A comprehensive systematic literature review of the burden of illness of Lennox-Gastaut syndrome on patients, caregivers, and society.

Fully elucidating the burden that Lennox-Gastaut syndrome (LGS) places on individuals with the disease and their caregivers is critical to improving outcomes and quality of life (QoL). This systematic literature review evaluated the global burden of illness of LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver burden, economic burden, and treatment burden (PROSPERO ID: CRD42022317413). MEDLINE, Embase, and the Cochrane Library were searched for articles that met predetermined criteria. After screening 1442 deduplicated articles and supplementary manual searches, 113 articles were included for review. A high clinical symptom burden of LGS was identified, with high seizure frequency and nonseizure symptoms (including developmental delay and intellectual disability) leading to low QoL and substantial care requirements for individuals with LGS, with the latter including daily function assistance for mobility, eating, and toileting. Multiple comorbidities were identified, with intellectual disorders having the highest prevalence. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems (including fatigue and sleep disturbances), social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically treated seizure events, inpatient costs, and medication requirements. Pharmacoresistance was common, and many individuals required polytherapy and treatment changes over time. Few studies focused on the humanistic burden. Quality concerns were noted for sample representativeness, disease and outcome measures, and reporting clarity. In summary, a high burden of LGS on individuals, caregivers, and health care systems was identified, which may be alleviated by reducing the clinical symptom burden. These findings highlight the need for a greater understanding of and better definitions for the broad spectrum of LGS symptoms and development of treatments to alleviate nonseizure symptoms.

A systematic literature review on the global epidemiology of Dravet syndrome and Lennox-Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality.

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5-28, prevalence = 5.8-60.8; DS: incidence proportion = 2.2-6.5, prevalence = 1.2-6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6-9.2 years; LGS, 2-15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person-years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.

A Phase 3 open-label study of the efficacy, safety and pharmacokinetics of buccally administered midazolam hydrochloride for the treatment of status epilepticus in pediatric Japanese subjects.

BACKGROUND: In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE. METHODS: A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed. RESULTS: The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation. CONCLUSIONS: The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.

Epidemiology of status epilepticus in the United States: A systematic review.

OBJECTIVES: Convulsive status epilepticus (CSE) is a life-threatening neurologic emergency, which is defined by the International League Against Epilepsy (ILAE) as bilateral tonic-clonic seizure activity lasting longer than 5 min, while absence status epilepticus (SE) and focal SE are specified as exceeding 10 min. Epidemiological evidence on SE is currently lacking, and the incidence is not well-known, especially in light of changes in the ILAE criteria for SE. The objectives of this systematic literature review were to describe the epidemiology of SE in the US population and the associated burden of illness. METHODS: A systematic review, including literature and pragmatic searches, was conducted. Literature searches were performed using MEDLINE, Embase, BIOSIS, and Web of Science electronic databases from inception to February 2019. Pragmatic searches of the gray literature were carried out using Google, Google Scholar, conference proceedings, and ClinicalTrials.gov to identify additional sources. Only US-based studies or multinational studies reporting US data of interest were included. RESULTS: In total, 69 sources were identified. The incidence of all SE in patients of all ages in the USA ranged from 18.3 to 41 per 100,000 people per year. Incidence of all-age CSE rose from 3.5 (1979) to 12.5 (2010) per 100,000 people per year. Status epilepticus incidence followed a bimodal (U-shaped) distribution, with the highest estimates in the first years of life (0-4 years) and after 60 years. Mortality associated with SE varied from 21% over 30 days to 31.2% over 10 years. For CSE, two studies reported similar in-hospital mortalities (9.2% and 10.7%). Median healthcare costs related to SE admission were approximately US$14,500 per adult (17-45 years) and US$8000 per child (0-16 years). CONCLUSIONS: There is a lack of recent data on the epidemiology and healthcare burden associated with SE. Reports of SE incidence in the USA are highly variable and predate the 2015 ILAE definition of SE. However, the available data suggest a high burden of illness.

Burden of disease in patients with a history of status epilepticus and their caregivers.

OBJECTIVE: Status epilepticus (SE) is a life-threatening neurological emergency with the potential for wide-ranging impact on patients and caregivers. In this study, the burden of disease in patients with a history of SE and their caregivers was assessed. METHODS: Adult patients as well as caregivers of children, adolescents, and adults who had experienced ≥1 SE event in the past 24 months completed an online survey. Functional, social, emotional, and economic burden in patients and caregivers was assessed. Burden was measured through concept-targeted questionnaires, including the US Centers for Disease Control and Prevention (CDC) Health-Related Quality of Life 4 (HRQoL-4) and the Work Productivity and Activity Impairment (WPAI) instruments. RESULTS: The 198 respondents comprised 49 adult patients, 51 caregivers of children, 47 caregivers of adolescents, and 51 caregivers of adults. Most patients (93.9%) were diagnosed with epilepsy. Patients' daily activities were highly affected, and many respondents reported a substantial long-term physical and mental impact on patients. The mean CDC HRQoL-4 score for unhealthy days per month ranged from 11.1 for caregivers of adults to 16.9 for caregivers of children. WPAI scores demonstrated a substantial impact on the ability of adult patients and all caregivers to work. Among respondents, caregivers of children reported the highest absenteeism from work (20%) and the lowest employment rate (33%). Proportions of caregivers reporting that their daily social life was impacted at least 'some of the time' ranged from 80% to 92%, with nearly half (47%) of caregivers of children responding that their social life was impacted 'all the time'. CONCLUSIONS: Status epilepticus episodes place a high burden on patients and caregivers. Notably, the burden appeared high across a variety of domains. This study highlights that the burden of disease is pronounced and wide-reaching and goes beyond the immediate physical and medical impact of an SE episode.

