Impact of Bacille Calmette-Guérin vaccination on the therapeutic schedule of infantile epileptic spasms syndrome: A 25-year Japanese single-center survey.

Adrenocorticotropic hormone (ACTH) therapy is effective for infantile epileptic spasms syndrome (IESS) but can induce immunosuppression. In Japan, Bacille Calmette-Guérin (BCG) vaccination, modified in 2013 to reduce osteitis/osteomyelitis risk, coincides with the peak onset age of IESS. This raises concerns about infection risks when administering ACTH therapy post-vaccination. To evaluate the impact of BCG vaccination timing on treatment decisions, we retrospectively reviewed the medical records of 86 IESS patients at our hospital (1996-2020). Infants who received ACTH therapy within eight weeks of BCG vaccination experienced no serious adverse events. Four patients deferred or opted out of ACTH therapy, with seizure remission taking 2-15 weeks. The overlap between IESS onset and BCG vaccination period presents clinical challenges in determining the appropriate timing for ACTH therapy. Further epidemiological and immunological research is needed to clarify the relationship between ACTH therapy and BCG-associated adverse events and to optimize treatment strategies and vaccination schedules.

Predictive modeling based on functional connectivity of interictal scalp EEG for infantile epileptic spasms syndrome.

OBJECTIVE: This study aims to delineate the electrophysiological variances between patients with infantile epileptic spasms syndrome (IESS) and healthy controls and to devise a predictive model for long-term seizure outcomes. METHODS: The cohort consisted of 30 individuals in the seizure-free group, 23 in the seizure-residual group, and 20 in the control group. We conducted a comprehensive analysis of pretreatment electroencephalography, including the relative power spectrum (rPS), weighted phase-lag index (wPLI), and network metrics. Follow-up EEGs at 2 years of age were also analyzed to elucidate physiological changes among groups. RESULTS: Infants in the seizure-residual group exhibited increased rPS in theta and alpha bands at IESS onset compared to the other groups (all p < 0.0001). The control group showed higher rPS in fast frequency bands, indicating potentially enhanced cognitive function. The seizure-free group presented increased wPLI across all frequency bands (all p < 0.0001). Our predictive model utilizing wPLI anticipated long-term outcomes at IESS onset (area under the curve 0.75). CONCLUSION: Our findings demonstrated an initial "hypersynchronous state" in the seizure-free group, which was ameliorated following successful treatment. SIGNIFICANCE: This study provides a predictive model utilizing functional connectivity and insights into the diverse electrophysiology observed among outcome groups of IESS.

Factors influencing efficacy and relapse of adrenocorticotropic hormone in infantile epileptic spasms syndrome.

BACKGROUND: Infantile epileptic spasms syndrome (IESS) is a severe epileptic condition characterized by persistent uncontrolled seizures, with some children experiencing recurrent seizures despite multiple pharmacological therapies. The prognostic risk factorsassociated with IESS remain unclear. This study aimed to evaluate the factors influencing the efficacy and relapse of adrenocorticotropic hormone (ACTH) treatment for IESS in infants, as well as to assess the correlation between the Burden of Amplitudes and Epileptiform Discharges (BASED) score and clinical outcomes. METHODS: A retrospective analysis was conducted on a cohort of 88 pediatric patients diagnosed with IESS who received ACTH therapy at our hospital from February 2016 to August 2023. Patients were categorized into response (n = 47) and non-response (n = 41) groups based on their treatment response at day 28. Responders were further classified into relapse and non-relapse groups. A modified Poisson regression model and receiver operating characteristic (ROC) curves were employed to evaluate the positive predictive values. RESULTS: In this study, a total of 47 patients (53.4 %) responded to ACTH treatment. Patients in the response group demonstrated significantly greater reductions in BASED scores by day 14 of ACTH treatment, yielding an area under the curve (AUC) of 0.859 (95 % CI: 0.782-0.937, P＜0.05), with a sensitivity of 68.1 % and a specificity of 95.1 %. The optimal cut-off point was established at ≥ 2, corresponding to a Youden index of 0.632. Notably, patientswho were on anti-seizure medications (ASMs) before ACTH treatment and those with developmental delay prior to the onset of spasms exhibited lower short-term response rates (P＜0.05), although these factors did not demonstrate predictive value. Among the responders, 20 cases (42.6 %) experienced a relapse, with only those patients showing specific abnormalities on cranial magnetic resonance imaging (MRI) exhibiting a statistically higher proportion of relapse. CONCLUSION: Patients receiving ASMs before ACTH treatment and those with developmental delays prior to the onset of spasms may have a less favorable therapeutic response. A reduction in BASED scores of 2 or greater by day 14 of ACTH treatment may signify a potentially positive treatment response. Additionally, patients with IESS who present with specific abnormalities on cranial MRI may have an increased likelihood of relapse following ACTH treatment.

