Seizure outcome of infantile spasms with focal cortical dysplasia

Purpose: This study sought to evaluate the seizure outcome of infantile spasms (IS) with focal cortical dysplasia (FCD). Methods: We retrospectively reviewed infantile spasms patients with FCD from 2004 to 2010. We investigated seizure outcome from antiepileptic drug (AED), ketogenic diet (KD), resective surgery, and analyzed the results according to individual imaging studies. Results: Among 404 patients of IS, FCD was confirmed in 51 patients. In retrospective review of brain MRI, only 21 patients (41.2%) were suspected of FCD before 1 year of age, but 45 patients (88.2%) became confirmed to FCD by MRI after the age of 1 year. Once the spasms were not controlled by 1 or 2 AEDs, the chance of becoming seizure free with additional third or more drugs was very low (2.3%). The seizure free rate was 33.3% (7/21) in patients treated with ketogenic diet, and 73.3% (22/30) in surgical patients, who were both intractable to AEDs. There were no significant differences in seizure free rate in both ketogenic diet and surgical patients, between MRI negative and positive patients prior to 1 year of age. Conclusions: KD and surgery should be considered in medically refractory IS with FCD.     

A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms.

The spontaneous remission rate and long-term outcome in 44 patients with infantile spasms not treated with hormonal drugs were studied. The cumulative spontaneous remission rate during the first 12 months after onset of infantile spasms, as determined by retrospective analysis, was as follows: 1 month, 2%; 2 months, 2%; 3 months, 5%; 4 months, 7%; 5 months, 9%; 6 months, 11%; 7 months, 11%; 8 months, 14%; 9 months, 16%; 10 months, 18%; 11 months, 25%; 12 months, 25%. The average age at follow-up was 80 months. Nine percent of patients had normal development or only mild impairment. The remainder showed various degrees of retardation. These data should be useful in the design and interpretation of therapeutic drug trials in patients with infantile spasms.     

Occurrence, outcome, and prognostic factors of infantile spasms and Lennox-Gastaut syndrome

PURPOSE: To analyze the occurrence, outcome, and prognostic factors of infantile spasms (IS) and the Lennox-Gastaut syndrome (LGS) in a defined population. METHODS: All children treated because of IS and LGS in the Department of Pediatrics, University of Oulu, from January 1, 1976, until December 31, 1993, who came from the primary catchment area of the hospital were included. Detailed information concerning their individual pre-, peri-, and postnatal medical histories and medical and laboratory examinations were compiled. RESULTS: Thirty-seven children (18 boys) had IS, and 25 (14 boys) had LGS. The occurrence of IS of 0.41/1,000 live births 195% confidence interval (CI), 0.29-0.57/1,000] did not differ significantly from that of LGS, which was 0.28/1,000 live births (95% CI, 0.18-0.41/1,000). Ten (27%) of the 37 patients with IS evolved to LGS, which was 40% of the LGS cases. All the 10 children with both IS and LGS had symptomatic epilepsy, were mentally retarded, and had active epilepsy at the end of approximately 10 years' follow-up. Twenty-six (87%) of the 30 symptomatic IS cases and all the 17 symptomatic LGS cases were due to either congenital or genetic etiologies. The outcome in cryptogenic IS cases was favorable; the risk for a poor neurologic and mental outcome was extremely low; odds ratio, 0.015 (95% Cl, 0.001-0.196), as it was for therapy-resistant epilepsy; odds ratio, 0.013 (95% CI, 0.001-0.166). In LGS patients, cryptogenic etiology did not decrease the risk for a poor outcome. CONCLUSIONS: Cryptogenic etiology is associated with a very low risk for a poor outcome in IS patients, but not in LGS patients. The outcome of IS children and the relation of IS to LGS are determined by the underlying brain disease, not by the epilepsy itself.     

