Basics
Description
- Infantile spasms (IS) are seizures commonly associated with West syndrome-a severe infantile epileptic encephalopathy often with poor developmental outcome.
- IS are characterized by sudden flexion, extension, or mixed flexion-extension of the neck, trunk, arms, and/or legs.
- IS can be subtle such as a mild contraction of the abdominal muscles or subtle movements of the head, shoulder, or eyes.
- IS can occur singly, but the clustering (often on awakening) is a key diagnostic feature.
- IS are commonly dismissed as "normal" movements or misdiagnosed as reflux/colic.
- West syndrome is classically the triad of (1) IS, (2) developmental delay, and (3) hypsarrhythmia-a chaotic, high amplitude EEG background typically associated with multifocal spikes.
Epidemiology
- The onset occurs in the 1st year of life in >90%, typically 3-12 months of age (peak onset 4-8 months, mean 6 months).
- Rarely occurs after 18 months of age
Incidence
The incidence is 2-3.5/10,000 live births.
Pathophysiology
- Unknown
- In 70-80% of cases, a specific condition is associated with IS; however, this does not necessarily suggest a direct cause-and-effect relationship with IS.
Associated Conditions
- Hypoxic-ischemic encephalopathy (HIE)
- Chromosomal disorders such as trisomy 21
- Brain malformation such as holoprosencephaly, malformations of cortical development (such as pachygyria or lissencephaly [including Miller-Dieker syndrome with deletion of 17p13.3], hemimegalencephaly, schizencephaly, heterotopia, and focal cortical dysplasia)
- Stroke
- Intraventricular/intraparenchymal hemorrhage
- Periventricular leukomalacia
- Tuberous sclerosis complex (TSC)
- Other neurocutaneous conditions such as neurofibromatosis type 1 (NF1), incontinentia pigmenti achromians (Hypomelanosis of Ito)
- Disorders of X-linked inheritance such as Aicardi syndrome (consider in girls with agenesis of the corpus callosum and chorioretinal lacunae)
- Hydrocephalus of various causes
- There is an expanding list of IS-associated genes: ARX, CDKL5, FOXG1, GRIN1, GIN2A, MAGI2, SPTAN1, MEF2C, SLC25A22, STXBP1, SCN1A, SCN2A, GABRB3, and ALG13.
- Trauma (any but often nonaccidental)
- Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy syndrome
- Infections: meningitis/encephalitis, TORCH
- Inborn errors of metabolism such as Menkes disease, disorders of amino acid metabolism (such as phenylketonuria and maple syrup urine disease), pyruvate dehydrogenase complex deficiency, mitochondrial disorders (such as Leigh syndrome), pyridoxine-dependent seizures, glucose transporter protein type 1 (GLUT1) deficiency, and uncommonly, organic acidurias (such as methylmalonic aciduria)
Diagnosis
History
- A description of spells including the timing of onset (single IS can precede clustering)
- Prenatal and perinatal history including complications of pregnancy or delivery, gestational and maternal ages, place of birth (for access to newborn screening)
- History of HIE (perinatal, cardiac arrest, near drowning, near-miss SIDS)
- History of miscarriages, early infant death, family members with birth marks or seizures (a family history of IS is rare but can occur)
- Developmental history including any loss of skills (loss of visual tracking or social smile)
Physical Exam
- Head circumference, dysmorphisms (such as Down syndrome or Miller-Dieker syndrome), cardiac murmur (rhabdomyoma in TSC), skin abnormalities (hypopigmented macules [may be present at birth in TSC and highlighted by the Wood's lamp] and caf © au lait spots [in NF1]), hepatomegaly (inborn errors of metabolism)
- Retinal evaluation (for metabolic disease and chorioretinal lacunae in Aicardi syndrome)
- Social smile, tracking, strength (head lag and axial slipping with the child held underarm in vertical suspension), tone, and reflexes
Diagnostic Tests & Interpretation
- Although nearly all children with IS have an abnormal EEG background, only 60% have hypsarrhythmia (or one of its variants). Thus, the presence of hypsarrhythmia is not required for the diagnosis or treatment of IS.
- The diagnosis is made with a video-EEG to characterize the spell and EEG background.
