Background
Infantile epileptic spasms syndrome (IESS) is a term proposed by the International League Against Epilepsy (ILAE) to broaden the classification of West syndrome by including infants who present with epileptic spasms but do not fulfill all the classical criteria of West syndrome. [1, 2] Traditionally, West syndrome is defined by a triad of epileptic spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and developmental stagnation or regression. However, IESS recognizes that some infants may exhibit epileptic spasms without showing all these features. For instance, the developmental impact might not be immediately evident, or the characteristic hypsarrhythmia on EEG may not be present.
The term IESS was suggested to include both classic West syndrome and cases where one or more of the traditional criteria are missing. This change aims to improve early diagnosis and treatment, as quicker intervention is associated with better outcomes. Additionally, the term "epileptic" was added to emphasize the epileptic nature of the syndrome, distinguishing it from nonepileptic conditions that might involve spasms.
This updated classification reflects a more inclusive and flexible approach to diagnosing and treating infantile spasms, acknowledging that variations exist in how the syndrome presents in different infants.
Etiology
Infantile epileptic spasms are believed to reflect abnormal interactions between the cortex and brainstem structures. Focal lesions early in life may secondarily affect other sites in the brain, and hypsarrhythmia may represent this abnormal activity arising from multiple brain sites. The frequent onset of infantile spasms in infancy suggests that an immature central nervous system (CNS) may be important in the syndrome’s pathogenesis.
The brain–adrenal axis also may be involved. One theory states that the effect of different stressors in the immature brain produces an abnormal, excessive secretion of corticotropin-releasing hormone (CRH), causing spasms. [3] The clinical response to adrenocorticotropic hormone (ACTH) and glucocorticoids can be explained by the suppression of CRH production.
An existing animal model of infantile epileptic spasms may provide better insight into the pathogenesis of this disorder. The model uses a sodium channel blocker, tetrodotoxin (TTX), that is infused into the hippocampus of rodents. This infusion has produced clinical spasms in rats with electrographic findings similar to those seen in human infantile spasms. [4]
Infantile epileptic spasms can be classified according to their suspected etiology as symptomatic, cryptogenic, or idiopathic.
Symptomatic
Patients are diagnosed with symptomatic infantile epileptic spasms if an identifiable factor is responsible for the syndrome. Virtually any disorder that can produce brain damage can be associated with infantile spasms. The list of etiologies can be subdivided into prenatal disorders, perinatal disorders, and postnatal disorders.
Prenatal disorders associated with infantile epileptic spasms include the following:
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Hydrocephalus
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Hydranencephaly
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Migrational disorders such as schizencephaly polymicrogyria
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Sturge-Weber syndrome
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Incontinentia pigmenti
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Tuberous sclerosis
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Trisomy 21
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Hypoxic-ischemic encephalopathy
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Congenital infections
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Trauma
Perinatal disorders giving rise to infantile epileptic spasms include the following:
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Hypoxic-ischemic encephalopathy
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Meningitis
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Encephalitis
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Trauma
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Intracranial hemorrhages
Postnatal disorders associated with infantile epileptic spasms include the following:
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Pyridoxine dependency
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Inborn errors of metabolism such as nonketotic hyperglycinemia, maple syrup urine disease, phenylketonuria, biotinidase deficiency, lysosomal disorders
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Mitochondrial encephalopathies
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Meningitis
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Encephalitis
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Trauma
Evaluating children with infantile epileptic spasms for possible tuberous sclerosis is critical, as this is the single most common disorder, accounting for 10–30% of prenatal cases of infantile spasm. Tuberosis sclerosis is an autosomally dominant inherited disease with variable manifestations, including cardiac tumors, kidney tumors, cutaneous malformations such as ash-leaf hypopigmented lesions, and seizures. [5]
Of patients with infantile epileptic spasms, 70–75% have symptomatic epilepsy; this percentage depends on the degree of sophistication of diagnostic studies. (The development of more exquisite neurodiagnostic techniques is expected to alter the relative proportion of symptomatic, cryptogenic, and idiopathic cases that has been reported.)
Cryptogenic
Patients have cryptogenic infantile epileptic spasms if no cause is identified but a cause is suspected and the epilepsy is presumed to be symptomatic.
