The refractory epilepsy screening tool for Lennox-Gastaut syndrome (REST-LGS).

BACKGROUND: The complex clinical presentation and progression of Lennox-Gastaut syndrome (LGS) can complicate the accurate diagnosis of this severe, lifelong, childhood-onset epilepsy, often resulting in suboptimal treatment. The Refractory Epilepsy Screening Tool for LGS (REST-LGS) was developed to improve the identification of patients with LGS. METHODS: Using the Modified Delphi Consensus, a group of experts developed and tested the REST-LGS Case Report Form (CRF) comprising 8 criteria (4 major, 4 minor) considered potentially indicative of LGS. Diagnosis-blinded specialist and nonspecialist raters at 2 epilepsy centers applied the CRF to deidentified patient records, including 1:1 records of patients with drug-resistant epilepsy or confirmed LGS. Interrater reliability was measured by Cohen's κ. Diagnosis was then unblinded to reveal common criteria for LGS or drug-resistant epilepsy. Cronbach's α was used to measure internal consistency between raters for all criteria combined. RESULTS: Of 200 patients, 81% to 85% met 1 to 3 major criteria. At both sites, moderate (κ, 0.41-0.60) to good (κ, 0.61-0.80) agreement on most criteria was reached between expert and nonexpert raters. Unblinding revealed that most patients with LGS met 3 major and 2 to 3 minor criteria, while patients with drug-resistant epilepsy met ≤1 major and only 1 to 2 minor criteria. Cronbach's α of raters at both sites was 0.64. CONCLUSIONS: The combined number of major/minor criteria on the CRF may be particularly indicative of LGS. Therefore, the REST-LGS may be a valuable clinical tool in identifying patients requiring further diagnostic evaluation for LGS.

Cognitive effects of adjunctive perampanel for partial-onset seizures: A randomized trial.

OBJECTIVE: Assess cognitive effects of adjunctive perampanel in adolescents. METHODS: In this double-blind study (ClinicalTrials.gov identifier: NCT01161524), patients aged 12 to <18 years with partial-onset seizures despite receiving 1-3 antiepileptic drugs were randomized (2:1) to perampanel or placebo. Perampanel was increased weekly in 2-mg increments to 8-12 mg/day (6-week titration; 13-week maintenance). Changes in neuropsychological outcomes were assessed at end of maintenance: Cognitive Drug Research (CDR) System Global Cognition Score (primary end point), five CDR System domain T-scores (secondary end points), letter fluency, category fluency, and Lafayette Grooved Pegboard Test (LGPT). RESULTS: One hundred thirty-three patients were randomized. In the full analysis set, there were no differences of perampanel (n = 79) vs. placebo (n = 44) in CDR System Global Cognition Score (least squares mean change, -0.6 vs. 1.6; p = 0.145), Quality of Working Memory (1.1 vs. 2.0; p = 0.579), or Power of Attention (-6.9 vs. -2.7; p = 0.219). There were small differences with perampanel vs. placebo in other CDR System domains: improvements in Quality of Episodic Memory (3.0 vs. -1.2; p = 0.012), and worsening in Continuity of Attention (-3.3 vs. 1.6; p = 0.013) and Speed of Memory (0.3 vs. 7.0; p = 0.032). Letter fluency, category fluency, and LGPT were not significantly different between groups. The most frequent adverse events with perampanel were dizziness (30.6%) and somnolence (15.3%). SIGNIFICANCE: Perampanel did not differ from placebo in the global cognitive score, two of five subdomains, and four other cognitive measures. Perampanel was worse on two and better on one subdomain.

Real-world use of the updated refractory epilepsy screening tool for Lennox-Gastaut syndrome.