Epileptic foci and networks in children with epilepsy after acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) develops along with status epilepticus and widespread subcortical white matter edema. We aimed to evaluate the epileptic foci and networks in two patients with epilepsy after AESD using simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI). METHODS: Statistically significant blood oxygen level-dependent (BOLD) responses related to interictal epileptiform discharges (IEDs) were analyzed using an event-related design of hemodynamic response functions with multiple peaks. RESULTS: Patient 1 developed focal seizures at age 10 years, one year after AESD onset. Positive BOLD changes were observed in the bilateral frontotemporal lobes, left parietal lobe, and left insula. BOLD changes were also observed in the subcortical structures. Patient 2 developed epileptic spasms at age two years, one month after AESD onset. Following total corpus callosotomy (CC) at age three years, the epileptic spasms resolved, and neurodevelopmental improvement was observed. Before CC, positive BOLD changes were observed bilaterally in the frontotemporal lobes. BOLD changes were also observed in the subcortical structures. After CC, the positive BOLD changes were localized in the temporal lobe ipsilateral to the IEDs, and the negative BOLD changes were mainly in the cortex and subcortical structures of the hemisphere ipsilateral to IEDs. CONCLUSION: EEG-fMRI revealed multiple epileptic foci and extensive epileptic networks, including subcortical structures in two cases with post-AESD epilepsy. CC may be effective in disconnecting the bilaterally synchronous epileptic networks of epileptic spasms after AESD, and pre-and post-operative changes in EEG-fMRI may reflect improvements in epileptic symptoms.

Epilepsy surgery in developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) present significant treatment challenges due to frequent, drug-resistant seizures and comorbidities that impact quality of life. DEEs include both developmental encephalopathy from underlying pathology and epileptic encephalopathy where seizures exacerbate cognitive and behavioral impairments. Classification by syndrome and etiology is essential for therapy and prognosis, with common syndromes like infantile epileptic spasms syndrome and Dravet syndrome having specific first-line treatments. Etiologies are predominantly genetic, structural, or combined, with targeted therapies increasingly available. Surgery aims to improve seizure control but also may improve development, if the epileptic encephalopathy can be ameliorated. Timely intervention can reduce seizures and epileptiform discharges, maximizing developmental potential and allowing reduction in antiseizure medication. In cases requiring extensive resections, new deficits may be offset by developmental gains. Studies indicate that parents are generally willing to accept some deficits for significant seizure reduction.

Epilepsy surgery for children with epileptic spasms: A systematic review and meta-analysis with focus on predictors and outcomes.

