RARE DISEASE
Cryptogenic late-onset epileptic spasms
Cryptogenic late-onset epileptic spasms
Cryptogenic late-onset epileptic spasms
Synonyms: Late-onset infantile spasms
Synonyms: Late-onset infantile spasms
Synonyms: Late-onset infantile spasms
Drug discovery
241
papers
On emerging therapies
Overview
Cryptogenic late-onset epileptic spasms (CLOES) is a rare epilepsy syndrome characterized by clusters of epileptic spasms emerging after 1 year of age, often accompanied by tonic seizures, atypical absences, and language/behavioral deficits [1][4][9]. EEG typically shows temporal/temporofrontal spike-wave activity without hypsarrhythmia [1][19]. Cognitive deterioration occurs in most cases, with up to 75% developing intellectual disability [4][14][16].
Burden
75% develop intellectual disability [4][14], with 50% progressing to severe epileptic encephalopathies like Lennox-Gastaut syndrome [6][16]. Drug resistance occurs in 60-70% [4][14], contributing to lifelong care needs [16]. Neurodevelopmental regression impacts education/vocational outcomes [13][19].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
241 drug discovery papers about Cryptogenic late-onset epileptic spasms. Recent publications:
241 drug discovery papers about Cryptogenic late-onset epileptic spasms. Recent publications:
categories:
Small molecules
small molecules
2026-04-30 | Threshold analysis of the patient’s route in infantile epileptic spasms syndrome: from the onset of spasms to first-line therapy
Background. Infantile epileptic spasms syndrome (IESS) is one of the most severe forms of early-onset epileptic encephalopathies and is associated with a high risk of pharmacoresistance, severe cognitive impairment, and premature mortality. Disease prognosis critically depends on the timeliness and adequacy of first-line therapy. Although delayed treatment of IESS is a universal problem, the specific stages of the patient care pathway at which delays occur may vary substantially depending on the organization of healthcare delivery. Aim. To identify key threshold stages of the patient care pathway and major barriers to timely initiation of rational therapy in children with IESS within the healthcare system of Saint Petersburg. Materials and methods. A retrospective observational study was conducted using the archive of the Epilepsy Clinic since 2018. A total of 130 children diagnosed with IESS according to International League Against Epilepsy criteria were included. Clinical and anamnestic data, magnetic resonance imaging findings, electroencephalography/video-electroencephalography monitoring results, and genetic testing data were analyzed. A threshold analysis of six consecutive stages of the patient care pathway was performed, from initial recognition of spasms to prescription of appropriate first-line therapy regimens. Early treatment response was assessed 2 weeks after therapy initiation Results. Developmental abnormalities prior to epileptic spasms onset were identified in 78 % of children; potentially epileptogenic magnetic resonance imaging abnormalities were found in 67 %. Causative genetic variants were detected in 18 % of the entire cohort. In 39 % of patients, the diagnosis was not established within the first month after spasm onset. In 96 (74 %) of 130 children, rational therapy was initiated more than one month after spasm onset. Six threshold points of potential treatment delay were identified. The main point of patient loss was late recognition of spasms at the stage of initial medical contact (loss of 27 out of 130 children). Moreover, delay at this stage deprived the child of any chance to receive timely therapy and constituted an insurmountable barrier to the subsequent steps of care. The second most important barrier was failure to initiate appropriate first-line therapy at treatment onset. The effectiveness of first-line therapy was more than 12-fold higher than that of standard antiseizure medications. Conclusion. Timely initiation of rational therapy in IESS is the result of passing through several consecutive threshold stages of the patient care pathway. The key systemic barriers in Saint Petersburg are late recognition of epileptic spasms and insufficient implementation of first-line therapy. These findings highlight the necessity of analyzing patient pathways within specific healthcare models and developing targeted programs for early detection and optimization of initial treatment.
