Biochemical mechanisms in pathogenesis of infantile epileptic spasm syndrome.

The molecular mechanisms leading to infantile epileptic spasm syndrome (IESS) remain obscure. The only common factor seems to be that the spasms are restricted to a limited period of infancy, during a certain maturational state. Here the current literature regarding the biochemical mechanisms of brain maturation in IESS is reviewed, and various hypotheses of the pathophysiology are put together. They include: (1) imbalance of inhibitory (NGF, IGF-1, ACTH, GABA) and excitatory factors (glutamate, nitrites) which distinguishes the different etiological subgroups, (2) abnormality of the hypothalamic pituitary adrenal (HPA) axis linking insults and early life stress, (3) inflammation (4) yet poorly known genetic and epigenetic factors, and (5) glucocorticoid and vigabatrin action on brain development, pinpointing at molecular targets of the pathophysiology from another angle. An altered maturational process may explain why so many, seemingly independent etiological factors lead to the same clinical syndrome and frequently to developmental delay. Understanding these factors can provide ideas for novel therapies.

Could prevention of infantile spasms have been possible in a historical cohort of 31 tuberous sclerosis patients?

Efforts to prevent epilepsy in infants with tuberous sclerosis complex (TSC) has been the focus of EPISTOP. PURPOSE: The present study was carried out to evaluate whether prevention could have been realistic. METHODS: A retrospective analysis by hospital chart review of 31 patients with TSC and infantile spasms (practically all patients) admitted to two tertiary hospitals, Children's Hospital, University of Helsinki and Kuopio in 1980-2000. Clinical history, early cognitive development, early clinical signs of TSC, clinical signs of suspicious seizures, first seizures and EEG, response to adrenocorticotropic hormone (ACTH) therapy, EEG and brain imaging were evaluated. RESULTS: Early development prior the spasms was apparently normal in 25 (80%). The first EEG ever performed for a child showed hypsarrhythmia in 16 (51%) or modified hypsarrhythmia in 10 (32%). Treatment lag was short (0-4, mean 2 weeks) and the primary response to ACTH favorable in 19 (64%). Etiological diagnostic workup of IS revealed TSC. In one single case (3%) the diagnosis of TSC could be made at birth due to a congenital cardiac rhabdomyoma. Three other rhabomyomas were diagnosed later. In brain imaging, subependymal periventricular calcifications or hypodense areas were seen in every patient at onset of IS. Other organ manifestations of TSC were retinal phakomas (6), polycystic kidneys (2), and renal angiolipomatosis (1). CONCLUSIONS: Preventive treatment of epileptic discharges could have been possible in a single case of neonatal rhabdomyoma suggesting that preventive treatment is challenging in everyday practice. The main obstacle is the delay of TSC diagnosis.

Teleneurology based management of infantile spasms during COVID-19 pandemic: A consensus report by the South Asia Allied West syndrome research group.

With telehealth services rescuing patients with chronic neurological disorders during the COVID-19 pandemic, there is a need for simplified teleneurology protocols for neurological disorders in children. Infantile spasms is an epileptic encephalopathy where treatment lag is a significant predictor of outcome. It is one such condition where telemedicine can make a remarkable difference when in-person consultations are delayed or are not possible. However, the adverse effect profile of the first-line therapeutic options, the need for frequent follow-up, underdeveloped telemedicine services, lack of a rational protocol, poor awareness about infantile spasms, a lesser level of parental understanding, and scarcity of pediatric neurologists are the major hurdles in developing countries. This paper provides a teleneurology based approach for the management of infantile spasms in developing countries during the COVID-19 pandemic. The cornerstones of this approach include the fundamental principles of management of infantile spasms, decentralization of patient care to local health providers, efforts for improving sensitivity and specificity of diagnosis, early initiation of first-line therapeutic options, and constant motivation of parents and local health providers to be vigilant for therapeutic response, adverse effects of therapy, and infections.

Management practices for West syndrome in South Asia: A survey study and meta-analysis.

