Infantile Epileptic Spasms Syndrome (West Syndrome)

Etiology

Infantile spasms can be classified into 2 well-known groups: symptomatic and cryptogenic. An additional subgroup of cryptogenic proposed by the International League Against Epilepsy (ILAE) is known as idiopathic infantile spasm.[1][3]

Symptomatic infantile spasms are described in patients with an “identified etiology and/or significant developmental delay at the time of spasm onset.”[1] The identified etiology is found in 60% to 70% of symptomatic infantile spasms cases.[4][5] Symptomatic infantile spasms can be divided into prenatal, perinatal, and postnatal.

Prenatal

• CNS malformations: Cortical dysplasia is the most common central nervous system (CNS) malformation to occur in the prenatal period, accounting for 30% of cases. Cerebral dysgenesis, lissencephaly, holoprosencephaly, and hemimegalencephaly account for the additional CNS malformations associated with infantile spasms.[5]
• Neurocutaneous disorders: Neurocutaneous disorders must be considered an etiology for infantile spasms. The most common neurocutaneous disorder associated with infantile spasms and accounting for 10% to 30% of prenatal causes is tuberous sclerosis complex (TSC), in which 68% of patients have infantile spasms.[5] The other neurocutaneous disorders with etiological associations to infantile spasms are nevus linearis sebaceous, incontinentia pigmenti, Ito syndrome, and neurofibromatosis type 1. These disorders are less commonly associated with infantile spasms than TSC but should be a part of the neurocutaneous etiologies of infantile spasms.
• Chromosome abnormalities: Down syndrome is the most common chromosomal abnormality associated with infantile spasms. Up to 15% of prenatal causes of infantile spasms are attributed to chromosome abnormalities, including 18q duplication, 7q duplication, deletion of the MAGI2 gene on chromosome 7q11.23-q21.11, and partial 2p trisomy.[6][7]
• Genetic mutations: In addition to chromosomal abnormalities, genetic mutations such as those encoding the forkhead protein G1, syntaxin-binding protein 1, calcium or calmodulin-dependent serine protein kinase, ALG13, pyridoxamine-5’-phosphate oxidase, and adenylosuccinate lyase are associated.[8][9][10]
• Inborn errors of metabolism: Twenty-five metabolic disorders have associations with infantile spasms. Phenylketonuria is the most common inborn error of metabolism with etiological associations to infantile spasms in countries where PKU is not identified at birth; this accounts for 12% of patients with PKU.[11]
• Congenital infections: Congenital infections are the last prenatal insult that must be considered with associations to infantile spasms. These congenital infections include toxoplasmosis, syphilis, cytomegalovirus infection, and Zika virus infection.[1] 

Perinatal

Though prenatal factors account for the greatest proportion of cases of symptomatic infantile spasms, perinatal causes of infantile spasms, including hypoxic-ischemic encephalopathy and neonatal hypoglycemia, also have etiologic associations with infantile spasms. Low birth weight is another factor 3 to 4 times more prominent in children with infantile spasms than in the general population. At this time, no association was found between infantile spasms and prematurity.[12][13]

Postnatal

The last etiological association with symptomatic infantile spasms is postnatal insults; these include traumatic injury, near drowning, tumors, and CNS infections with attribution of 15% to 67% of cases of symptomatic infantile spasms.[1]

As noted above, infantile spasms are classified as symptomatic when there is an identifiable cause in addition to developmental delay before the onset of spasms. Cryptogenic infantile spasms have 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.[1] 10% to 40% of patients are classified as cryptogenic. Cryptogenic infantile spasms are associated with a better prognosis as compared to symptomatic infantile spasms.[1] 

Recently, the ILAE has proposed an additional group to differentiate a subset of cryptogenic infantile spasms based on the presence or absence of developmental delay before the onset of symptoms, identified as idiopathic. Patients with idiopathic infantile spasms have normal development before the onset of symmetric spasms, a normal examination, normal neuroimaging, and hypsarrhythmic EEG pattern without focal epileptiform abnormalities.[3]

Epidemiology

Infantile spasm 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 annually.[1] The onset spans from the first week of life to 4.5 years, with an average onset age of 3 to 7 months.[14][15][16] Numerous studies have been performed to determine the likelihood of males versus females being diagnosed with infantile spasms without clear evidence. Some studies determine a slightly higher rate of males than females being affected, with a ratio of 60:40.[1] In regards to the genetics of infantile spasms, it appears to occur in all ethnic groups with a 1% to 7% family history of epilepsy of any type.[1][14] The epidemiology of infantile spasms is established, but the pathophysiology of the disease is evolving.