2025-12-16 | Infantile Spasms (West Syndrome): Integrating Genetic, Neurotrophic, and Hormonal Mechanisms Toward Precision Therapy
Background and Objectives: Infantile spasms (ISs), or West syndrome (WS), represent an early-onset epileptic encephalopathy in which diverse structural, genetic, metabolic, infectious, and neurocutaneous conditions converge on a shared pattern of hypsarrhythmia, clustered spasms, and later developmental impairment. Growing use of genomic diagnostics has revealed that variants in STXBP1, KCNQ2, GRIN2A, GRIN2B, and TSC-related genes are more common than previously recognized and can be linked to partially actionable pathways. This review aimed to synthesize current evidence on the multifactorial etiology, network-based pathogenesis, and evolving targeted therapies for ISs, with particular attention to TSC-related forms. Materials and Methods: A structured narrative review was undertaken of publications from 1990 to 2025 in PubMed, Scopus, Web of Science, and Embase using terms related to ISs, WS, genetics, mTOR, ACTH, vigabatrin, ketogenic diet, and precision therapies. Authoritative guidance from ILAE and AAN was incorporated. Clinical, molecular, and therapeutic data were grouped under etiological, pathogenetic, and management domains. Results: Structural causes remained the largest group, but combined genetic, genetic–structural, and metabolic etiologies accounted for about one third of contemporary cohorts. Early network disruption involving cortex, thalamus, basal ganglia, and brainstem, together with imbalances in NGF, BDNF, and IGF-1, explained why distinct primary insults produce a uniform electroclinical phenotype. Early treatment with ACTH or high dose prednisolone, with or without vigabatrin, was consistently associated with higher electroclinical remission and better developmental outcome. Everolimus and related mTOR inhibitors showed benefit in TSC-associated ISs, while agents directed at NMDA receptors or KCNQ channels are emerging for genotype defined subgroups. Conclusions: ISs should be approached as a heterogeneous but mechanistically convergent disorder in which rapid diagnosis, parallel genetic testing, and early disease modifying therapy improve prognosis. Integration of molecular profiling with standardized outcome monitoring is likely to move management from symptomatic seizure control to pathway-specific intervention.
2025-11-12 | Infantile Spasms in Inborn Errors of Metabolism: Diagnostic and Therapeutic Considerations
Infantile epileptic spasms syndrome is an early-onset epileptic encephalopathy. Its association with inborn errors of metabolism is underrecognized, and the treatment can be complicated by the biochemical vulnerability. This report showed individualized treatment in 2 patients with inborn errors of metabolism. The first patient was found to have propionic acidemia in the setting of encephalopathy by third day of life. Infantile epileptic spasms syndrome was diagnosed at 10 months. Levetiracetam was started, and vigabatrin was introduced following liver transplant, which resulted in seizure freedom. The second patient presented at 6 months with hyperammonemia and elevated orotic acid consistent with ornithine transcarbamylase deficiency. Infantile epileptic spasms syndrome was diagnosed 3 weeks later. Treatment with vigabatrin, adjunctive to levetiracetam, led to a brief period of seizure cessation. The patient was later treated with two 4-week courses of enteral prednisolone, leading to the cessation of spasm. These cases emphasize the complexity in managing infantile epileptic spasms syndrome in patients at high risk for metabolic decompensation.
