Terminology
The Infantile Spasms Syndrome (ISs) belongs to the group of “early epileptic encephalopathies” (EEE), characterized by severe, drug-resistant epileptic disorders, with onset in early life, associated to persistent EEG abnormalities and cognitive deficits. In several reports West Syndrome, infantile spasms, epileptic spasms, and infantile spasms syndrome (WS, IS, ES and ISs) are used interchangeably. Some authors have preferred to use use the term “IS” to indicate the ictal phenomenon and the term “ISs” to describe the (spectrum of) disorder(s) associated with IS (Pavon P et al., 2020).
Etiology
- ISs can result from various etiologies, including:
- Etiologic factors may act as single causal events or in complex associations.
- Structural defects
- Infectious agents
- Metabolic and immunologic defects
- Genetic abnormalities
- Hypoxic-ischemic encephalopathy is a frequent cause of ISs.
- Prenatal cerebral infections and stroke can cause permanent cerebral damage, leading to ISs.
- Many etiologic events share similar pathogenic mechanisms, such as those seen in tuberous sclerosis, complex malformation syndromes, or chromosomal abnormalities.
- Vascular events, infections, and metabolic and immunologic defects often act on a genetic predisposition.
- In approximately 35% of cases, the cause is unknown, often leading to a more favorable outcome.
- Different events may contribute to ISs, making a clear etiologic distinction challenging.
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Major study findings on etiologic factors
- Yuskaitis et al. [2013]:
- Among 133 infants with ISs of unknown origin:
- 15% had normal development
- 85% had developmental delays
- Among 133 infants with ISs of unknown origin:
- United Kingdom Infantile Spasms Study (UKISS) [2010]:
- Among 127 of 207 patients with proven etiological diagnosis:
- 10% had hypoxic-ischemic encephalopathy
- 8% had chromosomal abnormalities, complex malformation syndromes, or perinatal stroke
- 7% had tuberous sclerosis
- 5% had periventricular leukomalacia or hemorrhage
- Among 127 of 207 patients with proven etiological diagnosis:
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National Infantile Spasms Consortium Study Findings (Wirrell EC et al., 2015)
- Among 250 ISs patients, etiologic causes were identified in 161 (64.4%):
- 14.4% had genetic factors
- 10.0% had genetic-structural factors
- 10.8% had structural-congenital factors
- 22.4% had structural-acquired factors
- 4.8% had metabolic factors
- 2% had infectious factors
- Among 250 ISs patients, etiologic causes were identified in 161 (64.4%):
- Yuskaitis et al. [2013]:
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Genetic and Molecular Involvement
- Modern genetic technologies (array-CGH, NGS, WES, WGS) have identified more genes and copy number variants (CNVs) involved in ISs.
- Molecular/cellular anomalies can cause ISs:
- Directly by generating the neuronal/brain structural phenotype
- Indirectly by causing complex syndromic phenotypes (e.g., recognizable malformation syndromes, inborn errors of metabolism)
- By predisposing to vascular or infectious events
- Genetic causes can involve chromosomal abnormalities, large/single gene abnormalities, CNVs, or a combination of these factors.
- Majority of genes involved in ISs exhibit phenotypic heterogeneity, similar to other neurological disorders (Scheffer et al., 2017)
- Increased risk of ISs in families with a history of epileptic seizures (Dulac et al., 1993; Hemminki et al., 2006).
- Confirmed by reports of ISs in twins, such as monozygotic twins experiencing spasms within a short interval (Pavone et al., 1985; Coppola et al., 2010).
- Hypothesized that a time-related, preprogrammed molecular/cellular event may trigger the onset of spasms (Pavone et al., 1985).
- Environmental triggers may also affect genetically predisposed monozygotic twins simultaneously.
