Original Article Yonsei Med J 2019 Jan;60(1):106-114 https://doi.org/10.3349/ymj.2019.60.1.106 pISSN: 0513-5796 · eISSN: 1976-2437 Lennox-Gastaut Syndrome in Mitochondrial Disease Soonie Lee1*, Min-Seong Baek1*, and Young-Mock Lee1,2 1Department of Pediatrics, Yonsei University College of Medicine, Seoul; 2Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea. Purpose: Previous studies have shown that neurologic symptoms are dominant in patients with mitochondrial diseases, and most of these patients have seizure-related disorders. The epileptic classification of these patients as Lennox-Gastaut syndrome (LGS) is as high as 25%. This study aimed to investigate the clinical manifestations, diagnoses, treatments, and epilepsy in LGS, which is associated with mitochondrial disease. Materials and Methods: A retrospective study was conducted on 372 patients who were diagnosed with mitochondrial disease between 2006 and 2016. Of these 372 patients, 40 patients diagnosed with LGS were selected, and they were classified into two groups based on the history of West syndrome. Patient characteristics were reviewed, and associations between clinical factors and outcomes after the treatment were analyzed. Results: The proportion of individuals with mitochondrial disease with LGS with a history of West syndrome was 32.5%. Among the patients with mitochondrial disease with LGS, neonatal seizure (p=0.029), seizure as the first symptom (p=0.018), and gener- alized paroxysmal fast activity frequency on electroencephalogram (p=0.018) in the group with a history of West syndrome were statistically significantly high. The first symptom onset (0.6±0.4 yrs vs. 1.6±0.9 yrs, p=0.003) and first seizure onset (0.9±0.7 yrs vs. 3.9±3.1 yrs, p<0.001) were significantly faster in patients with a history of West syndrome. Conclusion: Close monitoring of the medical condition and early intervention might improve the prognosis of individuals with mitochondrial disease with LGS and a history of West syndrome. Key Words: Lennox-Gastaut syndrome, mitochondrial disease, West syndrome, pediatric, children INTRODUCTION requirements, such as the brain, heart, liver, and skeletal mus- cle system.2,3 Mitochondrial disease comprises a group of disorders re- Among the symptoms of mitochondrial disease, neurologic sulting from mitochondrial dysfunction and, in particular, symptoms are predominate, and seizures account for the from defects in the mitochondrial respiratory chain (MRC) greatest proportion thereof.4 Previous studies have shown that and associated abnormal oxidative phosphorylation.1,2 Lennox-Gastaut syndrome (LGS) accounts for a high propor- While mitochondrial dysfunction can occur in any organ, tion of epilepsies in mitochondrial diseases, and its prognosis higher incidences are recorded in organs with high-energy is poor.5,6 LGS is a severe childhood-onset epileptic encepha- lopathy, characterized by multiple seizure types and progres- sive mental retardation.5-7 The prognosis of patients with LGS Received: August 7, 2018 Revised: October 21, 2018 Accepted: November 1, 2018 follows a catastrophic course from drug resistance to epileptic Corresponding author: Young-Mock Lee, MD, PhD, Department of Pediatrics, encephalopathy.6 Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju- While several studies on mitochondrial disease and LGS ro, Gangnam-gu, Seoul 06273, Korea. Tel: 82-2-2019-3350, Fax: 82-2-2019-4881, E-mail: [email protected] have been conducted before, studies on LGS with mitochon- *Soonie Lee and Min-Seong Baek contributed equally to this work. drial disease in children are scarce. Therefore, this study •The authors have no potential conflicts of interest to disclose. aimed to analyze the clinical features, diagnosis, and treat- © Copyright: Yonsei University College of Medicine 2019 ment of children with mitochondrial disease with LGS. This is an Open Access article distributed under the terms of the Creative Com- mons Attribution Non-Commercial License (https://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and repro- duction in any medium, provided the original work is properly cited. 