Gastaut Syndrome Research Articles

Efficacy analysis of oral dexamethasone in the treatment of infantile spasms and infantile spasms related Lennox–Gastaut syndrome

ObjectiveTreatment with adrenocorticotropic hormone (ACTH) or a corticosteroid is the first choice for infantile spasms (IS), and vigabatrin is the first choice for children with tuberous sclerosis. Although corticosteroids may be also effective against IS and IS-related Lennox–Gastaut syndrome (LGS), the use of dexamethasone (DEX), a kind of corticosteroid, for these diseases has been rarely reported. This retrospective study aimed to evaluate the efficacy and tolerability of DEX for the treatment of IS and IS-related LGS.MethodsPatients diagnosed as having IS (including patients whose condition evolved to LGS after the failure of early treatment) in our hospital between May 2009 and June 2019 were treated with dexamethasone after failure of prednisone treatment. The oral dose of DEX was 0.15–0.3 mg/kg/d. Thereafter, the clinical efficacy, electroencephalogram (EEG) findings, and adverse effects were observed every 4–12 weeks depending on the individual patient’s response. Then, the efficacy and safety of DEX in the treatment of IS and IS-related LGS were retrospectively evaluated.ResultsAmong 51 patients (35 cases of IS; 16 cases of IS-related LGS), 35 cases (68.63%) were identified as responders to DEX treatment, comprising 20 cases (39.22%) and 15 cases (29.41%) with complete control and obvious control, respectively. To discuss the syndromes individually, complete control and obvious control were achieved in 14/35 and 9/35 IS cases and in 6/16 and 6/16 IS-related LGS cases, respectively. During DEX withdrawal, 11 of the 20 patients with complete control relapsed (9/14 IS; 2/6 LGS). The duration of dexamethasone treatment (including weaning) in most of the 35 responders was less than 1 year. However, 5 patients were treated with prolonged, low-dose maintenance therapy, which continued for more than 1.5 years. These 5 patients showed complete control, and 3 patients had no recurrence. Except for one child who died of recurrent asthma and epileptic status 3 months after stopping DEX, there were no serious or life-threatening adverse effects during DEX treatment.ConclusionOral DEX is effective and tolerable for IS and IS-related LGS. all LGS patients were evolved from IS in this study. The conclusion may not apply to patients with other etiology and courses of LGS. Even when prednisone or ACTH is failed, DEX may still be considered as a treatment option. For children who respond to DEX but do not show complete control after 6 months of treatment, prolonged treatment with low-dose DEX administered in the morning might be considered.

The Atlas of Monogenic Epilepsies

Epilepsy may be the consequence of several causes, including genetic anomalies, structural brain malformations, hypoxic-ischemic encephalopathy, brain tumors, and drugs, all contributing to the imbalance between excitatory and inhibitory neurons and modulatory interneurons, which in turn provoke abnormal, simultaneous electric discharge(s) involving part or all the brain.[1] [2] [3] In the pregenetic, pregenomic era, in most cases, the exact cause of such neuronal/interneuronal disequilibrium remained unknown and the term idiopathic epilepsy was used to define all the epilepsies without cause. At the same time, some specific epileptic syndromes were indicated by the eponym of the first physician who originally described the condition (e.g., West syndrome, Dravet syndrome, Ohtahara syndrome, Lennox–Gastaut syndrome) or by some characteristic clinical features (e.g., nocturnal frontal lobe epilepsy, absence epilepsy, epilepsy and mental retardation limited to females). In many of these occurrences, the distinct epileptic syndrome was defined mainly by its most relevant clinical feature (e.g., seizure semiology), associated comorbidities, and electroencephalographic patterns.[3] [4]

Efficacy of Soticlestat Treatment by Seizure Type in Patients with Dravet Syndrome or Lennox–Gastaut Syndrome in a Phase 2, Randomized, Placebo-controlled Study (ELEKTRA) (P11-1.002)

