RARE DISEASE
Infantile spasms syndrome
Infantile spasms syndrome
Infantile spasms syndrome
Synonyms: West syndrome
Synonyms: West syndrome
Synonyms: West syndrome
Drug discovery
18
drugs
With orphan designations
Overview
Infantile Spasms Syndrome (ISS), formerly West syndrome, is a severe developmental and epileptic encephalopathy characterized by epileptic spasms (tonic-flexor/extensor clusters), hypsarrhythmia on EEG, and neurodevelopmental regression. Onset typically occurs between 3-12 months, with peak incidence at 4-7 months [1][4][12]. Etiologies include structural brain abnormalities (e.g., hypoxic injury, tuberous sclerosis), genetic mutations, and metabolic disorders, though 20-30% remain cryptogenic [4][11][17]. Early treatment with hormonal therapy or vigabatrin improves developmental outcomes, but delayed diagnosis remains common due to subtle seizure semiology [3][5][16].
Burden
Mortality: 3–33%, often linked to underlying etiology or sepsis [4][14].
Neurodevelopmental: 70–90% experience cognitive impairment; 30–50% progress to refractory epilepsy (e.g., Lennox-Gastaut syndrome) [4][5][17].
Economic: High costs from therapies, hospitalizations, and caregiver work loss (median 12 days/year) [9][16].
Therapies
First-line: Hormonal therapy (ACTH/prednisolone) or vigabatrin (preferred for tuberous sclerosis) [3][5][13].
Second-line: Ketogenic diet, epilepsy surgery (for focal lesions), or adjunctive antiseizure medications (e.g., topiramate) [5][16].
Treatment response monitored by clinical spasms cessation and EEG normalization within 2 weeks [3][8].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,122 drug discovery papers about Infantile spasms syndrome, with 2 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,122 drug discovery papers about Infantile spasms syndrome, with 2 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-10 | Electrophysiological readout of ACTH-related neuroendocrine–immunomodulatory treatment response in infantile epileptic spasms syndrome: suppression of scalp ripple propagation networks
Background Adrenocorticotropic hormone (ACTH) is a first-line neuroendocrine–immunomodulatory therapy for infantile epileptic spasms syndrome (IESS), but noninvasive electrophysiological markers that objectively reflect treatment-related network changes remain limited. We investigated whether scalp putative ripple propagation network metrics provide markers of adrenocorticotropic hormone-related network response and early relapse risk. Methods In this retrospective multicenter study, children receiving first-time ACTH therapy were included if paired pre- and post-treatment scalp electroencephalography (EEG) recordings and at least 6 months of follow-up were available. Five-minute artifact-free interictal slow-wave-sleep segments were analyzed. Putative ripple propagation networks were constructed using a time-delay-based method. The primary metrics were post-treatment total network connection strength (total NCS) and its reduction ratio, with ripple count and ripple-count reduction ratio used as rate-based comparators. Results Sixty-one children were included; 27 achieved acute spasm freedom, and seven of these relapsed within 6 months. Baseline ripple count and network metrics did not distinguish subsequent responders from nonresponders. After adrenocorticotropic hormone therapy, acute responders showed marked suppression of putative ripple propagation network metrics, whereas nonresponders showed reduction in ripple count without comparable reductions in network metrics. Post-treatment total network connection strength and its reduction ratio differentiated acute responders from nonresponders, with areas under the curve (AUC) of 0.902 and 0.899, respectively. In exploratory analyses among acute responders, greater total network connection strength reduction was associated with sustained 6-month spasm freedom, although relapse-related estimates were limited by the small number of events. Conclusion Scalp putative ripple propagation networks provide a noninvasive electrophysiological readout of ACTH-related network modulation in infantile epileptic spasms syndrome. In contrast to ripple count alone, network connection strength captured whether treatment was accompanied by disruption of propagating high-frequency activity. These findings suggest that total NCS and its reduction ratio may serve as candidate markers of adrenocorticotropic hormone-related neuroendocrine–immunomodulatory therapy response, while their relevance to relapse risk requires prospective validation.
2026-06-26 | HMGB1-TLR4 signaling-mediated neuroinflammation contributes to the pathogenesis of infantile epileptic spasms syndrome in rats
Background: Infantile epileptic spasm syndrome (IESS) is a severe age-dependent epileptic encephalopathy in infancy with poor prognosis and unclear pathogenesis. Neuroinflammation plays a pivotal role in epileptogenesis, and the high-mobility group box 1 protein (HMGB1)-Toll-like receptor 4 (TLR4) axis acts as a core mediator of neuroinflammation. However, its specific role in IESS remains elusive. Objective: This study aimed to explore the HMGB1-TLR4-mediated neuroinflammatory mechanism in a rat model of IESS induced by prenatal stress combined with NMDA, and to evaluate the effects of anti-HMGB1 neutralizing antibody and adrenocorticotropic hormone (ACTH) on epileptic seizures and neuroinflammation, so as to provide novel therapeutic targets for clinical practice. Methods: Pregnant Sprague-Dawley rats were randomly divided into prenatal stress (PS) and non-prenatal stress (NPS) groups. PS rats received cold water immersion and hot air drying, while NPS rats were reared normally. On postnatal day 12 (P12), offspring in the PS group were intraperitoneally injected with NMDA to establish the IESS model, and the NPS group was assigned to blank control (BC) and negative control (NC) subgroups. Model rats were randomly divided into ACTH, anti-HMGB1, ACTH+anti-HMGB1, normal saline, and untreated groups. After intervention on P13, NMDA was re-administered, and seizure latency and severity score were recorded. At the end of the experiment, the expression of HMGB1 and TLR4 in brain tissue was detected, HMGB1 co-localization was observed, and the levels of iNOS, Arg1 and cytokines (IL-1β, IL-2R, IL-8, TNF-α) were measured. Results: Prenatal stress combined with NMDA successfully established a stable IESS model in young rats. The expression of HMGB1, TLR4, iNOS, IL-1β, IL-2R, IL-8 and TNF-α was significantly upregulated, while Arg1 was markedly downregulated. Treatment with ACTH, anti-HMGB1, and their combination prolonged seizure latency, reduced seizure severity, downregulated HMGB1 and TLR4 expression, suppressed HMGB1 levels in neurons, astrocytes and activated microglia, inhibited iNOS and proinflammatory cytokines, and promoted Arg1 expression, with the combined intervention showing the optimal efficacy. Conclusion: Prenatal stress combined with NMDA activates the HMGB1/TLR4 pathway and neuroinflammation in IESS rats. ACTH and anti-HMGB1, alone or in combination, alleviate neuroinflammation by inhibiting this pathway to ameliorate IESS, and the combined therapy yields the best therapeutic effect.
2026-01-24 | 'Pseudo-ataxic' negative myoclonic status in developmental and epileptic encephalopathy with spike-wave activation in sleep: Utility of ACTH therapy beyond west syndrome.
