Infantile spasms (IS) is a seizure disorder that was first described by William West in 1841 and has been referred to as West syndrome. It is a disorder that affects mostly those in the first year of life and is described as spasms with characteristic EEG changes known as hypsarrhythmia and a strong association with developmental delay or regression. Infantile spasms have been evaluated for over 170 years in regards to etiology, pathogenesis, clinical features, and diagnosis. The important features and the importance of early diagnosis and treatment are discussed below.
Infantile spasms can be classified into 2, well-known groupings of symptomatic and cryptogenic. An additional subgroup of cryptogenic proposed by the International League Against Epilepsy (ILAE) is known as idiopathic infantile spasm.
Symptomatic IS is described in patients with an “identified etiology and/or significant developmental delay at the time of spasm onset.” The identified etiology is found in 60% to 70% of symptomatic IS cases. Symptomatic IS can be divided into prenatal, perinatal, and postnatal timing when insult occurred.
Though prenatal factors account for the greatest proportion of causes of symptomatic IS, perinatal causes of IS to include hypoxic-ischemic encephalopathy and neonatal hypoglycemia also have etiologic associations with IS. Low birth weight is another factor that is 3 to 4 times more prominent in children with IS than that of the general population. At this time there has been no found associated between IS and prematurity.
The last etiological associations with symptomatic IS are postnatal insults; these include traumatic injury, near drowning, tumors, and CNS infections with attribution of 15% to 67% of cases of symptomatic IS.
As noted above, IS is classified as symptomatic when there is an identifiable cause in addition to developmental delay present prior to the onset of spasms. Cryptogenic IS has no identifiable cause and the following criteria: no other kind of seizures, a normal examination, a normal CT and MRI, recurrence of hypsarrhythmia between consecutive spasms of a cluster, and lack of any focal interictal or ictal EEG abnormalities. Ten percent to 40% of patients with IS will be classified as cryptogenic. Cryptogenic IS is associated with a better prognosis as compared to symptomatic IS. Recently the ILAE has proposed an additional group to differentiate a subset of cryptogenic IS based on the presence or absence of developmental delay prior to the onset of symptoms, which is identified as idiopathic. Patient’s with idiopathic IS have normal development before onset of symmetric spasms,, a normal examination, normal neuroimaging and hypsarrhythmic EEG pattern without focal epileptiform abnormalities.
IS is a unique and rare disorder with an incidence of 1.6 to 4.5 per 10,000 live births; this is roughly 2000 to 2500 new cases in the United States per year. The age of onset spans from the first week of life to 4.5 years of life with an average age of onset being 3 to 7 months of age. Numerous studies have been performed to determine the likelihood of males versus females to be diagnosed with IS without clear evidence. Some studies determine a slightly higher rate of males compared to females being affected with a ratio of 60:40  In regards to the genetics of IS, it appears to occur in all ethnic groups with a 1% to 7% percent family history of epilepsy of any type. The epidemiology of IS has been established, but the pathophysiology of the disease is evolving.
Current research using animal models is being performed to contribute to the understanding of the pathophysiology of IS. One theory in the pathophysiology of IS is that IS “results from a nonspecific insult at a critical point in the ontogenetic development of the brain.” Another is that abnormalities in the hypothalamic-pituitary-adrenal axis, due to immunologic dysfunction or stress from variable causes in early development may contribute to the pathogenesis of IS; this theory was developed from the responsiveness of IS to adrenocorticotropic hormone (ACTH) treatment as will later be discussed. Additional pathogenesis stems from the origin of epileptic spasms which primarily occur in the cerebral hemispheres or the brainstem. Each premise is supported by autopsy studies as well as neuroimaging, EEG findings, and neurotransmitter abnormalities.
Patients are grouped into symptomatic versus cryptogenic versus idiopathic IS, but clinicians must be able first to identify the clinical features that prompt further investigation of IS as a diagnosis. As stated above infantile spasms "are characterized by epileptic spasms with onset in infancy or early childhood that are usually associated with the EEG pattern of hypsarrhythmia, and also developmental regression." As the name indicates 90% of children affected by IS present at less than 1 year of age with a peak incidence of 3 to 7 months. Furthermore, as the name indicates, IS is defined by spasms that involve the muscles of the neck, trunk, and extremities; spasms may be flexor, extensor, or mixed flexor-extensor. Physicians may note movements such as head bobbing or body crunching. The spasms typically occur in 2 phases; the initial phase is sudden in onset, lasting less than 2 seconds, with brief contractions of 1 or more muscle groups. This is followed by a less intense, longer tonic phase lasting 2 to 10 seconds.
