Target System: Central Nervous System
Synonyms and related keywords: infantile spasms, hypsarrhythmia, developmental delay, West syndrome, mental retardation, epilepsy syndrome
Background: West syndrome is composed of the triad of infantile spasms, an interictal EEG pattern termed hypsarrhythmia, and mental retardation, although the diagnosis can be made even if one of the 3 elements is missing (according to the international classification). This severe epilepsy syndrome is an age-dependent expression of a damaged brain. The term “infantile spasms” has been used to describe the seizure type, the epilepsy syndrome, or both. In this article, the term “infantile spasms” is synonymous with West syndrome.
The syndrome's namesake, Dr W J West, gave the first detailed description of infantile spasms, as they occurred in his child. In a letter to the editor of The Lancet in 1841, West described the events as “bobbings” that “cause a complete heaving of the head forward towards his knees, and then immediately relaxing into the upright position … these bowings and relaxings would be repeated alternately at intervals of a few seconds, and repeated from 10 to 20 or more times at each attack, which attack would not continue more than 2 or 3 minutes; he sometimes has 2, 3 or more attacks in the day.”
This detailed clinical description was followed approximately 100 years later by the report of the typical interictal EEG pattern termed hypsarrhythmia. Most patients with infantile spasms have some degree of developmental retardation.
The eponym West syndrome was created in the early 1960s by Drs. Gastaut, Poirier, and Pampiglione.
Pathophysiology: Infantile 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 may be important in the 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, causing spasms. The clinical response to adrenocorticotropic hormone (ACTH) and glucocorticoids can be explained by suppression of corticotropin-releasing hormone (CRH) production.
Frequency:
* In the US: Infantile spasm constitutes 2% of childhood epilepsies but 25% of epilepsy with onset in the first year of life. The rate of infantile spasm is estimated between 2.5 to 6.0 per 10,000 live births. Its prevalence rate is 1.5-2.0 per 10,000 children aged 10 years or younger.
* Internationally: Infantile spasm 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.
Mortality/Morbidity: The premature death rate ranges from 5-31%. The upper limit comes from a study of 214 Finnish children with a history of infantile spasms who were followed for a mean 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.
Sex: Although males are affected slightly more often than females, no significant gender difference is noted.
Age: Ninety percent of infantile spasms begin in those younger than 12 months. Peak onset is at age 4-6 months.
History:
* Ictal manifestations
o Spasms begin with a sudden, rapid, tonic contraction of trunk and limb musculature that gradually relaxes over 0.5-2 seconds.
+ Contractions can last 5-10 seconds.
+ The intensity may vary from a subtle head nodding to a powerful contraction of the body.
+ Infantile spasms usually occur in clusters, often several dozens, separated by 5-30 seconds.
+ Spasms frequently occur just before sleep or upon awakening. They can be observed during sleep, although this is rare.
o Spasms can be flexor, extensor, or a mixture of flexion and extension.
+ Flexor spasms consist of brief contractions of the flexor muscles of the neck, trunks, and limbs, resulting in a brief jerk. They may resemble a self-hugging motion and often are associated with a cry. The patient then relaxes, and the jerk repeats. These attacks occur in clusters throughout the day and last anywhere from less than 1 minute to 10-15 minutes or longer in some patients.
+ Extensor spasms consist of contractions of the extensor musculature with sudden extension of the neck and trunk with extension and abduction of the limbs. Extensor spasms and asymmetric or unilateral spasms often are associated with symptomatic cases.
+ Mixed spasms are the most common type, consisting of flexion of the neck and arms with extension of the legs, or flexion of the legs with extension of the arms.
+ In different series the frequency of the 3 spasm types were 42-50% mixed, 34-42% flexor, and 19-23% extensor.
* Interictal manifestations: An arrest or regression in psychomotor development accompanies the onset of spasms in 70-95% of patients.
* Family history: A family history of infantile spasms is uncommon but as many as 17% of patients may have a family history of any epilepsy.
