dose between 800–2400 mg QD. Patients could add up to two additional antiepileptic drugs (AEDs). This post-hoc analysis focuses on the actual monotherapy subgroup, which included patients in Studies 045/046/050 who did not add additional AEDs. Study endpoints included treatment retention time, time on ESL monotherapy, change in standardized seizure frequency (SSF), change in quality of life (QoL) in epilepsy (QOLIE-31) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and incidence of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs related to allergic reaction, hyponatremia and thyroid function were also evaluated. ResultsThere were 274 patients in the Study 050 full intent-to-treat (ITT) population and 140 patients in the actual monotherapy subgroup. Median treatment retention time and time on ESL monotherapy were both >5 years. Median reduction in SSF from baseline was 66.4% in the full ITT population and 78.3% in the actual monotherapy subgroup; responder (≥50% reduction in SSF) rates were 62.4% and 74.3%, respectively. QOLIE-31 scores increased from baseline in the full ITT population and the actual monotherapy subgroup (4.1- and 7.5-point increases, respectively). MADRS scores decreased from baseline in both the full ITT population and the actual monotherapy subgroup (0.7- and 2.9-point decreases, respectively). TEAEs occurred in 85.4% of patients in the full ITT population and 81.4% of patients in the actual monotherapy subgroup. Incidences of SAEs and TEAEs leading to discontinuation, as well as dizziness, depression, fall, partial seizures with secondary generalization, and complex partial seizures, were higher in the full ITT population than in the actual monotherapy subgroup. Allergic reactions, hyponatremia, and hypothyroidism were infrequent, particularly in the actual monotherapy subgroup. ConclusionsThe results of this post-hoc analysis suggest that long-term treatment with ESL was effective and well tolerated, both as a monotherapy and in combination with other AEDs for FS. QoL and tolerability appeared to be better, and incidence of depression lower, in the patient population taking ESL as a monotherapy, compared with the population that included patients taking ESL as an adjunctive therapy.

Efficacy, safety, and tolerability of perampanel in Asian and non-Asian patients with epilepsy.

People of different ethnic or racial backgrounds may experience variations in pharmacokinetic and pharmacodynamic responses to drug therapies. Our post hoc analysis evaluated the efficacy, safety, and tolerability of perampanel in Asian and non-Asian populations with refractory focal seizures with or without focal to bilateral tonic-clonic (FBTC) seizures. This analysis pooled data from 4 randomized, placebo-controlled, phase-3 studies involving patients aged ≥12years who have focal seizures with or without FBTC seizures. Patients were receiving 2, 4, 8, or 12mg perampanel (or placebo) by the end of a 6-week titration period and for a further 13weeks during the maintenance phase. Efficacy endpoints included median percent change in seizure frequency per 28days, and 50% and seizure-freedom responder rates relative to baseline. The median percent change in seizure frequency per 28days from baseline was significantly greater than placebo for perampanel 8 and 12mg (-31.1% and -38.1% change, respectively; each P<0.0001) in the Asian population, and for perampanel 4, 8, and 12mg (-21.1% [P=0.0001], -26.3% [P<0.0001], and -27.7% [P=0.0001] change, respectively) in the non-Asian population. The 50% responder rate relative to baseline was significantly greater than placebo for perampanel 8 and 12mg (40.1% and 43.8%, respectively; each P<0.0001) in the Asian population, and for perampanel 4, 8, and 12mg (29.4% [P=0.0002], 32.8% [P<0.0001] and 34.5% [P=0.0001]), respectively, in the non-Asian population. Seizure-freedom rate among all patients was 4.9%-11.7% for perampanel 2, 4, 8, and 12mg. The most frequently reported treatment-emergent adverse events (TEAEs) across both populations were dizziness, somnolence, irritability, headache, and fatigue. The most common psychiatric TEAEs were aggression and irritability. Perampanel demonstrated a favorable and similar risk-benefit profile in both Asian and non-Asian populations with refractory focal seizures.

Pharmacokinetic evaluation of vigabatrin dose for the treatment of refractory focal seizures in children using adult and pediatric data

Vigabatrin is indicated as adjunctive therapy for refractory focal seizures. For children, European recommendations indicate maintenance doses varying from 30 to 100 mg/kg/day for this indication. Since cumulated dose was associated with retinal toxicity, it is essential to administrate the lowest effective dose to patients. This work was conducted with the purpose to determine the pediatric doses of vigabatrin that allow a similar exposure than effective doses in adults (2–3 g/day) through a pharmacokinetic (PK) study, using both pediatric and adult data. For this study, we focused on the active S(+) enantiomer of vigabatrin. First, the adult effective exposition range of vigabatrin-S was determined from an adult PK model. Then, this same model was scaled to the pediatric population using allometry and maturation principles to account for growth and development. The ability of the model to predict pediatric data was assessed by comparing population predictions with observed pediatric data. Finally, the extrapolated pediatric model was used to simulate pediatric expositions which were compared to the adult exposition range (36.5–77.9 mg.h/L). From those simulations, we determined that, for children aged between 3 months and 18 years, doses between 40 and 50 mg/kg/day allow vigabatrin-S expositions similar to those found in adults at the recommended posology. We proposed those doses as optimal maintenance doses that may be increased, if necessary, by slow titration.