Spasms range from a few to more than a hundred, occurring in clusters that range from less than one minute up to ten minutes. Also, spasms typically occur in the waking state or the daytime. Associated with the spasms include motor arrest, lasting up to 90 seconds, as well as rhythmic nystagmoid eye movements or eye deviation. One may also note changes in respiratory patterns Lastly, as described in the definition of IS, neurodevelopmental delay with regression of motor and cognitive abilities occurs. Developmental milestones at this stage include rolling over, sitting, crawling or babbling. Parents may also note the loss of social interactions, social smiles, or increased fussiness or silence.
Clinicians must be able to identify and begin early diagnostic testing for IS because time is important to prognosis.
The initial step, after a clinician has identified the clinical features of IS as above, is to perform electroencephalography (EEG). The EEG should get a full sleep-wake cycle and a full ictal event, best obtained with an overnight inpatient 24-hour video EEG. If the diagnosis is not clear on initial EEG, repeat or prolonged monitoring can be performed 1 to 2 weeks after the initial study. The characteristic EEG finding to diagnosis IS is a pattern known as hypsarrhythmia. This pattern comprises “very high voltage, random, slow waves and spikes in all cortical areas.” Spikes may occur in a generalized manner but are never rhythmic or organized as would be seen in childhood absence epilepsy. The other interictal patterns seen on EEG in a patient with IS are focal or multifocal spikes and sharp waves, diffuse or focal slowing, paroxysmal slow or fast bursts and slow spike and wave patterns.
After an EEG shows findings suggestive of IS, neuroimaging is the next diagnostic test that should be pursued. The etiology of IS is established in 70% of cases with neuroimaging. The imaging of choice, with the highest sensitivity, is MRI and should be the initial scanning method. It is recommended to repeat MRI imaging in six months if the initial MRI is normal and no other etiology is identified. In some cases of IS, there are diffuse structural brain diseases with no focal or lateralizing features on imaging studies that can be identified wi.th positron emission tomography. This should be pursued if suspected.
After clinical evaluation, EEG and MRI are obtained, and if there is no obvious cause of IS, then further metabolic and genetic testing should be obtained.
To further evaluate the metabolic etiologies of IS one should obtain studies such as pyridoxine challenge, urine for organic acids, serum lactate and amino acids, biotinidase determination, cerebrospinal fluid (CSF) analysis of neurotransmitters, lactic acid, amino acids, folate metabolites, glucose and glycine, and lastly, chromosomal studies.
The initial genetic testing of choice would include an epilepsy gene panel. If after thorough metabolic evaluation as well as the epilepsy gene panel no apparent cause of IS is identified then whole-exome sequencing should be considered. The patients with IS who do not have an identifiable cause after the above thorough evaluation will be classified in the grouping of cryptogenic IS which, as above, encompasses 10% to 40% of those with IS. Once diagnostic testing is completed the patient should begin treatment without delay.
The treatment of IS should be initiated immediately once IS is suspected with hormonal therapy, antiseizure medications or dietary changes. The first line treatment for IS is hormonal therapy with corticotropin, ACTH. ACTH is thought to work by suppression of corticotropin-releasing hormone that in animal models was found to be an endogenous neuropeptide that provoked convulsions. The above is a theory that will need further investigation to the exact mechanism of action of ACTH.
Once ACTH therapy is begun the time to effectiveness with a cessation of spasms was 7 to 12 days. Different dosing regimes have been cited, low vs high dose. The low dose regime consists of ACTH 20 to 30 units per day intramuscularly (IM) with reevaluation in 2 weeks, increasing to 40 units per day if spasms or hypsarrhythmia persist. The alternate high dose regime consists of ACTH 75 units/m2 IM twice daily for 2 weeks; this is followed by a taper for an additional 2 weeks..For both dosing regimes if relapse occurs a second course for 4 to 6 weeks is administered.
ACTH treatment does have side effects to include “hypertension, immune suppression, infection, electrolyte imbalances, GI disturbances, ocular opacities, hypertrophic cardiomyopathy, cerebral atrophy and growth impairment.” Due to these side effects a low dose, short-term therapy is recommended. While a patient is receiving treatment clinicians should monitor blood pressure, serum glucose, potassium and sodium, screen for cushingoid features and be cognizant of any signs of infection.