OBJECTIVE: To evaluate the Refractory Epilepsy Screening Tool for Lennox-Gastaut Syndrome (REST-LGS) for real-world identification of LGS in adults and to develop a scoring system for the tool. METHODS: A retrospective chart review of adults with drug resistant epilepsy (DRE) and intellectual development disorder (IDD) was conducted by 2 primary care providers blinded to diagnosis. The REST-LGS was designed via the Modified Delphi Consensus and was previously validated. This tool consists of 8 criteria (4 major, 4 minor) considered indicative of LGS. To account for missing data in the earlier validation study and to evaluate applicability in a real-world setting, the REST-LGS was refined to include a scoring system in which major criteria were more heavily weighted than minor criteria, producing categories of "likely" (>11 points), "possible" (8-11 points), and "unlikely" (<8 points) LGS. Statistical analyses were descriptive. RESULTS: Of the 100 patients included in the analysis, data for slow spike-waves in electroencephalography and seizure onset age - both major REST-LGS criteria - were missing for 46% and 42% of patients, respectively. The majority of patients met 4 of the 8 REST-LGS criteria (cognitive impairment since childhood, 71%; persistent seizures despite a trial of ≥2 antiseizure medications, 65%; seizure onset before the age of 12 years, 57%; ≥2 seizure types, 56%). All 4 major criteria were met in 22 patients (22%). The percentages of patients considered "likely," "possible," or "unlikely" to have LGS were 26%, 30%, and 44%, respectively. Of the 74 patients without a previous LGS diagnosis, 42 (57%) were identified as "possible" or "likely" to have LGS using REST-LGS. SIGNIFICANCE: In this analysis, the validated REST-LGS was evaluated in a real-world setting. The majority of previously undiagnosed patients were identified via REST-LGS as "possible" or "likely" to have LGS. Extensive missing data highlights challenges of LGS diagnosis in adults. PLAIN LANGUAGE SUMMARY: There is a need to identify adult patients with Lennox-Gastaut syndrome (LGS) so they can receive appropriate treatment. The Refractory Epilepsy Screening Tool for LGS (REST-LGS) questionnaire was designed by experts to identify whether patients with seizures that are not controlled by medications may have LGS. In this study, 2 physicians completed the REST-LGS using charts for 100 patients who experience seizures not controlled by medications. Of the patients who were previously diagnosed as not having LGS, the majority were "likely" or "possible" to have LGS based on the REST-LGS; therefore, the REST-LGS can identify patients for further evaluation.

Gastrointestinal manifestations in pediatric and adult patients with Rett syndrome: an analysis of US claims and physician survey data.

Aim: Patients with Rett syndrome (RTT) experience gastrointestinal (GI) manifestations. This study aimed to describe the prevalence of GI manifestations and the associated medical costs in patients with RTT in the USA. Patients & Methods: The study combined an insurance claims database analysis with a survey of 100 physicians experienced in RTT management. Results: GI manifestations affected 43.0% of 5940 patients, with increased prevalence in pediatric patients (45.6%) relative to adult patients (40.2%). Annualized mean medical cost of managing GI manifestations was $4473. Only 5.9-8.2% of neurologists and pediatricians ranked GI symptom management among the five most important treatment goals. Conclusion: Patients with RTT experience a high burden of GI manifestations, which translate to considerable medical costs. Importantly, the prevalence of GI manifestations was likely underestimated in this study, as only those symptoms which resulted in a healthcare encounter were captured.

Outpatient management of prolonged seizures and seizure clusters to prevent progression to a higher-level emergency: Consensus recommendations of an expert working group.