- An epilepsy protocol brain MRI to determine the etiology is strongly recommended.
- Early diagnosis and effective treatment can improve developmental outcome.
- The diagnostic and posttreatment EEG should include sleep, as the abnormal background is most often present during non-REM sleep.
- IS begins with an initial phasic contraction lasting 1-2 seconds, sometimes followed by a tonic contraction that can last 2-10 seconds.
- Most IS are clinically symmetric, but asymmetric spasms can occur and may indicate a focal brain lesion.
- The EEG background is typically high voltage and disorganized with multifocal spikes.
- The EEG correlate of IS is often a slow wave or sharp then slow wave followed by an electrodecrement (i.e., voltage attenuation).
- A 100-mg pyridoxine infusion during the EEG to assess for background improvement may help diagnose pyridoxine-dependent seizures.
Lab
- Testing should emphasize those conditions with a specific treatment:
- Ammonia level
- Serum lactic acid
- Biotinidase assay (assess newborn screen)
- Serum amino acids (assess newborn screen)
- Copper/ceruloplasmin (for Menkes disease)
- Consider lumbar puncture (LP) for GLUT1 deficiency (compare CSF to serum glucose).
- Urine organic acids (uncommon etiology, assess new born screen)
- Any metabolic, chromosomal, genetic, and CSF studies must be considered on an individual basis: karyotype and or microarray analysis (especially with dysmorphisms), IS-associated gene/panel testing, whole exome sequencing.
Imaging
- Epilepsy protocol, brain MRI is recommended.
- Consider PET to assess for or better define a lesion that may be correctable with surgery.
Diagnostic Procedures/Other
Consider LP for neurotransmitter and folate metabolites, tetrahydrobiopterin, and lactic acid.
Differential Diagnosis
- Normal movements confused with IS: Moro reflex and similar-appearing startle/arousal responses; normal sleep myoclonus and hypnagogic/hypnic jerks
- Nonepileptic movement disorders confused with IS: benign myoclonus of early infancy; posturing; hyperekplexia; colic and gastroesophageal reflux (Sandifer syndrome)
- Epileptic syndrome confused with IS: benign myoclonic epilepsy of infancy
- Neonatal epileptic encephalopathies that may include or evolve to IS: early infantile epileptic encephalopathy (Ohtahara syndrome); early myoclonic epilepsy
- Childhood epileptic encephalopathy that may include or evolve from IS: Lennox-Gastaut syndrome (LGS)
Treatment
Medication
First Line
- Generally accepted 1st-line medical treatments include adrenocorticotropic hormone (ACTH), high-dose oral corticosteroids (HOC), and vigabatrin.
- The etiology may determine the initial treatment: epilepsy surgery (such as tumor, hydrocephalus), ketogenic diet (such as GLUT1 deficiency, pyruvate dehydrogenase complex deficiency), vigabatrin (TSC).
- The approach should focus on an early "all or none" electroclinical remission with early changes in treatment if needed.
- If no clinical remission by 2 weeks, consider changing treatment.
- If there is clinical remission, confirm absence of spasms with EEG (at various durations).
- If spasms noted on EEG, consider modification of treatment.
- ACTH
- High rates of electroclinical remission have been reported with high-dose regimens (see Baram et al, 1996 for published regimen).
- However, one study of high-dose (150 U/m2/day) versus low-dose (20-30 U/day) found no difference in electroclinical remission.
- Short-course ACTH may limit side effects.
- Common: weight gain (increased appetite/fluid retention), irritability, poor sleep, hypertension
- Less common: hyperglycemia, electrolyte abnormalities (hypokalemia), hypertrophic cardiomyopathy, immunosuppression, gastritis/gastric ulcer, reduced bone mineral density, adrenal insufficiency/failure
- Rare: death most commonly due to immunosuppression with infection
- Inpatient admission is typically performed for initiation of treatment and caregiver education.
- Gastric acid suppression to avoid gastritis/gastric ulceration is typical.
- ≥1 time weekly during treatment: blood pressure, urine glucose, and stool guaiac
- One time weekly during treatment: electrolytes
- Treatment of hypertension may be needed (e.g., enalapril or a reduced dose of ACTH).