Developmental/Epileptic encephalopathy with spike and wave activation in sleep (DEE-SWAS) comprises a spectrum of childhood-onset epilepsies, characterized by near-continuous spike-wave discharges during non-REM sleep which can result in cognitive, behavioral, and motor regression. Negative myoclonic status in the context of DEE-SWAS is extremely rare, and management is difficult as conventional anti-seizure medications (ASM) and immunomodulatory therapies often show limited efficacy. Adrenocorticotropic hormone (ACTH), classically used for infantile spasms, has recently been reported as a potential therapy for refractory DEE-SWAS. We report a 7-year-old girl with prior developmental encephalopathy, who experienced recurrent unprovoked seizures from 5 years of age, followed by progressive ataxia and language regression. Clinical examination revealed facial dysmorphism, truncal and gait ataxia, oral apraxia with atonic head drops. Video EEG revealed background slowing with bilateral centro-parieto-temporal spikes markedly activated in sleep, with clusters of atonic neck and truncal drop seizures suggestive of negative myoclonic status leading to 'pseudo-ataxia'. Despite treatment with multiple ASM, intravenous methylprednisolone and immunoglobulin, there was worsening encephalopathy and anterior opercular syndrome. Given therapeutic refractoriness, ACTH was initiated. The patient showed dramatic improvement: resolution of status, a marked reduction in EEG spike-wave burden, recovery of gait and language to baseline, and restoration of social interaction. This case demonstrates for the first time the potential of ACTH in refractory DEE-SWAS with negative myoclonic status epilepticus, wherein conventional immunomodulation fails. The sustained clinical and electrographic improvement highlights the broader neuro-modulatory mechanisms of ACTH and supports its consideration in treatment algorithms. Larger prospective studies are warranted to compare the efficacy and safety profile of various corticosteroids in DEE.
2025-11-16 | Cardiac safety of low-dose ACTH therapy in infantile spasms: Evidence from electrocardiography and advanced echocardiography.
Infantile epileptic spasms syndrome (IESS) is a catastrophic epileptic encephalopathy of infancy. While adrenocorticotropic hormone (ACTH) remains the most effective first-line therapy, its cardiac safety profile, particularly at low doses, has not been systematically evaluated. This study aimed to investigate the effects of low-dose ACTH therapy on cardiac conduction and function using electrocardiography (ECG) and advanced echocardiography. This prospective controlled study included 24 infants with IESS and 24 age- and sex-matched healthy controls. All patients received low-dose ACTH (Synacthen® Depot, intramuscular; 0.5 mg/kg if < 10 kg, 1 mg/kg if ≥ 10 kg; 18 injections over 8 weeks). Serial 12-lead ECGs and echocardiographic assessments, including M-mode, Doppler, tissue Doppler imaging (TDI), and speckle-tracking strain, were performed at baseline and at 2, 4, and 6 months. Controls underwent single baseline assessments. No patient developed overt arrhythmia or hypertension during treatment. However, ECG analysis revealed progressive prolongation of PR, QRS, QT, QTc, Tp-Te, and Tp-Te-related ratios (p < 0.001). Echocardiography demonstrated significant increases in LVEDD, LVESD, LV mass, and MPI, with impaired diastolic relaxation and progressive deterioration of longitudinal and circumferential strain (p < 0.05). Subgroup analyses showed no significant differences among genetic, hypoxic-ischemic, and hypoxia-related etiologies. Even short-term, low-dose ACTH therapy is associated with subclinical conduction abnormalities and myocardial dysfunction in IESS patients. Routine cardiac monitoring, including advanced imaging modalities, should be integrated into ACTH protocols. Multidisciplinary management and larger multicenter studies are warranted to clarify the long-term cardiovascular implications of ACTH therapy in IESS.
2025-11-01 | The acid-base balance homeostasis reflected by urine pH in children with infantile epileptic spasm syndrome may be associated with response to adrenocorticotropic hormone treatment: a retrospective cohort study
IESS patients should receive first-line treatment immediately after spasm onset. The age of epileptic spasms onset and its etiology may help predict the efficacy of ACTH treatment. Serum inorganic phosphate levels and urinary pH levels seem to play an important role in the treatment of IESS with ACTH, and they may have indicative significance for precision treatment.
small molecules
2026-07-21 | Vigabatrin therapy for infantile epileptic spasms syndrome with periventricular leukomalacia.
Infantile epileptic spasm syndrome (IESS) and periventricular leukomalacia (PVL) cause developmental regression and poor neurological outcomes. The primary treatments for IESS include adrenocorticotropin and vigabatrin; however, no study has yet evaluated the efficacy of vigabatrin for patients with both IESS and PVL. Therefore, we investigated the efficacy and safety of vigabatrin in patients with both disorders. We retrospectively enrolled patients with IESS and PVL who were treated with vigabatrin. We performed ophthalmological examinations and electroretinography (ERG) before and after vigabatrin. Treatment response was defined as complete cessation of epileptic spasms and no other seizures after 3 months of vigabatrin. We investigated the responses to vigabatrin, doses used, and adverse effects. Seven patients (5 males) with IESS and PVL were treated with vigabatrin. The median age at vigabatrin initiation was 10 (range, 7-25) months. Three of the seven patients (42.8%) showed complete clinical cessation of epileptic spasms after 3 months of vigabatrin. The median duration between vigabatrin initiation and epileptic spasm cessation was 5 (range: 3-61) days. The adverse effects included poor feeding (n = 1) and abnormal ERG findings during vigabatrin therapy (n = 2). These ERG findings normalized after vigabatrin was reduced or stopped. No respiratory failure, increased secretion, or somnolence was observed. Vigabatrin was effective for treating 42.8% of our patients with both IESS and PVL. Vigabatrin was well tolerated, with only a mild effect observed in patients with IESS and PVL. Some treatment-related ERG abnormalities were normalized after vigabatrin was reduced or stopped.
2026-06-09 | PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic encephalopathy.
PARS2, encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability. While genetic associations between PARS2 and DEE have been established, the underlying molecular mechanisms remain poorly understood. This study integrates genetic analyses of clinical cases of infantile epileptic spasms syndrome (IESS) with functional assessments in PARS2-deficient animal models and cell models to elucidate these mechanisms. Our findings indicate that PARS2 deficiency disrupts mitochondrial integrity and impairs oxidative phosphorylation, resulting in elevated intracellular calcium levels. This calcium overload activates CaMKK2-AMPK-Drp1 signaling, promoting excessive mitochondrial fission and PINK1-Parkin-mediated mitophagy, ultimately leading to degradation of GPX4 and subsequent ferroptosis. Notably, pharmacological inhibition of Drp1 using Mdivi-1 successfully rescued mitochondrial fragmentation and mitigated ferroptosis. These results unveil a novel calcium-mitophagy-ferroptosis pathway as a crucial mechanism in PARS2-related DEE and propose a potential therapeutic strategy for DEE.
2026-05-20 | Blockade of Corticotropin-Releasing Hormone Receptor 1 Receptors in the Arcuate Nucleus May Effectively Treat Infantile Epileptic Spasms Syndrome
Targeting Corticotropin-Releasing Hormone Receptor 1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy. Chachua T, Yum MS, Chern CR, Vieira K, Velíšková J, Velíšek L. Targeting CRHR1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy. Children (Basel). 2026 Jan 14;13(1):125. doi: 10.3390/children13010125. PMID: 41597133; PMCID: PMC12840083. Background/Objectives: Infantile epileptic spasms syndrome (IESS) is a severe epilepsy of infancy. Corticotropin (ACTH) and vigabatrin are the only FDA-approved therapies. The efficacy of ACTH together with the strong convulsant effects of corticotropin-releasing hormone (CRH) suggests that excess CRH, secondary to impaired ACTH feedback, may contribute to spasms. We therefore hypothesized that CRH receptor 1 (CRHR1) antagonists would suppress spasms in a route- and drug-dependent manner. Methods: Using our validated rat model of IESS, in which prenatal priming with betamethasone was followed by postnatal triggering of spasms with N-methyl-D-aspartic acid (NMDA), we tested two CRHR1 antagonists, CP376395 and SN003, delivered intracranially (via intracerebroventricular or intraparenchymal infusion) or systemically. Results: Intracerebroventricular infusion of both antagonists suppressed spasms, with CP376395 providing more consistent effects. Intraparenchymal administration into the hypothalamic arcuate nucleus also reduced spasms, whereas misses into the mammillary bodies were ineffective, highlighting site specificity. Systemic administration yielded divergent results: SN003 robustly suppressed spasms, whereas CP376395 unexpectedly exacerbated them. No sex differences were observed. Conclusions: These findings demonstrate that CRHR1 blockade modifies experimental spasms in a route- and drug-specific manner and implicates discrete hypothalamic circuits, particularly those including the arcuate nucleus, in spasm generation. The divergent systemic responses between CP376395 and SN003 likely reflect differences in CRHR1 engagement (competitive and non-competitive antagonism, respectively) as well as differences in binding properties that may include differential network interactions beyond local CRH signaling or duration of receptor occupancy. In conclusion, SN003 may be a better option than CP376395 for further development as a CRHR1-targeted therapy pending additional pharmacokinetic/pharmacodynamic studies. Further work should explore dosing paradigms of CP376395 to determine if a therapeutic range for CP376395 exists.