OBJECTIVE: The management of prolonged seizures (PS) and seizure clusters (SC) is impeded by the lack of international, evidence-based guidance. We aimed to develop expert recommendations regarding consensus definitions of PS, SC, and treatment goals to prevent progression to higher-level emergencies such as status epilepticus (SE). METHODS: An expert working group, comprising 12 epileptologists, neurologists, and pharmacologists from Europe and North America, used a modified Delphi consensus methodology to develop and anonymously vote on statements. Consensus was defined as ≥75% voting "Agree"/"Strongly agree." RESULTS: All group members strongly agreed that termination of an ongoing seizure in as short a time as possible is the primary goal of rapid and early seizure termination (REST) and that an ideal medication for REST would start to act within 2 min of administration to terminate ongoing seizure activity. Consensus was reached on the terminology defining PS (with proposed thresholds of 5 min for prolonged focal seizures and 2 min for prolonged absence seizures and the convulsive phase of bilateral tonic-clonic seizures) and SC (an abnormal increase in seizure frequency compared with the individual patient's usual seizure pattern). All group members strongly agreed or agreed that patients who have experienced a PS should be offered a REST medication, and all patients who have experienced a SC should be offered an acute cluster treatment (ACT). Further, when prescribing a REST medication or ACT, a seizure action plan should be agreed upon in consultation with the patient and caregiver. SIGNIFICANCE: The expert working group had a high level of agreement on the recommendations for defining and managing PS and SC. These recommendations will complement the existing guidance for the management of acute seizures, with the possibility of treating them earlier to potentially avoid progression to more severe seizures, including SE.

Real-world clinical management of individuals with Rett syndrome: a physician survey.

BACKGROUND: Rett syndrome (RTT) is a severe neurodevelopmental disorder. Management strategies are heterogeneous with no clear definition of success. This study describes physician decision-making regarding diagnosis, therapeutic goals, and management strategies to better understand RTT clinical management in the US. METHODS: This study was conducted among practicing physicians, specifically neurologists and pediatricians in the US with experience treating ≥2 individuals with RTT, including ≥1 individuals within the past two years. In-depth interviews with five physicians informed survey development. A cross-sectional survey was then conducted among 100 physicians. RESULTS: Neurologists had treated more individuals with RTT (median: 12 vs. 5, p < 0.001) than pediatricians throughout their career and were more likely to report being "very comfortable" managing RTT (31 vs. 4%, p < 0.001). Among physicians with experience diagnosing RTT (93%), most evaluated symptoms (91%) or used genetic testing (86%) for RTT diagnoses; neurologists used the 2010 consensus diagnostic criteria more than pediatricians (54 vs. 29%; p = 0.012). Improving the quality of life (QOL) of individuals with RTT was the most important therapeutic goal among physicians, followed by improving caregivers' QOL. Most physicians used clinical practice guidelines to monitor the progress of individuals with RTT, although neurologists relied more on clinical scales than pediatricians. Among all physicians, the most commonly treated symptoms included behavioral issues, epilepsy/seizures, and feeding issues. Management strategies varied by symptom, with referral to appropriate specialists being common across symptoms. A large proportion of physicians (37%) identified the lack of novel therapies and reliance on symptom-specific management as an unmet need. CONCLUSION: Although most physicians had experience and were comfortable diagnosing and treating individuals with RTT, better education and support among pediatricians is warranted. Additionally, novel treatments that target multiple symptoms associated with RTT could reduce the burden and improve the QOL of individuals with RTT and their caregivers.

Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures.