Physical:
* General physical examination
o Physical examination can be important in helping to identify specific etiologies that may have both systemic and neurological symptoms (eg, tuberous sclerosis complex).
o Often a patient with infantile spasms has normal findings on general physical examination. No pathognomonic physical findings are present in patients with infantile spasms.
o If abnormalities in the general physical examination are noted (eg, adenoma sebaceum, ash leaf macules), specific etiologies may be suggested.
o Use a Wood lamp to examine the skin.
o Patients may exhibit moderate-to-severe growth delay; this is a nonspecific finding and more a reflection of the underlying brain injury than of a specific epilepsy syndrome.
* Neurologic examination
o The neurologic examination in patients with infantile spasms demonstrates abnormalities in mental status function, specifically deficits in cognitive function consistent with developmental delay or regression.
o Abnormalities in level of consciousness, cranial nerve function, and motor/sensory/reflex examination are nonspecific findings and more a reflection of the underlying brain injury or effect of anticonvulsant medications than of the syndrome.
o No pathognomonic findings are present on neurologic examination in patients with infantile spasms.
Causes: Infantile spasms (West syndrome) can be classified according to its suspected etiology as symptomatic, cryptogenic, or idiopathic.
* Symptomatic
o Patients are diagnosed with symptomatic infantile spasms if an identifiable factor is responsible for the syndrome. Virtually any disorder that can produce brain damage can be associated with infantile spasms.
o The list of etiologies can be subdivided into prenatal disorders, perinatal disorders, and postnatal disorders.
+ Prenatal disorders include hydrocephalus, microcephaly, hydranencephaly, schizencephaly, polymicrogyria, Sturge-Weber syndrome, incontinentia pigmenti, tuberous sclerosis, trisomy 21, hypoxic-ischemic encephalopathies, congenital infections, and trauma.
+ Perinatal disorders include hypoxic-ischemic encephalopathies, meningitis, encephalitis, trauma, and intracranial hemorrhages.
+ Postnatal disorders include pyridoxine dependency, nonketotic hyperglycinemia, maple syrup urine disease, phenylketonuria, mitochondrial encephalopathies, meningitis, encephalitis, degenerative diseases, biotinidase deficiency, and trauma.
o Evaluating children with infantile spasms for possible tuberous sclerosis is critical, as this is the single most common disorder, comprising 10-30% of prenatal cases. 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. In more than a few patients, the family diagnosis of tuberous sclerosis is found only after a child presents with infantile spasms, and an extensive workup of the child and subsequently the family reveals the genetic disease.
o Of patients with infantile spasms, 70-75% have symptomatic epilepsy. This percentage depends on the degree of sophistication of diagnostic studies. Development of more exquisite neurodiagnostic techniques will alter the relative proportion of symptomatic, cryptogenic, and idiopathic cases.
* Cryptogenic
o Patients have cryptogenic infantile spasms if no cause is identified but a cause is suspected and the epilepsy is presumed to be symptomatic.
o The proportion of cryptogenic cases varies from 8-42%. This wide range may be related to variations in the definition of the term "cryptogenic" and the age of diagnosis, since assessment of developmental level in early infancy is difficult.
* Idiopathic
o Patients may be considered to have idiopathic infantile spasms if normal psychomotor development occurs prior to the onset of symptoms, no underlying disorders or definite presumptive causes are present, and no neurological or neuroradiological abnormalities exist. Some investigators use the terms "idiopathic" and "cryptogenic" interchangeably.
o The percentage of idiopathic cases reportedly is 9-14%.
* Family history: A family history of infantile spasms is uncommon but as many as 17% of patients may have a family history of any epilepsy.