Pathophysiology

Current research using animal models is being performed to contribute to understanding the pathophysiology of infantile spasms. One theory in the pathophysiology of infantile spasms is that it “results from a nonspecific insult at a critical point in the ontogenetic development of the brain.”[17] 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 infantile spasms; this theory was developed from the responsiveness of the condition to adrenocorticotropic hormone (ACTH) treatment.[18][19] Additional pathogenesis stems from the origin of epileptic spasms, which primarily occur in the cerebral hemispheres or the brainstem. Autopsy studies and neuroimaging, EEG findings, and neurotransmitter abnormalities support each premise.[20][21][22]

History and Physical

Patients are grouped into symptomatic versus cryptogenic versus idiopathic infantile spasms, but clinicians must be able first to identify the clinical features that prompt further investigation for 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 developmental regression.[1] As the name indicates, 90% of children affected by infantile spasms present at less than 1 year of age with a peak incidence of 3 to 7 months.[14][16] Furthermore, as the name indicates, infantile spasms are defined by spasms that involve the muscles of the neck, trunk, and extremities; spasms may be flexor, extensor, or mixed flexor-extensor.[14] Clinicians may note movements such as head bobbing or body crunching. The spasms typically occur in 2 phases; the initial phase is sudden 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.[23]

Spasms range from a few to more than a hundred, occurring in clusters ranging from less than 1 minute to 10 minutes.[1] Also, spasms typically happen in the waking state or the daytime.[24] 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.[23] Lastly, as described in the definition of infantile spasms, neurodevelopmental delay with regression of motor and cognitive abilities occurs.[1] Developmental milestones include rolling over, sitting, crawling, or babbling. Parents may also note the loss of social interactions, social smiles, or increased fussiness or silence.[1]

All the above typically occurs through several stages:

1. The first stage is relatively mild, with infrequent and isolated spasms. This is associated with developmental regression.
2. The mild stage then progresses to a more severe stage with increased frequency and clustering of spasms. The developmental regression noted in stage 1 is more pronounced.
3. A progressive decrease in spasm frequency and severity characterizes the last stage. Spasms may completely resolve and be replaced by other types of seizures.[1][25]

Clinicians must be able to identify and begin early diagnostic testing for infantile spasms because the time to recognition and treatment is important to prognosis.

Evaluation

After a clinician has identified the clinical features of infantile spasms, the initial step 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 unclear on the initial EEG, repeat or prolonged monitoring can be performed 1 to 2 weeks after the initial study.[26][27] The characteristic EEG finding to diagnose infantile spasms is a pattern known as hypsarrhythmia. This pattern comprises “very high voltage, random, slow waves and spikes in all cortical areas.”[14] Spikes may occur in a generalized manner but are never rhythmic or organized, as seen in childhood absence epilepsy.[28] The other interictal patterns seen on EEG in a patient with infantile spasms are focal or multifocal spikes and sharp waves, diffuse or focal slowing, paroxysmal slow or fast bursts, and slow spike and wave patterns.[28]

Neuroimaging is the next diagnostic test after an EEG shows findings suggestive of infantile spasms. The etiology of infantile spasms 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.[29] Repeat MRI imaging in 6 months is recommended if the initial MRI is normal and no other etiology is identified.[28] In some cases of infantile spasms, there are diffuse structural brain diseases with no focal or lateralizing features on imaging studies that are identified with positron emission tomography and should be pursued if suspected.[29]

After clinical evaluation, EEG and MRI are obtained, and if there is no obvious cause of infantile spasms, then further metabolic and genetic testing should be obtained.

To further evaluate the metabolic etiologies of infantile spasms, 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.[14]

The initial genetic testing of choice would include an epilepsy gene panel. If, after thorough metabolic evaluation and the epilepsy gene panel, no apparent cause of infantile spasms is identified, then whole-exome sequencing should be considered.[10] The patients with infantile spasms who do not have an identifiable cause after the above evaluation are classified in the grouping of cryptogenic infantile spasms, which encompasses 10% to 40% of those with the disorder. Once diagnostic testing is completed, the patient should begin treatment without delay.

