Does response to vagus nerve stimulation for drug-resistant epilepsy differ in patients with and without Lennox-Gastaut syndrome?

INTRODUCTION: Literature on outcomes of patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive vagus nerve stimulation (VNS) lacks information on seizure types and the time course of therapeutic effects. We have therefore performed what is to our knowledge the largest and most in-depth analysis of the effectiveness of VNS in LGS patients paying special attention to the impact of VNS Therapy on individual seizure types. METHODS: The VNS Therapy Outcomes Registry includes over 7000 patients. A propensity score matching method was employed to match patients with LGS to non-LGS patients with drug-resistant epilepsy (DRE). Overall seizure frequencies were assessed prior to implantation and at 3-, 6-, 12-, 18-, and 24-month follow-ups to derive the main study outcomes: response rates and time to first response. RESULTS: A total of 564 LGS patients with sufficient data were identified in the registry and matched 2:1 to 1128 non-LGS patients. Responder rates at 24 months were 57.5% in the LGS group and 61.5% in the non-LGS group. Median seizure frequency reduction at 24 months was 64.3% versus 66.7% in the LGS versus non-LGS group, respectively. In both groups, VNS was most effective at reducing focal aware seizures, "other" seizures, generalized-onset non-motor seizures, and drop attacks with relative reduction rates for these seizure types at 24 months exceeding 90% in both groups. Time-to-first response did not differ between the groups; however, there was a significantly higher proportion of patients who regressed from bilateral tonic-clonic (BTC) seizure response in the LGS group versus the non-LGS group at 24 months: 22.4% versus 6.7%; p = .015. CONCLUSIONS: Although limited by its retrospective design, the study shows that the effectiveness of VNS is comparable in DRE patients with and without LGS; however, LGS patients may be more prone to fluctuating control of BTCs.

Evolution of Infantile Spasms to Lennox-Gastaut Syndrome: What Is There to Know?

OBJECTIVE: Children with infantile spasms may develop Lennox-Gastaut syndrome. The diagnostic criteria for Lennox-Gastaut syndrome are vague, and many experts use varying combinations of the following criteria for diagnosis: paroxysmal fast activity on electroencephalography (EEG), slow spike and wave on EEG, developmental delay, multiple seizure types, and nocturnal tonic seizures. Our objective was to determine the prevalence of Lennox-Gastaut syndrome in a high-risk cohort of children with a history of infantile spasms and the characteristics of infantile spasms that were associated with the diagnosis of Lennox-Gastaut syndrome. METHODS: Children with infantile spasms who were diagnosed and treated at Children's Hospital Colorado between 2012 and 2018 were included. Lennox-Gastaut syndrome was defined as having 3 of 5 of the following characteristics: paroxysmal fast activity, slow spike and wave, current developmental delay, multiple seizure types, or tonic seizures. Descriptive statistics were performed using median and interquartile range. Univariable analysis was performed with Pearson chi-square, Fisher exact, or the Kruskal-Wallis test. RESULTS: Ninety-seven children met inclusion criteria, and 36% (35/97) met criteria for Lennox-Gastaut syndrome. Developmental delay and history of seizures prior to the onset of infantile spasms were identified as risk factors for the development of Lennox-Gastaut syndrome (P = .003) as was poor response to first treatment for spasms (P = .004). Children with an unknown etiology of infantile spasms were less likely to develop Lennox-Gastaut syndrome (P = .019). Eighty percent (28/35) of the children who met Lennox-Gastaut syndrome criteria lacked a documented diagnosis. CONCLUSIONS: Thirty-six percent of children with infantile spasms met criteria for Lennox-Gastaut syndrome. Risk factors for development of Lennox-Gastaut syndrome were developmental delay and seizures prior to the onset of infantile spasms and poor response to first treatment for infantile spasms. Children with an unknown etiology of infantile spasms were less likely to develop Lennox-Gastaut syndrome. Eighty percent of the children who met our criteria were not given a documented diagnosis of Lennox-Gastaut syndrome, which highlights the fact that many children may not be receiving a diagnosis of Lennox-Gastaut syndrome. We recommend establishing clear guidelines for the diagnosis of Lennox-Gastaut syndrome to ensure that the diagnosis is being made accurately.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

[Transional syndrome: from West to Lennox-Gastaut syndromes]. / Síndrome transicional: del síndrome de West al síndrome de Lennox-Gastaut.