2023-12-20 | 15 years of real‐world data on the use of vigabatrin in individuals with infantile epileptic spasm syndrome
Abstract Objective This study was undertaken to evaluate our treatment algorithm for infantile epileptic spasms syndrome (IESS) used between 2000 and 2018. We initiated vigabatrin (VGB), and steroids were added if the electroclinical response (spasms and electroencephalogram [EEG]) to VGB was not obtained or incomplete. Methods Individuals with IESS treated with VGB were recruited from our hospital clinical data warehouse based on electronic health records (EHRs) generated since 2009 and containing relevant keywords. We confirmed the diagnosis of IESS. Clinical, EEG, imaging, and biological data were extracted from the EHRs. We analyzed factors associated with short‐term response, time to response, relapse, time to relapse of spasms, and the presence of spasms at last follow‐up. Results We collected data from 198 individuals (female: 46.5%, IESS onset: 6 [4.5–10.3] months, follow‐up: 4.6 [2.5–7.6] years, median [Q1–Q3]) including 129 (65.2%) with identifiable etiology. VGB was started 17 (5–57.5) days after IESS diagnosis. A total of 113 individuals were responders (57.1% of the cohort), 64 with VGB alone and 38 with VGB further combined with steroids (56.6% and 33.6% of responders, respectively). Among responders, 33 (29%) experienced relapses of spasms, mostly those with later onset of spasms ( p = .002) and those who received VGB for <24 months after spasms cessation compared to a longer duration on VGB (45% vs. 12.8%, p = .003). At follow‐up, 92 individuals were seizure‐free (46.5% of the whole cohort), including 26 free of therapy (13.1%). One hundred twelve individuals (56.6%) were still receiving VGB, with a duration of 3.2 (1.75–5.7) years. Significance Our sequential protocol introducing VGB then adding steroids is an effective alternative to a combined VGB–steroids approach in IESS. It avoids steroid‐related adverse events, as well as those from VGB–steroid combination. According to our data, a period of 7 days seems sufficient to assess VGB response and enables the addition of steroids rapidly if needed. Continuing VGB for 2 years may balance the risk of relapse and treatment‐induced adverse events.
2023-10-19 | Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome
Infantile epileptic spasms syndrome (IESS) is one of the most common epileptic encephalopathies of infancy, with typical clinical features defined by a triad of epileptic spasms, hypsarrhythmia, and developmental delay. Genetic factors are important causes of IESS. The SETD1A (SET Domain Containing 1A) gene encodes a histone lysine methyltransferase that activates gene transcription through histone H3 lysine K4 methylation. Mutations in the SETD1A gene have been associated with schizophrenia, and some have been reported to cause seizures. Herein, we report a case of IESS caused by a SETD1A gene mutation. Video electroencephalography showed hypsarrhythmia. No specific findings were obtained after brain MRI and metabolic work-up. The seizures disappeared after treatment with adrenocorticotropic hormone, vitamin B6, and valproic acid during hospitalization. Genetic testing revealed that the child had a variant (NM_014712.3:c.3005_3,006 delAG, p.Glu1002Glyfs*20) in exon 12 of the SETD1A gene, representing a de novo mutation. There have been no previous reports on the SETD1A gene causing infantile spasms. We also summarize the existing literature on SETD1A gene-related epilepsy to provide a reference for clinical diagnosis and treatment.
proteins
2024-10-11 | Factors Influencing the Response of Infantile Epileptic Spasm Syndrome Patients to ACTH as Repeated First-Line Therapy
Objective The treatment of infantile epileptic spasm syndrome (IESS) aims to achieve spasm control. Current first-line interventions include hormonal therapy (adrenocorticotropic hormone [ACTH] and corticosteroids) and vigabatrin. Despite treatment, the response rate remains at around 40%, with some patients experiencing relapse after initial control. In certain cases, a second course of first-line therapy may be warranted. This study aims to perform a secondary analysis of data from previously published studies by our research group to elucidate factors influencing the efficacy of ACTH when re-administering it after first-line treatment failure. Methods We conducted a retrospective analysis of clinical data from children with IESS who had failed or relapsed following initial first-line therapy and subsequently received ACTH at our institution as a second-line treatment. We examined such variables as etiological classification, interval between treatments, age at first epileptic seizure, radiological findings, and changes in pharmacological treatment modalities to assess their impact on the short-term response to the second administration of first-line therapy. Results Among 128 IESS patients identified, 50 (39.1%) achieved a short-term