The proportion of cryptogenic cases varies from 8% to 42%. This wide range may be related to variations in the definition of the term cryptogenic and the age of patients at diagnosis, since assessment of developmental level in early infancy is difficult.
Idiopathic
Patients may be considered to have idiopathic infantile epileptic spasms if normal psychomotor development occurs prior to the onset of symptoms, no underlying disorders or definite presumptive causes are present, and no neurologic or neuroradiologic abnormalities exist. Some investigators use the terms idiopathic and cryptogenic interchangeably. The percentage of idiopathic cases reportedly is 9–14%.
Genetics
There has been an increased understanding of the role of genetic defects in the etiology of infantile epileptic spasms, such that there are panels of genetic mutations that are commercially available for testing. In addition to the genetic mutations in TSC1 and TSC2, which cause tuberous sclerosis, [5] specific genetic defects have been identified in many patients with early onset of infantile epileptic spasms, including mutations in the gene ARX on the short arm of chromosome X, which is associated with a wide variety of structural brain abnormalities, and a mutation in the cyclin-dependent kinase-like protein 5 (CDKL5).
Epidemiology
Frequency
Infantile epileptic spasms syndrome (IESS) constitutes 2% of childhood epilepsies but 25% of epilepsy with onset in the first year of life. The rate of IESS is estimated to be 2.5–6.0 cases per 10,000 live births. Its prevalence rate is 1.5–2.0 cases per 10,000 children aged 10 years or younger.
IESS occurs in 0.05 (Estonia) to 0.41 (Oulu, Finland) of 1000 live births and in 1.4% (Estonia), 4.2% (Odense, Denmark), and 7.6% (Tampere, Finland) of children with epilepsy.
Sex- and age-related demographics
Although males are affected by IESS slightly more often than females, no significant gender difference is noted. Ninety percent of infantile epileptic spasms begin in infants younger than 12 months. Peak onset is at age 4–6 months. [6]
Prognosis
The long-term overall prognosis for patients with infantile epileptic spasms symdrome (IESS) is poor and is related directly to the condition’s etiology. [7, 8] Infants with idiopathic infantile epipleptic spasms have a better prognosis than do infants with symptomatic infantile epileptic spasms. Only 14% of infants with symptomatic West syndrome have normal or borderline-normal cognitive development, compared with 28–50% of infants with idiopathic infantile epilpetic spasms. Intellectual disability is severe in 70% of patients, often with psychiatric problems such as autistic features or hyperactivity.
Infrequently, spasms may persist in adulthood. It has been found that 50–70% of patients develop other seizure types and that 18–50% of patients will develop Lennox-Gastaut syndrome or some other form of symptomatic generalized epilepsy. [6, 9]
Subsets of patients among the symptomatic infantile epileptic spasms group seem to have a better prognosis. A retrospective study of 17 children with trisomy 21 and infantile spasms found that 13 of 16 survivors were seizure free for more than 1 year and that 10 patients were no longer taking anticonvulsants.
A study of 15 children with neurofibromatosis type 1 and infantile spasms also reported a relatively benign seizure and cognitive outcome.
Favorable prognostic factors also include the following:
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Cryptogenic or idiopathic etiology
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Age of onset of over 4 months
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Absence of atypical spasms and partial seizures
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Absence of asymmetrical EEG abnormalities
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Short time from onset to treatment
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Early, sustained response to treatment
Infants with symptomatic infantile epileptic spasms have been shown to be at higher risk for the development of autism spectrum disorders, compared with those infants with cryptogenic or idiopathic spasms. [10, 11]
Mortality
The premature death rate for IESS ranges from 5% to 31%. The upper limit comes from a study of 214 Finnish children with a history of infantile spasms who were followed for a mean period of 25 years (range, 20–30 y). Most of the deaths (61%) occurred at or before age 10 years, while only 10% occurred after age 20 years.
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Mountainous, chaotic, disorganized rhythms with superimposed multifocal spikes demonstrating hypsarrhythmia in a boy aged 8 months with infantile spasms and developmental delay. Courtesy of E Wyllie.