West syndrome or infantile spasms is an epileptic encephalopathy, classified as generalized epilepsies and syndromes. There are multiple reports of the evolution from West to Lennox-Gastaut syndrome of 25 up to 60%, without a specific cause is determined. It has been reported that they may be only an epileptic entity age dependent that it would be in relation to the degree of brain immaturity. In this retrospective review of 130 cases of West syndrome, only 14 (10.7%) evolved to Lennox-Gastaut. Having received in all cases vigabatrin as a treatment, makes us suppose that the low incidence could be related to the use of this drug. Given that vigabatrin has a gabaergic action and increased levels of ACTH, may explain this relationship but this must be confirmed with the best knowledge of the intimate mechanisms of these serious epileptic encephalopathies.

Síndrome transicional: del síndrome de West al síndrome de Lennox-Gastaut / Transional syndrome: from West to Lennox-Gastaut syndromes

El síndrome de West o espasmos infantiles, es una encefalopatía epiléptica clasificada como epilepsias y síndromes generalizados. Hay múltiples informes de la evolución de síndrome de West a síndrome de Lennox-Gastaut de un 25 hasta 60%, sin reconocerse una causa específica. Se ha comunicado que pueden ser solo una entidad epiléptica dependiente de la edad y que estaría en relación con el grado de inmadurez cerebral. En esta revisión retrospectiva de 130 casos de espasmos infantiles, solo 14 (10.7%) evolucionaron a Lennox-Gastaut. El haber recibido en todos los casos vigabatrina como tratamiento nos hace suponer que la baja incidencia podría estar relacionada con el uso de este fármaco. Dado que la vigabatrina tiene una acción gabaérgica y aumenta los niveles de ACTH podría explicar esta relación, pero esto deberá confirmarse con el mejor conocimiento de los mecanismos íntimos de estas graves encefalopatías.

West syndrome or infantile spasms is an epileptic encephalopathy, classified as generalized epilepsies and syndromes. There are multiple reports of the evolution from West to Lennox-Gastaut syndrome of 25 up to 60%, without a specific cause is determined. It has been reported that they may be only an epileptic entity age dependent that it would be in relation to the degree of brain immaturity. In this retrospective review of 130 cases of West syndrome, only 14 (10.7%) evolved to Lennox-Gastaut. Having received in all cases vigabatrin as a treatment, makes us suppose that the low incidence could be related to the use of this drug. Given that vigabatrin has a gabaergic action and increased levels of ACTH, may explain this relationship but this must be confirmed with the best knowledge of the intimate mechanisms of these serious epileptic encephalopathies.

Lennox-Gastaut syndrome: a comprehensive review.

Lennox-Gastaut syndrome (LGS) is considered an epileptic encephalopathy and is defined by a triad of multiple drug-resistant seizure types, a specific EEG pattern showing bursts of slow spike-wave complexes or generalized paroxysmal fast activity, and intellectual disability. The prevalence of LGS is estimated between 1 and 2% of all patients with epilepsy. The etiology of LGS is often divided into two groups: identifiable (genetic-structural-metabolic) in 65 to 75% of the patients and LGS of unknown cause in others. Lennox-Gastaut syndrome may be considered as secondary network epilepsy. The seizures in LGS are usually drug-resistant, and complete seizure control with resolution of intellectual and psychosocial dysfunction is often not achievable. Reduction in frequency of the most incapacitating seizures (e.g., drop attacks and tonic-clonic seizures) should be the major objective. Valproate, lamotrigine, and topiramate are considered to be the first-line drugs by many experts. Other effective antiepileptic drugs include levetiracetam, clobazam, rufinamide, and zonisamide. The ketogenic diet is an effective and well-tolerated treatment option. For patients with drug resistance, a further therapeutic option is surgical intervention. Corpus callosotomy is a palliative surgical procedure that aims at controlling the most injurious seizures. Finally, vagus nerve stimulation offers reasonable seizure improvement. The long-term outcome for patients with LGS is generally poor. This syndrome is often associated with long-term adverse effects on intellectual development, social functioning, and independent living.