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Direct Involvement of Genes:
- Mutations in the Aristaless-related homeobox (ARX1) gene and Cyclin-dependent Kinase-like 5 (CDKL5) gene, located on chromosome Xp22, are linked to complex malformation phenotypes with IS/ES (Pavone et al., 2013; Paciorkowski et al., 2011 with ISs, are expressed in GABAergic interneurons and cause ISs due to neuronal cell disruption during embryogenesis (Guerrini et al., 2005)
- Boutry-Kryza et al. (2015) identified anomalies in CNVs in up to 15% of patients, including specific point mutations in CDKL5 and STXBP1
- Microdeletions in regions 2q24.3, 5q14.3, and 9p34, and microduplications in 2q24.3 and Xp28.11.93 were recorded.
- Potential risk factors for ISs identified, such as 16p12.1 deletions involving the NEDD4 and CALN1 genes.
- Study on 56 Chinese families identified 17 novel ISs-candidate genes using WES:
- ATP2A2, CD99L2, CLCN6, CYFIP1, CYFIP2, GNB1, GPT2, HUWE 1, KMT2D, MYO18A, NOS3, RYR1, RYR2, RYR3, TAF1, TECTA, and UBA (Peng J et al., 2018).
- Other gene mutations reported in association with ISs include
- STXBP1 (Deprez L et al., 2010; Saitsu H et al., 2010)
- KCNQ2 (Kato M et al., 2013)
- GRIN2B and GRIN2A (Lemke JR et al., 2014; Boutry-Kryza N et al., 2015)
- MAGI2 (Marshall CR et al., 2008)
- SPTAN, FOXG1, and NSD1 (Lux AL, 2013)
- WDR45 (Morikawa M et al., 2017; Takano K et al., 2016)
- KCNQ2 R198Q (Millichap JJ et al., 2017)
- SLC1A4 (variant) (Conroy J et al., 2016)
- RARS2 (Ngoh A et al., 2016)
- UBA5 (Daida A et al., 2018)
- IARS2 (Takezawa Y et al., 2018)
- hCDKL5 (Jdila MB et al., 2019)
- PHACTR1 (Hamada N et al., 2019)
- ISs children with 5q31.2-q31.3 microdeletions involving the PURA gene (Shimojima et al., 2018). De novo mutations in the PURA gene cause PURA syndrome, characterized by severe intellectual disability, epilepsy, feeding difficulties, neonatal hypotonia, respiratory and gastrointestinal problems, eye anomalies, endocrine defects, exaggerated startle responses, hypersomnolence, and hypothermia (Reijnders MRF et al., 2018)
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Structural Brain Disorders:
- Well-known causes of ISs include:
- Lissencephaly
- Focal cortical dysplasia
- Polymicrogyria
- Hydranencephaly (Neville BG, 1972)
- Hemimegalencephaly
- Genetic Associations:
- PAFAH1B1/LIS1 and DCX genes are associated with ISs in about 80% of children with classical lissencephaly.
- De novo heterozygous mutation of KIF2A gene in a child with lissencephaly, developmental delay, and IS (Tian G et al., 2016).
- Chromosomal abnormalities linked to ISs:
- Unbalanced translocation 3p26.2-10p15.1 and 6q22.31 duplication in a child with IS and periventricular nodular heterotopia (Jones K et al., 2016).
- Homozygous nonsense mutation in B3GALNT2 gene in a child with Walker-Warburg syndrome, ISs, and sensorineural hearing loss (Al Dhaibani MA et al., 2018)
- Well-known causes of ISs include:
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Complex Malformation Syndromes:
- Down Syndrome:
- Study of 183 Down syndrome patients revealed 15 with epileptic seizures, 4 of whom had ISs (Romano C et al., 1990)
- Prevalence of epileptic seizures in Down syndrome patients ranges from 1 to 13%, with 6-32% presenting with ISs (Tapp et al., 2015).
- Pallister-Killian Syndrome:
- Caused by mosaicism for tetrasomy of chromosome 12p.
- Features include skin pigmentation, bitemporal alopecia, rugged face, epileptic seizures, intellectual disability, and late-onset epileptic spasms (Cerminara C et al., 2010).
- Williams-Beuren Syndrome (WBS):
- Associated with a chromosomal microdeletion manifesting with facial features, heart problems, intellectual disability, and happy behavior.