To conduct a systematic review of the literature regarding rates and predictors of favorable seizure outcome after resective surgery for epileptic spasms (ES) in pediatric patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed. We searched PubMed, EMBASE, and Cochrane CENTRAL for articles published on the prevalence or incidence of epileptic spasm since 1985. Abstract, full-text review, and data extraction were conducted by two independent reviewers. Meta-analysis was performed to assess overall seizure freedom rate. Subject-level analysis was performed on a subset of studies to identify prognostic indicators. A total of 21 retrospective studies (n = 531) were included. Meta-analysis of all studies demonstrated a pooled seizure freedom rate of 68.8%. Subject-level analysis on 18 studies (n = 360) demonstrated a significant association between duration of spasms and recurrence of spasms after surgery, with an estimated increased risk of 7% per additional year of spasms prior to operation. Patients who underwent resective surgery that was not a hemispherectomy (i.e., lobectomy, lesionectomy, etc.) had an increased recurrence risk of 57% compared to patients who had undergone hemispherectomy. Resective surgery results in seizure freedom for the majority of pediatric patients with epileptic spasms. Patients who undergo hemispherectomy have lower risk of recurrence than patients who undergo other types of surgical resection. Increased duration of spasms prior to surgery is associated with increased recurrence risk after surgery. PLAIN LANGUAGE SUMMARY: Children with epileptic spasms (ES) that do not respond to medications may benefit from surgical treatment. Our study reviewed existing research to understand how effective surgery is in treating ES in children and what factors predict better outcomes. Researchers followed strict guidelines to search for and analyze studies published since 1985, finding 21 studies with a total of 531 patients. They found that, on average, nearly 70% of children became seizure-free after surgery. Further individual analysis of 360 patients showed that longer duration of spasms before surgery increased the risk of spasms returning by 7% per year. Additionally, children who had less extensive surgeries, such as removal of only a specific part of the brain, had a 57% higher risk of seizure recurrence compared to those who had a hemispherectomy, which removed or disconnected half of the brain. Overall, the study concludes that surgery can often stop seizures, especially when more extensive surgery is performed and when the surgery is done sooner rather than later.

Have epilepsy outcomes changed for children with tuberous sclerosis complex in Queensland, Australia?

OBJECTIVE: Historically, epilepsy has been the most frequently presenting feature of tuberous sclerosis complex (TSC). Advances in TSC health care have occurred over the past decade; thus, we studied whether TSC epilepsy outcomes have changed. METHOD: A retrospective chart review was undertaken for all children with TSC in Queensland, Australia. Epilepsy outcome and TSC diagnosis data were extracted, and data were compared between children born before 2012 with those born in or after 2012. RESULTS: In this retrospective cohort, TSC diagnosis in children born in or after 2012 is now predominantly antenatal (51%, p < .05). Most patients with epilepsy are now known to have TSC before they develop epilepsy. Despite earlier TSC diagnosis, the frequency of epilepsy (85%) has not changed (p = .92), but diagnosis trends toward an earlier age (median = 3 months for patients born in or after 2012 vs. 5.5 months for those born before 2012, p = .23). Most (95%) patients had focal seizures as their initial clinical seizure type; it was rare (5%) for epileptic spasms (ES) to be the initial seizure type. The frequency of ES was lower in patients born in or after 2012 (36% vs. 50%, p = .27). Infantile (<24 months) onset ES was not associated with worse epilepsy outcome. Late onset ES was seen in 14%, and these patients had a lower rate of epilepsy remission. Lennox-Gastaut syndrome was seen in 7%. Febrile/illness-related status epilepticus occurred in 12% of patients, between 1 and 4 years of age. Despite many (78%) patients having multiple daily seizures at maximal seizure frequency, and 74% meeting criteria for treatment-refractory epilepsy, most patients achieved epilepsy remission (66%), either with epilepsy surgery (47%) or with age (53%). At the time of inclusion in this study, only 21% of patients had uncontrolled frequent (daily to 3 monthly) seizures and 14% had uncontrolled infrequent (3 monthly to <2 yearly) seizures. SIGNIFICANCE: This study provides updated information that informs the counseling of parents of newly diagnosed pediatric TSC patients.

Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants.

OBJECTIVE: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature. METHODS: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. RESULTS: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum. SIGNIFICANCE: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.

Diagnostic evaluation of patients with epileptic spasms in the era of next-generation sequencing.