2026-05-18 | Clinical application of HMGB1-TLR4 signaling pathway-mediated neuroinflammatory markers in infantile epileptic spasms syndrome.
Infantile epileptic spasms syndrome (IESS) is a severe age-specific epileptic encephalopathy with unclear pathogenesis, and neuroinflammation is involved in its progression. The HMGB1-TLR4 signaling pathway, a key neuroinflammatory mediator in various epilepsies, has not been studied for its role and clinical biomarker potential in IESS. A retrospective study included 66 IESS patients treated with a modified prednisone regimen and 53 age-matched healthy controls. Serum HMGB1, TLR4, IL-1β, IL-2, IL-2R, IL-8 and TNF-α were detected by ELISA/chemiluminescent immunoassay in IESS patients (pre- and 2-week post-treatment) and controls; clinical data were collected via electronic medical records and follow-up. IESS patients had significantly higher serum HMGB1, TLR4, IL-2, IL-2R, IL-8 and TNF-α than controls (P < 0.05; no IL-1β difference, P>0.05), and these elevated indicators decreased markedly post-treatment (P < 0.05). Logistic regression showed identified etiology and focal seizures were risk factors for short-term prednisone ineffectiveness, while ΔPre-Post HMGB1 was a protective factor (P < 0.05). Long-term follow-up (≥18 months) found identified etiology to be a risk factor for uncontrolled epilepsy and poor neurodevelopment (P < 0.05); early spasm remission and long-term seizure control were protective factors for neurodevelopment (P < 0.05). The HMGB1-TLR4 pathway mediates neuroinflammation in IESS pathogenesis and may serve as a therapeutic target. A high ΔPre-Post HMGB1 level was identified as a protective factor against short-term treatment failure of prednisone, indicating that dynamic monitoring of HMGB1 has clinical value for predicting short-term treatment responses to prednisone, though it does not predict long-term seizure control or neurodevelopmental outcomes. Identified etiology is a common risk factor for poor IESS outcomes, highlighting the importance of early etiological screening and sustained seizure control for IESS management.
2026-05-12 | Fast sleep spindles as a potential prognostic marker of developmental outcome in infantile epileptic spasms syndrome
OBJECTIVE: The presence or absence of sleep spindles in patients with infantile epileptic spasms syndrome (IESS) has been proposed as a potential predictor of cognitive outcome; however, the validity of this predictor remains uncertain. This study aimed to establish the utility of sleep spindle characteristics as prognostic markers of developmental outcomes in patients with IESS. METHODS: We retrospectively analyzed 26 patients with IESS who underwent longitudinal electroencephalography (465 recordings) to assess the presence, frequency, duration, and location of spindles. Patients were divided into two groups based on their developmental outcomes. The good outcome group consisted of patients with a developmental quotient (DQ) of ≥50, whereas the poor outcome group comprised patients with a DQ of <50. We compared the clinical and spindle characteristics between these two groups. RESULTS: The good and poor outcome groups comprised 11 and 15 patients, respectively. In the univariate analysis, known etiology, developmental delay (DQ < 70) at spasm onset, and the absence of fast spindles (≥13 Hz) within 3 months after spasm onset were significantly more common in the poor outcome group than in the good outcome group. Multivariate Firth logistic regression analysis showed that only the absence of fast spindles within 3 months after spasm onset was significantly associated with poor developmental outcomes. SIGNIFICANCE: The absence of fast sleep spindles may be a valuable predictor of developmental outcomes in IESS compared with the established developmental prognostic factors reported by previous studies. Our results show the importance of the early organization of fast spindles to obtain favorable developmental outcomes in patients with IESS. PLAIN LANGUAGE SUMMARY: We studied electroencephalography during sleep in 26 children with infantile epileptic spasms syndrome (IESS) to see if certain patterns, called sleep spindles, relate to later development. Children who did not show fast sleep spindles (≥13 Hz) within 3 months after spasm onset were more likely to have poor developmental outcomes. This finding suggests that the early appearance of fast sleep spindles may be an important marker of better brain development in children with IESS.
antibodies
2026-04-01 | XLID-Infantile Spasms ( See also ARX -Associated XLID)
Abstract XLID with infantile spasms and hypsarrhythmia. Mutations in ARX have also been found in a spectrum of XLID entities, including X-Linked Lissencephaly with Abnormal Genitalia, Partington syndrome and Nonsyndromal XLID.
2025-08-11 | A zebrafish model unravels the role of PHF21A in neurodevelopment and epilepsy.
The PHF21A gene encodes the protein BRAF histone deacetylase complex 80 (BHC80), which is primarily expressed in the human brain and essential for neurodevelopment and seizures. However, the implications of PHF21A variants in human disease pathogenesis have yet to be fully elucidated. Whole-exon sequencing was performed on three patients with PHF21A variants. The associated phenotype was validated using a phf21ab-knockout zebrafish model generated via CRISPR/Cas9 technology. Three patients exhibited de novo PHF21A pathogenic variants associated with infantile epileptic spasm syndrome (IESS). Notably, developmental delay was evident in all cases prior to seizure onset. One patient presented with comorbid autism spectrum disorder (ASD) and macrocephaly. Brain MRI of two patients showed widening of the frontotemporal subarachnoid space and ventriculomegaly. Following therapeutic intervention, two patients achieved seizure remission. To further elucidate the functional consequences of PHF21A deficiency, we conducted comprehensive morphological, behavioral, and electrophysiological analyses in phf21ab-knockout zebrafish model. Compared with the cas9 control group, compared with the Cas9 control group, the phf21ab knockout group exhibited significant reductions in the area of the forebrain, midbrain, and whole brain. Electrophysiological assessments revealed epileptiform discharges in 6 of 25 phf21ab-knockout zebrafish. These findings collectively suggest that PHF21A pathogenic variants exert substantial impacts on neurodevelopment and seizure disorders. The observed neuroanatomical alterations and epileptogenic activity in the zebrafish model reveal an important role of PHF21A in neurodevelopment and epilepsy.
2025-07-29 | TUBA1A-related tubulinopathy associated with the infantile epileptic spasms syndrome and atypical absence seizures.
Patients with TUBA1A pathogenic variants may present with complex brain malformation, intellectual disability, and epilepsy. The epilepsy phenotype is varied, ranging from mild to severe, with epileptic spasms and focal seizures being the most common seizure types. We report on an infant with a TUBA1A variant presenting with an evolving epileptic encephalopathy. Initially, this patient presented with infantile epileptic spasms syndrome, with the eventual appearance of atypical absence seizures before the age of 1 year. We discuss the initial diagnostic uncertainty that was raised by the finding of early onset absence epilepsy and review the other TUBA1A-related seizure types reported in the literature.
2025-04-07 | Unraveling Infantile Epileptic Spasms in the Context of Primary Mitochondrial Disease (P2-6.004)
To elucidate presentation of infantile epileptic spasms syndrome (IESS) in primary mitochondrial disease (PMD)
2024-10-14 | An Unusual Presentation of Infantile Epileptic Spasm Syndrome in a Child
Cite this article as: Yıldırım M, Özkara KA, Çiçek S, Bektaş Ö, Teber S. An unusual presentation of infantile epileptic spasm syndrome in a child. Turk Arch Pediatr. 2024;59(6):603-604.
gene therapies
2025-12-21 | Dual developmental effects of ARX poly-alanine mutations on human cortical excitatory and inhibitory neurons.