OBJECTIVES: Considering the dearth of literature on West syndrome (WS) from South Asian countries, this study aimed to evaluate the management practices in South Asia by an online survey and meta-analysis. METHODS: An online questionnaire was sent to 223 pediatric neurologists/pediatricians in India, Pakistan, Myanmar, Sri Lanka, Bhutan, Nepal, and Bangladesh. Their responses were evaluated and supplemented by a meta-analysis. RESULTS: Of 125 responses received (response rate: 56%), around 60% of responders observed male preponderance and an approximate lead-time-to-treatment (LTTT) of 4-12 weeks. The commonest etiology observed was a static structural insult (88.6% of responders). Most commonly used first-line drug (country-wise) was as follows: India-adrenocorticotropin hormone (ACTH, 50%); Pakistan-oral steroids (45.5%); Myanmar, Sri Lanka, and Nepal-oral steroids (94.4%); Bangladesh-ACTH (2/2); Bhutan-vigabatrin (3/5). ACTH and vigabatrin are not available in Myanmar and Nepal. The most commonly used regime for ACTH was maximal-dose-at-initiation-regime in India, Sri Lanka, and Bangladesh and gradually escalating-regime in Pakistan. Maximum dose of prednisolone was variable-most common response from India: 3-4 mg/kg/d; Pakistan, Bhutan, and Bangladesh: 2 mg/kg/d; Sri Lanka, Nepal, and Myanmar: 5-8 mg/kg/d or 60 mg/d. The total duration of hormonal therapy (including tapering) ranged from 4 to 12 weeks (67/91). Most responders considered cessation of spasms for four weeks as complete response (54/111) and advised electroencephalography (EEG; 104/123) to check for hypsarrhythmia resolution. Difficult access to pediatric EEG in Bhutan and Nepal is concerning. More than 95% of responders felt a need for more awareness. The meta-analysis supported the preponderance of male gender (68%; confidence interval [CI]: 64%-73%), structural etiology(80%; CI 73%-86%), longer LTTT (2.4 months; CI 2.1-2.6 months), and low response rate to hormonal therapy(18% and 28% for ACTH and oral steroids respectively) in WS in South Asia. SIGNIFICANCE: This study highlights the practices and challenges in the management of WS in South Asia. These include a preponderance of male gender and structural etiology, a longer LTTT, difficult access to pediatric EEG, nonavailability of ACTH and vigabatrin in some countries, and low effectiveness of hormonal therapy in this region.

ACTH Treatment of Infantile Spasms: Low-Moderate- Versus High-Dose, Natural Versus Synthetic ACTH-A Retrospective Cohort Study.

BACKGROUND: High dosages of natural adrenocorticotropic hormone are used in many centers in the United States for the treatment of infantile spasms. However, lower dosages of synthetic adrenocorticotropic hormone (tetracosactide) might be equally efficient as high dosages. We analyzed the treatment options for infantile spasms, especially regarding the adrenocorticotropic hormone dosage and the formulation (natural versus synthetic) and evaluated which options were more effective in a retrospective cohort from 1960 to 1976. METHODS: We compared the short-term response rates of patients treated with high dosages of natural adrenocorticotropic hormone (120 IU/day) (N = 31) (Group1) with those of patients treated with low-moderate dosages of natural adrenocorticotropic hormone (40 IU/day) (N = 52) (Group2). We also compared the short-term response rates of patients treated with natural adrenocorticotropic hormone (N = 83) with those of patients treated with synthetic adrenocorticotropic hormone, (N = 23) (Group3). The responses were evaluated clinically and by electroencephalography at two to three weeks after the onset of therapy. RESULTS: A response was seen in 24 of 31 children treated with high dosages and in 43 of 52 children treated with low-moderate dosages of natural adrenocorticotropic hormone (P = 0.56). All children with an unknown etiology responded to both high and low-moderate dosages of natural adrenocorticotropic hormone. The proportion of children with a good early response to synthetic adrenocorticotropic hormone (16 of 23) did not differ from the proportion of children with a good early response treated with natural adrenocorticotropic hormone (67 of 83) (P = 0.25). CONCLUSIONS: High dosages of adrenocorticotropic hormone are not more effective than low-moderate dosages in the short term for treating infantile spasms. Synthetic adrenocorticotropic hormone is equally effective as natural adrenocorticotropic hormone.

Infantile Spasms: Outcome in Clinical Studies.