- ISs reported in a WBS patient with a large deletion on chromosome 7q11.23-q21.11 embedding the MAGI2 gene (Marshall et al., 2008).
- Other Syndromes with Anecdotal Cases of ISs:
- Schinzel-Giedon Syndrome
- Smith-Lemli-Opitz Syndrome
- Smith-Magenis Syndrome
- Sotos Syndrome (Lux AL, 2013)
- Noonan-like Syndrome:
- Epileptic spasms reported in a male infant with PPP1CB-associated Noonan-like syndrome (Lin CH et al., 2018).
- Down Syndrome:
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Syndromes with ISs as Presenting Features:
- PEHO Syndrome:
- A rare, progressive encephalopathy presenting with edema, hypsarrhythmia, optic atrophy, and cerebellar atrophy.
- Mutation in ZNHIT3 gene identified as primary cause (Anttonen AK et al., 2017).
- Aicardi Syndrome:
- Affects females, characterized by corpus callosum agenesis, retinal lacunes, severe intellectual disability, and ISs with asymmetric hypsarrhythmia on EEG.
- Brain tumors, especially in the choroid plexus, also reported (Trifiletti RR et al., 1995).
- PEHO Syndrome:
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Inborn Errors of Metabolism and ISs (Infantile Spasms)
- Phenylketonuria (PKU):
- Caused by a mutation in the gene encoding the enzyme phenylalanine hydroxylase (PAH).
- PAH converts phenylalanine into tyrosine and other components.
- In the pre-screening era, PKU incidence was 1 in 5000 newborns.
- Symptoms included skin hypopigmentation, severe developmental delay, and seizures, including ISs.
- Untreated PKU results in severe brain demyelination and gray matter abnormalities.
- A more severe subtype is related to tetrahydrobiopterin (BH4) deficit, a coenzyme of PAH, causing constant developmental delay and ISs in untreated patients ( Al Hafid N et al., 2015).
- Neurometabolic Disorders:
- Early-onset inborn errors of metabolism may present with ISs as their first manifestation.
- Alrifai et al. (2014):
- In a group of 80 children with ISs, 10 (12.5%) were diagnosed with neurometabolic disorders:
- Leigh-like disorder
- Ethylmalonicaciduria
- Non-ketotichyperglycinemia (GCSH gene)
- Hyperinsulinemic hypoglycemia (HHF17)
- Short-chain acyl-coenzyme A dehydrogenase deficiency (ACADS gene)
- Molybdenum cofactor deficiency (MOCS12; GPHN gene)
- Primary carnitine deficiency (SLC22A5 gene)
- Neonatal hypoglycemia secondary to hypopituitarism (CPHD15)
- In a group of 80 children with ISs, 10 (12.5%) were diagnosed with neurometabolic disorders:
- Other disorders associated with ISs:
- Glycine encephalopathy (GLDC and GCST genes)
- DEND (KCNJ 11 gene)
- Methylmalonicaciduria (MUT gene)
- Maple syrup urine disease (BCKDHA, BCKDHB, DBT, and DLD genes)
- Propionic acidemia (PCCA and PCCB genes)
- Phenylketonuria (PKU):
- Neurodegenerative Disorders:
- ISs reported in:
- Globoid cell leukodystrophy (Krabbe disease) (GALC gene) (Gullotta F et al., 1979)
- Menkes disease (ATP7A gene) (Smpokou P et al., 2015)
- ISs reported in:
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Rare Disorders Associated with ISs:
- Cerebrotendineous xanthomatosis (CYP27A1 gene) ( Larson A et al., 2017)
- Glucose transport 1 deficiency (mutations in exon 9 of the SLC2A1 gene) (Lee HH & Hur YJ, 2016)
- Disorders of glycosylation (ALG1,6,11 genes: subtypes CDG and CDG 1x) ( Pereira AG et al., 2017)
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Pyridoxine-Dependent Epilepsy (PDE):
- Presents with various types of severe seizures, including ISs.
- Caused by a mutation in the ALDH7A1 gene, encoding alfa-amino-adipic-semialdehyde (alfa AASA) dehydrogenase (antiquitin).