Infantile spasms (IS), a severe childhood epilepsy with an incidence of 1.6-4.5 per 10,000 live births, often lead to lifelong intellectual disability. Up to 5% of affected males carry mutations in the Aristaless-related homeobox (ARX) gene. The lack of human-specific models for developmental epilepsy limits progress, making organoids a promising alternative. We use human cortical organoids (COs) and ganglionic eminence organoids (GEOs) to model poly-alanine expansion (PAE) mutations in ARX. PAE mutations increase cortical progenitor proliferation and accelerate early cortical development. ARX expression is upregulated in patient-derived COs at 30 days in vitro (DIV), correlating with altered cell cycle gene expression. We observe enhanced, cell-autonomous interneuron migration, which is rescued by CXCR4 inhibition. ARXPAE assembloids exhibit early network hyperactivity. These findings highlight the utility of human brain organoids in uncovering ARXPAE-driven mechanisms and represent a critical step toward developing targeted therapies for IS and related developmental epilepsies.
2024-07-18 | The Utility of Genetic Testing in Infantile Epileptic Spasms Syndrome: A Step-Based Approach in the Next-Generation Sequencing Era.
To evaluate the utility of genetic testing for etiology-specific diagnosis (ESD) in infantile epileptic spasms syndrome (IESS) with a step-based diagnostic approach in the next-generation sequencing (NGS) era. The study cohort consisted of 314 patients with IESS, followed by the Pediatric Neurology Division of Ege University Hospital between 2005 and 2021. The ESD was evaluated using a step-based approach: step I (clinical phenomenology), step II (neuroimaging), step III (metabolic screening), and step IV (genetic testing). The diagnostic utility of genetic testing was evaluated to compare the early-NGS period (2005 to 2013, n = 183) and the NGS era (2014 to 2021, n = 131). An ESD was established in 221 of 314 (70.4%) infants with IESS: structural, 40.8%; genetic, 17.2%; metabolic, 8.3%; immune-infectious, 4.1%. The diagnostic yield of genetic testing increased from 8.9% to 41.7% in the cohort during the four follow-up periods. The rate of unknown etiology decreased from 34.9% to 22.1% during the follow-up periods. The genetic ESD was established as 27.4% with genetic testing in the NGS era. The genetic testing in the NGS era increased dramatically in subgroups with unknown and structural etiologies. The diagnostic yields of the epilepsy panels increased from 7.6% to 19.2%. However, the diagnostic yield of whole exome sequencing remained at similar levels during the early-NGS period at 54.5% and in the NGS era at 59%. The more genetic ESD (27.4%) was defined for IESS in the NGS era with the implication of precision therapy (37.7%).
2024-06-20 | ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.
The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
2024-04-25 | Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective.
CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype–phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.
2021-05-14 | West syndrome: a comprehensive review.
Since its first clinical description (on his son) by William James West (1793-1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2) hypsarrhythmia, and (3) developmental arrest or regression as "West syndrome", new and relevant advances have been recorded in this uncommon disorder. New approaches include terminology of clinical spasms (e.g., infantile (IS) vs. epileptic spasms (ES)), variety of clinical and electroencephalographic (EEG) features (e.g., typical ictal phenomena without EEG abnormalities), burden of developmental delay, spectrum of associated genetic abnormalities, pathogenesis, treatment options, and related outcome and prognosis. Aside the classical manifestations, IS or ES may present with atypical electroclinical phenotypes (e.g., subtle spasms; modified hypsarrhythmia) and may have their onset outside infancy. An increasing number of genes, proteins, and signaling pathways play crucial roles in the pathogenesis. This condition is currently regarded as a spectrum of disorders: the so-called infantile spasm syndrome (ISs), in association with other causal factors, including structural, infectious, metabolic, syndromic, and immunologic events, all acting on a genetic predisposing background. Hormonal therapy and ketogenic diet are widely used also in combination with (classical and recent) pharmacological drugs. Biologically targeted and gene therapies are increasingly studied. The present narrative review searched in seven electronic databases (primary MeSH terms/keywords included West syndrome, infantile spasms and infantile spasms syndrome and were coupled to 25 secondary clinical, EEG, therapeutic, outcomes, and associated conditions terms) including MEDLINE, Embase, Cochrane Central, Web of Sciences, Pubmed, Scopus, and OMIM to highlight the past knowledge and more recent advances.
other
2026-03-30 | DTaP-induced infantile epileptic spasms syndrome high-risk window: Insights from school-age children.
To determine the specific high-risk characteristics and temporal window associated with Diphtheria, Tetanus, and acellular Pertussis (DTaP) vaccine-precipitated infantile epileptic spasms syndrome (IESS), providing evidence for optimizing vaccination safety strategies, we conducted a multicenter retrospective cohort study of 564 patients with long-term follow-up (6.5-10.5 y). Patients were stratified by seizure onset interval into Vaccination-proximate (≤72 hours) and distant (>72 hours) groups. The proximate group (n = 53, 9.4%) exhibited a significantly younger age distribution (median [IQR]: 5.0 [3.0-6.0] vs. 5.0 [4.0-7.0] months, p = .04) and higher DTaP exposure (71.7% vs. 51.3%). Multivariable logistic regression in an etiologically analytic cohort (n = 541) identified the DTaP primary series as a significant independent precipitant for rapid onset (Dose 1: OR = 4.00; Doses 2 & 3: OR = 4.67) compared to other inactivated vaccines. Crucially, no increased risk was observed for the DTaP booster (Dose 4) or non-DTaP inactivated vaccines. Kaplan-Meier analysis confirmed a steep rise in seizure incidence within 72 hours post-primary DTaP. Long-term follow-up revealed no significant differences in all-cause mortality, seizure remission, or educational placement (p > .05) between groups, indicating that vaccination merely precipitated disease onset without altering the etiology-determined prognosis. This study, based on the full-course observation of school-aged children, is the first to validate the specificity of the DTaP-IESS association. The DTaP primary series is a critical precipitating factor for rapid onset (≤72 hours) in infants with underlying epileptogenic susceptibility. We recommend a stratified immunization strategy for high-risk infants: adhering to schedules for non-DTaP vaccines while adopting a prudent "delay-but-not-refuse" approach for DTaP to balance neurological safety with herd immunity.
1984-10-10 | Pyretotherapy as treatment in West's syndrome.