Encefalopatías epilépticas / Epileptic encephalopathies

Según la Comisión de Clasificación y Terminología de la Liga Internacional contra la Epilepsia (ILAE), el término ‘encefalopatía epiléptica’ refleja la noción de que la actividad epiléptica en sí misma puede contribuir a la génesis de graves discapacidades cognitivas o comportamentales, más allá de lo que sería de esperar de la patología subyacente a la epilepsia. No obstante, en muchos casos resulta difícil deslindar la contribución relativa de las crisis epilépticas y la causa subyacente en la génesis de los déficits cognitivos. Algunos síndromes epilépticos, como los de West, Lennox-Gastaut o Dravet, se asocian con una alta probabilidad de rasgos encefalopáticos. Las causas más frecuentes de encefalopatía epiléptica son la encefalopatía hipóxico-isquémica, las malformaciones cerebrales, incluyendo las displasias corticales, las alteraciones cromosómicas o genéticas, la esclerosis tuberosa y las enfermedades metabólicas (AU)

According to the International League Against Epilepsy’s (ILAE) Commission on Classification and Terminology, the term ‘epileptic encephalopathy’ reflects the notion that epileptic activity in itself can contribute to the genesis of severe cognitive or behavioural disabilities, beyond what could be expected from the pathology underlying the epilepsy. However, in many cases it is difficult to define the boundary between the relative contribution of the epileptic seizures and the underlying cause in the genesis of cognitive deficits. Some epileptic syndromes, such as those of West, Lennox-Gastaut or Dravet, are associated to a high probability of encephalopathic traits. The most frequent causes of epileptic encephalopathy are hypoxic-ischaemic encephalopathy, brain malformations, including cortical dysplasias, chromosomal or genetic disorders, tuberous sclerosis and metabolic diseases (AU)

Drug-resistant epilepsy after treatment for childhood acute lymphocytic leukaemia: from focal epilepsy to Lennox-Gastaut syndrome.

Drug-resistant epilepsy, not associated with acute brain complications or central nervous system leukaemic involvement, can develop in patients treated for acute lymphocytic leukaemia during childhood. It has been postulated that this rare complication may be due to CNS oncological treatment neurotoxicity, related to intrathecal drugs, such as methotrexate, and brain radiotherapy. We report four patients who developed drug-resistant epilepsy sometime after receiving treatment for acute lymphocytic leukaemia. All patients were female and received intrathecal methotrexate. One received additional intrathecal cytarabine, and two concomitant brain radiotherapy. Two developed Lennox-Gastaut type syndrome, one multifocal epilepsy, and one focal epilepsy related to a radiotherapy-induced cavernous angioma. The development of drug-resistant epilepsy after treatment for acute lymphocytic leukaemia is a rare complication that may vary, from focal epilepsy to an epileptic encephalopathy. This may appear even years after the treatment has finished and is most likely associated with treatment-related neurotoxicity.

Therapeutic effects of the ketogenic diet in children with Lennox-Gastaut syndrome.

OBJECTIVE: The aim of this study was to evaluate the efficacy of the ketogenic diet (KD) on the clinical and electroencephalographic (EEG) features of Lennox-Gastaut syndrome (LGS) and explore the relationships between EEG changes and clinical efficacy. METHODS: We retrospectively studied 47 patients with LGS who accepted KD therapy between May 2011 and May 2015. Clinical efficacy and EEG features such as background activity, abnormal interictal epileptic discharges (IEDs) and the discharge location were evaluated prior to and at 3 and 6 months after therapy. Responders were defined as ≥50% seizure reduction. RESULTS: At 3 months of treatment, 23 patients (48.9%) had ≥50% seizure reduction. Seven patients (14.9%) discontinued treatment between 3 and 6 months because of lack of efficacy or inability to adhere to the diet. At 6 months of treatment, 4 patients (10%) were seizure free, 5 (12.5%) had ≥90% seizure reduction, 12 (30%) had a reduction of 50-89%, and 19 (47.5%) had <50% reduction. Patients with improved EEG background and reduced IEDs had an improved seizure reduction rate compared with patients without change in EEG background or IEDs (p<0.01). CONCLUSIONS: The results show that the KD is effective in LGS. It can control seizures and improve EEG abnormalities. Early improvement in the EEG background and a reduction in IEDs may be predictors of a patient's response to diet.

The Expanding Clinical Spectrum of Genetic Pediatric Epileptic Encephalopathies.