- Symptoms include partial and generalized seizures, atonic and myoclonic seizures, convulsive status epilepticus, and ISs (van Karnebeek CD et al., 2016; Gospe SM Jr et al., 2001)
- Can manifest with atypical features, late onset, and varying responses to pyridoxine.
- Metabolic disturbances may include hypoglycemic episodes, lactic acidosis, and electrolyte anomalies.
- Neurotransmitter and neuroimaging abnormalities may precede ISs onset (Gospe SM Jr et al., 2001)
- Treatment with large daily supplements of pyridoxine can result in symptom disappearance (van Karnebeek CD et al., 2016)
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Neurocutaneous Disorders (Phacomatoses) and ISs (Infantile Spasms)
- ISs may be one of the earliest manifestations in neurocutaneous disorders.
- Affected children typically show associations of congenital skin and eye anomalies, central and peripheral nervous system structural abnormalities or tumors, and neurological manifestations.
- Often associated with systemic involvement such as heart, vessels, lung, kidney, and bone abnormalities (Ruggieri M et al., 2008; Islam MP & Roach ES., 2015; Ruggieri M & Praticò AD, 2015)
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Tuberous Sclerosis Complex (TSC):
- Most common neurocutaneous disorder associated with ISs (Curatolo P et al., 2008; Chu-Shore CJ et al., 2010)
- Up to >90% of TSC-affected children present with different types of epileptic seizures (Chu-Shore CJ et al., 2010)
- Caused by mutations in the TSC1 or TSC2 genes, affecting the hamartin/tuberin complex and mTOR pathway.
- Leads to neuronal/interneuronal disruption, malformation of brain cortical migration and layering, cortical tubers, white matter anomalies, subependymal nodules, subependymal giant cell astrocytoma, and brain cysts (Curatolo P et al., 2018)
- Basis for susceptibility to epileptic seizures and neurodevelopmental, behavioral, and cognitive defects (de Vries PJ et al., 2018)
- Focal cortical tuber resection in TSC patients with drug-resistant epilepsy showed important decreases or cessation of seizures (Song J et al., 2018; Fohlen M et al., 2018)
- New treatments with mTOR inhibitors proposed for drug-resistant epilepsy, including ISs, but faced criticism due to side effects and poor efficacy over time (Ji S et al., 2017; Franz DN et al., 2018; Curatolo P et al., 2018)
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Neurofibromatosis Type 1 (NF1):
- Genetic predisposition to develop benign and sometimes malignant central or peripheral nervous system and systemic tumors due to loss of neurofibromin (NF1 gene product) (Ruggieri M et al., 2008; Ruggieri M & Praticò AD, 2015; Ruggieri M et al., 1999; Monroe CL et al., 2017)
- In a cohort of 630 NF1 patients:
- 37 (5.87%) suffered from epileptic seizures
- Most common seizure types were partial and primary generalized
- Only two children had ISs (Hsieh HY et al., 2011)
- Large multicenter study and systematic review found:
- NF1 children with ISs represented only 1.5% of the NF1 population
- Most had a more favorable outcome (Ruggieri M et al., 2009)
- Seizures, epilepsy, and ISs in NF1 related to disruption in the ras/NF1-related MEK/MAPK/ERK signaling pathway (Ruggieri M et al., 2009)
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Sturge-Weber Syndrome (SWS):
- Features include capillary vascular malformations of the embryonic facial vasculature, leptomeninges, and choroidal eye layer
- Caused by somatic mutations in the GNAQ gene, responsible for vessel and neuronal development
- Most frequent clinical manifestations are epileptic seizures, cognitive, and behavioral abnormalities.
- Seizures occur in up to:
- 77% of patients with unilateral brain involvement
- 92% with bilateral brain involvement (Raches D et al., 2012)
- Seizures mainly partial and tonic-clonic generalized types (Raches D et al., 2012)
- ISs sporadically recorded (Raches D et al., 2012)
- Pigmentary Mosaicism of (the Hypomelanosis of) Ito Type:
- Seizures and Epilepsy:
- Occasionally includes ISs.