response. Comparative analysis indicated that responders had a shorter duration since initial first-line therapy (median 1.00 [interquartile range, IQR 0.00, 2.00] vs. 1.75 [IQR 0.50, 3.88] months), were younger at the time of repeated treatment (median 11 [IQR 8, 17] vs. 16 [IQR 10, 24] months, p = 0.008), and were less likely to present with additional seizure types during spasm episodes (12.0% vs. 28.2%, p = 0.030). A multivariate logistic regression model, adjusted for selected variables, revealed that a higher age at the onset of the first epileptic seizure and prior response to first-line therapy were associated with increased odds of achieving a short-term response to subsequent ACTH treatment (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.39, 7.23, p = 0.014). Conversely, older age at the time of repeated first-line treatment, older age at the spasm onset, and an etiology of congenital structural anomalies without genetic aberrations were associated with lower odds of a short-term response (OR = 0.85, 95% CI = 0.78, 0.92, p < 0.001; OR = 0.43, 95% CI = 0.16, 0.82, p = 0.032; OR = 0.18, 95% CI = 0.04, 0.69, p = 0.016). Conclusion A subset of children with IESS may benefit from a second trial of ACTH therapy even after initial first-line treatment failure, with over one-third of patients achieving a short-term response. However, patients with congenital structural anomalies without genetic alterations may not be suitable candidates for further ACTH therapy. Additionally, an older age at the first epileptic seizure onset correlates with a higher likelihood of a short-term response, while a later age at spasm onset inversely affects the probability of response. Younger age at the time of ACTH re-treatment may also increase the chances of a short-term response. Consideration for ACTH therapy may be warranted in relapse cases after an initial short-term response to first-line treatment.
2022-02-11 | Effectiveness of ACTH in Patients with Infantile Spasms
(1) Background: West syndrome is a severe, refractory, epileptic syndrome that usually appears in infancy or early childhood. ACTH is one of the more effective drugs for treating this condition. (2) Aim of the study and methods: The objective of our study was to examine short-term efficacy (during treatment schedule) and long-term outcome of intramuscular 0.02 mg/kg/day ACTH (tetracosactide) depot, used concomitantly with other antiepileptic drugs (AEDs) in patients with infantile spasms who did not achieve seizure cessation or relapse when taking only the AEDs. The drug efficacy was evaluated in retrospective and prospective analyses of 50 patients diagnosed with infantile spasms. (3) Results: Complete cessation of spasms was achieved in 42 cases (84%). EEG improvement was seen in 41 (82%) patients who responded to ACTH therapy. Information on the clinical course of 28 patients was obtained duringlong-term follow-up. In 17 (60.7%) cases, seizures were still present. Normal or near-normal development was observed in 11 out of 28 children (39%). ACTH used concomitantly with other AEDis a highly effective treatment with acceptable side effects. (4) Conclusion: Randomized controlled clinical trialswith long-term follow-up are needed to compare the effectiveness of ACTH in polytherapy and monotherapy. Dyskinesias as a potential side effect observed in our study group should be investigated in the following studies.
2016-06-01 | Effectiveness of once-daily high-dose ACTH for infantile spasms
There is insufficient evidence to recommend a specific protocol for treatment of infantile spasms (IS) and a lack of standardization among, and even within, institutions. Twice-daily dosing (for the first two weeks) of high-dose natural ACTH for IS is used by many centers and recommended by the National Infantile Spasms Consortium (NISC). Conversely, it is our practice to use once-daily dosing of high-dose natural ACTH for IS. In order to determine the effectiveness of our center's practice, we retrospectively reviewed 57 cases over the past four years at Boston Children's Hospital (BCH). We found that 70% of infants were spasm-free at 14 days from ACTH initiation and 54% continued to be spasm-free at 3-month follow-up. Electroencephalogram showed resolution of hypsarrhythmia (when present on the pretreatment EEG) in all responders. Additionally, once-daily dosing of ACTH was well tolerated. We performed a meta-analysis to compare our results against the reports of published literature using twice-daily high-dose ACTH for treatment of IS. The meta-analysis revealed that our results were comparable to previously published outcomes using twice-daily ACTH administration for IS treatment. Our experience shows that once-daily dosing of ACTH is effective for treatment of IS. If larger prospective trials can confirm our findings, it would obviate the need for additional painful injections, simplify the schedule, and support a universal standardized protocol.