Four cases of West's syndrome (generalized myoclonic spasms, arrest of psychomotor development and hypsarrhythmia) which were found to be resistant to the classical treatment (ACTH, prednisone, nitrazepam, clonazepam, etc.) are reported. In these cases, high fever (pyretotherapy) induced by TBA vaccine (typhoid and paratyphoid) was used. Within the next eight days following treatment with pyretotherapy, the clinical conditions of these children showed a gradual decrease of generalized myoclonic spasms and an improvement of their mental and neurological status. The follow-up electroencephalograms showed cessation of the hypsarrhythmia. The study of these cases and their electro-clinical correlates suggests that pyretotherapy is a useful procedure in this extremely disabling condition.
proteins
2026-08-10 | Electrophysiological readout of ACTH-related neuroendocrine–immunomodulatory treatment response in infantile epileptic spasms syndrome: suppression of scalp ripple propagation networks
Background Adrenocorticotropic hormone (ACTH) is a first-line neuroendocrine–immunomodulatory therapy for infantile epileptic spasms syndrome (IESS), but noninvasive electrophysiological markers that objectively reflect treatment-related network changes remain limited. We investigated whether scalp putative ripple propagation network metrics provide markers of adrenocorticotropic hormone-related network response and early relapse risk. Methods In this retrospective multicenter study, children receiving first-time ACTH therapy were included if paired pre- and post-treatment scalp electroencephalography (EEG) recordings and at least 6 months of follow-up were available. Five-minute artifact-free interictal slow-wave-sleep segments were analyzed. Putative ripple propagation networks were constructed using a time-delay-based method. The primary metrics were post-treatment total network connection strength (total NCS) and its reduction ratio, with ripple count and ripple-count reduction ratio used as rate-based comparators. Results Sixty-one children were included; 27 achieved acute spasm freedom, and seven of these relapsed within 6 months. Baseline ripple count and network metrics did not distinguish subsequent responders from nonresponders. After adrenocorticotropic hormone therapy, acute responders showed marked suppression of putative ripple propagation network metrics, whereas nonresponders showed reduction in ripple count without comparable reductions in network metrics. Post-treatment total network connection strength and its reduction ratio differentiated acute responders from nonresponders, with areas under the curve (AUC) of 0.902 and 0.899, respectively. In exploratory analyses among acute responders, greater total network connection strength reduction was associated with sustained 6-month spasm freedom, although relapse-related estimates were limited by the small number of events. Conclusion Scalp putative ripple propagation networks provide a noninvasive electrophysiological readout of ACTH-related network modulation in infantile epileptic spasms syndrome. In contrast to ripple count alone, network connection strength captured whether treatment was accompanied by disruption of propagating high-frequency activity. These findings suggest that total NCS and its reduction ratio may serve as candidate markers of adrenocorticotropic hormone-related neuroendocrine–immunomodulatory therapy response, while their relevance to relapse risk requires prospective validation.
2026-06-26 | HMGB1-TLR4 signaling-mediated neuroinflammation contributes to the pathogenesis of infantile epileptic spasms syndrome in rats
Background: Infantile epileptic spasm syndrome (IESS) is a severe age-dependent epileptic encephalopathy in infancy with poor prognosis and unclear pathogenesis. Neuroinflammation plays a pivotal role in epileptogenesis, and the high-mobility group box 1 protein (HMGB1)-Toll-like receptor 4 (TLR4) axis acts as a core mediator of neuroinflammation. However, its specific role in IESS remains elusive. Objective: This study aimed to explore the HMGB1-TLR4-mediated neuroinflammatory mechanism in a rat model of IESS induced by prenatal stress combined with NMDA, and to evaluate the effects of anti-HMGB1 neutralizing antibody and adrenocorticotropic hormone (ACTH) on epileptic seizures and neuroinflammation, so as to provide novel therapeutic targets for clinical practice. Methods: Pregnant Sprague-Dawley rats were randomly divided into prenatal stress (PS) and non-prenatal stress (NPS) groups. PS rats received cold water immersion and hot air drying, while NPS rats were reared normally. On postnatal day 12 (P12), offspring in the PS group were intraperitoneally injected with NMDA to establish the IESS model, and the NPS group was assigned to blank control (BC) and negative control (NC) subgroups. Model rats were randomly divided into ACTH, anti-HMGB1, ACTH+anti-HMGB1, normal saline, and untreated groups. After intervention on P13, NMDA was re-administered, and seizure latency and severity score were recorded. At the end of the experiment, the expression of HMGB1 and TLR4 in brain tissue was detected, HMGB1 co-localization was observed, and the levels of iNOS, Arg1 and cytokines (IL-1β, IL-2R, IL-8, TNF-α) were measured. Results: Prenatal stress combined with NMDA successfully established a stable IESS model in young rats. The expression of HMGB1, TLR4, iNOS, IL-1β, IL-2R, IL-8 and TNF-α was significantly upregulated, while Arg1 was markedly downregulated. Treatment with ACTH, anti-HMGB1, and their combination prolonged seizure latency, reduced seizure severity, downregulated HMGB1 and TLR4 expression, suppressed HMGB1 levels in neurons, astrocytes and activated microglia, inhibited iNOS and proinflammatory cytokines, and promoted Arg1 expression, with the combined intervention showing the optimal efficacy. Conclusion: Prenatal stress combined with NMDA activates the HMGB1/TLR4 pathway and neuroinflammation in IESS rats. ACTH and anti-HMGB1, alone or in combination, alleviate neuroinflammation by inhibiting this pathway to ameliorate IESS, and the combined therapy yields the best therapeutic effect.
2026-01-24 | 'Pseudo-ataxic' negative myoclonic status in developmental and epileptic encephalopathy with spike-wave activation in sleep: Utility of ACTH therapy beyond west syndrome.
Developmental/Epileptic encephalopathy with spike and wave activation in sleep (DEE-SWAS) comprises a spectrum of childhood-onset epilepsies, characterized by near-continuous spike-wave discharges during non-REM sleep which can result in cognitive, behavioral, and motor regression. Negative myoclonic status in the context of DEE-SWAS is extremely rare, and management is difficult as conventional anti-seizure medications (ASM) and immunomodulatory therapies often show limited efficacy. Adrenocorticotropic hormone (ACTH), classically used for infantile spasms, has recently been reported as a potential therapy for refractory DEE-SWAS. We report a 7-year-old girl with prior developmental encephalopathy, who experienced recurrent unprovoked seizures from 5 years of age, followed by progressive ataxia and language regression. Clinical examination revealed facial dysmorphism, truncal and gait ataxia, oral apraxia with atonic head drops. Video EEG revealed background slowing with bilateral centro-parieto-temporal spikes markedly activated in sleep, with clusters of atonic neck and truncal drop seizures suggestive of negative myoclonic status leading to 'pseudo-ataxia'. Despite treatment with multiple ASM, intravenous methylprednisolone and immunoglobulin, there was worsening encephalopathy and anterior opercular syndrome. Given therapeutic refractoriness, ACTH was initiated. The patient showed dramatic improvement: resolution of status, a marked reduction in EEG spike-wave burden, recovery of gait and language to baseline, and restoration of social interaction. This case demonstrates for the first time the potential of ACTH in refractory DEE-SWAS with negative myoclonic status epilepticus, wherein conventional immunomodulation fails. The sustained clinical and electrographic improvement highlights the broader neuro-modulatory mechanisms of ACTH and supports its consideration in treatment algorithms. Larger prospective studies are warranted to compare the efficacy and safety profile of various corticosteroids in DEE.
2025-11-16 | Cardiac safety of low-dose ACTH therapy in infantile spasms: Evidence from electrocardiography and advanced echocardiography.
Infantile epileptic spasms syndrome (IESS) is a catastrophic epileptic encephalopathy of infancy. While adrenocorticotropic hormone (ACTH) remains the most effective first-line therapy, its cardiac safety profile, particularly at low doses, has not been systematically evaluated. This study aimed to investigate the effects of low-dose ACTH therapy on cardiac conduction and function using electrocardiography (ECG) and advanced echocardiography. This prospective controlled study included 24 infants with IESS and 24 age- and sex-matched healthy controls. All patients received low-dose ACTH (Synacthen® Depot, intramuscular; 0.5 mg/kg if < 10 kg, 1 mg/kg if ≥ 10 kg; 18 injections over 8 weeks). Serial 12-lead ECGs and echocardiographic assessments, including M-mode, Doppler, tissue Doppler imaging (TDI), and speckle-tracking strain, were performed at baseline and at 2, 4, and 6 months. Controls underwent single baseline assessments. No patient developed overt arrhythmia or hypertension during treatment. However, ECG analysis revealed progressive prolongation of PR, QRS, QT, QTc, Tp-Te, and Tp-Te-related ratios (p < 0.001). Echocardiography demonstrated significant increases in LVEDD, LVESD, LV mass, and MPI, with impaired diastolic relaxation and progressive deterioration of longitudinal and circumferential strain (p < 0.05). Subgroup analyses showed no significant differences among genetic, hypoxic-ischemic, and hypoxia-related etiologies. Even short-term, low-dose ACTH therapy is associated with subclinical conduction abnormalities and myocardial dysfunction in IESS patients. Routine cardiac monitoring, including advanced imaging modalities, should be integrated into ACTH protocols. Multidisciplinary management and larger multicenter studies are warranted to clarify the long-term cardiovascular implications of ACTH therapy in IESS.