Switching from an oral dopamine receptor agonist to rotigotine transdermal patch: a review of clinical data with a focus on patient perspective.

INTRODUCTION: Dopamine receptor agonists (DAs) are commonly used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms ('dopamine receptor agonist' OR 'rotigotine') AND 'switch'. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

Augmentation of restless leg syndrome (Willis-Ekbom disease) during long-term dopaminergic treatment.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common sensorimotor disorder that can generally be effectively managed in the primary care clinic. However, some treatment complications may arise. According to the recommendations of the International Restless Legs Syndrome Study Group, non-ergot dopamine-receptor agonists have over the past years been one of the first-line treatments for patients with RLS/WED requiring pharmacological therapy. Augmentation is the main complication of long-term dopaminergic treatment of RLS/WED and is defined as an overall worsening of symptoms beyond pretreatment levels in patients who experienced an initial positive therapeutic response. Once identified on the basis of its characteristic clinical features, augmentation requires careful management. In order to provide clinicians with a comprehensive understanding of this common treatment complication, this review discusses the clinical features of augmentation, and its differentiation from morning rebound, symptom fluctuations and natural disease progression. Reported incidences of augmentation in clinical trials of dopaminergic RLS/WED therapies are summarized. Finally, the hypothetical pathophysiology of augmentation and the current recommendations for management of patients with augmented RLS/WED symptoms are discussed.

Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome.

Rotigotine is a nonergoline dopamine receptor agonist with structural similarity to dopamine. Rotigotine binds to the D1 through D5 dopamine receptors, having several times more affinity than dopamine does to the D2 and D3 receptors. Although rotigotine was demonstrated to restore locomotor activity in animal models of Parkinson's disease (PD), the rapid metabolism of rotigotine limited the development of an orally administered formulation. Rotigotine's high lipid solubility and extended duration of action when applied to the skin in experimental models of PD suggested that rotigotine was a candidate for transdermal application. The constant transdermal delivery of rotigotine over 24 h is hypothesized to approximate continuous agonist-receptor stimulation, which conceptually more closely mimics physiologic striatal dopamine receptor function. Randomized clinical studies have demonstrated rotigotine's efficacy, safety, and tolerability in patients with early- and advanced-stage PD, including improvements in motor symptoms and off-time. Although the etiology is unknown, restless legs syndrome (RLS) is thought to involve dopaminergic dysregulation. Randomized clinical studies also have demonstrated the efficacy of rotigotine in improving the symptoms of moderate-to-severe primary RLS. This review examines rotigotine's developmental history for transdermal administration leading to its approval for the treatment of early- and advanced-stage PD and moderate-to-severe primary RLS.

Prevalencia de esófago de barrett en pacientes con carcinoma colorrectal / Prevalence of barrettïs esophagus in patients with colorectal carcinoma

Objetivo: determinar la prevalencia del esófago de Barrett (EB) en pacientes con diagnóstico de carcinoma colorrectal (CCR), y posibles factores asociados en un periodo de cuatro meses y 15 días (1 de marzo al 15 de junio de 1999). Sede: Hospital de Oncología del Centro Médico Nacional Siglo XXI, IMSS. Material y método: estudio transversal, prospectivo, observacional y comparativo; se estudiaron 48 pacientes con diagnóstico de cáncer colorrectal corroborado histológicamente, a todos se les practicó panendoscopia con toma de biopsia y a ocho pacientes con esófago de Barrett, se les practicó colonoscopia. Resultados: fueron 30 hombres y 18 mujeres con edad promedio de 53 años; la estirpe histológica fue adenocarcinoma en 100 por ciento de los casos; el tumor se localizó en 43.7 por ciento en el recto. La prevalencia de EB en este estudio fue de 22.9 por ciento, lo que implica un OR calculado de 36.43 (p = 0.00000) y 3.09 (p = 0.00007) de presentar EB cuando se tiene CCR. En la población en general, la prevalencia de EB se ha calculado de 0.78 a 2 por ciento. No hubo significancia estadística respecto a edad, hábito tabáquico y/o alcoholismo. De los ocho pacientes con EB sin antecedentes de CCR, en 1 se diagnosticó un pólipo tubulovelloso (12.5 por ciento). Conclusiones: si bien los resultados no son concluyentes para afirmar la asociación CCR/EB, la alta prevalencia justifica practicar panendoscopia a pacientes portadores de carcinoma colorrectal y síntomas de enfermedad acidopéptica.

Severa cifosis lumbar post-quirúrgica, en presencia de síndrome de Marfan: informe de un caso / Post-operative severe lumbar kyphosis in a patient who has Marfa's Syndrome

Se presenta el caso de una paciente de 14 años de edad con síndrome de Marfan que desarrolló severa cifosis postquirúrgica en la región lumbar; que se constituyó en una grotesca deformidad del tronco. La paciente se presentó habiendo sido operada con tres pares de barras de Harrington que no corrigieron la deformidad. El tratamiento definitivo consistió en osteotomías y alambrado de la funsión posterior, función anterior con un injerto autógeno de peroné de T-10 a L-4. El tratamiento finalmente fue resolutivo de la severa deformidad. Solamente se encontró un caso similar reportado en la literatura