2011-06-30 | Treatment of infantile spasms: emerging insights from clinical and basic science perspectives.
Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments of infantile spasms, novel conceptual and experimental approaches to infantile spasms treatment, and a perspective on remaining clinical challenges and current research questions are presented here. This summary derives from a meeting of specialists in infantile spasms clinical care and research held in New York City on June 14, 2010.
small molecules
2026-04-30 | Threshold analysis of the patient’s route in infantile epileptic spasms syndrome: from the onset of spasms to first-line therapy
Background. Infantile epileptic spasms syndrome (IESS) is one of the most severe forms of early-onset epileptic encephalopathies and is associated with a high risk of pharmacoresistance, severe cognitive impairment, and premature mortality. Disease prognosis critically depends on the timeliness and adequacy of first-line therapy. Although delayed treatment of IESS is a universal problem, the specific stages of the patient care pathway at which delays occur may vary substantially depending on the organization of healthcare delivery. Aim. To identify key threshold stages of the patient care pathway and major barriers to timely initiation of rational therapy in children with IESS within the healthcare system of Saint Petersburg. Materials and methods. A retrospective observational study was conducted using the archive of the Epilepsy Clinic since 2018. A total of 130 children diagnosed with IESS according to International League Against Epilepsy criteria were included. Clinical and anamnestic data, magnetic resonance imaging findings, electroencephalography/video-electroencephalography monitoring results, and genetic testing data were analyzed. A threshold analysis of six consecutive stages of the patient care pathway was performed, from initial recognition of spasms to prescription of appropriate first-line therapy regimens. Early treatment response was assessed 2 weeks after therapy initiation Results. Developmental abnormalities prior to epileptic spasms onset were identified in 78 % of children; potentially epileptogenic magnetic resonance imaging abnormalities were found in 67 %. Causative genetic variants were detected in 18 % of the entire cohort. In 39 % of patients, the diagnosis was not established within the first month after spasm onset. In 96 (74 %) of 130 children, rational therapy was initiated more than one month after spasm onset. Six threshold points of potential treatment delay were identified. The main point of patient loss was late recognition of spasms at the stage of initial medical contact (loss of 27 out of 130 children). Moreover, delay at this stage deprived the child of any chance to receive timely therapy and constituted an insurmountable barrier to the subsequent steps of care. The second most important barrier was failure to initiate appropriate first-line therapy at treatment onset. The effectiveness of first-line therapy was more than 12-fold higher than that of standard antiseizure medications. Conclusion. Timely initiation of rational therapy in IESS is the result of passing through several consecutive threshold stages of the patient care pathway. The key systemic barriers in Saint Petersburg are late recognition of epileptic spasms and insufficient implementation of first-line therapy. These findings highlight the necessity of analyzing patient pathways within specific healthcare models and developing targeted programs for early detection and optimization of initial treatment.
