Effect of Early Diagnosis and Treatment on the Prognosis of Children with Epilepsy Accompanied by Continuous Spikes and Waves during Slow Wave Sleep
Ju Jiahua1, Lu Weijuan2*
1. Department of Pediatrics, Gaoyou People’s Hospital Affiliated to Soochow University, Gaoyou, Jiangsu, 225600, China;
2. Department of Pediatrics, Haimen Hospital of TCM, Haimen, Jiangsu, 226100, China
*Corresponding Author: Lu Weijuan, E-mail: jcm025@126.com
Objective: To emphasize the importance of early diagnosis and treatment on the prognosis of children with epilepsy accompanied by continuous spikes and waves during slow wave sleep (CSCW).
Methods: The clinical characteristics, electroencephalogram (ECG) features, treatment and prognosis of 12 children with CSCW in our hospital were retrospectively analyzed, and the followup of 6 months to 4 years was given.
Results: Imaging showed that 8 children suffered from brain lesions, while other 4 were normal. The initial onset of 10 children was at night, whereas 2 began with absence seizure in lucid interval, and they gradually appeared comprehensive brain function decline, meanwhile, ECG was characterized by continuous discharge during slow wave sleep. After 3 months of treatment with valproic acid, clonazepam, lamotrigine and hormones, the clinical symptoms and ECG of 10 children improved significantly, in which 3 ones recurred after 6 months of comprehensive treatment.
Conclusion: The early manifestation of CSWS is untypical, and hence, early diagnosis and treatment can ameliorate the epileptic seizures of children, effectively inhibit epileptic electrical activity and has favorable prognosis.
Key words: Epilepsy with continuous spikes and waves syndrome during slow wave sleep; Electroencephalogram; Epileptic seizures; Diagnosis; Prognosis
Epilepsy with continuous spikes and waves during slow wave sleep (CSWS), a sort of rarely-encountered disease in Neurology Department, is an epilepsy syndrome affecting cognitive function in childhood, usually accompanied by comprehensive brain functional damage, various formations of epilepsy onset and neurodevelopment problems [1]. Its clinical manifestations include epilepsy seizure, different degrees of comprehensive brain functional decline and electroencephalogram electrical status epilepticus during sleep (ESES), and the incidence approximately occupies 0. 2 % ~ 0.5 % of epilepsy in childhood [2]. Besides, it is difficult to be identified in clinic, leading to delayed treatment. Hence, early diagnosis, effective treatment and termination of continuous spike and slow-wave discharge can ameliorate the prognosis of children [3]. In this study, the clinical data of 12 children diagnosed as CSWS in our hospital was retrospectively analyzed to deepen the cognition on this disease, improve the techniques of diagnosis and treatment.
Materials and Methods
General data
All of 12 children with CSWS in Department of Pediatrics in our hospital from June 2004 to June 2013 had specific family history, past history, present history, records of nervous system and skull computed tomography (CT) or magnetic resonance imaging (MRI) results, in which males and females were 8 and 4 cases, respectively. Diagnostic criteria: All children conformed to the diagnostic criteria of CSWS: a. onset in childhood; b. various kinds of seizures mainly at night except for the tonic seizure in clinic; c. extensive spike and slow-wave discharge indicated by EEG and the discharge index during slow wave sleep ≥85%; d. local lesions or extensive spike and slow waves in waking state indicated by EEG; e. usually suffering from different degrees of dyskinesia, cognitive and language disorders; e. good prognosis, namely stoppage of epileptic seizures and spike and slow-wave discharge in puberty. Besides, significant secondary diffuse spike and ware complex was excluded. They went to see doctors at the age of 3.4 ~ 11.3 years, with the median age of 6.5 years and disease course from 8 months to 4.2 years. The clinical symptoms of all children belonged to clonic seizures, in which 2 suffered from the seizure on one side of the body accompanied by similarly typical absence seizure, 8 from untypical absence seizure accompanied by myoclonus or falling off caused by atonic seizure, 1 from convulsion in the corner of the mouth accompanied by absence seizure and 1 from tonic clonic seizure. Their daily seizures were 0 ~ 15 times. They all had different degrees of abnormal intelligence and psychological behaviors as well as dyskinesia, cognitive and language disorders, in which 8 had high-risk factors in perinatal period, 5 had asphyxia history, 4 were accompanied by hypoxic ischemic encephalopathy (HIE), 3 had the history of febrile convulsion and 2 had family history. Skull CT and MRI examinations were conducted in 4 and 8 children, respectively. There were manifestations of abnormal brain lesions in 8 children like diffuse or unilateral encephalatrophy and porencephaly, and no conspicuously abnormal imaging results in other 4. EEG data: After hospitalization, all children were given twice of video electroencephalogram (VEEG), each time being ≥2 h, or long-term EEG monitoring > 22 h. According to 10 ~ 20 system of international criteria, EEG recording electrodes were placed, with lead 16 tracing and bilateral electrodes as reference. The sleep was induced by drugs (10 chloral hydrate, 0.5 mL/kg), or natural sleep was adopted. Provocative tests like photic stimulation and overventilation were performed conventionally, and the recording time included sobriety and at least one of complete sleep cycle [4].