Children with infantile spasms are likely to have a poor outcome. Outcome measures for infantile spasms include primary response to treatment, relapse of spasms, neurological development, death, and progression to another type of epilepsy (Consensus Statements of the WEST Delphi Group 2004). This review is based mainly on prospective studies and emphasizes data about the current first-line drugs, adrenocorticotropic hormone, vigabatrin, and prednisolone, taking into account the proportion of patients with known and unknown etiology, which has a very strong effect on seizure outcome. In most studies, hormonal treatment (adrenocorticotropic hormone or prednisolone) is the optimal monotherapy, except for patients with tuberous sclerosis complex, in whom vigabatrin appears superior. Combination therapy (hormones plus vigabatrin) may well be more effective than either agent alone. The underlying etiology is the most important prognostic factor. In studies with a long follow-up (up to 50 years), a favorable cognitive outcome has been observed in approximately one quarter of patients and complete seizure freedom in one-third. Autism is relatively frequent, and premature mortality is high throughout life. Modifiable prognostic factors include early recognition of the spasms with prompt treatment, short duration of hypsarrhythmia, prompt treatment of relapses of spasms and multifocal epileptic discharges, and early treatment of adverse effects. It is hoped that eventually advanced genetics and molecular data will allow an understanding of the pathogenetic mechanisms of many specific etiologies to allow disease-specific treatment such as is emerging for tuberous sclerosis.

18q12.3-q21.1 microdeletion detected in the prenatally alcohol-exposed dizygotic twin with discordant fetal alcohol syndrome phenotype.

BACKGROUND: A pair of dizygotic twins discordantly affected by heavy prenatal alcohol exposure (PAE) was reported previously by Riikonen, suggesting the role of genetic risk or protective factors in the etiology of alcohol-induced developmental disorders. Now, we have re-examined these 25-year-old twins and explored genetic origin of the phenotypic discordancy reminiscent with fetal alcohol syndrome (FAS). Furthermore, we explored alterations in DNA methylation profile of imprinting control region at growth-related insulin-like growth factor 2 (IGF2)/H19 locus in twins' white blood cells (WBC), which have been associated earlier with alcohol-induced genotype-specific changes in placental tissue. METHODS: Microarray-based comparative genomic hybridization (aCGH) was used to detect potential submicroscopic chromosomal abnormalities, and developmental as well as phenotypic information about twins were collected. Traditional bisulfite sequencing was used for DNA methylation analysis. RESULTS: Microarray-based comparative genomic hybridization revealed a microdeletion 18q12.3-q21.1. in affected twin, residing in a known 18q deletion syndrome region. This syndrome has been associated with growth restriction, developmental delay or intellectual deficiency, and abnormal facial features in previous studies, and thus likely explains the phenotypic discordancy between the twins. We did not observe association between WBCs' DNA methylation profile and PAE, but interestingly, a trend of decreased DNA methylation at the imprinting control region was seen in the twin with prenatal growth retardation at birth. CONCLUSIONS: The microdeletion emphasizes the importance of adequate chromosomal testing in examining the etiology of complex alcohol-induced developmental disorders. Furthermore, the genotype-specific decreased DNA methylation at the IGF2/H19 locus cannot be considered as a biological mark for PAE in adult WBCs.

CSF nerve growth factor (ß-NGF) is increased but CSF insulin-like growth factor-(IGF-1) is normal in children with tuberous sclerosis and infantile spasms.

Tuberous sclerosis is associated with epilepsy that is often refractory. We examined cerebrospinal fluid (CSF) concentrations for neurotrophins, nerve growth factor (ß-NGF) and insulin-like growth factor (IGF-1) in children with infantile spasms between 1997 and 2010. We classified the patients as follows: tuberous sclerosis (n = 5), cryptogenic spasms (n = 6), postinfectious spasms (n = 5) and other symptomatic spasms (n = 22). We had 22 age- and sex-matched controls for CSF-NGF and 14 for CSF-IGF-1. The median of CSF-NGF was higher in those with tuberous sclerosis, 56 (minimum-maximum, 8.0-131) ng/L, in relative to age- and sex-matched controls, 6.7 (0.0-22) ng/L, and symptomatic infantile spasms, 0.0 (0.0-4.5) ng/L or cryptogenic cases of infantile spasms, 6.2 (3.9-8.8) ng/L, respectively. CSF-NGF were highest in children with postinfectious aetiology, 408 (89-778) ng/L. CSF-IGF-1 of tuberous sclerosis, 0.65 (0.35-0.98) µg/L, did not differ from the cryptogenic spasms, 0.68 (0.32-0.87) µg/L, or from age- and sex-matched controls 0.52 (0.22-0.77) µg/L. Patients with tuberous sclerosis and cryptogenic spasms had normal development prior the ACTH therapy. We suggest that increased CSF-NGF might indicate a persistent activation of inflammatory pathways in cortical tubers in tuberous sclerosis and this would reflect in CSF concentrations.