2025-11-01 | The acid-base balance homeostasis reflected by urine pH in children with infantile epileptic spasm syndrome may be associated with response to adrenocorticotropic hormone treatment: a retrospective cohort study
IESS patients should receive first-line treatment immediately after spasm onset. The age of epileptic spasms onset and its etiology may help predict the efficacy of ACTH treatment. Serum inorganic phosphate levels and urinary pH levels seem to play an important role in the treatment of IESS with ACTH, and they may have indicative significance for precision treatment.
small molecules
2026-07-21 | Vigabatrin therapy for infantile epileptic spasms syndrome with periventricular leukomalacia.
Infantile epileptic spasm syndrome (IESS) and periventricular leukomalacia (PVL) cause developmental regression and poor neurological outcomes. The primary treatments for IESS include adrenocorticotropin and vigabatrin; however, no study has yet evaluated the efficacy of vigabatrin for patients with both IESS and PVL. Therefore, we investigated the efficacy and safety of vigabatrin in patients with both disorders. We retrospectively enrolled patients with IESS and PVL who were treated with vigabatrin. We performed ophthalmological examinations and electroretinography (ERG) before and after vigabatrin. Treatment response was defined as complete cessation of epileptic spasms and no other seizures after 3 months of vigabatrin. We investigated the responses to vigabatrin, doses used, and adverse effects. Seven patients (5 males) with IESS and PVL were treated with vigabatrin. The median age at vigabatrin initiation was 10 (range, 7-25) months. Three of the seven patients (42.8%) showed complete clinical cessation of epileptic spasms after 3 months of vigabatrin. The median duration between vigabatrin initiation and epileptic spasm cessation was 5 (range: 3-61) days. The adverse effects included poor feeding (n = 1) and abnormal ERG findings during vigabatrin therapy (n = 2). These ERG findings normalized after vigabatrin was reduced or stopped. No respiratory failure, increased secretion, or somnolence was observed. Vigabatrin was effective for treating 42.8% of our patients with both IESS and PVL. Vigabatrin was well tolerated, with only a mild effect observed in patients with IESS and PVL. Some treatment-related ERG abnormalities were normalized after vigabatrin was reduced or stopped.
2026-06-09 | PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic encephalopathy.
PARS2, encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability. While genetic associations between PARS2 and DEE have been established, the underlying molecular mechanisms remain poorly understood. This study integrates genetic analyses of clinical cases of infantile epileptic spasms syndrome (IESS) with functional assessments in PARS2-deficient animal models and cell models to elucidate these mechanisms. Our findings indicate that PARS2 deficiency disrupts mitochondrial integrity and impairs oxidative phosphorylation, resulting in elevated intracellular calcium levels. This calcium overload activates CaMKK2-AMPK-Drp1 signaling, promoting excessive mitochondrial fission and PINK1-Parkin-mediated mitophagy, ultimately leading to degradation of GPX4 and subsequent ferroptosis. Notably, pharmacological inhibition of Drp1 using Mdivi-1 successfully rescued mitochondrial fragmentation and mitigated ferroptosis. These results unveil a novel calcium-mitophagy-ferroptosis pathway as a crucial mechanism in PARS2-related DEE and propose a potential therapeutic strategy for DEE.
2026-05-20 | Blockade of Corticotropin-Releasing Hormone Receptor 1 Receptors in the Arcuate Nucleus May Effectively Treat Infantile Epileptic Spasms Syndrome
Targeting Corticotropin-Releasing Hormone Receptor 1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy. Chachua T, Yum MS, Chern CR, Vieira K, Velíšková J, Velíšek L. Targeting CRHR1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy. Children (Basel). 2026 Jan 14;13(1):125. doi: 10.3390/children13010125. PMID: 41597133; PMCID: PMC12840083. Background/Objectives: Infantile epileptic spasms syndrome (IESS) is a severe epilepsy of infancy. Corticotropin (ACTH) and vigabatrin are the only FDA-approved therapies. The efficacy of ACTH together with the strong convulsant effects of corticotropin-releasing hormone (CRH) suggests that excess CRH, secondary to impaired ACTH feedback, may contribute to spasms. We therefore hypothesized that CRH receptor 1 (CRHR1) antagonists would suppress spasms in a route- and drug-dependent manner. Methods: Using our validated rat model of IESS, in which prenatal priming with betamethasone was followed by postnatal triggering of spasms with N-methyl-D-aspartic acid (NMDA), we tested two CRHR1 antagonists, CP376395 and SN003, delivered intracranially (via intracerebroventricular or intraparenchymal infusion) or systemically. Results: Intracerebroventricular infusion of both antagonists suppressed spasms, with CP376395 providing more consistent effects. Intraparenchymal administration into the hypothalamic arcuate nucleus also reduced spasms, whereas misses into the mammillary bodies were ineffective, highlighting site specificity. Systemic administration yielded divergent results: SN003 robustly suppressed spasms, whereas CP376395 unexpectedly exacerbated them. No sex differences were observed. Conclusions: These findings demonstrate that CRHR1 blockade modifies experimental spasms in a route- and drug-specific manner and implicates discrete hypothalamic circuits, particularly those including the arcuate nucleus, in spasm generation. The divergent systemic responses between CP376395 and SN003 likely reflect differences in CRHR1 engagement (competitive and non-competitive antagonism, respectively) as well as differences in binding properties that may include differential network interactions beyond local CRH signaling or duration of receptor occupancy. In conclusion, SN003 may be a better option than CP376395 for further development as a CRHR1-targeted therapy pending additional pharmacokinetic/pharmacodynamic studies. Further work should explore dosing paradigms of CP376395 to determine if a therapeutic range for CP376395 exists.
2026-05-18 | Clinical application of HMGB1-TLR4 signaling pathway-mediated neuroinflammatory markers in infantile epileptic spasms syndrome.
Infantile epileptic spasms syndrome (IESS) is a severe age-specific epileptic encephalopathy with unclear pathogenesis, and neuroinflammation is involved in its progression. The HMGB1-TLR4 signaling pathway, a key neuroinflammatory mediator in various epilepsies, has not been studied for its role and clinical biomarker potential in IESS. A retrospective study included 66 IESS patients treated with a modified prednisone regimen and 53 age-matched healthy controls. Serum HMGB1, TLR4, IL-1β, IL-2, IL-2R, IL-8 and TNF-α were detected by ELISA/chemiluminescent immunoassay in IESS patients (pre- and 2-week post-treatment) and controls; clinical data were collected via electronic medical records and follow-up. IESS patients had significantly higher serum HMGB1, TLR4, IL-2, IL-2R, IL-8 and TNF-α than controls (P < 0.05; no IL-1β difference, P>0.05), and these elevated indicators decreased markedly post-treatment (P < 0.05). Logistic regression showed identified etiology and focal seizures were risk factors for short-term prednisone ineffectiveness, while ΔPre-Post HMGB1 was a protective factor (P < 0.05). Long-term follow-up (≥18 months) found identified etiology to be a risk factor for uncontrolled epilepsy and poor neurodevelopment (P < 0.05); early spasm remission and long-term seizure control were protective factors for neurodevelopment (P < 0.05). The HMGB1-TLR4 pathway mediates neuroinflammation in IESS pathogenesis and may serve as a therapeutic target. A high ΔPre-Post HMGB1 level was identified as a protective factor against short-term treatment failure of prednisone, indicating that dynamic monitoring of HMGB1 has clinical value for predicting short-term treatment responses to prednisone, though it does not predict long-term seizure control or neurodevelopmental outcomes. Identified etiology is a common risk factor for poor IESS outcomes, highlighting the importance of early etiological screening and sustained seizure control for IESS management.