Pediatric epileptic encephalopathies represent a clinically challenging and often devastating group of disorders that affect children at different stages of infancy and childhood. With the advances in genetic testing and neuroimaging, the etiologies of these epileptic syndromes are now better defined. The various encephalopathies that are reviewed in this article include the following: early infantile epileptic encephalopathy or Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome, severe myoclonic epilepsy in infancy (Dravet syndrome), Landau-Kleffner syndrome, Lennox-Gastaut syndrome, and epileptic encephalopathy with continuous spike-and-wave during sleep. Their clinical features, prognosis as well as underlying genetic etiologies are presented and updated.

A case of Lennox-Gastaut syndrome in a patient with FOXG1-related disorder.

Lennox-Gastaut syndrome (LGS) is a drug-resistant epileptic encephalopathy of childhood with a heterogeneous etiology. Recently, genome-wide association studies have led to the identification of new de novo mutations associated with this epileptic syndrome. Herein, we report an 8-year-old child with intellectual disability, severe postnatal microcephaly, Rett-like features, and LGS, carrying a de novo missense mutation in the forkhead box G1 (FOXG1) gene. This gene is responsible for FOXG1 syndrome, characterized by severe postnatal microcephaly, moderate postnatal growth deficiency, mental retardation with poor social interaction, stereotyped behavior and dyskinesias, absent language, sleep disorders, and epilepsy. Nonspecific epilepsy syndromes have been associated with this genetic disorder. Thus, we hypothesize that FOXG1 might be a new candidate gene in the etiology of LGS and suggest screening for this gene in cases of LGS with concomitant microcephaly and clinical features overlapping with Rett syndrome.

Caracterización etiológica del síndrome de Lennox-Gastaut sintomático / Etiological characterization of the symptomatic Lennox-Gastaut syndrome

Introducción: el síndrome de Lennox-Gastaut es una encefalopatía epiléptica dependiente de la edad, de gran severidad, por su farmacorresistencia y las discapacidades asociadas.Objetivos: caracterizar el síndrome de Lennox-Gastaut sintomático según sexo, edad de inicio y diagnóstico, tipo de crisis predominantes, hallazgos en neuroimagen y etiología.Métodos: estudio descriptivo, retrospectivo con una muestra de 36 pacientes egresados del servicio de neuropediatría del Hospital Pediátrico Juan M. Márquez , con diagnóstico de síndrome de Lennox-Gastaut sintomático y que tuvieran estudios de neuroimagen (tomografía axial computarizada y resonancia magnética nuclear). Las variables cualitativas se describieron estadísticamente mediante frecuencias absolutas y cifras porcentuales. Para los porcentajes de interés, se calculó su intervalo de confianza con el 95 por ciento de confiabilidad (IC 95 por ciento )Resultados y conclusiones: el síndrome de Lennox-Gastaut sintomático fue más frecuente en varones, que comenzaron con epilepsia antes del año de edad, el 33 por ciento presentó síndrome de West. Más del 60 por ciento se diagnosticó antes de los 4 años de edad. Las crisis más frecuentes fueron las tónicas y atónicas de cuello. La tomografía axial computarizada permite localizar zonas de atrofia y pocas lesiones estructurales, que se precisan por resonancia magnética nuclear como alteraciones de la migración neuronal. Después de las malformaciones del sistema nervioso central, la causa más frecuente fue la hipoxia perinatal(AU)

Introduction: the Lennox-Gastaut syndrome is an age-dependent epileptic encephalopathy very severe due to its drug-resistance and the associated inabilities. Objectives: to characterize the symptomatic Lennox-Gastaut syndrome, according to sex, onset age and diagnosis, type of predominant crises, findings in neuroimage and etiology. Methods: a retrospective and descriptive study was conducted in 36 patients discharged from the neuropediatric service of the Juan Manuel Márquez Children Hospital diagnosed with symptomatic Lennox-Gastaut syndrome and underwent neuroimage studies (computerized axial tomography and nuclear magnetic resonance). Qualitative variables were statistically described by means of absolute frequencies and percentage figures. For interesting percentages, its 95 percent confidence interval (CI) was estimated (95 percent CI). Results and conclusions: the symptomatic Lennox-Gastaut syndrome was more frequent in males starting with epilepsy before one year old. The 33 percent had West's syndrome. More than 60 percent was diagnosed before the four years old. The more frequent crises were the tonic and atonic ones of neck. The CAT allows locating zones of atrophy and few structural lesions signaled b y nuclear magnetic resonance (NMR) as alterations of neuronal migration. After the central nervous system (CNS) malformations, the more frequent cause was the perinatal hypoxia(AU)