PURPOSE: To evaluate the efficacy and tolerability of adjunctive levetiracetam in very young children (aged 1 month to <4 years) with partial-onset seizures inadequately controlled with one or two antiepileptic drugs. METHODS: This multicenter, double-blind, randomized, placebo-controlled study consisted of a 48-h inpatient baseline video-EEG (electroencephalography) and a 5-day inpatient treatment period (1-day up-titration; 48-h evaluation video-EEG in the last 2 days). Children who experienced at least two partial-onset seizures during the 48-h baseline video-EEG were randomized to either levetiracetam [40 mg/kg/day (age 1 to <6 months); 50 mg/kg/day (age >or=6 months to <4 years] or placebo. RESULTS: Of 175 patients screened, 116 patients were randomized [60 levetiracetam; 56 placebo; intent-to-treat (ITT) population], and 111 completed the study. The responder rate in average daily partial-onset seizures frequency (48-h video-EEG monitoring; primary efficacy variable) was 43.1% for levetiracetam [modified ITT (mITT) = 58] versus 19.6% for placebo (mITT = 51; p=0.013), with odds ratio for response 3.11 [95% confidence interval (CI), 1.22-8.26]. The median percent reduction from baseline in average daily partial-onset seizure frequency was 43.6% for levetiracetam and 7.1% for placebo with a median difference between treatment groups of 39.2% (95% CI, 17.5-62.2; p < 0.001). In general, levetiracetam was well tolerated. Treatment-emergent adverse events were reported by 55.0% levetiracetam- and 44.6% placebo-treated patients (ITT population). The most frequently reported adverse events were somnolence (13.3% levetiracetam, 1.8% placebo) and irritability (11.7% levetiracetam, 0% placebo). DISCUSSION: Adjunctive levetiracetam is an efficacious and well-tolerated treatment for partial-onset seizures in infants and young children.

Development of a classifier to identify patients with probable Lennox-Gastaut syndrome in health insurance claims databases via random forest methodology.

Objective: Describe the development of a claims-based classifier utilizing machine learning to identify patients with probable Lennox-Gastaut syndrome (LGS) from six state Medicaid programs. Methods: Patients were included if they had ≥2 medical claims ≥30 days apart for specified or unspecified epilepsy, excluding those with ≥1 claim for petit mal status. The LGS classifier utilized a random forest algorithm, a compilation of thousands of binary decision trees in which machine-generated predictor variables split the data set into branches that predict the presence or absence of LGS. To construct the splitting rules, the importance of each candidate variable was determined by calculating the mean decrease in Gini impurity. Training and testing were performed on two data sets (30% and 70%) using a "true" LGS and non-LGS patient population. Performance was compared with logistic regression and single tree methodology. Results: Using a 60% probability threshold, which yielded the highest sensitivity (97.3%) and specificity (95.6%), the classifier identified approximately 4% of patients with epilepsy as probable LGS. The most important input variables included number of distinct antiepileptic drugs received, epilepsy-related outpatient/inpatient visits, electroencephalogram procedures and claims for delayed development. The random forest methodology outperformed logistic regression and single tree methodology. Most of the important LGS predictor characteristics identified by the classifier were statistically significantly associated with LGS status (p < .05). Conclusions: The claims-based LGS classifier showed high sensitivity and specificity, outperformed single tree and logistic regression methodologies and identified a prevalence of probable LGS that was similar to previously published estimates.

Challenges in identifying Lennox-Gastaut syndrome in adults: A case series illustrating its changing nature.

The variable presentation and progression of Lennox-Gastaut syndrome (LGS) can make it difficult to recognize, particularly in adults. To improve diagnosis, a retrospective chart review was conducted on patients who were diagnosed as adults and/or were followed for several years after diagnosis. We present 5 cases that illustrate changes in LGS features over time. Cases 1 and 2 were diagnosed by age 8 with intractable seizures, developmental delay, and abnormal EEGs with 1.5-2 Hz SSW discharges. However, seizure type and frequency changed over time for both patients, and the incidence of SSW discharges decreased. Cases 3, 4, and 5 were diagnosed with LGS as adults based on current and past features and symptoms, including treatment-resistant seizures, cognitive and motor impairment, and abnormal EEG findings. While incomplete, their records indicate that an earlier LGS diagnosis may have been missed or lost to history. These cases demonstrate the need to thoroughly and continuously evaluate all aspects of a patient's encephalopathy, bearing in mind the potential for LGS features to change over time.

Medical costs are reduced when children with intractable epilepsy are successfully treated with the ketogenic diet.