Epidemiologic features of infantile spasms in Slovenia

PURPOSE: To determine the epidemiologic features of infantile spasms (ISs) in Slovenia. METHODS: Medical records of all children with ISs in Slovenia in the period from 1985 to 1995, based on community pediatrician referrals to four hospitals, including all pediatric EEG laboratories, were retrospectively studied. The outcome was assessed by a follow-up study in 1998. RESULTS: Forty-seven children with ISs were identified over an 11-year interval. The cumulative incidence was 2.06 per 10,000 live births. Among 29 (61.7%) children with symptomatic etiology, 14 cases had prenatal etiology [tuberous sclerosis (TS), seven; vascular insult, three; cerebral malformations, three; Down syndrome, one child], 14 perinatal and one postnatal cause: anoxic brain damage after cardiac surgery. Cryptogenic and idiopathic etiology were diagnosed in 13 (27.6%) and five (10.6%) of 47 cases, respectively. The age of onset of ISs ranged from 2 to 10 months. As initial treatment, steroids were used in 19 children (remission in 10); vigabatrin in seven (remission in four), and other antiepileptic drugs (AEDs) in 20 children (remission in six). According to the follow-up study, 18 (38.3%) children were seizure free, and 14 of them had normal mental development. Among 29 mentally retarded children (14 severely), 26 belonged to the symptomatic group. Four children died. CONCLUSIONS: The incidence of ISs in Slovenia is similar to that in some parts of the United States, but lower than that in Finland or Sweden. The outcome depends mainly on etiology. Additional neuroimaging studies are needed for evaluation of cryptogenic cases.     

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study

Purpose: Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors. Methods: Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression. Key Findings: Age of onset ranged (77 infants) from <1 to 10 months (mean 5.2, standard deviation 2.1). Lead time to treatment was 7 days or less in 11, 8–14 days in 16, 15 days to 1 month in 8, 1–2 months in 15, >2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64–5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3–0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p = 0.004). Significance: Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants.     

A controlled study of prednisone therapy in infantile spasms.

A controlled study of 12 patients with infantile spasms was performed to determine the effectiveness of prednisone treatment. Patients were monitored serially, using a time-synchronized polygraphic and video system. Three patients (25%) showed prompt reduction in seizure frequency and normalization of the EEG after institution of treatment. The remaining patients showed no improvement in seizure frequency or significant change in the EEG.     

婴儿痉挛症脑干听觉诱发电位中的γ频带

目的 观察婴儿痉挛症患者脑干听觉诱发电位中γ频带成分。方法 用子波变换分别对正常婴儿、婴儿痉挛症患儿、经过一段时间治疗后的婴儿痉挛症患儿脑干听觉诱发电位信号进行多尺度分析。观察脑干听觉诱发电位信号多尺度成分的分尺度功率随尺度的分布。结果 婴儿痉挛症患儿的脑干听觉诱发电位信号的γ频带的成分缺损严重，其分尺度功率远低于正常婴儿，婴儿痉挛症患儿经过一段时间治疗后脑干听觉诱发电位信号的γ频带成分明显改善，其分尺度功率接近正常婴儿。结论 γ频带对信启在脑干中的接收、传输、加工、综合、反馈等高级功能和人脑的认知活动具有重要作用，γ频带成分缺损导致的信息传导阻滞是引起患儿智能发育迟滞的原因。     

Informative value of magnetic resonance imaging and EEG in the prognosis of infantile spasms

PURPOSE: To investigate the informative value of EEG and cranial magnetic resonance imaging (cMRI) in the prognosis of infantile spasms (ISs); 86 patients with ISs were included in this study. METHODS: All cases had epileptic spasms, psychomotor retardation, and hypsarrhythmia in at least one of their EEGs. cMRIs and laboratory tests necessary for etiologic diagnosis were completed in all cases. Patients were followed up periodically both clinically and by video-EEGs for >1 year. Clinical information was categorized on the basis of four spheres as epilepsy, psychosocial development, motor development, and overall clinical condition, with each category being evaluated under three levels of involvement as good, moderate, and severe, depending on selected parameters. A similar scale was applied for the EEG results and for the cMRI findings. Clinical parameters were correlated to EEG and cMRI results, by Spearman test. Other statistical tests used were Kruskal-Wallis chi(2) and Mann-Whitney U analysis as multiple comparison by post hoc Bonferroni correction. RESULTS: A severe overall clinical course was observed in 64% of patients, whereas this incidence was 58% and 44% in the EEG follow-up and cMRI parameters, respectively. In regard to prognosis, a significant correlation was determined between the clinical and the EEG course. This relation was the most prominent in psychosocial developmental parameters and least prominent in the motor development. cMRI findings, however, were correlated only with motor development. CONCLUSIONS: cMRI and repeated EEG recordings, especially when assessed together, may provide complementary information regarding the prognosis in ISs.     