OBJECTIVE: Epileptic spasms (ES) can be caused by a variety of etiologies. However, in almost half of cases, the etiology is unidentified. With the advent of next-generation sequencing (NGS), the recognition of genetic etiologies has increased. METHODS: We retrospectively reviewed the medical records of patients with ES who were evaluated in the comprehensive epilepsy program at King Fahad Specialist Hospital Dammam between 2009 and 2022. RESULTS: Our data show that in 57.7% of patients with ES, the etiology was unidentified after a standard clinical evaluation and neuroimaging. Of these patients, n = 25 (35.2%) received a genetic diagnosis after some form of genetic testing, and 3.1% of patients from specialized metabolic work indicated the need for genetic testing to confirm the diagnosis. Karyotyping led to a diagnosis in 3.6% of patients, and chromosomal microarray led to a diagnosis in 7.1%. An NGS epilepsy gene panel (EP) was done for 45 patients, leading to a diagnosis in 24.4% (n = 11). Exome sequencing was done for 27 patients, including n = 14 with non-diagnostic panel testing; it led to a diagnosis in 37.3% (n = 10). Exome sequencing led to a diagnosis in 61.5% of patients without a previous panel test and in only two patients who had previously had a negative panel testing. SIGNIFICANCE: In this article, we present the diagnostic evaluations of ES for a cohort of 123 patients and discuss the yield and priority of NGS for evaluating ES. Our findings suggest that exome sequencing has a higher diagnostic yield for determining the etiology of ES in patients for whom the etiology is still unclear after an appropriate clinical assessment and a brain MRI.

Radiographic and Tomographic Study of the Cranial Bones in Children with the Idiopathic Type of West Syndrome.