<h3>Objective:</h3> To develop a post hoc analysis of soticlestat treatment efficacy by seizure type in patients with Dravet syndrome (DS) or Lennox–Gastaut syndrome (LGS) in ELEKTRA (NCT03650452), a phase 2, randomized, placebo-controlled study of adjunctive soticlestat (≤300 mg BID, weight-adjusted) in children aged 2–17 years with DS demonstrating ≥3 convulsive seizures/28 days, or with LGS demonstrating ≥4 drop seizures/28 days at baseline. <h3>Background:</h3> DS and LGS involve developmental delay and frequent epileptic activity. The published ELEKTRA study investigated efficacy and safety of soticlestat, a cholesterol 24-hydroxylase inhibitor, in children with DS or LGS. Primary endpoint was change in convulsive (DS) and drop (LGS) seizure frequencies. <h3>Design/Methods:</h3> Post hoc efficacy analyses determined percent change in seizure frequency from baseline, by seizure type. Patients’ caregivers recorded seizure number and type throughout the baseline and full (20-week) treatment periods, including generalized tonic–clonic, focal to bilateral tonic–clonic, focal with motor signs and atonic seizures. <h3>Results:</h3> Of 141 enrolled patients, 126 (89%) completed ELEKTRA. The modified intent-to-treat population received ≥1 doses of study drug and had ≥1 efficacy assessments (DS, n=51; LGS, n=88). Median seizure frequency changes from baseline in patients with DS receiving soticlestat (placebo): generalized tonic–clonic seizures, −27.2% [n=14] (19.5%, n=21); focal to bilateral tonic–clonic seizures, −73.9% [n=9] (8.4%, n=4). Median seizure frequency changes from baseline in patients with LGS receiving soticlestat (placebo): generalized tonic–clonic seizures, −33.4% [n=17] (−20.0%, n=11); focal seizures with motor signs, −64.3% [n=10] (−21.1%, n=7); atonic seizures, −33.9% [n=16] (−17.9%; n=13); focal to bilateral tonic–clonic seizures, −41.3% [n=6] (none observed). <h3>Conclusions:</h3> Reduced median frequency of specific seizure types was observed in patients receiving soticlestat as adjunctive therapy. Investigation of soticlestat adjunctive therapy for these seizure types in other epilepsies is warranted (phase 3 studies ongoing for DS and LGS). Study funded by Takeda Pharmaceutical Company Limited. <b>Disclosure:</b> Dr. Pathi Jagannatham has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Dr. Pathi Jagannatham has received personal compensation for serving as an employee of GlaxoSmithKline. Dr. Pathi Jagannatham has stock in Takeda Pharmaceuticals. Dr. Pathi Jagannatham has stock in GlaxoSmithKline. Dr. Dlugos has received research support from NIH. The institution of Dr. Dlugos has received research support from The Epilepsy Study Consortium. Yasir Khan has nothing to disclose. Dr. Hsiao has received personal compensation for serving as an employee of Takeda Pharmaceutical Company. Dr. Hsiao has stock in Takeda Pharmaceutical Company. Dr. Benitez has received personal compensation for serving as an employee of Takeda . Mahnaz Asgharnejad, PharmD has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Mahnaz Asgharnejad, PharmD has stock in GlaxoSmithKline. Mahnaz Asgharnejad, PharmD has stock in Takeda Pharmaceuticals.

Corpus Callosotomy for Drug Resistant Epilepsy. Long Term Outcome in Adult Population. (S44.005)