A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group

PURPOSE: To reach a broad consensus on case definitions, outcomes, and outcome measures that will ease future study design and facilitate comparison of data from different studies of infantile spasms and West syndrome. METHODS: Persons who had recently presented or published first-author original research in this field were invited to participate in an e-mail Delphi process and to invite other investigators or clinicians who they thought might participate. RESULTS: The process consisted of six rounds, anonymous except to the facilitator. In total, responses were received from 46 participants. The final statement was approved by 31 participants from 15 countries. It concluded that the primary clinical outcome, cessation of spasms, should denote absence of witnessed spasms from within 14 days of commencement of treatment, and for > or =28 consecutive days from the last witnessed spasm. Primary electroclinical outcome denotes cessation of spasms with resolution of hypsarrhythmia. West syndrome should be a defined subset of the syndrome of infantile spasms. An infantile spasms single-spasm variant should be recognized. Ways are suggested of handling subtle spasms in the context of clinical studies. It proposes a standard for reporting modifying and atypical features of hypsarrhythmia, a minimal set of baseline characteristics and outcomes that should be reported in trials of infantile spasms, and suggests a standard definition of relapse. Consensus was not reached on a definition of hypsarrhythmia. CONCLUSIONS: We reached a clear consensus on many aspects of study design for the investigation of infantile spasms, although incomplete consensus was found on how to define EEG criteria.     

Expansion of the first polyalanine tract of the ARX gene in a boy presenting with generalized dystonia in the absence of infantile spasms

Mutations in the Aristaless-related homeobox (ARX) gene are associated with pleiotropic phenotypes including infantile spasms, mental retardation and dystonia. However, relatively consistent genotype-phenotype correlations have been emphasized in prior reports. We report a boy presenting with mental retardation, tonic seizures and dystonia but without infantile spasms. Gene sequencing detected an additional seven GCG repeats in the first polyalanine tract of the ARX gene, a mutation which leads to an expansion of the normal 16 alanine residues to 23. The same ARX gene mutation has been reported in patients with infantile spasms, but was absent in the present case. This finding highlights the diverse phenotypic spectrum that may result from ARX gene mutations.     

Use of ACTH and prednisolone in infantile spasms: Experience from a developing country

BACKGROUND: Adrenocorticotrophic hormone (ACTH) and prednisone are both used to treat infantile spasms (IS) in West syndrome. In many countries, ACTH is expensive and difficult to obtain whereas, prednisone or prednisolone are cheap, given orally and easily available. AIMS: The purpose of this retrospective data analysis was to compare the efficacy and cost of ACTH and prednisolone in the treatment of IS from the perspective of a developing country. METHODS: Patients admitted with West syndrome in Children's Hospital, Islamabad, between January 1995 and December 2001 were included in the analysis. The diagnosis was made after eliciting a history of characteristic seizures and detecting hypsarrhythmia on the EEG. Parents were offered the use of either ACTH administered by intramuscular injection or prednisolone given orally. ACTH was expensive and difficult to obtain whereas prednisolone was cheap and easily available. RESULTS: One hundred and five children were included in the study. Sixty-three were boys and their age ranged from 2 months to 3 years with a mean of 11 months. Thirty-three children received ACTH injections; 27 showed improvement and 11 remained spasms free after discontinuation of injections. Seventy-two patients were given oral prednisolone, 51 responded and 17 remained spasms free after oral steroids were stopped. Overall outcome was similar in both groups. The cost of ACTH injection was more than 100 times the cost of oral prednisolone. CONCLUSION: No significant difference was seen in the final outcome in both treatment groups. Since prednisolone is inexpensive, easily available and given orally, it is the preferred mode of therapy.     

Insulin‐like growth factor‐1 is associated with cognitive outcome in infantile spasms