Response to Early Coenzyme Q10 Supplementation Is not Sustained in CoQ10 Deficiency Caused by CoQ2 Mutation

BackgroundCOQ2 mutations cause a rare infantile multisystemic disease with heterogeneous clinical features. Promising results have been reported in response to Coenzyme Q10 treatment, especially for kidney involvement, but little is known about the long-term outcomes. MethodsWe report four new patients from two families with the c.437G→A (p.Ser146Asn) mutation in COQ2 and the outcomes of two patients after long-term coenzyme Q10 treatment. ResultsIndex cases from two families presented with vomiting, nephrotic range proteinuria, and diabetes in early infancy. These patients were diagnosed with coenzyme Q10 deficiency and died shortly after diagnosis. Siblings of the index cases later presented with neonatal diabetes and proteinuria and were diagnosed at the first day of life. Coenzyme Q10 treatment was started immediately. The siblings responded dramatically to coenzyme Q10 treatment with normalized glucose and proteinuria levels, but they developed refractory focal clonic seizures beginning at three months of life that progressed to encephalopathy. ConclusionsIn our cohort with CoQ10 deficiency, neurological involvement did not improve with oral coenzyme Q10 treatment despite the initial recovery from the diabetes and nephrotic syndrome.

Clonazepam add-on therapy for refractory epilepsy in adults and children.

Epilepsy affects about 50 million people worldwide, nearly a quarter of whom have drug-refractory epilepsy. People with drug-refractory epilepsy have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. To assess the efficacy and tolerability of clonazepam when used as an add-on therapy for adults and children with refractory focal onset or generalised onset epileptic seizures, when compared with placebo or another antiepileptic agent. We searched the following databases on 14 September 2017: Cochrane Epilepsy Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 14 September 2017), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). Double-blind randomised controlled studies of add-on clonazepam in people with refractory focal or generalised onset seizures, with a minimum treatment period of eight weeks. The studies could be of parallel or cross-over design. Two review authors independently selected studies for inclusion, extracted relevant data, and assessed trial quality. We contacted study authors for additional information. No double-blind randomised controlled trials met the inclusion criteria. There is no evidence from double-blind randomised controlled trials for or against the use of clonazepam as an add-on therapy for adults and children with refractory focal or generalised onset epileptic seizures.

The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset POLG-related mitochondrial disease.

SummaryFocal status epilepticus in POLG‐related mitochondrial disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr POLG mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re‐emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full‐time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by mitochondrial disease.

A review of the pharmacology and clinical efficacy of brivaracetam.

Brivaracetam (BRV; Briviact) is a new antiepileptic drug (AED) approved for adjunctive treatment of focal (partial-onset) seizures in adults. BRV is a selective, high-affinity ligand for synaptic vesicle 2A (SV2A) with 15- to 30-fold higher affinity than levetiracetam, the first AED acting on SV2A. It has high lipid solubility and rapid brain penetration, with engagement of the target molecule, SV2A, within minutes of administration. BRV has potent broad-spectrum antiepileptic activity in animal models. Phase I studies indicated BRV was well tolerated and showed a favorable pharmacokinetic profile over a wide dose range following single (10–1,000 mg) and multiple (200–800 mg/day) oral dosing. Three pivotal Phase III studies have demonstrated promising efficacy and a good safety and tolerability profile across doses of 50–200 mg/day in the adjunctive treatment of refractory focal seizures. Long-term data indicate that the response to BRV is sustained, with good tolerability and retention rate. BRV is highly effective in patients experiencing secondarily generalized tonic–clonic seizures. Safety data to date suggest a favorable psychiatric adverse effect profile in controlled studies, although limited postmarketing data are available. BRV is easy to use, with no titration and little drug–drug interaction. It can be initiated at target dose with no titration. Efficacy is seen on day 1 of oral use in a significant percentage of patients. Intravenous administration in a 2-minute bolus and 15-minute infusion is well tolerated. Here, we review the pharmacology, pharmacokinetics, and clinical data of BRV.

Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepineacetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

Diagnosis, monitoring and treatment of tuberous sclerosis complex: A South African consensus response to international guidelines

Tuberous sclerosis complex (TSC) is a genetic disorder with multi-system manifestations and a high burden of disease. In 2013, an international panel of TSC experts revised the guidelines for the diagnosis, surveillance and treatment of the disorder. In South Africa (SA), a local multidisciplinary group of healthcare professionals and TSC researchers reviewed the international guidelines to generate an SA consensus clinical update on the identification, diagnosis, treatment and lifelong monitoring of individuals who live with TSC. We strongly endorse dissemination and use of the international guidelines for the assessment, monitoring and treatment of TSC. In addition, we strongly support access to genetic testing and to mTOR (mammalian target of rapamycin) inhibitors to treat subependymal giant cell astrocytomas not amenable to surgery and renal angiomyolipomas larger than 3 cm, and as adjunctive treatment for refractory focal seizures. We await with interest results from mTOR inhibitor trials of skin and TSC-associated neuropsychiatric disorders (TAND). With regard to training, we recommend the inclusion of TSC in undergraduate and postgraduate medical and health sciences curricula, and the promotion of other continuing professional development events to raise awareness about TSC. We also support the development of a TSC user/carer/parent organisation to provide an informal support network for families across SA. We acknowledge that some progress has been made in recent years in SA, but much remains to be done. We hope that this SA consensus clinical update based on the international guidelines will make a positive contribution to increase knowledge and improve clinical care for all patients who live with TSC in SA, and their families.

Health-related quality of life in double-blind Phase III studies of brivaracetam as adjunctive therapy of focal seizures: A pooled, post-hoc analysis.

The effect of adjunctive brivaracetam on health-related quality of life (HRQoL) was assessed in a post-hoc analysis using pooled data from three randomized, double-blind, placebo-controlled Phase III studies in patients with refractory focal seizures (NCT00490035, NCT00464269, and NCT01261325). The Patient-Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) was completed at randomization, and weeks 4, 8 (in two of three studies), and 12 (end of the treatment period). Mean change from baseline to week 12 or early discontinuation, and percentage of patients with clinically meaningful improvement were reported for the placebo and brivaracetam 50, 100, and 200mg/day groups. At baseline, mean QOLIE-31-P scores were similar between treatment groups. At week 12 or early discontinuation, mean (standard deviation) changes from baseline in QOLIE-31-P total score were 2.8 (12.7), 3.0 (14.0), 2.4 (14.0), and 3.0 (12.1) points for the placebo and brivaracetam 50, 100, and 200mg/day groups, respectively, indicating HRQoL improved slightly over time during the treatment period, but was similar for placebo and brivaracetam groups. All subscale score changes were positive, indicating stable or improved HRQoL over time. The brivaracetam 100 and 200mg/day groups showed the largest differences compared with placebo in Seizure Worry subscale scores (7.3 and 8.8 vs. 5.0 points). Approximately 40% of patients had improvements in QOLIE-31-P scores beyond the Minimal Important Change (MIC) thresholds. The subgroup of ≥50% focal seizure frequency responders had higher improvements for all treatment arms and all subscales than for those in the overall pooled population. In this post-hoc analysis, adjunctive brivaracetam treatment was shown to be associated with stable or improving overall HRQoL over time, similar to placebo, with modest improvements in subscales sensitive to efficacy, and no deterioration in subscales sensitive to tolerability. These results reflect the known efficacy and tolerability profile of brivaracetam.

Sleep quality and daytime sleepiness in patients treated with adjunctive perampanel for focal seizures.

The purpose of this study was to evaluate subjective sleep quality and daytime sleepiness in patients receiving adjunctive perampanel for focal seizures. We conducted a multicenter, prospective, interventional, open-label study in patients aged >16 with focal seizures who received adjunctive perampanel (flexible dosing: 2-12mg). Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness with the Epworth Sleepiness Scale (ESS) at baseline and 3 and 6months after initiating perampanel. Patients with modifications in their baseline AEDs or sleep medications were excluded. In 72 patients with drug-resistant focal seizures, mean baseline PSQI score (±standard deviation) was 7.26 (±4.6), and ESS was 6.19 (±4.2). At 3months (median perampanel dose: 4mg), there was no significant mean change from baseline in ESS score (n=61) and a significant improvement in PSQI (-1.51 points; n=44; p=0.007), driven mainly by improved sleep efficiency (p=0.012). In the 31 patients with 6-month data, ESS (but not PSQI) improved significantly at 6months vs baseline (p=0.029). The only factor significantly correlated with sleep parameters was number of baseline AEDs (higher number correlated with worse daytime sleepiness). Seizure frequency was reduced significantly from baseline at 3 and 6months. In bivariate analysis, neither PSQI nor ESS was associated with seizure frequency, suggesting that the changes in daytime sleepiness and sleep quality may be independent of the direct effect on seizures. Adjunctive perampanel did not worsen sleep quality or daytime sleepiness at 3months and reduced daytime sleepiness in patients continuing perampanel for 6months. Perampanel may be a suitable AED in patients with sleep disorders, in addition to refractory focal seizures.