106 www.eymj.org Soonie Lee, et al. MATERIAls AND METHods terms of clinical variables. In this study, the proportion of mi- tochondrial disease with LGS with history of West syndrome Patients and study design was 32.5%. The medical records of pediatric patients who were diagnosed with mitochondrial disease were reviewed; the patients were Statistical analysis followed up regularly at the Department of Pediatrics of All analyses were conducted using the Statistical Package for Gangnam Severance Hospital between January 2006 and Jan- the Social Sciences (SPSS) version 22.0 (IBM Corp., Armonk, uary 2016. The study population consisted of 40 patients NY, USA). Descriptive statistics were used including the mean, (16.1%) diagnosed with LGS, among the 248 patients (67%) standard deviation (SD), median, and range. Parametric t- diagnosed with epilepsy and 372 patients who were diag- tests and chi-square tests were applied to evaluate differences nosed with mitochondrial disease based on the diagnostic between groups. p values <0.05 were considered statistically criteria of Bernier, et al.8 The study protocol was approved by significant. the Institutional Review Board of the Yonsei University Gang- nam Severance Hospital (4-2011-0463), and written informed consent was obtained from the parents or legal guardians of REsults all patients. General characteristics and clinical status of Data collection of the clinical characteristics and mitochondrial disease at the last visit diagnostic evaluation for mitochondrial disease A total of 40 pediatric patients were diagnosed with LGS with Diagnostic evaluations for mitochondrial disease were per- mitochondrial disease (Table 1). Among the patients, 17 pa- formed by laboratory studies, histology studies, and enzymat- tients (42.5%) were male, and 23 patients (57.5%) were female. ic and imaging studies. The degree of serum lactic acidosis In most cases, there was no history of birth abnormality. In re- was defined as mild, moderate, or severe if the increase over gards to birth history, small for gestational age was most fre- the normal reference values was at least two-, three-, or four- quently recorded. fold, respectively. Data on brain magnetic resonance imaging The initial symptoms of the patients varied, and the most (MRI) and magnetic resonance spectroscopy study were also common first symptom was seizure (50%), followed by de- collected. Muscle biopsies were performed surgically from the layed development (40%), ataxia, hemiparesis, perinatal as- quadriceps muscle, and routine histologic, immunohisto- phyxia, and loss of consciousness. The mean age of the occur- chemical, and electron microscopic examinations were con- rence of the first symptom was 1.5 years (1.5±0.9), and the ducted. Biochemical assays to evaluate MRC enzyme activity mean age of the first seizure onset as an initial symptom was 3 were also performed, defining the enzyme to be defective years (3.0±3.3). The mean age of diagnosis of LGS was 5 years. when residual enzyme activity was <10% of the reference val- Mitochondrial disease with LGS with a history of West syn- ue.9 Mitochondrial DNA mutation was confirmed in two pa- drome comprised 32.5%. The duration of transition to LGS af- tients who suffered mitochondrial encephalomyopathy, lactic ter diagnosis from West syndrome was 1.6 years (1.6±1.8). acidosis, and stroke-like episodes (MELAS) and Leigh syn- Each patient was regularly followed up at the institute. The drome, respectively. mean duration of follow-up from the onset of the first symp- tom was 11 years; from the first seizure, 9.4 years; and from Data collection regarding diagnosis and treatment LGS diagnosis, 7.8 years. options for Lennox-Gastaut syndrome All patients had involvement of the central nervous system, The diagnostic criteria for LGS included multiple seizure followed by the gastrointestinal and respiratory systems, and types, a specific inter-ictal electroencephalogram (EEG) pat- various organs were affected. Functional state was classified tern of diffuse slow background combined with generalized as mild for self-ambulation, moderate for wheelchair bound- slow spike wave (GSSW) in an awake state and generalized ing, and severe for bedridden state and progressed from 60% paroxysmal fast activity (GPFA) during sleep, and progressive to severe. At the last visit, respiratory assistance was required cognitive impairment. Seizure outcomes were assessed seri- for 15% of the patients, and 37.5% of the patients were receiv- ally according to seizure type (tonic, tonic-clonic, myoclonic, ing enteral tube feeding. atonic, atypical absence, epileptic spasms, and focal seizures) up to and including the most recent visit.10 The treatment was Diagnostic evaluations of mitochondrial disease divided into antiepileptic drug (AED), ketogenic diet, and sur- Serum lactic acid levels were increased in 13 patients (Table gery. Ketogenic diet was assessed based on the frequency of 2). Serum levels of lactic acid were found to be mildly in- seizures 6 months after the start of the diet. creased, moderately increased, and severely increased in 22.5, Patients with LGS were divided into two groups based on a 5, and 5% of patients, respectively. In terms of syndromic di- history of West syndrome. The two groups were compared in agnosis, nonspecific