BACKGROUND: Neither radiological phenotypic characteristics nor reconstruction CT scan has been used to study the early anatomical disruption of the cranial bone in children with the so-called idiopathic type of West syndrome. MATERIAL AND METHODS: The basic diagnostic measures and the classical antiepileptic treatments were applied to these children in accordance with the conventional protocol of investigations and treatment for children with West syndrome. Boys from three unrelated families were given the diagnosis of the idiopathic type of West syndrome, aged 7, 10 and 12 years old. Parents underwent extensive clinical examinations. Three parents (age range of 28-41 year) were included in this study. All children showed a history of intellectual disabilities, cryptogenic epileptic spasms and fragmented hypsarrhythmia. These children and their parents were referred to our orthopedic departments because of variable skeletal deformities. Variable forms of skeletal deformities were the motive for the families to seek orthopedic advice. A constellation of flat foot, torticollis and early-onset osteoarthritis were observed by the family doctor. Apparently, and from the first clinical session in our practice, we felt that all these children are manifesting variable forms of abnormal craniofacial contour. Thereby, we immediately performed detailed cranial radiological phenotypic characterization of every affected child, as well as the siblings and parents, and all were enrolled in this study. All affected children underwent whole-exome sequence analysis. RESULTS: The craniofacial phenotype of all children revealed apparent developmental anatomical disruption of the cranial bones. Palpation of the skull bones showed unusual palpable bony ridges along different sutural locations. A 7-year-old child showed abnormal bulging over the sagittal suture, associated with bilateral bony ridges over the squamosal sutures. AP skull radiograph of a 7-year-old boy with West syndrome showed facial asymmetry with early closure of the metopic suture, and other sutures seemed ill-defined. A 3D reconstruction CT scan of the skull showed early closure of the metopic suture. Another 3D reconstruction CT scan of the skull while the patient was in flexion showed early closure of the squamosal sutures, pressing the brain contents upward, causing the development of a prominent bulge at the top of the mid-sagittal suture. A reformatted 3D reconstruction CT scan confirmed the bilateral closure of the squamosal suture. Examination of the parents revealed a similar skull radiographic abnormality in his mother. A 3D reformatted frontal cranial CT of a 35-year-old mother showed early closure of the metopic and sagittal sutures, causing a mid-sagittal bony bulge. A 10-year-old boy showed an extremely narrow frontal area, facial asymmetry and a well palpable ridge over the lambdoid sutures. A 3D axial reconstruction CT scan of a 10-year-old boy with West syndrome illustrated the asymmetry of the posterior cranial bones along the lambdoid sutures. Interestingly, his 28-year-old mother has been a client at the department of spine surgery since she was 14 years old. A 3D reconstruction CT scan of the mother showed a noticeable bony ridge extending from the metopic suture upwards to involve the sagittal suture (red arrow heads). The black arrow shows a well demarcated bony ridge over the squamosal suture. A 3D reconstruction CT scan of the skull and spine showed the thick bony ridge of the metopic and the anterior sagittal as well as bilateral involvement of the squamosal, causing apparent anterior narrowing of the craniofacial contour. Note the lumbar scoliosis. A 12-year-old boy showed brachycephaly. A lateral skull radiograph of a 12-year-old boy with West syndrome showed premature sutural fusion, begetting an abnormal growth pattern, resulting in cranial deformity. The nature of the deformity depends on which sutures are involved, the time of onset and the sequence in which individual sutures fuse. In this child, brachycephalic secondary to craniosynostosis, which occurred because of bilateral early ossification of the coronal sutures, led to bi-coronal craniosynostosis. Thickened frontal bones and an ossified interclinoid ligament of the sella turcica were encountered. The lateral skull radiograph of a 38-year-old mother with a history of poor schooling achievements showed a very similar cranial contour of brachycephaly, thickening of the frontal bones and massive ossification of the clinoid ligament of the sella turcica. Maternal history revealed a history of multiple spontaneous miscarriages in the first trimester of more than five times. Investigating his parents revealed a brachycephalic mother with borderline intelligence. We affirm that the pattern of inheritance in the three boys was compatible with the X-linked recessive pattern of inheritance. Whole-exome sequencing showed non-definite phenotype/genotype correlation. CONCLUSIONS: The aim of this study was sixfold: firstly, to refute the common usage of the term idiopathic; secondly, we feel that it could be possible that West syndrome is a symptom complex rather than a separate diagnostic entity; thirdly, to further detect the genetic carrier, we explored the connection between the cranial bones in children with West syndrome with what has been clinically observed in their parents; fourthly, the early life anatomical disruptions of the cranial bones among these children seem to be heterogeneous; fifthly, it shows that the progressive deceleration in the development of this group of children is highly connected to the progressive closure of the cranial sutures; sixthly, we affirm that our findings are novel.

The Utility of Genetic Testing in Infantile Epileptic Spasms Syndrome: A Step-Based Approach in the Next-Generation Sequencing Era.

BACKGROUND: 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. METHODS: 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). RESULTS: 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%. CONCLUSIONS: The more genetic ESD (27.4%) was defined for IESS in the NGS era with the implication of precision therapy (37.7%).

Risk of autism spectrum disorder in children with infantile epileptic spasms syndrome: a retrospective study in a single center in Brazil.

OBJECTIVE: This study aimed to investigate the prevalence of autism spectrum disorder and its possible correlations with clinical characteristics in patients with infantile epileptic spasms syndrome in a single center in Brazil. METHODS: This retrospective cross-sectional study examined 53 children with the diagnosis of infantile epileptic spasms syndrome prior to an autism spectrum disorder assessment. Participants were divided into two groups based on the presence or absence of autism spectrum disorder. Available variables (sex, medications, median age at onset of infantile epileptic spasms syndrome, and presence of comorbidities) were compared using Mann-Whitney U or chi-square tests. RESULTS: Among the included patients, 12 (23 %) were diagnosed with autism spectrum disorder, corresponding to a relative risk of 0.29 (95 % confidence interval 0.174-0.492). The age at the first seizure ranged from 3 to 15 months, with a mean of 6.65 months. This age significantly differed between participants with autism spectrum disorder (10.58 months) and those without (5.43 months), p<0.001. CONCLUSION: Children with infantile epileptic spasms syndrome have a higher risk of being diagnosed with autism spectrum disorder. Later age of onset and period of spasm occurrence might be predisposing risk factors.