- Recorded in children and adults with skin pigmentary anomalies.
- Characterized by hypopigmented whorls and streaks following the lines of Blaschko.
- Lines of Blaschko reflect the arrangement and migration patterns of pigmentary cells in the human embryo and postnatal life.
- Associated Abnormalities:
- Extra-cutaneous abnormalities affecting:
- Eyes
- Musculoskeletal system
- Nervous system
- Complex malformation phenotype known as hypomelanosis of Ito.
- Reflects somatic mosaicism for unknown pigmentary genes [88, 89].
- Extra-cutaneous abnormalities affecting:
- Epilepsy and ISs:
- Likely due to minor mosaic migration disordering.
- Manifests as white matter disarray.
- Typically associated with more severe complex neurological phenotypes [89, 90].
- Likely due to minor mosaic migration disordering.
- Seizures and Epilepsy:
- Role of Immunity in ISs (Infantile Spasms):
- Hypothesized Role:
- Recent studies suggest immunologic events may trigger ISs.
- Observations indicate that some genes involved in ISs pathogenesis also play crucial roles in inflammatory cascades and signaling pathways [91].
- Genetic Involvement:
- Lemke et al. [31]:
- Reported mutations in the GRIN2B gene in two children with ISs. GRIN2B encodes the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are involved in various neurological disorders [31].
- Lemke et al. [31]:
- Immune Response:
- Elevated titers of antibodies against the voltage-gated potassium-channel complex (VGKC) proteins was reported in a 4-month-old infant with ISs whose antibody titer was 201 pmol/L (normal values < 100) [92].
- Hypothesized Role:
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Pathogenesis of ISs (Infantile Spasms)
- Complex and Multifactorial Nature:
- A number of factors can cause ISs, making it difficult to explain each event causing ISs
- Examples of ISs Origins:
- Whole Cortical Involvement:
- Seen in conditions like lissencephaly.
- Focal Cortical Disarrangements:
- Observed in children with polymicrogyria or cortical tubers and white matter disarray secondary to Tuberous Sclerosis Complex (TSC).
- Subcortical Impairment:
- Occurs in children with hydranencephaly.
- Whole Cortical Involvement:
- Disruption of Brain Networks:
- Likely involves disruption of normal brain neuronal/interneuronal networks at molecular, receptor, or cellular levels [15, 16].
- Leads to abnormal interactions between cortical and subcortical structures [93].
- Focal cortical lesions may spread to the basal ganglia, leading to the generalized clinical appearance of spasms and the hypsarrhythmia pattern [93–95].
- Cognitive and Behavioral Associations:
- Cognitive/Intellectual Disability and Autism Spectrum Disorder (ASD):
- Often associated with or preceding the onset of ISs.
- Deletions of SCN2A and SCN3A genes found in a young boy with ASD and ISs supports the hypothesis of a genetic predisposing background leading to ISs and a mixed cognitive/behavioral defect, including intellectual disability and ASD [96].
- Cognitive/Intellectual Disability and Autism Spectrum Disorder (ASD):
- Complex and Multifactorial Nature:
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ISs vs. West Syndrome (WS)
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West Syndrome (WS):
- Regarded as a subtype of ISs.
- Most frequently reported subtype, presenting in about 90% of ISs cases.
- Encompasses a triad:
- Infantile spasms
- Hypsarrhythmia
- Developmental arrest or regression
- Classical Presentation:
- Short episodes of abrupt flexion of the trunk and neck, and adduction of the arms.
- Onset in infancy or early childhood.
- Bilaterally symmetric tonic spasms lasting a few seconds, occurring at wakening and in clusters.
- EEG shows a hypsarrhythmic pattern with chaotic, high-amplitude slow waves and discharges of waves and spikes.
- Associated with psychomotor delay or developmental regression [11, 12].
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Infantile Spasms (ISs):
- Newer term for ISs is Epileptic Spasms (ES).
- Component of WS.
- Clinical Definition:
- Abrupt contractions followed by tonic contraction lasting a few seconds.