<h3>Objective:</h3> Favorable outcome of corpus callosotomy is reported in pediatric population with intractable epilepsy and it is considered standard of care for patients with drop attacks. Our objective is to compare the long term outcome of corpus callosotomy for drug resistant epilepsy in adult population. <h3>Background:</h3> Corpus callosotomy is a palliative neurosurgical procedure for patients with medically drug-resistant epilepsy who are not candidates for resective epilepsy surgery. Corpus callosotomy is most commonly performed in children with epilepsy, either as an anterior two-thirds disconnection of corpus callosum or as a complete disconnection. Good long-term outcomes against drop attacks have been reported in a population-based prospective study and the risk of a persistent complication is low. <h3>Design/Methods:</h3> 17 adults with idiopathic generalized epilepsy, frontal lobe epilepsy and Lennox Gastaut Syndrome (LGS) were followed for the outcome measures of seizure and antiepileptic drug (AED) burden and quality of life (QoL). Data was extracted from patients registered in our RedCap database. <h3>Results:</h3> 17 patients fulfill the inclusion criteria. 4 underwent conventional corpus callsotomy and 14 had laser interstitial thermal therapy (LITT). 7 had failed prior Vagal Nerve Stimulator and 10 did not have VNS. All patients who had conventional procedure had complications and none from the LITT group reported complications. 11 patients reported presence of seizures and 6 were seizure free. None of the patients had persistent drop attacks, while 4 had convulsive seizures and 11 had mild focal impaired awareness seizures. More than 70 % of the patients reported improvement in speech, social abilities and activities of daily living. <h3>Conclusions:</h3> Corpus callosotomy for drug resistant epilepsy in adults provide significant improvement when observed for decreasing in seizure burden, reduction in medication and improvement of quality of life. LITT carries a low risk for complication and similar efficacy when compared with conventional one and should be utilize more frequently. <b>Disclosure:</b> Miss Proteasa has nothing to disclose. Dr. Proteasa has nothing to disclose. Dr. Lado has a non-compensated relationship as a Board Member with American Epilepsy Society that is relevant to AAN interests or activities. Dr. Lado has a non-compensated relationship as a Officer with National Association of Epilepsy Centers that is relevant to AAN interests or activities.

Long-Term Treatment Effects of Soticlestat in Patients with Dravet Syndrome or Lennox–Gastaut Syndrome: Interim Data from the ENDYMION 1 Trial (S44.004)

Long-Term Treatment Effects of Soticlestat in Patients with Dravet Syndrome or Lennox–Gastaut Syndrome: Interim Data from the ENDYMION 1 Trial (S44.004)

NUS1 Exon 2 Deletion: A Crossover Between Epilepsy and Movement Disorders (P12-1.009)

<h3>Objective:</h3> We present two cases of patients presenting with epilepsy and a concomitant movement disorder found to have a heterozygous pathogenic variant in NUS1 with a deletion in exon 2. <h3>Background:</h3> The NUS1 gene is associated with autosomal dominant developmental and epileptic encephalopathy. Movement disorders such as tremor, ataxia, and myoclonus have been reported, though this clinical phenotype is not well defined. <h3>Design/Methods:</h3> Case Series <h3>Results:</h3> <h3>Case 1:</h3> A 54-year-old man with a history of schizophrenia and moderate intellectual disability presented to Movement Disorders Clinic with debilitating ataxia and multifocal myoclonus involving limbs and facial muscles and to Epilepsy Clinic for generalized epilepsy. Seizure semiology was generalized tonic-clonic. The patient’s father reportedly had tremor and seizures; however, patient was under guardianship of a caregiver with limited familial information. MRI brain was unremarkable. EEG captured myoclonic jerks without a cortical correlate. Seizures were well controlled on Keppra and Depakote. <h3>Case 2:</h3> A 25-year-old woman presented to Epilepsy Clinic for Lennox Gastaut Syndrome and to Movement Disorders Clinic for an action tremor with action-induced myoclonus. Epilepsy started at age 2 and was refractory shortly after onset with concurrent global developmental delay. Seizure semiologies included atonic, clonic, absence, and generalized tonic-clonic. Her epilepsy was well controlled on Epidiolex, lamotrigine, and clobazam. MRI brain was unremarkable. Interictal EEG showed background slowing, paroxysmal beta frequency activities, and generalized slow spike and wave discharges. Depakote was previously weaned with no improvement in tremor or myoclonus. A genetic panel (INVITAE™) revealed a heterozygous pathogenic variant in NUS1 with a deletion in exon 2 in both cases. <h3>Conclusions:</h3> Despite epilepsy being well controlled, our cases had an ongoing debilitating movement disorders. In patients with epilepsy who present with subcortical myoclonus, ataxia, or tremor, a genetic panel should be considered as well as referral to Movement Disorders for interdisciplinary management. <b>Disclosure:</b> Dr. Terpak has nothing to disclose. Dr. Schuck has nothing to disclose. Dr. Culpepper has nothing to disclose. Dr. Shneyder has nothing to disclose. Dr. Krishnaiengar has nothing to disclose. Dr. Zarroli has nothing to disclose.