2025-12-16 | Infantile Spasms (West Syndrome): Integrating Genetic, Neurotrophic, and Hormonal Mechanisms Toward Precision Therapy
Background and Objectives: Infantile spasms (ISs), or West syndrome (WS), represent an early-onset epileptic encephalopathy in which diverse structural, genetic, metabolic, infectious, and neurocutaneous conditions converge on a shared pattern of hypsarrhythmia, clustered spasms, and later developmental impairment. Growing use of genomic diagnostics has revealed that variants in STXBP1, KCNQ2, GRIN2A, GRIN2B, and TSC-related genes are more common than previously recognized and can be linked to partially actionable pathways. This review aimed to synthesize current evidence on the multifactorial etiology, network-based pathogenesis, and evolving targeted therapies for ISs, with particular attention to TSC-related forms. Materials and Methods: A structured narrative review was undertaken of publications from 1990 to 2025 in PubMed, Scopus, Web of Science, and Embase using terms related to ISs, WS, genetics, mTOR, ACTH, vigabatrin, ketogenic diet, and precision therapies. Authoritative guidance from ILAE and AAN was incorporated. Clinical, molecular, and therapeutic data were grouped under etiological, pathogenetic, and management domains. Results: Structural causes remained the largest group, but combined genetic, genetic–structural, and metabolic etiologies accounted for about one third of contemporary cohorts. Early network disruption involving cortex, thalamus, basal ganglia, and brainstem, together with imbalances in NGF, BDNF, and IGF-1, explained why distinct primary insults produce a uniform electroclinical phenotype. Early treatment with ACTH or high dose prednisolone, with or without vigabatrin, was consistently associated with higher electroclinical remission and better developmental outcome. Everolimus and related mTOR inhibitors showed benefit in TSC-associated ISs, while agents directed at NMDA receptors or KCNQ channels are emerging for genotype defined subgroups. Conclusions: ISs should be approached as a heterogeneous but mechanistically convergent disorder in which rapid diagnosis, parallel genetic testing, and early disease modifying therapy improve prognosis. Integration of molecular profiling with standardized outcome monitoring is likely to move management from symptomatic seizure control to pathway-specific intervention.
2025-11-12 | Infantile Spasms in Inborn Errors of Metabolism: Diagnostic and Therapeutic Considerations
Infantile epileptic spasms syndrome is an early-onset epileptic encephalopathy. Its association with inborn errors of metabolism is underrecognized, and the treatment can be complicated by the biochemical vulnerability. This report showed individualized treatment in 2 patients with inborn errors of metabolism. The first patient was found to have propionic acidemia in the setting of encephalopathy by third day of life. Infantile epileptic spasms syndrome was diagnosed at 10 months. Levetiracetam was started, and vigabatrin was introduced following liver transplant, which resulted in seizure freedom. The second patient presented at 6 months with hyperammonemia and elevated orotic acid consistent with ornithine transcarbamylase deficiency. Infantile epileptic spasms syndrome was diagnosed 3 weeks later. Treatment with vigabatrin, adjunctive to levetiracetam, led to a brief period of seizure cessation. The patient was later treated with two 4-week courses of enteral prednisolone, leading to the cessation of spasm. These cases emphasize the complexity in managing infantile epileptic spasms syndrome in patients at high risk for metabolic decompensation.
2023-12-20 | 15 years of real‐world data on the use of vigabatrin in individuals with infantile epileptic spasm syndrome
Abstract Objective This study was undertaken to evaluate our treatment algorithm for infantile epileptic spasms syndrome (IESS) used between 2000 and 2018. We initiated vigabatrin (VGB), and steroids were added if the electroclinical response (spasms and electroencephalogram [EEG]) to VGB was not obtained or incomplete. Methods Individuals with IESS treated with VGB were recruited from our hospital clinical data warehouse based on electronic health records (EHRs) generated since 2009 and containing relevant keywords. We confirmed the diagnosis of IESS. Clinical, EEG, imaging, and biological data were extracted from the EHRs. We analyzed factors associated with short‐term response, time to response, relapse, time to relapse of spasms, and the presence of spasms at last follow‐up. Results We collected data from 198 individuals (female: 46.5%, IESS onset: 6 [4.5–10.3] months, follow‐up: 4.6 [2.5–7.6] years, median [Q1–Q3]) including 129 (65.2%) with identifiable etiology. VGB was started 17 (5–57.5) days after IESS diagnosis. A total of 113 individuals were responders (57.1% of the cohort), 64 with VGB alone and 38 with VGB further combined with steroids (56.6% and 33.6% of responders, respectively). Among responders, 33 (29%) experienced relapses of spasms, mostly those with later onset of spasms ( p = .002) and those who received VGB for <24 months after spasms cessation compared to a longer duration on VGB (45% vs. 12.8%, p = .003). At follow‐up, 92 individuals were seizure‐free (46.5% of the whole cohort), including 26 free of therapy (13.1%). One hundred twelve individuals (56.6%) were still receiving VGB, with a duration of 3.2 (1.75–5.7) years. Significance Our sequential protocol introducing VGB then adding steroids is an effective alternative to a combined VGB–steroids approach in IESS. It avoids steroid‐related adverse events, as well as those from VGB–steroid combination. According to our data, a period of 7 days seems sufficient to assess VGB response and enables the addition of steroids rapidly if needed. Continuing VGB for 2 years may balance the risk of relapse and treatment‐induced adverse events.