- Involvement mainly of muscles of the neck, trunk, and limbs with abduction or adduction of the arms.
- Spasms may appear in flexion, extension, or mixed patterns.
- Episodes of cry or scream may precede or follow the spasm.
- Spasms occur in rapid sequence, mostly before sleep or on awakening.
- Severe ictal phenotypes may occur during sleep.
- During crises, eyes may be fixed or deviated, with possible cardiac and respiratory involvement.
- Post-crises, affected children may be irritable or drowsy [17, 97, 98].
- May occur with facial grimacing, transient focal movements, and blinking [11, 99].
- Onset:
- Typically between 4 and 9 months, peaking around the 6th month of life.
- In 80-90% of cases, spasms manifest within the first year.
- Early symptoms may be unnoticed by parents
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Atypical Patterns:
- Atypical clinical and EEG manifestations of ISs are well known.
- May be related to the child's age at onset and underlying etiologic factors.
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ISs—Atypical Presentations vs. Association of Spasms with Other Seizure Types:
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Subtle Spasms:
- ISs may present with hypsarrhythmia but without clearly definable clinical signs.
- Subtle spasms include:
- Slow abnormal limb movements
- Facial grimacing
- Isolated fixed eyes
- Slow trunk rotation
- Can be associated with other seizure types.
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Atonic Spasms:
- Xue et al. [102]:
- Recorded three different patterns in 12 ISs children:
- Spasms-atonic
- Pure atonic
- Atonic-spasms seizures
- Recorded three different patterns in 12 ISs children:
- Xue et al. [102]:
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Clusters without Hypsarrhythmia:
- Caraballo et al. [103]:
- Studied 48 patients presenting with IS in clusters without hypsarrhythmia:
- Group 1 (30/48): Well-defined electroclinical syndrome with IS manifesting mainly in infancy.
- Group 2 (18/48): Variable patterns of electroclinical syndromes manifesting as epileptic encephalopathies other than ISs.
- Among these, nine had features of Lennox-Gastaut syndrome, four had myoclonic and atonic seizures, two had Dravet Syndrome (one with epilepsy of infancy with migrating focal seizures), others had non-convulsive status epilepticus with atypical absences, and subacute sclerosing panencephalitis.
- Studied 48 patients presenting with IS in clusters without hypsarrhythmia:
- Caraballo et al. [103]:
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Single ES:
- Defined as no other spasms occurring for 1 minute before and after each other.
- Caraballo et al. [104]:
- Evaluated 16 children with this phenotype:
- 9/16 showed a hypsarrhythmic EEG pattern.
- 7/16 did not show hypsarrhythmia.
- Other types of seizures were also recorded, both before and during their epileptic spasms.
- Evaluated 16 children with this phenotype:
- Tarodo et al. [105]:
- Reported an infant with a triad of clusters of IS, vertical binocular nystagmus, and focal tonic seizures during a single ictal event.
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Age of Presentation and Clinical Patterns:
- Age of presentation of spasms generally correlates with clinical and EEG patterns, with some exceptions.
- Miller-Dieker Syndrome Case:
- Initially, subtle spasms with modified hypsarrhythmia.
- Later, typical IS with focal discharges on EEG [106].
- Berg et al. [107]:
- Analyzed infants with spasms vs. other seizure types:
- Age at onset of typical spasms: 6.1 months.
- Age at onset of spasms at slightly older ages: 6.9 months.
- Age at onset of other-than-IS seizure types: 4.7 months (p < 0.0001).
- No correlation between gestational age and age at onset of spasms.
- Analyzed infants with spasms vs. other seizure types:
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- Differential Diagnosis
- Clinical Disorders Mimicking ISs:
- Benign spasms of infancy:
- Usually manifest in the first year of life.
- Myoclonic epilepsy of infancy.
- Benign spasms of infancy:
- Diagnostic Assessment Steps:
- Initial Steps:
- Take an accurate family history.
- Perform a detailed general physical examination.
- Focus on a full neurological assessment, including fundoscopy.