Insulin-Like Growth Factors in the Pathogenesis of Neurological Diseases in Children.

Insulin-like growth factors play a key role for neuronal growth, differentiation, the survival of neurons and synaptic formation. The action of IGF-1 is most pronounced in the developing brain. In this paper we will try to give an answer to the following questions: Why are studies in children important? What clinical studies in neonatal asphyxia, infantile spasms, progressive encephalopathy-hypsarrhythmia-optical atrophy (PEHO) syndrome, infantile ceroid lipofuscinosis (INCL), autistic spectrum disorders (ASD) and subacute sclerosing encephalopathy (SSPE) have been carried out? What are IGF-based therapeutic strategies? What are the therapeutic approaches? We conclude that there are now great hopes for the therapeutic use of IGF-1 for some neurological disorders (particularly ASD).

Treatment of autistic spectrum disorder with insulin-like growth factors.

There are no treatments for the core symptoms of autistic spectrum disorder (ASD), but there is now more knowledge on emerging mechanisms and on mechanism-based therapies. In autism there are altered synapses: genes affected are commonly related to synaptic and immune function. Dysregulation of activity-dependent signaling networks may have a key role the etiology of autism. There is an over-activation of IGF-AKT-mTor in autism spectrum disorders. Morphological and electro-physiological defects of the cerebellum are linked to system-wide ASD-like behavior defects. The molecular basis for a cerebellar contribution has been demonstrated in a mouse model. These have led to a potential mechanism-based use of drug targets and mouse models. Neurotrophic factors are potential candidates for the treatment. Insulin-like growth factor-1 (IGF-1) is altered in autism. It reduces neuro-inflammation: by causing changes of cytokines such as IL-6 and microglial function. IGF-1 reduces the defects in the synapse. It alleviates NMDA-induced neurotoxicity via the IGF-AKT-mTor pathway in microglia. IGF-1 may rescue function in Rett syndrome and ASD caused by changes of the SCHANK3 gene. There are recently pilot studies of the treatment of Rett syndrome and of SCHANK3 gene deficiency syndromes. The FDA has granted Orphan drug designations for Fragile X syndrome, SCHANK3 gene deficiency syndrome and Rett syndrome.

WONOEP appraisal: Molecular and cellular biomarkers for epilepsy.

Peripheral biomarkers have myriad potential uses for treatment, prediction, prognostication, and pharmacovigilance in epilepsy. To date, no single peripheral biomarker has demonstrated proven effectiveness, although multiple candidates are in development. In this review, we discuss the major areas of focus including inflammation, blood-brain barrier dysfunction, redox alterations, metabolism, hormones and growth factors.

Infantile spasms and 15q11.2q13.1 chromosome duplication in two successive generations.

Familial cases of West syndrome have been reported only in Japan. In that study no chromosomal analyses were made. It has been suggested that microarray analysis should be included in the diagnostic evaluation of patients with infantile spasms and developmental delay, when an evaluation for structural brain lesions and metabolic disorders reveal no abnormal findings. We report here the first case of infantile spasms and 15q11.2q13.1 chromosome duplication in two successive generations. The daughter and mother with infantile spasms, and the autistic son had the duplication. The clinical course of infantile spasms was very similar in the mother and daughter. The spasms were primarily considered to be of unknown aetiology. Chromosomal microarray analysis revealed a 6.2 Mb size 15q11.2q13.1 duplication. The duplication belongs to the 15q11q13 duplication syndrome (OMIM 608636) which when maternally derived is characterised by neuro-behavioural disorders like autism, hypotonia, cognitive deficit, language delay and epilepsy. The proportion of patients with unknown aetiology for infantile spasms will decrease when more careful chromosomal studies are made. Our report expands the phenotype of chromosome 15q duplication syndrome and is the first report of this abnormality in two successive generations of infantile spasms.