Cognitive debrief of the Clinical Global Impression of Improvement for Nonseizure Symptoms measure in Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS): The Caregiver Perspective (P14-1.002)

Cognitive debrief of the Clinical Global Impression of Improvement for Nonseizure Symptoms measure in Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS): The Caregiver Perspective (P14-1.002)

Efficacy of Cannabidiol in Pediatric Patients: Postmarket Experience at a Single Center

AbstractThe purpose of this research was to determine the postmarket efficacy and safety of cannabidiol in pediatric patients with Lennox–Gastaut's syndrome (LGS), Dravet's syndrome (DS), and other drug-resistant epilepsy (DRE). This was a single-center, retrospective cohort study in pediatric patients who received prescription cannabidiol at a single center. The primary outcome was the reduction in seizure frequency of all seizure types as measured by the Engel outcome scale at 3 months after initiation of cannabidiol. Thirty-six patients were included. The most common outcome in all three groups was an Engel Class III outcome 3 months following initiation of cannabidiol. Most patients in all groups experienced some clinical benefit and only 33% of patients experienced no clinical benefit. The maximum tolerated dose of cannabidiol at 3 months ranged from 5 to 31 mg/kg/d with a median of 17.9, 13.2, and 18.0 mg/kg/d in the LGS, DS, and DRE (other) groups, respectively. Eight patients discontinued cannabidiol at 3 months and only two patients were hospitalized after initiation of therapy. Seventy-five percent of patients did not report any adverse side effects. Based on the Engel outcome scale utilized within this study, pediatric patients with LGS, DS, and DRE (other) may experience a worthwhile improvement in seizure frequency while on cannabidiol. Further studies are needed to determine the long-term efficacy and safety of cannabidiol and discern predictors of response to therapy.

Frontoparietal 18F-FDG-PET hypo-metabolism in Lennox-Gastaut syndrome: Further evidence highlighting the key network

IntroductionLennox Gastaut syndrome (LGS) can be conceptualised as a “secondary network epilepsy”, in which the shared electroclinical manifestations reflect epileptic recruitment of a common brain network, despite a range of underlying aetiologies. We aimed to identify the key networks recruited by the epileptic process of LGS using interictal 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (18F-FDG-PET). MethodsGroup analysis of cerebral 18F-FDG-PET, comparing 21 patients with LGS (mean age = 15 years) and 18 pseudo-controls (mean age = 19 years), studied at Austin Health Melbourne, between 2004 and 2015. To minimise the influence of individual patient lesions in the LGS group, we only studied brain hemispheres without structural MRI abnormalities. The pseudo-control group consisted of age- and sex-matched patients with unilateral temporal lobe epilepsy, using only the hemispheres contralateral to the side of epilepsy. Voxel-wise permutation testing compared 18F-FDG-PET uptake between groups. Associations were explored between areas of altered metabolism and clinical variables (age of seizure onset, proportion of life with epilepsy, and verbal/nonverbal ability). Penetrance maps were calculated to explore spatial consistency of altered metabolic patterns across individual patients with LGS. ResultsAlthough not always readily apparent on visual inspection of individual patient scans, group analysis revealed hypometabolism in a network of regions including prefrontal and premotor cortex, anterior and posterior cingulate, inferior parietal lobule, and precuneus (p < 0.05, corrected for family-wise error). These brain regions tended to show a greater reduction in metabolism in non-verbal compared to verbal LGS patients, although this difference was not statistically significant. No areas of hypermetabolism were detected on group analysis, although ∼25 % of individual patients showed increased metabolism (relative to pseudo-controls) in the brainstem, putamen, thalamus, cerebellum, and pericentral cortex. DiscussionInterictal hypometabolism in frontoparietal cortex in LGS is compatible with our previous EEG-fMRI and SPECT studies showing that interictal bursts of generalised paroxysmal fast activity and tonic seizures recruit similar cortical regions. This study provides further evidence that these regions are central to the electroclinical expression of LGS.

Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance

Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD's effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases.

Highly purified cannabidiol improves stability and postural tone in adult patients with Lennox-Gastaut syndrome: A case series.

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy associated with numerous neurological signs and symptoms. Altered postural tone and the need for a caregiver-assisted wheelchair are features characterizing patients with LGS. Highly purified cannabidiol (CBD) is a novel antiseizure medication (ASM) recommended for seizure treatment, in combination with clobazam, in patients with LGS. Adding CBD to the previous ASM treatment helps in reducing seizure frequency, specifically drop seizures, in patients with LGS in both clinical trials and real-world studies. However, no data about drug effects on postural tone, motor activity, gait, and stability are available. In this case series, three adult patients diagnosed with LGS were treated with CBD as an add-on. During the follow-up, a slight improvement in seizure frequency was observed. Unexpectedly, an amelioration in postural tone and stability, measured using the validated Gross Motor Function Classification System, was also detected. Our case series suggests that CBD may help in managing patients with LGS regarding seizure control and in improving other aspects of the clinical spectrum of the disease, such as postural tone and stability. The mechanisms at the basis of this improvement may be related, other than seizure reduction, to the drug's effect on the brain locomotor centers, as demonstrated in animal model studies.

Cannabidiol for the treatment of refractory epilepsy in children: a critical review of the literature.

Objective:The aim of this current report was to present a critical review of the use of cannabidiol (CBD) in the treatment of refractory epilepsies in the pediatric population.Data source:Literature review was carried out in the Medline (PubMed), Cochrane, and Scientific Electronic Library Online (SciELO) databases with the descriptors “Cannabidiol” and “Epilepsy.” The search was not limited by the date of publication, language, or study design. A total of 69 articles were included in the review.Data synthesis:The efficacy of CBD in treating epileptic seizures has been confirmed by randomized controlled trials for Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. The incidence of side effects reported in subjects of the studies is high. However, most studies indicate a good safety profile and tolerance to the drug, with most of the adverse effects being mild to moderate and transient.Conclusions:There is no consensus on the release of CBD as a therapeutic tool by the drug regulatory agencies worldwide. However, the use of CBD is promising since it has presented satisfactory results in crisis control in well-designed studies. In addition, this drug has a good safety and tolerance profile. However, further studies with a long follow-up period are needed to confirm its usefulness and the long-term safety in pediatric patients.

Treatment with Cenobamate in Adult Patients with Lennox–Gastaut Syndrome: A Case Series

Background. Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) in which drug resistance to antiepileptic drugs (AEDs) is common. Focal-onset seizures (FOS) are among the seizure types characterizing LGS. Cenobamate (CNB) is a new AED indicated for the treatment of FOS and it has shown promising results in terms of seizure frequency reduction in both clinical trials and real-world experience. To date, the use of CNB in patients with DEEs is limited to Dravet syndrome. Methods: This was a retrospective study aimed to determine the 12-month effectiveness and tolerability of CNB in patients with LGS following real-world practice. Results: Four patients with LGS receiving CNB treatment were identified. At 12 months from starting CNB, the reduction in baseline seizure frequency ranged from 25 to 74%, with two patients achieving ≥50% seizure reduction. CNB was generally well tolerated and adjustments in doses of concomitant AEDs were required. Conclusions: CNB may represent a promising therapeutic option in patients with drug-resistant epilepsy associated with LGS. Further research is needed to confirm this preliminary evidence.

A Pilot Study on the Use of Low Doses of CBD to Control Seizures in Rare and Severe Forms of Drug-Resistant Epilepsy.