Treatment methods
After hospitalization, all children were regulated by antiepileptic drugs [5], in which 6 were treated with valproic acid plus clonazepam and 6 with valproic acid, clonazepam and lamotrigine. All of them were given hormone treatment, and the specific administration was as follows: first, intravenous injection of methylprednisolone 20 mg/(kg• d) for 3 d as impact therapy, then oral administration of prednisone 1.5 ~ 2.0 mg/ (kg• d) for 1 month and 1.0 ~ 1.5 mg/(kg• d) for 1 month, at last, gradually reducing the dose. The course of treatment was 3 ~ 6 months. When leaving hospital, 3 children didn’t have seizures, and the seizures of other 9 were decreased by 75%, with seizure lessened and duration conspicuously shortened. In addition, VEEG indicated that the pathological conditions of 12 children were improved by varying degrees.
Clinical characteristics
Epileptic seizures occurring in all children mainly included generalized clonic seizure, tonic clonic seizure, myoclonic absence seizure, absence seizure and unilateral limb clonus or mouth and facial seizure. Besides, different degrees of damage were presented in neuropsychiatric aspect, including various behavior disorders like language barrier, decreased temporal orientation, forgetfulness, learning disability, distraction, hyperactivity and fussiness, intelligence quotient lower than normal level and dyskinesia [6].
EEG characteristics
EEG background activities of 8 children were in normal range, 3 suffered from moderating rhythm in occipital region and 1 from decreased amplitude of electrical activity in the left side of the brain. In waking state, 2 children frequently occurred absence seizure by VEEG, and EEG was 1.5 ~ 3.5 Hz of spike and slow wave discharge at the same term, whereas there were no seizures in other 10 cases. During non-rapid eye movement (NREM) sleep, bilateral leads of ESES were monitored in all children, with discharge index over 85%, in which 4 ones were limited to sinciput and had no clinical seizures (Figure 1). During rapid eye movement (REM) sleep, extensive spike and slow waves faded away significantly, occasionally appearing paroxysmal discharge or focal slow waves. The sleep spindles in all children were reduced. EEG background rhythm was basically normal in waking state, whereas spike and slow-wave discharge or focal slow waves can be presented after waking. 

Figure 1 EEG Manifestation in one Case of CSWS during NREM Sleep

Neuroimaging characteristics
There were abnormal brain lesion manifestations in 8 children like diffuse or unilateral atelencephalia or encephalatrophy, porencephaly and abnormal grey matter, and no conspicuously abnormal imaging results in other 4.
After leaving hospital, 12 children continued to take antiepileptic drugs, in which 5 orally took prednisone to perform sequential therapy. In addition, they all had a re-examination of VEEG or dynamic EEG every 3 months or half a year. For those only taking antiepileptic drugs, there were still 3 children suffering from clinical seizures, but the times was decreased, and EEG showed SWI was about 70% during NREM sleep.