Purpose: The molecular mechanisms that lead to long‐term consequences of infantile spasms (IS) are poorly understood. Insulin‐like growth factor‐1 (IGF‐1) is regulated by insults that might be stressful to the brain, and is crucial for early brain development. The aim of the present study was to correlate cerebrospinal fluid (CSF) levels of IGF‐1 with antecedent insults and cognitive outcome. Methods: We studied CSF IGF‐1 and the adrenocorticotropic hormone (ACTH) concentrations in infants with idiopathic IS (IIS), symptomatic IS (SIS), and controls. Results: Infants with IIS had CSF IGF‐1 concentrations similar to those of the control children, but children with SIS had markedly low CSF IGF‐1 concentrations. In addition, CSF ACTH concentrations were significantly lower in the children with SIS than in those with IIS. High CSF IGF‐1 concentrations were associated with an idiopathic etiology, absence of early (pre‐ or perinatal) insults or stress, normal brain imaging studies, good response to ACTH therapy, and favorable cognitive outcome. Low CSF IGF‐1 concentrations were associated with low CSF ACTH concentrations, a history of early insults or stress, cerebral atrophy, poor response to therapy, and poor cognitive outcome. Discussion: In children with IS, insults or stress in early life may affect the synthesis of IGF‐1, which might play a role in the reduction of certain cognitive functions.     

微信群延续性指导模式对婴儿痉挛症患儿生酮饮食保留率的影响

目的探讨微信群延续性指导模式在生酮饮食(Ketogenic Diet,KD)治疗婴儿痉挛症(Infantile Spasms,IS)中对治疗保留率及有效率的影响。方法回顾性分析2017年1月—2019年6月于江西省儿童医院进行KD治疗的40例IS患儿病例资料,其中男23例,女17例,平均年龄(19.90±13.10)月龄,平均病程(9.95±7.61)个月,随机分为对照组(20例)及观察组(即微信群延续性指导组20例),并随访1年,比较两组的保留率及疗效。结果观察组及对照组的一般资料比较,差异无统计学意义(P>0.05),具有可比性。在KD治疗9、12个月时,观察组的保留率显著高于对照组(P均<0.05),有效率亦显著高于对照组(P均<0.05),且无发作率较对照组显著增高(35%vs.10%,35%vs.15%)。结论微信群延续性指导模式可增加IS患儿的KD治疗长期保留率,从而增加其治疗的有效率。     

CSF protein profile in infantile spasms. Influence of etiology and ACTH or dexamethasone treatment

CSF proteins in 107 children ranging from 3 to 24 months of age were analyzed by means of quantitative zone electrophoresis on agarose gel. Subjects included 50 children with infantile spasms, 41 children without CNS disease serving as controls, and 16 infants with acute aseptic meningitis who demonstrated the protein pattern of blood-CSF barrier disturbance. Children with infantile spasms were subdivided into several groups according to etiological categories: symptomatic (pre-, peri-, and postnatal), doubtful, and cryptogenetic. Before any treatment was started, these children showed the protein profile of increased permeability of the blood-CSF barrier, especially for albumin. There was an association between the severity of the changes and the etiological category. Changes were most marked in the symptomatic group, intermediate in the doubtful group, and slight in the cryptogenetic group. No child with infantile spasms of doubtful or unknown etiology revealed changes of the immunoglobulin-containing gamma fractions. Ten children who had received adrenocorticotropic hormone (ACTH) or dexamethasone for 2-11 weeks no longer showed any protein leakage into the CSF. The period of ACTH or dexamethasone treatment was characterized by the following findings: the disappearance or reduction of hypsarrhythmia; the reappearance of normal cerebrovascular permeability for protein; and the occurrence of reversible dilatation of the subarachnoid and intraventricular spaces.     

Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life

Purpose: No population‐based study has investigated the risk of autism spectrum disorders (ASDs) in children after unprovoked seizures with onset in the first year of life. Our objective was to determine whether infantile spasms were related to risk of ASD as compared to unprovoked seizures with onset in the first year of life after adjusting for symptomatic origin of seizures. Methods: This is a population‐based case‐control study nested in a cohort of children with unprovoked seizures in the first year of life. The cohort comprised 95 children, 34 boys and 61 girls. Cases were defined as children with ASD, controls were without ASD, and exposure was a history of infantile spasms. The Mantel‐Haenszel test and logistic regression were used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Results: The crude OR for ASD associated with infantile spasms was 5.53 (95% CI 1.25–23.06). Stratification on age and gender did not change the OR. The OR for ASD associated with infantile spasms adjusted for symptomatic seizures was 1.55 (95% CI 0.33–7.37), while the OR for ASD associated with symptomatic seizures adjusted for infantile spasms was 8.73 (95% CI 1.88–40.54). Restriction to mental age 24 months or higher yielded higher ORs. Discussion: Infantile spasms predicted high risk for ASD, but this was to a large extent explained by the association of ASD with symptomatic origin of seizures.