2023-10-19 | Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome
Infantile epileptic spasms syndrome (IESS) is one of the most common epileptic encephalopathies of infancy, with typical clinical features defined by a triad of epileptic spasms, hypsarrhythmia, and developmental delay. Genetic factors are important causes of IESS. The SETD1A (SET Domain Containing 1A) gene encodes a histone lysine methyltransferase that activates gene transcription through histone H3 lysine K4 methylation. Mutations in the SETD1A gene have been associated with schizophrenia, and some have been reported to cause seizures. Herein, we report a case of IESS caused by a SETD1A gene mutation. Video electroencephalography showed hypsarrhythmia. No specific findings were obtained after brain MRI and metabolic work-up. The seizures disappeared after treatment with adrenocorticotropic hormone, vitamin B6, and valproic acid during hospitalization. Genetic testing revealed that the child had a variant (NM_014712.3:c.3005_3,006 delAG, p.Glu1002Glyfs*20) in exon 12 of the SETD1A gene, representing a de novo mutation. There have been no previous reports on the SETD1A gene causing infantile spasms. We also summarize the existing literature on SETD1A gene-related epilepsy to provide a reference for clinical diagnosis and treatment.
proteins
2024-10-11 | Factors Influencing the Response of Infantile Epileptic Spasm Syndrome Patients to ACTH as Repeated First-Line Therapy
Objective The treatment of infantile epileptic spasm syndrome (IESS) aims to achieve spasm control. Current first-line interventions include hormonal therapy (adrenocorticotropic hormone [ACTH] and corticosteroids) and vigabatrin. Despite treatment, the response rate remains at around 40%, with some patients experiencing relapse after initial control. In certain cases, a second course of first-line therapy may be warranted. This study aims to perform a secondary analysis of data from previously published studies by our research group to elucidate factors influencing the efficacy of ACTH when re-administering it after first-line treatment failure. Methods We conducted a retrospective analysis of clinical data from children with IESS who had failed or relapsed following initial first-line therapy and subsequently received ACTH at our institution as a second-line treatment. We examined such variables as etiological classification, interval between treatments, age at first epileptic seizure, radiological findings, and changes in pharmacological treatment modalities to assess their impact on the short-term response to the second administration of first-line therapy. Results Among 128 IESS patients identified, 50 (39.1%) achieved a short-term response. Comparative analysis indicated that responders had a shorter duration since initial first-line therapy (median 1.00 [interquartile range, IQR 0.00, 2.00] vs. 1.75 [IQR 0.50, 3.88] months), were younger at the time of repeated treatment (median 11 [IQR 8, 17] vs. 16 [IQR 10, 24] months, p = 0.008), and were less likely to present with additional seizure types during spasm episodes (12.0% vs. 28.2%, p = 0.030). A multivariate logistic regression model, adjusted for selected variables, revealed that a higher age at the onset of the first epileptic seizure and prior response to first-line therapy were associated with increased odds of achieving a short-term response to subsequent ACTH treatment (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.39, 7.23, p = 0.014). Conversely, older age at the time of repeated first-line treatment, older age at the spasm onset, and an etiology of congenital structural anomalies without genetic aberrations were associated with lower odds of a short-term response (OR = 0.85, 95% CI = 0.78, 0.92, p < 0.001; OR = 0.43, 95% CI = 0.16, 0.82, p = 0.032; OR = 0.18, 95% CI = 0.04, 0.69, p = 0.016). Conclusion A subset of children with IESS may benefit from a second trial of ACTH therapy even after initial first-line treatment failure, with over one-third of patients achieving a short-term response. However, patients with congenital structural anomalies without genetic alterations may not be suitable candidates for further ACTH therapy. Additionally, an older age at the first epileptic seizure onset correlates with a higher likelihood of a short-term response, while a later age at spasm onset inversely affects the probability of response. Younger age at the time of ACTH re-treatment may also increase the chances of a short-term response. Consideration for ACTH therapy may be warranted in relapse cases after an initial short-term response to first-line treatment.