Infantile Epileptic Spasms Syndrome Complicated by Leigh Syndrome and Leigh-Like Syndrome: A Retrospective, Nationwide, Multicenter Case Series.

BACKGROUND: Six percent of patients with Leigh syndrome (LS) present with infantile epileptic spasms syndrome (IESS). However, treatment strategies for IESS with LS remain unclear. This retrospective study aimed to evaluate the efficacy and safety of treatment strategies in patients with IESS complicated by LS and Leigh-like syndrome (LLS). METHODS: We distributed questionnaires to 750 facilities in Japan, and the clinical data of 21 patients from 15 hospitals were collected. The data comprised treatment strategies, including adrenocorticotropic hormone (ACTH) therapy, ketogenic diet (KD) therapy, and antiseizure medications (ASMs); effectiveness of each treatment; and the adverse events. RESULTS: The median age at LS and LLS diagnosis was 7 months (range: 0 to 50), whereas that at the onset of epileptic spasms was 7 (range: 3 to 20). LS was diagnosed in 17 patients and LLS in four patients. Seven, two, five, and seven patients received ACTH + ASMs, ACTH + KD + ASMs, KD + ASMs, and ASMs only, respectively. Four (44%) of nine patients treated with ACTH and one (14%) of seven patients treated with KD achieved electroclinical remission within one month of treatment. No patients treated with only ASMs achieved electroclinical remission. Seven patients (33%) achieved electroclinical remission by the last follow-up. Adverse events were reported in four patients treated with ACTH, none treated with KD therapy, and eight treated with ASMs. CONCLUSION: ACTH therapy shows the best efficacy and rapid action in patients with IESS complicated by LS and LLS. The effectiveness of KD therapy and ASMs in this study was insufficient.

Characteristics of malignant brain tumor-associated epileptic spasms.

Although epilepsy is the most common comorbidity of brain tumors, epileptic spasms rarely occur. Brain tumors associated with epileptic spasms are mostly low-grade gliomas. To date, few studies in the literature have reported on malignant (Grades 3-4) brain tumors associated with epileptic spasms. Thus, we aimed to investigate the characteristics of malignant brain tumor-associated epileptic spasms. We retrospectively reviewed patients with malignant brain tumors and epileptic spasms in our institution. Data on demographics, tumor histology, magnetic resonance imaging, epileptic spasm characteristics, electroencephalography, and treatment responsiveness were also collected. Six patients were included. In all cases, the brain tumors occurred in infancy in the supratentorial region and epileptic spasm onset occurred after the completion of brain tumor treatment. Anti-seizure medication did not control epileptic spasms; two patients were seizure-free after epileptic surgery. Although all patients had developmental delays caused by malignant brain tumors and their treatment, developmental regression proceeded after epileptic spasm onset. Two patients who achieved seizure-free status showed improved developmental outcomes after cessation of epileptic spasms. This is the first report of the characteristics of malignant brain tumor-associated epileptic spasms. Our report highlights a difficulties of seizure control and possibillity of efficacy of epileptic surgery in this condition. In malignant brain tumor-associated epileptic spasms, it is important to proceed with presurgical evaluation from an early stage, bearing in mind that epileptic spasms may become drug-resistant.

Identification and treatment of surgically-remediable causes of infantile epileptic spasms syndrome.