The other hormonal therapy that has potential effectiveness in IS treatment are corticosteroids. At this time as there is only probable effectiveness of corticosteroids the optimal preparation, dosing and duration has not been established. The probable effective dose is prednisone 2 mg/kg per day for a 6-week course. Other alternative treatment are available for initial treatment of IS.
An alternative initial treatment for IS after consideration of ACTH is vigabatrin. Vigabatrin is a GABA-transaminase inhibitor, this allows for increased GABA in the CNS. The time to cessation of spasms after the initiation of Vigabatrin is slightly longer than that of ACTH with a range from 12 to 35 days.. Vigabatrin dosing is initiated at 50 mg/kg per day; dosing can be escalated to 100 to 50 mg/kg per day if required. The typical length of treatment with vigabatrin is 6 to 9 months; clinicians must closely monitor for adverse effects as vigabatrin is known to cause peripheral visual field defects that are permanent and persist even with discontinuation of the drug. Other side effects that must be monitored for include sedation, irritability, insomnia and hypotonia.
In regards to comparison to ACTH, vigabatrin is inferior to ACTH when assessing short-term outcomes. Vigabatrin has been found to be more effective, though, when treating IS in infants that have tuberous sclerosis . Research continues to test the effectiveness of new antiseizure medications in the treatment of IS, but further clinical trials will need to occur prior to the recommended use.
In cases that are refractory to initial treatment with ACTH or Vigabatrin, clinicians may consider initiation of a ketogenic diet. The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. In one study after 1 month of the ketogenic diet, 35% of patients were seizure free with an additional 30% seizure free by the third month. At this time it is recommended that the ketogenic diet be an adjunct to ACTH or vigabatrin or cases refractory to treatment.
Surgical treatment is another consideration for refractory IS if a focal-cortical structural, metabolic abnormality or neurodevelopmental arrest/regression is noted. Once treatment starts, continued monitoring of the patient for side effects as well as treatment effectiveness must occur. To monitor the effectiveness of treatment one most record the complete cessation of spasms with a repeat EEG that shows resolution of hypsarrhythmia. Despite the above treatment regimens there are still questions and further research being pursued regarding the mechanism, optimal drug, dose, duration of therapy, and importance of prompt initiation of treatment.
The differential diagnosis for IS is broad including mild diagnoses such as colic, gastroesophageal reflux, spasticity, benign neonatal sleep myoclonus, or excessive startles or Moro reflexes up to more severe diagnosis. Differentials should also include tonic reflex seizures of early infancy, brain injury, and severe myoclonic epilepsies. As visual observation alone cannot distinguish between the above, IS clinicians must consider infantile spasms when considering what might be normal infant behavior. Further testing must be performed if clinical suspicion is high for IS.
With continued research regarding infantile spasm and its etiologies, pathogenesis, diagnosis, and treatment the overall prognosis of IS is poor. Mortality rates of IS range from 3% to 33%. Not only are mortality rates high but other adverse outcomes including seizures, in up to 60% of patients, and moderated to severe neurodevelopmental disability commonly occur after cessation of the initial spasms. It has been thoroughly demonstrated that cryptogenic IS has a better prognosis than symptomatic IS. Better outcomes have also been seen in those with short delays between presentation and initiation of treatment as well as in those who respond to ACTH. This reinforces why it is important as clinicians to be aware of the signs of IS and the diagnostic strategies and best practices; time is prognosis for IS.
After the diagnosis of IS has been established, thorough patient and parent education are imperative. Discussions regarding the possibility of neurodevelopmental delay, seizures and mortality must occur. Clinicians and family members should also establish medical and psychosocial treatment plans. Providing the family with resources including fact sheets, forums, and treatment options can help family members with self-education to supplement the education provided by a physician.
Because of the complex nature of infantile spasms and the need for prompt diagnosis and initiation of treatment, strict interprofessional communication must occur. Care coordination includes coordination between general pediatricians, a pediatric neurologist, nurses, pharmacists, and therapists. Emergency medical physicians may also be part of care coordination as they will likely evaluate the patient initially when the parents note spasms. Once the emergency room (ER) physician has suspicion for IS, a pediatric neurologist and the patient's general pediatrician should be contacted to evaluate the patient and begin diagnostic measures. They should involve nursing in parent education and coordination of appointments and diagnostic imaging. Once a diagnosis is made, a pharmacist can assist in medicine distribution and dosing, as well as parent education, on medication side effects. The patients should also start occupational, speech, and physical therapy due to the likelihood of developmental delays and regression. Caring for patients with infantile spasms is complex and requires extensive interprofessional communication to improve patient outcomes.
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