Treatment / Management

The treatment of infantile spasms should be initiated immediately once infantile spasms are suspected with hormonal therapy, antiseizure medications, or dietary changes. The first line of treatment for infantile spasms is hormonal therapy with corticotropin, ACTH.[14][30] ACTH is thought to work by suppressing a corticotropin-releasing hormone that, in animal models, was found to be an endogenous neuropeptide that provoked convulsions.[31][32] The above theory needs further investigation into ACTH's exact mechanism of action.(A1)

Once ACTH therapy was begun, the effectiveness with a cessation of spasms was 7 to 12 days.[33][34] Different dosing regimes, low vs high dose, have been cited. 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.[29] The alternate high dose regime consists of ACTH 75 units/m² IM twice daily for 2 weeks, followed by a taper for 2 weeks.[33][35][36] For both dosing regimes, if relapse occurs, a second course for 4 to 6 weeks is administered.[14](A1)

ACTH treatment does have side effects, including “hypertension, immune suppression, infection, electrolyte imbalances, GI disturbances, ocular opacities, hypertrophic cardiomyopathy, cerebral atrophy and growth impairment.”[37] Due to these side effects, low-dose, short-term therapy is recommended.[29] When a patient receives treatment, clinicians should monitor blood pressure, serum glucose, potassium, and sodium, screen for cushingoid features, and be cognizant of any signs of infection.[1](A1)

The other hormonal therapy that has potential effectiveness in infantile spasms treatment is corticosteroids. At this time, the optimal preparation, dosing, and duration have not been established as there is only probable effectiveness of corticosteroids.[26] The probable effective dose is prednisone 2 mg/kg per day for a 6-week course.[37] Other alternatives are available for initial treatment.(A1)

An alternative initial treatment for infantile spasms after consideration of ACTH is vigabatrin. Vigabatrin is a GABA-transaminase inhibitor, allowing for increased CNS GABA.[38] The time to cessation of spasms after the initiation of vigabatrin is slightly longer than that of ACTH, ranging from 12 to 35 days.[39] Vigabatrin dosing is initiated at 50 mg/kg daily; dosing can be escalated to 100 to 50 mg/kg per day if required.[1] 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 with discontinuation of the drug.[1] Other side effects that must be monitored include sedation, irritability, insomnia, and hypotonia.[1](B2)

One study suggests that the combination of vigabatrin, ACTH, or corticosteroids is superior to ACTH or corticosteroids alone.[40]

Regarding comparison to ACTH, vigabatrin is inferior to ACTH when assessing short-term outcomes.[37] However, vigabatrin is more effective when treating infantile spasms in infants with tuberous sclerosis.[28] Research continues to test the effectiveness of new antiseizure medications in treating infantile spasms, but further clinical trials will need to occur before the recommended use.[37](A1)

One recent randomized trial sought to assess the efficacy of therapy by using the term freedom from treatment failure. They defined freedom from treatment failure as evaluation at 60 days that required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. This cohort showed that freedom from treatment failure rates were calculated as follows: ACTH 88/190 (46%), oral steroids 42/95 (44%), and Vigabatrin 32/87 (37%).[41](B2)

Topiramate and levetiracetam have efficacy at ameliorating spasms and halting hysparrhythmia.[30](A1)

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.[29] 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.[29] Similar results were found in a systematic review of the literature. They evaluated 13 observational trials in which the ketogenic diet resulted in 64.7% of patients experiencing a spasm reduction >50%, and 34.61% were spasm-free.[42] At this time, the ketogenic diet can be an adjunct to ACTH or Vigabatrin or cases refractory to treatment.(A1)

Surgical treatment is another consideration for refractory infantile spasms if a focal-cortical structural, metabolic abnormality, or neurodevelopmental arrest or regression is noted.[43][44][45] (B2)

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 must record the complete cessation of spasms with a repeat EEG that shows the resolution of hypsarrhythmia.[14] Despite the above treatment regimens, there are still questions, and further research is being pursued regarding the mechanism, optimal drug, dose, duration of therapy, and importance of prompt initiation of treatment.(B3)

Differential Diagnosis

The differential diagnosis for infantile spasm 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.[23] As visual observation alone cannot distinguish between the above, clinicians must consider infantile spasms when considering what might be normal infant behavior.[46] Further testing must be performed if clinical suspicion is high.

Prognosis

With continued research regarding infantile spasms and their etiologies, pathogenesis, diagnosis, and treatment, the overall prognosis of infantile spasms is poor. Mortality rates of infantile spasms range from 3% to 33%.[46] 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.[29][47][29] Cryptogenic infantile spasms have a better prognosis than symptomatic infantile spasms.[29] Better outcomes have also been seen in those with short delays between presentation and initiation of treatment and those who respond to ACTH. This reinforces why clinicians need to be aware of the signs of infantile spasms and the diagnostic strategies and best practices; time is the prognosis.

Complications

In addition to a high risk of persistent epilepsy, babies with infantile spasms commonly have neurodevelopmental problems, including the following:

• Eyesight
• Speech
• Hearing
• Writing skills
• Fine and gross motor development
• Autistic traits