INTRODUCTION: Infantile epileptic spasms syndrome (IESS) is a common developmental and epileptic encephalopathy with poor long-term outcomes. A substantial proportion of patients with IESS have a potentially surgically remediable etiology. Despite this, epilepsy surgery is underutilized in this patient group. Some surgically remediable etiologies, such as focal cortical dysplasia and malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), are under-diagnosed in infants and young children. Even when a surgically remediable etiology is recognised, for example, tuberous sclerosis or focal encephalomalacia, epilepsy surgery may be delayed or not considered due to diffuse EEG changes, unclear surgical boundaries, or concerns about operating in this age group. AREAS COVERED: In this review, the authors discuss the common surgically remediable etiologies of IESS, their clinical and EEG features, and the imaging techniques that can aid in their diagnosis. They then describe the surgical approaches used in this patient group, and the beneficial impact that early epilepsy surgery can have on developing brain networks. EXPERT OPINION: Epilepsy surgery remains underutilized even when a potentially surgically remediable cause is recognized. Overcoming the barriers that result in under-recognition of surgical candidates and underutilization of epilepsy surgery in IESS will improve long-term seizure and developmental outcomes.

Total callosotomy ameliorates epileptic activity and improves cognitive function in a patient with Miller-Dieker syndrome.

Miller-Dieker syndrome (MDS) is characterized by facial abnormalities and lissencephaly and is caused by a microdeletion in the region containing the LIS1 gene at chromosome 17p13.3. We report a case in which postnatal neuroimaging revealed severe lissencephaly. A 9-month-old boy presented with infantile spasms syndrome. Because of the refractory course of seizures and continued poor vitality, total corpus callosotomy was performed at 28 months of age. Intraoperative electroencephalogram (EEG) showed that the bilateral synchronous epileptiform discharges disappeared immediately after the disconnection. Postoperatively, the epileptic spasms (ES) in clusters disappeared, and single ES followed by focal seizures became the main symptom. The patient smiled more and became more responsive to stimuli. Postoperative scalp interictal EEG showed desynchronized multifocal spike and wave discharges with a marked decrease in the bilateral synchronous spike and wave discharges. Our findings suggest that the corpus callosum is involved in the mechanism ES in clusters in MDS-associated lissencephaly, and total callosotomy could be a therapeutic option.

Optimization of vigabatrin dosage in children with epileptic spasms: A population pharmacokinetic approach.

AIMS: Vigabatrin is an antiepileptic drug used to treat some forms of severe epilepsy in children. The main adverse effect is ocular toxicity, which is related to the cumulative dose. The aim of the study is to identify an acceptable exposure range, both through the development of a population pharmacokinetic model of vigabatrin in children enabling us to calculate patient exposure and through the study of therapeutic response. METHODS: We performed a retrospective study including children with epilepsy followed at Necker-Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed-effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range. RESULTS: We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3-18). A 2-compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC0-24 between 264 and 549 mg.h.L-1. CONCLUSIONS: The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients.

Novel copy number variations and phenotypes of infantile epileptic spasms syndrome.

We summarize the copy number variations (CNVs) and phenotype spectrum of infantile epileptic spasms syndrome (IESS) in a Chinese cohort. The CNVs were identified by genomic copy number variation sequencing. The CNVs and clinical data were analyzed. 74 IESS children with CNVs were enrolled. 35 kinds of CNVs were identified. There were 11 deletions and 5 duplications not reported previously in IESS, including 2 CNVs not reported in epilepsy. 87.8% were de novo, 9.5% were inherited from mother and 2.7% from father. Mosaicism occurred in one patient with Xq21.31q25 duplication. 16.2% (12/74) were 1p36 deletion, and 20.3% (15/74) were 15q11-q13 duplication. The age of seizure onset ranged from 17 days to 24 months. Seizure types included epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. All patients displayed developmental delay. Additional features included craniofacial anomaly, microcephaly, congenital heart defects, and hemangioma. 29.7% of patients were seizure-free for more than 12 months, and 70.3% still had seizures after trying 2 or more anti-seizure medications. In conclusion, CNVs is a prominent etiology of IESS. 1p36 deletion and 15q duplication occurred most frequently. CNV detection should be performed in patients with IESS of unknown causes, especially in children with craniofacial anomalies and microcephaly.

Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine.

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as TSC1, TSC2, CDKL5, ARX, KCNQ2, STXBP1 and SCN2A. Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored.