Juliann M. Paolicchi, MA, MD
DESCRIPTION 
- An epileptic encephalopathy of infancy or early childhood consisting of myoclonic seizures and an associated electroencephalographic pattern: High-voltage slowing, asynchrony, disorganization, and multifocal spikes (hypsarrhythmia).
- Seizures can be flexor, extensor, mixed flexor/extensor, or arrest/akinetic. They occur in clusters, typically upon awakening or drowsiness, and can have focal features. Associated phenomena include nystagmus, eye deviation, autonomic features (flushing, pallor, and pupillary dilation), or a cry at the conclusion of the spasm.
- The combination of infantile spasms (ISs), hypsarrhythmia, and developmental arrest is known as West syndrome.
- ISs are symptomatic if the child has a coexistent neurologic condition, developmental delay at presentation, or if a specific etiology can be identified. They are cryptogenic if no underlying cause is found.
EPIDEMIOLOGY
Incidence
- Incidence is 0.16–0.42 per 10,000 live births. In tuberous sclerosis (TS), the incidence is 68%.
Prevalence
- Prevalence is around 1:3,200 to 1:3,500 of live births with a nearly equal ratio of boys:girls.
RISK FACTORS
- Almost any cause of pre-, perinatal or early infantile brain injury may lead to ISs, including infection, hypoxic–ischemic injury, trauma, stroke, and cerebral dysgenesis.
Genetics
- Most cases are sporadic with a positive family history present in 3–6%.
- TScomplex (TSC) may be sporadic or autosomal dominant.
- X-linked ISs syndromes (ARX, CDKL-5, STXBP1) show variable penetrance.
ETIOLOGY
- Genetic syndromes:
- Neurocutaneous disorders: TSC, Sturge-Weber syndrome, incontinentia pigmenti, and neurofibromatosis type I
- Down syndrome
- X-linked ISs syndromes: ARX, CDKL5, Aicardi syndrome
- Autosomal ISs syndromes:
- Miller-Dieker syndrome (17p13.3), 18q and 7q duplication, partial 2p trisomy, and STXBP1 and MAGI2 deletions
- Metabolic disorders:
- Malformations of cortical development, especially lissencephaly and hemi-megalencephaly
- Approximately, 40% of ISs are cryptogenic
COMMONLY ASSOCIATED CONDITIONS
- Intrauterine infection, CNS infections
- Cerebral malformations: Malformation of cortical development
- Hypoxic-ischemic encephalopathy, perinatal asphyxia, prenatal/perinatal stroke
- Abusive head trauma
- Intraventricular hemorrhage
- Genetic and neurocutaneous conditions
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HISTORY
- Prenatal and perinatal history, including maternal age, pregnancy complications, perinatal difficulties
- Family history of TS, epilepsy, or previous children with IS or early infant demise
- Developmental history to establish any pre-existing developmental delay.
- Description of spells to differentiate spasms from nonepileptic seizures
PHYSICAL EXAM
- General growth parameters, especially head circumference. Microcephaly suggests pre-existing brain abnormality, poorer prognosis
- Dysmorphism (Down stigmata)
- Retinal defects as in Aicardi syndrome or metabolic diseases
- Hepatomegaly, suggesting inborn errors of metabolism or congenital infection
- Careful skin examination, including Wood lamp examination, should be performed for evidence of neurocutaneous disorders, especially the hypo-pigmented macules associated with TS.
- Neurologic examination: Particular attention should be paid to level of alertness (visual attentiveness often impaired at presentation), developmental milestones, and motor tone.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- Routine blood studies:
- Electrolytes, calcium
- Glucose (although generally unrevealing)
- Chromosomal analysis:
- Karotype for Down's phenotype
- Screening for clinical or radiologic evidence of TS. Genetic testing available for otherneurocutaneous disorders, if suspected
- Chromosome microarray for suspected genetic or cryptogenic cases
- Specific genetic panels available for IS-associated syndromes
- Metabolic screening, including blood lactate, pyruvate, and ammonia. Serum amino acids, cholesterol panel (pyridoxine disorders), urine organic acids. Review neonatal metabolic screening for phenylketonuria and biotidinase.
- TORCH titers if suspicion for congenital infection or microcephaly
Imaging
Initial Approach
- MRI is the single most useful laboratory test for etiologic diagnosis; intracranial calcifications associated with intrauterine infections and TS are more apparent on CT, but CT is rarely needed.
Follow-Up & Special Considerations
- Positron emission tomography (PET) imaging for refractory ISs, and suspected cortical malformations
Diagnostic Procedures/Other
- EEG: A prolonged EEG that includes sleep is recommended. Ictal video-EEG recording is optimal. The characteristic finding is hypsarrhythmia, a background interictal pattern of disorganized, high-voltage activity with bursts of multifocal, and generalized epileptic activity. Hemispheric asymmetry and focal epileptiform abnormalities are not uncommon. Early in IS, hypsarrhythmia may not be present or present only in deep sleep, so serial EEGs or epilepsy monitoring may be necessary. The ictal EEG pattern typically consists of an initial slow wave followed by low-amplitude fast activity (14–16 Hz) or diffuse attenuation, referred to as an electrodecremental response.
- Infants with signs of TS should undergo cardiologic and ophthalmologic evaluation, renal ultrasound; evaluation, and genetic counseling for family members.
- Pyridoxine or folinic acid challenge during EEG
- If no etiology is indentified, consider lumbar puncture for lactic acid, amino acids, folate metabolites, glucose, glycine, and abnormalities of neurotransmitter levels.