Due to its anticonvulsant properties, cannabidiol can be supportive as an adjuvant therapy in the management of drug resistant epilepsy. This retrospective observational study evaluates the intensity and frequency of the seizures of patients with drug-resistant epilepsy that have been treated with antiepileptic medication associated with CBD in low doses for at least 12 months. Thirty-four patients were included in the study. The most frequent diagnosis of epilepsy was focal symptomatic epilepsy and Lennox-Gastaut syndrome (35.2%). During the follow-up, there was a statistically significant decrease in the seizure frequency (t student p &lt; 0.001). A high proportion of patients, 16, concluded the study with a total control of the seizures reaching a 100% improvement, 12 reported ≥ 75% improvement, 3 ≥ 50%, and 2 ≥ 25%; only 1 patient had an improvement of less than 25%. This is the first Latin American study that demonstrates that long-term CBD added to the usual drugs significantly reduces the frequency, duration, and type of seizures in the different etiologies of epilepsy, being especially effective on the seizures that are the most incapacitating, improving the quality of life of the individual and their family.

GABAergic Neurotransmission in Human Tissues Is Modulated by Cannabidiol.

Recently, the potential use of phytocannabinoids (pCBs) to treat different pathological conditions has attracted great attention in the scientific community. Among the different pCBs, cannabidiol (CBD) has showed interesting biological properties, making it a promising molecule with a high security profile that has been approved for treatment as an add-on therapy in patients afflicted by severe pharmaco-resistant epilepsy, including Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS) and tuberous sclerosis complex (TSC). CBD is pharmacologically considered a "dirty drug", since it has the capacity to bind different targets and to activate several cellular pathways. GABAergic impairment is one of the key processes during the epileptogenesis period able to induce a generalized hyperexcitability of the central nervous system (CNS), leading to epileptic seizures. Here, by using the microtransplantation of human brain membranes approach in Xenopus oocytes and electrophysiological recordings, we confirm the ability of CBD to modulate GABAergic neurotransmission in human cerebral tissues obtained from patients afflicted by different forms of pharmaco-resistant epilepsies, such as DS, TSC, focal cortical dysplasia (FCD) type IIb and temporal lobe epilepsy (TLE). Furthermore, using cDNAs encoding for human GABAA receptor subunits, we found that α1β2 receptors are still affected by CBD, while classical benzodiazepine lost its efficacy as expected.

Lennox Gastaut Syndrome – A strategic shift in diagnosis over time?

BackgroundLennox Gastaut Syndrome (LGS) is an epilepsy syndrome presenting in childhood, classically characterised by a triad of cognitive or developmental impairment, multiple seizure types and EEG features of slow-spike waves (SWW), with or without paroxysmal fast activity (PFA) in sleep. There is increasing scientific opinion in favour of a less rigid approach to LGS diagnosis and this clinical audit attempts to shed light on how the LGS diagnostic criteria used may have changed over time, in a large tertiary paediatric neurology unit (Great Ormond Street Hospital (GOSH), London, UK). MethodsElectronic patient records were reviewed for patients with a diagnosis of LGS made at GOSH within two time periods, 2014-2017 and 2018-2021. Patient demographics, aetiology, clinical features, EEG features, investigation results and medications were reviewed. Findings were compared against the International League Against Epilepsy (ILAE) Diagnostic Manual criteria for LGS diagnosis (the classical triad plus PFA in sleep). Existing GOSH data regarding total number of new epilepsy referrals to GOSH and ICD10 codes (including all epilepsy and epilepsy syndromes) per year were also used to review LGS diagnoses as proportions of new epilepsy referrals and total number of epilepsy diagnoses. Results5 LGS diagnoses were made in 2014-2017 compared to 40 diagnoses made in 2018-2021. There was a steep increase in the number of LGS diagnoses and LGS diagnoses as a proportion of total epilepsy diagnoses in the last 4 years, coinciding with the licensing of cannabidiol for management of LGS in the UK in 2018. There was a much less marked increase in LGS diagnoses as a proportion of epilepsy referrals from 2018 (and an as yet unexplained high proportion in 2014). The 2014-17 cohort fit a more classical LGS diagnostic criteria of the triad plus presence of PFA on sleep EEG (100% in 2014-17 vs 68% in 2018-21), with a more classical preceding history of infantile spasms (80% in 2014-17 vs 23% in 2018-21). Common seizure types were similar in both groups and a male preponderance was also noted in both groups. Cannabidiol use in LGS patients has also increased over time, all prescribed after 2018. ConclusionsDespite the limitations of the small numbers of patients in each group, the results of this clinical audit are in keeping with changing clinical trends in favour of a broader LGS diagnostic criteria. The combination of this less rigid diagnostic criteria, the steep increase in diagnosis seen from 2018 onwards (coinciding with UK cannabidiol licencing for LGS in 2018) and the fact that most of the LGS patients in both groups are currently prescribed cannabidiol, may reflect a strategic shift in attitude towards LGS diagnosis or an increase in referrals for LGS, possibly to help facilitate access to novel treatments.