The ketogenic diet is used for children with drug refractory epilepsies. Although this diet was developed early in the 20th century, its use was infrequent until recently. One of the concerns about the ketogenic diet is the cost of initiating the diet. The process generally involves an inpatient visit that can last several days. In this study, the health care costs for 15 children with drug refractory epilepsy who received their care at Vanderbilt University Medical Center were compared for the period of time 6 to 12 months before they began the ketogenic diet and 6 to 12 months after they began the ketogenic diet. All comparisons within each child were done on the same amount of time before and after initiation of the diet. Total costs affiliated with care for the 15 children were: $352,820.20 for the prediet period, $41,221.91 for the diet initiation, and $149,436.86 for the postdiet-initiation period. We conclude that successful maintenance on the ketogenic diet provides a substantial financial benefit.

Opsoclonus associated with salmonellosis in a 6-week-old infant.

A 6-week-old male infant presented with 2 days of fever, emesis, and diarrhea, associated with episodic and chaotic rapid eye movements, determined to be opsoclonus. An electroencephalogram (EEG) obtained during the events was normal. He was treated empirically for meningitis, and an initial workup for neuroblastoma including urine homovanillic acid and vanillylmandelic acid levels, abdominal ultrasonography, and computed tomography (CT) of the chest, abdomen, and pelvis was negative. Stool and blood cultures were positive for Salmonella, and antibiotic regimen was adjusted appropriately. Over the next few days, his fever, emesis, and diarrhea subsided, and the opsoclonus resolved by hospital day 6. He was back to baseline by hospital day 9. Although there have been cases of parainfectious opsoclonus associated with Lyme disease, enterovirus, Streptococcus, and West Nile virus, this represents the first reported pediatric case of opsoclonus associated with salmonellosis. Only 2 such cases in adults have been reported in the literature.

Adjunctive levetiracetam in patients aged 1 month to <4 years with partial-onset seizures: subpopulation analysis of a prospective, open-label extension study of up to 48 weeks.

BACKGROUND: In a recent double-blind, placebo-controlled study, adjunctive levetiracetam (LEV) was reported to be effective and well tolerated during 5-day treatment in patients aged 1 month to <4 years with partial-onset seizures. A study was planned to fulfill the regulatory requirement to evaluate the long-term safety of LEV as adjunctive therapy for partial-onset seizures in pediatric patients. OBJECTIVE: This study evaluated the long-term effectiveness and tolerability of adjunctive LEV in infants and young children with partial-onset seizures. METHODS: This was a prospective, open-label, outpatient, multicenter study (N01148; ClinicalTrials.gov identifier NCT00152516) conducted as an extension of a previously published study (N01009; NCT00175890). Patients were enrolled from 3 sources, as follows: (1) patients who had completed study N01009; (2) patients who had failed screening for entry into study N01009 but fulfilled the eligibility criteria for entry into this study; and (3) patients who were directly enrolled. The study consisted of a 2- to 4-week retrospective baseline period (and a 3- to 10-day prospective baseline period for directly enrolled patients), a 2- to 8-week uptitration/conversion period, and a maintenance period. Eligible patients were required to have epilepsy with partial-onset seizures, treated with a stable regimen of 1 or 2 antiepileptic drugs. Patients received adjunctive LEV, 20 to 80 mg/kg/d, for up to 48 weeks (total study duration). The primary variable for effectiveness was the percentage reduction from baseline in the weekly frequency of partial-onset seizures, as recorded in patients' diaries. Data for effectiveness were also analyzed by age strata (1 month to <1 year, 1 to <2 years, and 2 to <4 years). Neuropsychological assessment was conducted with the Bayley Scales of Infant Development, Second Edition (BSID-II). All analyses were performed on observed data, and the last-observation-carried-forward approach was not used. The intent-to-treat (ITT) population was defined as all patients who took at least one dose of LEV during the study. Treatment-emergent adverse events (TEAEs) were assessed by observation, spontaneous reporting, standard questions, review of diary cards, and neuropsychologists' clinical reports. Additional measures included physical and neurologic examinations, vital signs, ECGs, routine blood chemistry, and routine hematology assessments. RESULTS: The study included 152 patients in the ITT population. In total, 51.3% (78/152) of the patients were male, and mean (SD) age was 23.5 (12.4) months. The mean LEV maintenance dose was 56.1 (16.2) mg/kg/d, and the median (Q1-Q3) treatment duration was 287.8 (209.0-295.5) days. Ninety-seven patients (63.8%) completed the study. The BSID-II subpopulation included 51 patients. During maintenance, the overall median (Q1-Q3) percentage reduction from baseline in the weekly frequency of partial-onset seizures was 56.0% (-10.9% to 92.8%), which was sustained over time and appeared comparable across the age strata (1 month to <1 year, n = 25, 50.9%; 1 to <2 years, n = 48, 58.0%; and 2 to <4 years, n = 59, 55.0%). The overall responder rate (ie, ≥50% reduction from baseline in weekly partial-onset seizures) was 53.8% (71/132), was maintained over time, and was consistent across the age strata (1 month to <1 year, 52.0%; 1 to <2 years, 56.3%; and 2 to <4 years, 52.5%). Mean BSID-II raw scores for psychomotor development and behavioral functioning remained static, whereas mental development appeared to improve over time, although this was not tested statistically. At least one TEAE was reported in 143 patients (94.1%). The most frequently reported TEAEs were pyrexia (60/152; 39.5%), upper respiratory tract infection (42/152; 27.6%), and vomiting (28/152; 18.4%). The most common TEAEs affecting the central nervous system were convulsion (25/152; 16.4%), irritability (19/152; 12.5%), and somnolence (16/152; 10.5%). Most TEAEs (77.0%) were mild or moderate in intensity. CONCLUSION: Adjunctive LEV treatment for up to 48 weeks was associated with effective and sustained seizure control and had an acceptable tolerability profile in this small, selected population of infants and young children aged 1 month to <4 years with partial-onset seizures.