2022-02-11 | Effectiveness of ACTH in Patients with Infantile Spasms
(1) Background: West syndrome is a severe, refractory, epileptic syndrome that usually appears in infancy or early childhood. ACTH is one of the more effective drugs for treating this condition. (2) Aim of the study and methods: The objective of our study was to examine short-term efficacy (during treatment schedule) and long-term outcome of intramuscular 0.02 mg/kg/day ACTH (tetracosactide) depot, used concomitantly with other antiepileptic drugs (AEDs) in patients with infantile spasms who did not achieve seizure cessation or relapse when taking only the AEDs. The drug efficacy was evaluated in retrospective and prospective analyses of 50 patients diagnosed with infantile spasms. (3) Results: Complete cessation of spasms was achieved in 42 cases (84%). EEG improvement was seen in 41 (82%) patients who responded to ACTH therapy. Information on the clinical course of 28 patients was obtained duringlong-term follow-up. In 17 (60.7%) cases, seizures were still present. Normal or near-normal development was observed in 11 out of 28 children (39%). ACTH used concomitantly with other AEDis a highly effective treatment with acceptable side effects. (4) Conclusion: Randomized controlled clinical trialswith long-term follow-up are needed to compare the effectiveness of ACTH in polytherapy and monotherapy. Dyskinesias as a potential side effect observed in our study group should be investigated in the following studies.
2016-06-01 | Effectiveness of once-daily high-dose ACTH for infantile spasms
There is insufficient evidence to recommend a specific protocol for treatment of infantile spasms (IS) and a lack of standardization among, and even within, institutions. Twice-daily dosing (for the first two weeks) of high-dose natural ACTH for IS is used by many centers and recommended by the National Infantile Spasms Consortium (NISC). Conversely, it is our practice to use once-daily dosing of high-dose natural ACTH for IS. In order to determine the effectiveness of our center's practice, we retrospectively reviewed 57 cases over the past four years at Boston Children's Hospital (BCH). We found that 70% of infants were spasm-free at 14 days from ACTH initiation and 54% continued to be spasm-free at 3-month follow-up. Electroencephalogram showed resolution of hypsarrhythmia (when present on the pretreatment EEG) in all responders. Additionally, once-daily dosing of ACTH was well tolerated. We performed a meta-analysis to compare our results against the reports of published literature using twice-daily high-dose ACTH for treatment of IS. The meta-analysis revealed that our results were comparable to previously published outcomes using twice-daily ACTH administration for IS treatment. Our experience shows that once-daily dosing of ACTH is effective for treatment of IS. If larger prospective trials can confirm our findings, it would obviate the need for additional painful injections, simplify the schedule, and support a universal standardized protocol.
2011-06-30 | Treatment of infantile spasms: emerging insights from clinical and basic science perspectives.
Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments of infantile spasms, novel conceptual and experimental approaches to infantile spasms treatment, and a perspective on remaining clinical challenges and current research questions are presented here. This summary derives from a meeting of specialists in infantile spasms clinical care and research held in New York City on June 14, 2010.
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