DIFFERENTIAL DIAGNOSIS
- Nonepileptic disorders:
- Benign myoclonus
- Benign sleep myoclonus
- Paroxysmal torticollis
- Posturing related to gastroesophageal reflux (Sandifer syndrome)
- Shuddering spells
- Hyperexplexia, or exaggerated startle Myoclonic epilepsies of infancy and other epilepsy syndromes: Such as early myoclonic encephalopathy, Lennox–Gastaut syndrome
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MEDICATION
First Line
- Primary options for treatment are adrenocorticotropic hormone (ACTH) and vigabatrin. A clear consensus on treatment of choice has not been reached. ACTH is the historical treatment option, and high- and low-dose protocols are in use.Treatment is initiated at 150 U/m2/d IM (high dose) or 20–30 U/d (low dose) for 1–2 weeks.
- If the low-dose protocol is not effective after 2 weeks, high dose at 40 U/d is given; the dose is gradually tapered over 1–3 months. A recent study showed no difference in efficacy between high- and low-dose protocols but the high-dose group had a greater side effects. A recent consensus report recommended high-dose ACTH for 2 weeks followed by a taper.
- Vigabatrin is considered the 1st-line agent for IS secondary to TSC. Dosing is initiated at 50 mg/kg/d and increased to 100–200 mg/kg/d for efficacy. The duration of therapy is not established due to potential complication visual-field constriction. Comparison trials with ACTH suggest better tolerance, similar long-term outcomes, but potentially less short-term efficacy.
Second Line
- A trial of pyridoxine (100 mg IV) and folinic acid (2.5 mg IV) should be considered to rule out pyridoxine and folinic acid deficiency/dependency.
- Topiramate (at dosages up to 20–60 mg/kg/d)
- Zonisamide (5–15 mg/kg/d)
- Clonazepam (0.1–0.15 mg/kg/d)
- Nitrazepam (0.5–3.5 mg/kg/d)
- Prednisone (2 mg/kg/d)
- Additional: Valproate, tiagabine
ADDITIONAL TREATMENT
General Measures
The goal of treatment is cessation of spasms and resolution of the EEG. Serial treatment trials are recommended if spasms persist, since failure of one treatment choice does not preclude success with another.
Issues for Referral
Management of IS should be referred to a pediatric neurologist. Additional consultative services may include ophthalmology and genetics.
Additional Therapies
Given association of IS and developmental delay, referral should be made for early intervention services.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Reports exist of successful treatment of IS with daily high-dose pyridoxine (200–300 mg/d).
SURGERY/OTHER PROCEDURES
Surgery may be indicated in malformations of cortical development and treatment refractory IS, especially due to TS and focal cortical dysgenesis. Surgical resection is focused on areas of hypometabolism identified on PET, identifiable cortical dysgenesis, or hypometabolic tubers in TS. Referral to a pediatric epilepsy center is recommended for presurgical evaluation.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
If patient appears ill, focus on ABCs before treatment of spasms. ISs themselves rarely threaten vital functions.
Admission Criteria
- At the onset, patients are often admitted to an epilepsy monitoring unit for diagnosis and to start etiologic investigation and treatment regimen.
- Patients are typically admitted for the initiation of and education about ACTH therapy.
- Vigabatrin therapy and other anti-epileptic therapies can be initiated without hospitalization.
IV Fluids
Nursing
While ACTH is initiated, patient is monitored for blood pressure, stool guiac and urine glucose.
Discharge Criteria
Discharge is determined by establishment of the diagnosis, initiation of the etiologic evaluation, patient education, and, in the case of ACTH, tolerance of initiated therapy.
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FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Close follow-up of patients is recommended to follow efficacy and side effects of treatment.
- Follow-up EEGs are obtained at regular intervals to determine the efficacy of treatment on the resolution of the EEG findings.
- For ACTH therapy, weekly monitoring of BP, glucose, electrolytes, BUN/creatinine, stool guaiac, and signs of infection is recommended.
DIET
- The ketogenic diet has been shown in a prospective trial to be effective in refractory IS. The ketogenic diet should be administered and monitored by a trained nutritionist.
PATIENT EDUCATION
- Parents/caregivers require education in the diagnosis and outcome of IS, side effects of therapy, and need for close follow-up and communication during therapeutic course.
- Given the frequently associated developmental delays, parents/caregivers should be informed about resources for children with disabilities in their communities and may qualify for special medical insurance programs (SSI).
- Parents/caregivers require extensive training in ACTH administration, managing side effects and precautions regarding immunosuppression.
PROGNOSIS
- Developmental retardation occurs in 85% of patients, and long-term outcome is dependent on underlying etiology. Cryptogenic IS is associated with a better prognosis than symptomatic IS.
- Of cases, 10% achieve normal cognitive, physical, and educational development.
- Of children, 50–90% develop other seizure types, most commonly in the symptomatic group. 27–50% develop severe epileptic encephalopathy (Lennox–Gastaut syndrome).
COMPLICATIONS
- ACTH therapy: Weight gain, irritability, sleep disturbance, hyperglycemia, hypertension, electrolyte abnormalities, cardiomyopathy, immunosuppression, gastritis/GI bleeding
- Vigabatrin therapy: Visual field constriction/peripheral retinal injury, hypotonia, drowsiness, irritability, and reversible MRI abnormalities
- Refractory IS can be associated with development of chronic epileptic encephalopathy (Lennox–Gastaut Syndrome).
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