Long-term tolerability and efficacy of lamotrigine in infants 1 to 24 months old.

This open-label study was designed to evaluate the long-term tolerability and efficacy of lamotrigine in 1- to 24-month-old infants with partial seizures. The study enrolled both lamotrigine-naïve patients and patients who had been previously exposed to lamotrigine in a randomized, double-blind, placebo-controlled study. Patients (n = 204) received lamotrigine according to a dosing schedule that depended on prior experience with lamotrigine and concurrent antiepileptic drug therapy for up to 48 weeks or their second birthday, whichever occurred last. Total duration of lamotrigine exposure (which included exposure during the placebo-controlled study in lamotrigine-experienced patients) was >/=24 weeks in 92% of patients, >/=48 weeks in 70% of patients, and >/=72 weeks in 20% of patients. A total of 20 (10%) patients (8 lamotrigine-naïve patients and 12 lamotrigine-experienced patients) transitioned to lamotrigine monotherapy. The most common adverse events were pyrexia (45% of patients), upper-respiratory tract infection (28%), and ear infection (22%). The only adverse event considered reasonably attributable to study medication in >2% of patients was irritability (n = 10; 5% of patients). No cases of serious rash were reported. The median percent reduction from baseline in partial seizure frequency in the sample as a whole was 74%. Seizure frequency was reduced by >/=50% from pre-lamotrigine baseline in 62% of patients in the sample as a whole, 60% of the lamotrigine-naïve subgroup, and 63% of the lamotrigine-experienced subgroup. In the sample as a whole, 13% of patients were seizure free during the Treatment Phase. Investigators considered clinical status at the last clinic visit to be improved (mildly, moderately, or markedly) relative to prelamotrigine clinical status in 76% of patients (150/197) and to be unchanged in 19% (37/197). In this study-the first large prospective investigation of the long-term tolerability and efficacy of an antiepileptic drug in a patient population 2 years and younger-lamotrigine administered for up to approximately 72 weeks was well tolerated and associated with good seizure control.