2026-05-12 | Fast sleep spindles as a potential prognostic marker of developmental outcome in infantile epileptic spasms syndrome
OBJECTIVE: The presence or absence of sleep spindles in patients with infantile epileptic spasms syndrome (IESS) has been proposed as a potential predictor of cognitive outcome; however, the validity of this predictor remains uncertain. This study aimed to establish the utility of sleep spindle characteristics as prognostic markers of developmental outcomes in patients with IESS. METHODS: We retrospectively analyzed 26 patients with IESS who underwent longitudinal electroencephalography (465 recordings) to assess the presence, frequency, duration, and location of spindles. Patients were divided into two groups based on their developmental outcomes. The good outcome group consisted of patients with a developmental quotient (DQ) of ≥50, whereas the poor outcome group comprised patients with a DQ of <50. We compared the clinical and spindle characteristics between these two groups. RESULTS: The good and poor outcome groups comprised 11 and 15 patients, respectively. In the univariate analysis, known etiology, developmental delay (DQ < 70) at spasm onset, and the absence of fast spindles (≥13 Hz) within 3 months after spasm onset were significantly more common in the poor outcome group than in the good outcome group. Multivariate Firth logistic regression analysis showed that only the absence of fast spindles within 3 months after spasm onset was significantly associated with poor developmental outcomes. SIGNIFICANCE: The absence of fast sleep spindles may be a valuable predictor of developmental outcomes in IESS compared with the established developmental prognostic factors reported by previous studies. Our results show the importance of the early organization of fast spindles to obtain favorable developmental outcomes in patients with IESS. PLAIN LANGUAGE SUMMARY: We studied electroencephalography during sleep in 26 children with infantile epileptic spasms syndrome (IESS) to see if certain patterns, called sleep spindles, relate to later development. Children who did not show fast sleep spindles (≥13 Hz) within 3 months after spasm onset were more likely to have poor developmental outcomes. This finding suggests that the early appearance of fast sleep spindles may be an important marker of better brain development in children with IESS.
antibodies
2026-04-01 | XLID-Infantile Spasms ( See also ARX -Associated XLID)
Abstract XLID with infantile spasms and hypsarrhythmia. Mutations in ARX have also been found in a spectrum of XLID entities, including X-Linked Lissencephaly with Abnormal Genitalia, Partington syndrome and Nonsyndromal XLID.
2025-08-11 | A zebrafish model unravels the role of PHF21A in neurodevelopment and epilepsy.
The PHF21A gene encodes the protein BRAF histone deacetylase complex 80 (BHC80), which is primarily expressed in the human brain and essential for neurodevelopment and seizures. However, the implications of PHF21A variants in human disease pathogenesis have yet to be fully elucidated. Whole-exon sequencing was performed on three patients with PHF21A variants. The associated phenotype was validated using a phf21ab-knockout zebrafish model generated via CRISPR/Cas9 technology. Three patients exhibited de novo PHF21A pathogenic variants associated with infantile epileptic spasm syndrome (IESS). Notably, developmental delay was evident in all cases prior to seizure onset. One patient presented with comorbid autism spectrum disorder (ASD) and macrocephaly. Brain MRI of two patients showed widening of the frontotemporal subarachnoid space and ventriculomegaly. Following therapeutic intervention, two patients achieved seizure remission. To further elucidate the functional consequences of PHF21A deficiency, we conducted comprehensive morphological, behavioral, and electrophysiological analyses in phf21ab-knockout zebrafish model. Compared with the cas9 control group, compared with the Cas9 control group, the phf21ab knockout group exhibited significant reductions in the area of the forebrain, midbrain, and whole brain. Electrophysiological assessments revealed epileptiform discharges in 6 of 25 phf21ab-knockout zebrafish. These findings collectively suggest that PHF21A pathogenic variants exert substantial impacts on neurodevelopment and seizure disorders. The observed neuroanatomical alterations and epileptogenic activity in the zebrafish model reveal an important role of PHF21A in neurodevelopment and epilepsy.
2025-07-29 | TUBA1A-related tubulinopathy associated with the infantile epileptic spasms syndrome and atypical absence seizures.
Patients with TUBA1A pathogenic variants may present with complex brain malformation, intellectual disability, and epilepsy. The epilepsy phenotype is varied, ranging from mild to severe, with epileptic spasms and focal seizures being the most common seizure types. We report on an infant with a TUBA1A variant presenting with an evolving epileptic encephalopathy. Initially, this patient presented with infantile epileptic spasms syndrome, with the eventual appearance of atypical absence seizures before the age of 1 year. We discuss the initial diagnostic uncertainty that was raised by the finding of early onset absence epilepsy and review the other TUBA1A-related seizure types reported in the literature.
2025-04-07 | Unraveling Infantile Epileptic Spasms in the Context of Primary Mitochondrial Disease (P2-6.004)
To elucidate presentation of infantile epileptic spasms syndrome (IESS) in primary mitochondrial disease (PMD)
2024-10-14 | An Unusual Presentation of Infantile Epileptic Spasm Syndrome in a Child
Cite this article as: Yıldırım M, Özkara KA, Çiçek S, Bektaş Ö, Teber S. An unusual presentation of infantile epileptic spasm syndrome in a child. Turk Arch Pediatr. 2024;59(6):603-604.
gene therapies
2025-12-21 | Dual developmental effects of ARX poly-alanine mutations on human cortical excitatory and inhibitory neurons.
Infantile spasms (IS), a severe childhood epilepsy with an incidence of 1.6-4.5 per 10,000 live births, often lead to lifelong intellectual disability. Up to 5% of affected males carry mutations in the Aristaless-related homeobox (ARX) gene. The lack of human-specific models for developmental epilepsy limits progress, making organoids a promising alternative. We use human cortical organoids (COs) and ganglionic eminence organoids (GEOs) to model poly-alanine expansion (PAE) mutations in ARX. PAE mutations increase cortical progenitor proliferation and accelerate early cortical development. ARX expression is upregulated in patient-derived COs at 30 days in vitro (DIV), correlating with altered cell cycle gene expression. We observe enhanced, cell-autonomous interneuron migration, which is rescued by CXCR4 inhibition. ARXPAE assembloids exhibit early network hyperactivity. These findings highlight the utility of human brain organoids in uncovering ARXPAE-driven mechanisms and represent a critical step toward developing targeted therapies for IS and related developmental epilepsies.
2024-07-18 | The Utility of Genetic Testing in Infantile Epileptic Spasms Syndrome: A Step-Based Approach in the Next-Generation Sequencing Era.
To evaluate the utility of genetic testing for etiology-specific diagnosis (ESD) in infantile epileptic spasms syndrome (IESS) with a step-based diagnostic approach in the next-generation sequencing (NGS) era. The study cohort consisted of 314 patients with IESS, followed by the Pediatric Neurology Division of Ege University Hospital between 2005 and 2021. The ESD was evaluated using a step-based approach: step I (clinical phenomenology), step II (neuroimaging), step III (metabolic screening), and step IV (genetic testing). The diagnostic utility of genetic testing was evaluated to compare the early-NGS period (2005 to 2013, n = 183) and the NGS era (2014 to 2021, n = 131). An ESD was established in 221 of 314 (70.4%) infants with IESS: structural, 40.8%; genetic, 17.2%; metabolic, 8.3%; immune-infectious, 4.1%. The diagnostic yield of genetic testing increased from 8.9% to 41.7% in the cohort during the four follow-up periods. The rate of unknown etiology decreased from 34.9% to 22.1% during the follow-up periods. The genetic ESD was established as 27.4% with genetic testing in the NGS era. The genetic testing in the NGS era increased dramatically in subgroups with unknown and structural etiologies. The diagnostic yields of the epilepsy panels increased from 7.6% to 19.2%. However, the diagnostic yield of whole exome sequencing remained at similar levels during the early-NGS period at 54.5% and in the NGS era at 59%. The more genetic ESD (27.4%) was defined for IESS in the NGS era with the implication of precision therapy (37.7%).