Diagnostics and age-related evolution of Lennox–Gastaut syndrome. Management in diverse patient age periods

Lennox–Gastaut syndrome is an epileptic encephalopathy with onset in childhood. The classical triad of diagnostic criteria is well known: 1) presence of various types of refractory epileptic seizures (tonic, atypical absences, myoclonic, tonic/atonic drop attacks, generalized tonic-clonic, focal); 2) cognitive disorders with frequent behavioral disorders (not always evident by the beginning of epileptic seizures); 3) generalized, slow (≤2.5 Hz) spike-wave activity of wakefulness and generalized paroxysmal fast activity on sleep electroencephalogram. Despite the seizure onset usually occurring before the age of 8 (peak at 3–5) years old, the Lennox–Gastaut syndrome is often featured with a lifelong course. Many patients with this syndrome suffer from refractory epilepsy in adulthood, however, not always being provided a proper syndromological diagnosis. Expanding the criteria to diagnose the Lennox–Gastaut syndrome discussed here would allow to choose a proper treatment algorithm. Rufinamide is the drug of the second choice in the adjunctive therapy of epileptic seizures associated with Lennox–Gastaut syndrome. However, a pediatric-to-adult clinic transition of patients with Lennox–Gastaut syndrome may pose some obstacles. Herein, an effective patient management requires not only seizure control, but also improvement of patient's quality of life by influencing cognitive and behavioral issues, sleep disorders, disability (both physical and social), educational problems and employment.

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies.

The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous heterogeneity in cognitive, behavioural and developmental impairments that is complex and can change naturally over time; there is a lack of standardised instruments for evaluating these outcomes in developmental and epileptic encephalopathies, with a reliance on subjective evaluations by proxy (caregivers); and treatment regimes are complex involving multiple ASMs as well as other drugs.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-022-00955-9.

Hemispherectomy with corpus callosotomy in pediatric Lennox Gastaut Syndrome associated encephalomalacia cyst: The first case in Indonesia

&#x0D; &#x0D; &#x0D; Lennox-Gastaut syndrome (LGS) is a form of severe epileptic encephalopathy in children. LGS with encephalomalacia cysts is rare in children. We report a six-year-old mentally retarded boy who was referred for an intractable seizure. Seizures were tonic, atonic, and dialeptic in frequency. EEG showed generalized SSW discharges of 1.5-2 Hz, polyspikes, and burst suppression typical for LGS. Head MRI showed an encephalomalacia cyst in the right subcortical temporoparietal lobes with hemiatrophy in the right cerebral hemisphere. He was already treated with three antiepileptic drugs, but the seizures persisted. The patient was then performed right hemispherectomy and corpus callosotomy. It resulted in a good response. A combination of hemispherectomy and corpus callosotomy could be promising in this form of epilepsy disease. Seizure reduction was achieved and showed cognitive improvement and hemiparesis.&#x0D; &#x0D; &#x0D;

Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy.

Despite the availability of more than 30 antiseizure medications (ASMs), the proportion of patients who remain refractory to ASMs remains static. Refractory seizures are almost universal in patients with epileptic encephalopathies. Since many of these patients are not candidates for curative surgery, there is always a need for newer ASMs with better efficacy and safety profile. Recently, the anti-obesity medication fenfluramine (FFA) has been successfully repurposed, and various regulatory agencies approved it for seizures associated with Dravet and Lennox–Gastaut syndromes. However, there is a limited in-depth critical review of FFA to facilitate its optimal use in a clinical context. This narrative review discusses and summarizes the antiseizure mechanism of action of FFA, clinical pharmacology, and clinical studies related to epilepsy, focusing on efficacy and adverse effects.