However, 9 months later, the seizures increased, symptoms repeated, and then hormone impact therapy was given again. It was found in the follow-up after 1 year that the seizures of 3 children disappeared completely. Five children treated with hormones didn’t encounter the seizures, EEG showed SWI was about 50% during NREM sleep, and EEG epileptiform discharges disappeared after 1.8 years. Both EEG and cognitive conditions of 5 children above were improved markedly 3 months after treatment. The clinical seizure of children with CSWS as a benign process disappeared approximately in puberty, and ESES also faded away at last. 
CSWS is a sort of special epilepsy syndrome in childhood, commonly encountered in boys, with onset age of 2 months to 12 years old and peak age of 4 ~ 8 years old. For most patients, the neuro-psychological development is normal before onset, while 33% ~ 50% ones are accompanied by abnormal nervous system or neuroimaging, such as cerebral palsy or other static encephalopathy. After treatment, the clinical seizures become less, psychology and learning function are improved obviously, but the decreased SWI during NREM sleep is unmarked by EEG, which is closely related to abnormal basis of brain structures [7]. Notably, 3 children in our study were previously diagnosed as symptomatic epilepsy, resulting in the worsened pathological condition due to ignoring the diagnosis of this syndrome. Typical epileptic seizures belong to nocturnal partial motor seizures or generalized seizures, accompanied by falling off which is the distinctive seizure of CSW. After onset, the patients will suffer from comprehensive psychomotor retardation, arrested or retrograde development, especially the language, intelligence quotient and spatial skills. In clinic, it is likely to be diagnosed as epileptic brain injury or other epilepsy syndromes [8-9].
EEG characteristic of CSWS is ESES during slow wave sleep, with reduced spindles and mostly significant in the sinciput, even more than that during the initial NREM sleep, and meanwhile SWI is also the highest. After that, SWI index can be fluctuated during NREM sleep. In this study, all children had EEG characteristic changes of this syndrome. Twelve children were only given routine EEG examinations in the past, leading to delayed or improper diagnosis and treatment to a certain extent, so the children with various epileptic seizures accompanied by arrested or retrograde development of intelligence and physical strength should be monitored EEG with complete sleep cycle [10]. At present, except for antiepileptic drugs in the treatment of CSWS, immunoglobulin, ketosis dietary and surgical operations are still under discussion, but the efficiency of hormones has been confirmed by more and more scholars [11]. The hormones can ameliorate the patients’ prognosis by reducing clinical seizures and EEG SWI, whereas its action mechanisms, specific courses and doses are not unified at current. It was reported in literature that after 3 months of treatment with hormones, the clinical symptoms could be improved, while the recurrent patients were usually those not treated with hormones or irregular administration. In this study, the clinical seizures of 12 children were ameliorated in a short term after methylprednisolone and prednisone respectively as impact and sequential therapies were applied, in which the definite cognitive function and EEG improvement occurred in 5 cases mostly after 3 months and 3 cases suffered from recurrence 9 months after the initial administration of methylprednisolone. However, under the condition of maintaining original antiepileptic drugs, application of hormones as impact therapy could still achieve satisfactory effects, and 8 months after treatment, epileptiform discharges disappeared, which further confirms that hormone was one of the important methods to effectively treat CSWS.
After administration of valproic acid, clonazepam, lamotrigine and hormones, the seizures markedly became less and EEG was improved obviously, which might be related to prolonging the half life, improving plasma drug concentration, enhancing synaptic after action, inhibiting the release of excited amino acids, stabilizing membrane potential gradually, controlling seizures and inhibiting epileptic electrical activities. The patients with CSWS still encounter mental and behavior disorders even after ESES disappears, and its severity and duration are associated with ESES severity and duration [12]. Hence, the effective way to improve ESES in an early period is to ameliorate neuropsychiatric symptoms.
Misdiagnosis can easily arise due to the initial formation of epileptic seizures and focal discharge of EEG, consequently resulting in improper selection of drugs. Therefore, the pediatricians should comprehensively consider the epileptic classifications and cautiously select antiepileptic drugs on the basis of EEG. In one word, for treating CSWS, early diagnosis and application of antiepileptic drugs, especially the hormones, can reduce the seizures, and significantly ameliorate the quality of life. Besides, researching the data of children with CSWS is conductive to understanding the severe consequences of this rare disease in order to timely diagnose and treat. 

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