2024-06-20 | ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.
The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
2024-04-25 | Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective.
CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype–phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.
2021-05-14 | West syndrome: a comprehensive review.
Since its first clinical description (on his son) by William James West (1793-1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2) hypsarrhythmia, and (3) developmental arrest or regression as "West syndrome", new and relevant advances have been recorded in this uncommon disorder. New approaches include terminology of clinical spasms (e.g., infantile (IS) vs. epileptic spasms (ES)), variety of clinical and electroencephalographic (EEG) features (e.g., typical ictal phenomena without EEG abnormalities), burden of developmental delay, spectrum of associated genetic abnormalities, pathogenesis, treatment options, and related outcome and prognosis. Aside the classical manifestations, IS or ES may present with atypical electroclinical phenotypes (e.g., subtle spasms; modified hypsarrhythmia) and may have their onset outside infancy. An increasing number of genes, proteins, and signaling pathways play crucial roles in the pathogenesis. This condition is currently regarded as a spectrum of disorders: the so-called infantile spasm syndrome (ISs), in association with other causal factors, including structural, infectious, metabolic, syndromic, and immunologic events, all acting on a genetic predisposing background. Hormonal therapy and ketogenic diet are widely used also in combination with (classical and recent) pharmacological drugs. Biologically targeted and gene therapies are increasingly studied. The present narrative review searched in seven electronic databases (primary MeSH terms/keywords included West syndrome, infantile spasms and infantile spasms syndrome and were coupled to 25 secondary clinical, EEG, therapeutic, outcomes, and associated conditions terms) including MEDLINE, Embase, Cochrane Central, Web of Sciences, Pubmed, Scopus, and OMIM to highlight the past knowledge and more recent advances.
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2026-03-30 | DTaP-induced infantile epileptic spasms syndrome high-risk window: Insights from school-age children.
To determine the specific high-risk characteristics and temporal window associated with Diphtheria, Tetanus, and acellular Pertussis (DTaP) vaccine-precipitated infantile epileptic spasms syndrome (IESS), providing evidence for optimizing vaccination safety strategies, we conducted a multicenter retrospective cohort study of 564 patients with long-term follow-up (6.5-10.5 y). Patients were stratified by seizure onset interval into Vaccination-proximate (≤72 hours) and distant (>72 hours) groups. The proximate group (n = 53, 9.4%) exhibited a significantly younger age distribution (median [IQR]: 5.0 [3.0-6.0] vs. 5.0 [4.0-7.0] months, p = .04) and higher DTaP exposure (71.7% vs. 51.3%). Multivariable logistic regression in an etiologically analytic cohort (n = 541) identified the DTaP primary series as a significant independent precipitant for rapid onset (Dose 1: OR = 4.00; Doses 2 & 3: OR = 4.67) compared to other inactivated vaccines. Crucially, no increased risk was observed for the DTaP booster (Dose 4) or non-DTaP inactivated vaccines. Kaplan-Meier analysis confirmed a steep rise in seizure incidence within 72 hours post-primary DTaP. Long-term follow-up revealed no significant differences in all-cause mortality, seizure remission, or educational placement (p > .05) between groups, indicating that vaccination merely precipitated disease onset without altering the etiology-determined prognosis. This study, based on the full-course observation of school-aged children, is the first to validate the specificity of the DTaP-IESS association. The DTaP primary series is a critical precipitating factor for rapid onset (≤72 hours) in infants with underlying epileptogenic susceptibility. We recommend a stratified immunization strategy for high-risk infants: adhering to schedules for non-DTaP vaccines while adopting a prudent "delay-but-not-refuse" approach for DTaP to balance neurological safety with herd immunity.
1984-10-10 | Pyretotherapy as treatment in West's syndrome.
Four cases of West's syndrome (generalized myoclonic spasms, arrest of psychomotor development and hypsarrhythmia) which were found to be resistant to the classical treatment (ACTH, prednisone, nitrazepam, clonazepam, etc.) are reported. In these cases, high fever (pyretotherapy) induced by TBA vaccine (typhoid and paratyphoid) was used. Within the next eight days following treatment with pyretotherapy, the clinical conditions of these children showed a gradual decrease of generalized myoclonic spasms and an improvement of their mental and neurological status. The follow-up electroencephalograms showed cessation of the hypsarrhythmia. The study of these cases and their electro-clinical correlates suggests that pyretotherapy is a useful procedure in this extremely disabling condition.
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Drug Discovery Landscape
18 orphan drug designations for Infantile spasms syndrome, including 3 approved therapies.
18 orphan drug designations for Infantile spasms syndrome, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Tricaprilin | small molecules | EMA | 2022-11-10 | — | Veristat Spain S.L. |
vigabatrin [Vigafyde] | small molecules | FDA | 2022-10-12 | 2024-06-17 | Pyros Pharmaceuticals, Inc. |
tricaprilin | small molecules | FDA | 2020-10-27 | — | Cerecin, Inc. |
Synthetic-adrenocorticotropic hormone | peptides | FDA | 2020-09-25 | — | Amzell B.V. |
vigabatrin and cosyntropin | small molecules | FDA | 2017-11-01 | — | West Therapeutic Development, LLC |
Cannabidiol | small molecules | EMA | 2017-10-16 | — | Jazz Pharmaceuticals Ireland Limited |
cosyntropin | peptides | FDA | 2017-08-02 | — | West Therapeutic Development, LLC |
1-(2-chlorophenyl)-1-(S)-hydroxy-2-(S)-carbamoyloxy-propane | small molecules | FDA | 2017-03-20 | — | Bio-Pharm Solutions, Co., Ltd. |
tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride | small molecules | FDA | 2016-06-20 | — | Anavex Life Sciences Corp. |
cannabidiol | small molecules | FDA | 2016-06-13 | — | Jazz Pharmaceuticals Research UK Limited |
cannabidiol | small molecules | FDA | 2015-07-23 | — | Benuvia Operations LLC |
tetracosactide hexaacetate (beta 1-24-corticotrophin) | peptides | FDA | 2012-10-31 | — | Cerium Pharmaceuticals, Inc. |
carisbamate | small molecules | FDA | 2012-03-16 | — | SK Life Science, Inc. |
(1s,3s)-3-amino-4-(difluoromethylene)cyclopentanecarboxylic acid hydrochloride [CPP-115] | small molecules | EMA | 2012-02-09 | — | Catalent Pharma Solutions Limited |
(1S,3S)-3-amino-4-(difluoromethylene)cyclopentanecarboxylic acid hydrochloride, (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid hydrochloride | small molecules | FDA | 2010-09-15 | — | Catalyst Pharmaceuticals, Inc. |
repository corticotropin or adrenocorticotropic hormone [H.P. Acthar Gel] | peptides | FDA | 2003-05-21 | 2010-10-15 | Questcor Pharmaceuticals, Inc. |
vigabatrin [Sabril] | small molecules | FDA | 2000-06-12 | 2009-08-21 | H. Lundbeck A/S |
Ganaxolone | small molecules | FDA | 1994-05-25 | — | Immedica Pharma AB |
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