- High-dose oral corticosteroids
- High-dose regimens are recommended (see Lux et al, 2004 for published regimen)
- The side effects, initial hospital admittance, and monitoring are the same as for ACTH.
- Vigabatrin
- Initially, 50 mg/kg/24 h (divided twice daily) and increased by 50 mg/kg/24 h every 3 days to a maximum dose of 150-200 mg/kg/24 h (divided twice daily)
- If there is no response in 2 weeks, use an alternative and taper vigabatrin off.
- With electroclinical remission, the dose can be continued for 6 months and then weaned.
- Risk of permanent peripheral visual field loss
- The incidence and degree of retinal injury with short courses of vigabatrin (e.g., 6 months) are unknown but appear to be low.
- The short-term rates of clinical remission appear to be superior with hormone treatment (ACTH or HOC) compared to vigabatrin, and this may impact later developmental outcome (at least for those with an unknown etiology).
Second Line
- Ketogenic diet: treatment of choice for some conditions and can be effective for others
- Zonisamide (5-15 mg/kg/day divided twice daily)
- Valproic acid: Consider POLG mutation analysis before starting (15-45 mg/kg/day in 2-3 divided doses).
- Oral pyridoxine: Some cases of pyridoxine-dependent seizures require longer treatment trials (e.g., 10 mg/kg/day for several weeks).
- Topiramate: not a 1st-line treatment due to the low-response rates, but commonly used and occasionally effective (10-30 mg/kg/day once daily or divided twice daily)
Surgery/Other Procedures
- Can be effective and should be considered early (generally after failed 1st-line treatment)
- Examples: functional hemispherectomy for stroke and hemimegalencephaly, shunting of hydrocephalus, and resection of a tumor for focal cortical dysplasia
Inpatient Considerations
Initial Stabilization
After the ABCs, consider metabolic stabilization and treatment of convulsive seizures if presenting with IS (IS themselves are typically not life-threatening.).
Ongoing Care
Prognosis
- Prognosis depends on the underlying etiology and associated conditions.
- Best prognosis in those with unknown etiology and normal development before diagnosis
- About 1/3 die early (most from underlying disease and uncommonly from treatment).
- Spontaneous remission of IS can occur (cumulative rate of 25%, 1 year from onset).
- Regardless of treatment, IS typically remits (persisting beyond 7 years of age in only 8%).
- Early, successful, and sustained electroclinical remission, as well as a short time-lag to treatment, is necessary for optimal outcome
- About 1/3 with electroclinical remission will experience a relapse requiring treatment.
- About 1/2 have other seizure types (occurring before, after, or at the time of IS onset).
- 1/5-1/2 will evolve to LGS.
- 1/5-1/4 will have a favorable outcome (normal or slightly impaired intelligence).
- About 1/3 will have autism (common in TSC).
- About 2/5 will have cerebral palsy.
Complications
For hormone treatment: Hold non-live vaccines for 2 months and live vaccines for 6 months.
Additional Reading
- Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms. Pediatrics. 1996;97(3):375-379. [View Abstract]
- Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. 2004;364(9447):1773-1778. [View Abstract]
- Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia. 2010;51(10):2175-2189. [View Abstract]
Codes
ICD09
- 345.60 Infantile spasms, without mention of intractable epilepsy
- 345.61 Infantile spasms, with intractable epilepsy
ICD10
- G40.822 Epileptic spasms, not intractable, w/o status epilepticus
- G40.824 Epileptic spasms, intractable, without status epilepticus
SNOMED
- 28055006 West syndrome (disorder)
- 432031000124101 Infantile spasms, non-refractory (disorder)
- 230417001 Symptomatic West syndrome
FAQ
- Q: Should I prescribe an abortive medication for longer clusters of IS?
- A: Generally, No. IS do not typically respond acutely to benzodiazepines.
- Q: My patient has IS and an abnormal EEG but no hypsarrhythmia. Should I treat him?
- A: Yes. Treat the seizures with 1st-line therapy; only 60% will have hypsarrhythmia.
- Q: Caregivers report that IS has resolved with treatment. Do I need the EEG?
- A: Yes. IS can be subtle making them difficult to detect. In addition, you must have evidence of EEG background improvement.