- Aim to exclude systemic anomalies involving:
- Skin
- Face
- Heart
- Limbs
- Internal organs
- Genital organs
- Video-EEG Recording:
- Conduct a complete video-EEG recording.
- If ISs diagnosis is confirmed, proceed with further diagnostic steps.
- Further Diagnostic Steps:
- Ultrasound examination of the heart and internal organs.
- Magnetic resonance (MR) study of the brain (and spine, if indicated by clinical findings).
- Genetic Testing:
- Array-CGH analysis to search for chromosomal abnormalities and/or deletions/duplications.
- Further genetic testing includes:
- Oriented NGS analysis.
- NGS analysis comprehensive for whole epilepsy gene panels.
- When available, conduct WES and WGS to complete genomic analyses, especially in cases negative to array-CGH and NGS.
- Metabolic Assessment:
- Mandatory when the disorder shows rapid progression
- Initial Steps:
- Clinical Disorders Mimicking ISs:
Treatment of Infantile Spasms Syndrome (ISs):
- Early Diagnosis:
- Essential for effective response.
- Begin with a bolus of pyridoxine (150 mg in 5-10 min) to exclude pyridoxine-dependent epilepsy:
- Rapid improvement of spasms and EEG abnormalities indicates pyridoxine-dependent epilepsy.
- Standard Treatment:
- Adrenocorticotrophic Hormone (ACTH):
- Dosage varies by institution.
- Study on 200 ISs children: 2-3 IU/kg/day more effective than 1.1-1.9 IU/kg/day or 3.1-4 IU/kg/day (p < 0.01) [112].
- Most studies suggest low doses are as effective as high doses [113].
- Treatment duration: 3-4 weeks.
- Side effects: immunosuppression, infections, hypertension, metabolic reactions, renal failure [93, 110].
- Prednisolone:
- Effective at 40-60 mg/day for 14 days [114].
- May regulate ISs-related immune dysregulation [110].
- Some studies show better control of spasms with prednisolone compared to ACTH [115], but other studies show no significant difference [116].
- Pyridoxine:
- Additional therapy to ACTH or prednisolone with contradictory results [117].
- Ketogenic Diet:
- High fats, adequate proteins, low carbohydrates.
- Effective in reducing/stopping spasms and normalizing EEG [118].
- Modified ketogenic diet (MCT oil, ATKINS diet) shows seizure reduction in about 45% of children [119, 120].
- Adrenocorticotrophic Hormone (ACTH):
- Antiepileptic Drugs:
- Common and effective drugs include:
- Nitrazepam, levetiracetam, sodium valproate, topiramate, zonisamide, rufinamide, clobazam, perampanel, and vigabatrin (VGB).
- VGB widely used:
- Starting dosage: 50 mg/kg/day up to 150 mg/kg/day.
- Higher doses more effective in cessation of spasms and EEG resolution [121].
- Side effects: retinal toxicity (21-34% of infants treated >6 months), VGB-associated brain abnormalities (VABAM) [122].
- Combination of ACTH and VGB effective in reducing ISs and improving EEG anomalies [124, 125].
- Study on 66 children: remission of spasms in 33% with VGB alone, 39.4% with VGB and prednisolone [126].
- No improved developmental or epilepsy outcomes with VGB and hormonal treatment vs. hormonal therapy alone [110].
- Experimental treatment with VGB analogue (CCP-115) proposed [127].
- Study on 24 patients: sodium valproate (VPA) alone or with clonazepam/nitrazepam effective in 45.8% [128].
- Developmental delay reported with VPA, acute liver failure associated with POLG mutations [129].
- Second treatment after initial failure effective in one third of cases [130].
- Common and effective drugs include:
- Surgical Treatment:
- Rarely indicated.
- Considered when well-documented focal epileptogenesis is present and pharmacologic treatment fails.
- Indicated for children with focal structural lesions confirmed by MRI, PET scan, and EEG abnormalities [108].
- Emergent Antiepileptic Therapies:
- Targeted drug therapies based on genetic research:
- Rapamycin/everolimus for TSC1/TSC2 (mTOR pathway) [136].