Long-term mortality of patients with West syndrome.

Objective: To study long-term survival and mortality among patients with West syndrome. Methods: The study population included all children born in 1960-1976 and treated for West syndrome in three tertiary care hospitals in Helsinki, Finland. The participants were prospectively followed for five decades for survival. Death data were derived from the National Causes of Death Register of the Population Register Center of Statistics Finland. Results: During follow-up, 102 (49%) of 207 patients had died at the mean age of 19 years. The mean overall annual mortality rate was 15.3 per 1,000 patient-years. The rates ranged from 18.2 per 1,000 after 10 years to 17.2 per 1,000 after 20 years and 15.4 per 1,000 patient-years after 40 years of follow-up. One fourth (25%) had died by 17.2 (95% CI 11.8-22.7) years and 50% by 48.6 (95% CI 38.5-NA) years of follow-up. Etiology at onset was symptomatic in 87% patients and cryptogenic in 13%; 6 of the latter 26 patients later turned out to be symptomatic. The mean annual mortality rate was 3.7 per 1,000 for 4 patients with cryptogenic etiology and 17.6 per 1,000 for those with symptomatic etiology. The hazard of death was fivefold in patients with symptomatic etiology versus cryptogenic etiology. The overall autopsy rate was 73%. Pneumonia was the most frequent cause of death (46%). All patients who died of pneumonia had symptomatic etiology. SUDEP occurred in 10 patients and was the most common epilepsy-related cause of death (10%). Significance: Risk of excess death of participants with West syndrome is not limited to early age but continues into adulthood, particularly in those with symptomatic etiology, and leads to death in half the cases at around 50 years of age. Measures should be directed to prevent pneumonia, the most common overall cause, and SUDEP, the most frequent seizure-related cause, of death.

Psychological distress of children with early-onset type 1 diabetes and their mothers' well-being.

AIM: Few studies have focused on the psychological adjustment of pre-adolescent children with type 1 diabetes. This study examined psychosocial functioning in nine- and 10-year-old children with early-onset type 1 diabetes, and their mothers, and associations between psychosocial functioning and diabetes management. METHODS: The mothers of 63 children with early-onset diabetes and 86 healthy children evaluated their own psychosocial functioning, and their child's, with standardised rating scales. We used general linear models to analyse the children's behaviour problems and the mothers' well-being. Associations between the children's behaviour problems, diabetes-related measures and the mothers' well-being were studied with partial correlations. RESULTS: Children with diabetes had more internalising problems than the controls (p = 0.001), and these were associated with poor glycaemic control at the early stage of the illness (p = 0.033) and the use of insulin pumps in girls (p = 0.004). Mothers in the diabetes group had more child-related stress than the controls (p < 0.001), and poorer well-being was associated with the children's behavioural problems (p < 0.024). CONCLUSION: Children with early-onset diabetes faced an increased risk of internalising problems in middle childhood. The mothers' psychological distress was associated with children's behaviour problems rather than their diabetes.

Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study.

AIM: The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy. METHOD: In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22). RESULTS: Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for <1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively. INTERPRETATION: VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin.

Recent advances in the pharmacotherapy of infantile spasms.

Adrenocorticotrophic hormone (ACTH), oral corticosteroids and vigabatrin are now first-line treatments for infantile spasms in the US and Europe. There is now increased knowledge regarding the role of ACTH, corticosteroids and vigabatrin (e.g. efficacy, doses, side effects, treatment in specific aetiological subtypes of infantile spasms), and other antiepileptic drugs (i.e. topiramate, valproate, zonisamide, sulthiame, levetiracetam, lamotrigine, pyridoxine, ganaxolone), as well as adjunctive flunarizine and novel drugs not yet in clinical use for infantile spasms (i.e. pulse rapamycin and melanocortin receptor agonists). The existence of a latent period, weeks to months following a precipitating brain insult, raises the possibility of preventive interventions. Recent experimental data emerging from animal models of infantile spasms have provided optimism that new and innovative treatments can be developed, and knowledge that drug treatment can affect long-term cognitive outcome is increasing. The aim of this article is to review recent developments in the pharmacotherapy of infantile spasms and to highlight the practical implications of the latest research.