- Memantine targeting GRIN2 A (NMDA) receptor [137].
- Retigabine (ezogabine) for voltage-gated potassium channel (KCNQ2)-related ISs [138].
- Targeted drug therapies based on genetic research:
Clinical Outcome of Infantile Spasms (ISs):
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Developmental Delay:
- Ranges from mild to severe.
- May occur prior to, concurrent with, or following the onset of IS.
- Early signs are difficult to recognize but may include:
- Hypotonia
- Abnormal archaic reflexes
- Lethargy
- Poor reactivity
- These developmental features are related to serial epileptic seizures and underlying molecular/cellular pathogenic events.
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Intellectual Outcome:
- Study on 147 subjects with ISs at adult age using psychological tests or educational status:
- 25 attended school normally with an IQ > 85.
- 11 were slightly impaired with an IQ of 68-85.
- 36 had mild learning disabilities with an IQ of 40-60.
- 75 had severe impairment with an IQ < 40 [139, 140].
- Study on 147 subjects with ISs at adult age using psychological tests or educational status:
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Association with Autism Spectrum Disorder (ASD):
- Frequently reported.
- Historical observation of ASD features in the West's son [11, 15, 141].
- Strasser et al. [142]:
- ASD reported in 19.9% of subjects with ISs compared to 4.7% of other epilepsy types.
- Study on 214 Subjects:
- 33 (13%) diagnosed with ASD [143].
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Seizure Remission and Frequency:
- Long-term follow-up of 147 subjects (20-35 years):
- Seizure remission in one third of cases.
- Daily or monthly seizures in another third.
- Less frequent seizures in the remaining third [140–144].
- Krijgh et al. [145]:
- At 8 weeks and 1 year follow-up of 162 subjects:
- 64 (40%) were seizure-free.
- At 8 weeks and 1 year follow-up of 162 subjects:
- IS tends to disappear within 3 to 4 years of age.
- Transition from IS to Lennox-Gastaut syndrome occurs in 18% of cases [139, 140].
- Long-term follow-up of 147 subjects (20-35 years):
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Fatal Evolution:
- Reported in 13% of cases:
- Granstrom [146]
- Riikonen in a series of 214 children with ISs [147].
- Reported in 13% of cases:
Factors Influencing the Outcome of Children with ISs (Infantile Spasms):
-
Treatment Response:
- Poor response to treatment negatively affects outcome.
-
Evolution to Other Epileptic Syndromes:
- Transition to other syndromes impacts prognosis.
-
Developmental Delay and Intellectual Disability:
- Degree of developmental delay and intellectual disability influences outcome.
-
Behavioral Disturbances:
- Includes autism spectrum disorders.
-
General Clinical Impairment:
- Worsening secondary to treatment side effects.
-
Recurrence of Seizures:
- Considered a negative factor for prognosis.
- Leads to intellectual disability [6, 7].
-
Major Negative Prognostic Factors:
- Underlying Etiological Event:
- Major negative effects in prognosis are related to the underlying molecular/cellular etiological event causing the syndrome [148].
- GulMert et al. [149]:
- Relevant prognostic factors include:
- Etiology
- Age at time of presentation
- Late and inappropriate treatments
- Poor outcomes associated with:
- Severe brain malformations
- Post-infectious diseases
- Primary genetic causes [140]
- Relevant prognostic factors include:
- Underlying Etiological Event:
-
Efficacy of Treatment:
- Limited in most cases when the pathogenic/etiologic event is severe.
- Therapeutic Developments:
- Combined therapy has shown to produce good results.
- Targeted genetic treatments represent potential future hope for severe conditions like ISs.
- Future developments in therapies, based on both new and existing molecules, are anticipated.
- Advances in molecular targeted therapy may represent the best approach to mitigate the harmful effects of WS.
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Key source:
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Cite this: Cite this: ICNApedia contributors.Infantile Spasms Syndrome. ICNApedia, The Child Neurology Knowledge Environment. 21 November 2024. Available at: https://icnapedia.org/knowledgebase/articles/infantile-spasms-syndrome Accessed 21 November 2024.