Other Problems to be Considered:
Benign myoclonus of early infancy
Myoclonic-astatic epilepsy
Lab Studies:
* Prior to initiating therapy, consider obtaining some or all of the following laboratory studies:
o Complete blood count with differential, liver panel, renal panel with electrolytes and glucose, calcium, magnesium, phosphorus, and urinalysis with microscopic examination
o Metabolic workup including glucose, liver panel, serum lactate and pyruvate, plasma ammonia, serum and urine amino acids, urine organic acids, and serum biotinidase
o Blood, urine, and cerebrospinal fluid cultures if an infection is suspected
o Cerebrospinal fluid analysis for cell count, glucose, protein, bacterial and viral culture, lactate, pyruvate, and amino acids
Imaging Studies:
* Overview
o About 70-80% of patients have abnormal findings on neuroimaging studies.
o Magnetic resonance imaging (MRI) of the brain provides a more detailed evaluation than does a computed tomography (CT) scan of the brain.
o Imaging studies should be obtained prior to starting ACTH or steroid therapy, as these therapies are associated with the appearance of apparent brain atrophy as treatment continues.
* CT scan
o Structural brain anomalies such as hydrocephalus, hydranencephaly, schizencephaly, and agenesis of corpus callosum can be recognized easily by CT scans.
o In addition, cerebral calcifications can be observed in patients with tuberous sclerosis or congenital infections.
* MRI: MRI scans are superior to CT scans in detecting areas of cortical dysgenesis, disorders of neuronal migration, or disorders of myelination.
Other Tests:
* Electroencephalogram
o Always perform an EEG in patients with suspected infantile spasms, since the diagnosis depends on the presence of specific EEG findings.
o If possible, obtain prolonged video-EEG telemetry to record both waking and sleep EEG to assist in confirming a suspected diagnosis. A routine 20-minute EEG may not capture the patient while both awake and asleep and thus may miss specific important EEG findings.
* Interictal electroencephalogram
Click image for a full size view
o Hypsarrhythmia is the characteristic interictal EEG pattern and consists of chaotic, high- to extremely high-voltage polymorphic delta and theta rhythms with superimposed multifocal spikes and wave discharges (see Image above). Multiple variations of this pattern are possible, including focal or asymmetric hypsarrhythmia.
o In one study of 77 patients with infantile spasms, unilateral hypsarrhythmia and asymmetric ictal EEG changes during spasms often occurred together and correlated with focal or asymmetric cerebral lesions on imaging studies. Patients with symmetric hypsarrhythmia and infantile spasms rarely had focal or asymmetric cerebral lesions on imaging studies (most had structural diffuse brain lesions) and overall had better chances for a normal outcome.
o In a study of 26 patients with infantile spasms, 6 patients (23%) had asymmetric hypsarrhythmia. All 6 had symptomatic infantile spasms and 5 had focal abnormalities on examination or imaging study (4 ipsilateral to the lesion, 1 contralateral). These focal abnormalities may identify a subset of patients with West syndrome who are candidates for focal cortical resections.
* Ictal electroencephalogram
o Eleven different types of ictal patterns have been identified in patients with West syndrome.
o In one study, the most common pattern found in 38% of patients with seizures was a high-voltage, frontal dominant, generalized slow-wave transient followed by voltage attenuation, also termed an electrodecremental episode. These electrodecremental episodes were a feature in 71% of the seizures.
o No close correlation exists between the type of seizure and the EEG pattern.
* Ophthalmic examination: Ophthalmic examination may reveal chorioretinitis from congenital infections, chorioretinal lacunar defects in patients with Aicardi syndrome, or retinal tubers in patients with tuberous sclerosis.
* Wood lamp: Tuberous sclerosis is the single most common recognizable cause of West syndrome. Therefore, a careful examination of the skin for the characteristic hypopigmented lesions of tuberous sclerosis is mandatory. The unaided bedside identification of these lesions may be more difficult in patients with light complexions.
Procedures:
* Lumbar puncture
o In young infants with early onset of West syndrome, consider a lumbar puncture as part of a full sepsis workup to look for signs of meningitis.
o In older infants in whom no clear signs of infection are present, a lumbar puncture also is useful in evaluating metabolic causes of West syndrome such as nonketotic hyperglycinemia.
Treatment
Medical Care:
* The goals of treatment for infants with West syndrome are the best quality of life with no seizures, the fewest adverse effects from treatment, and the least number of medications.
* Medications such as ACTH and conventional antiepileptic medications (AEDs) are the mainstay of therapy for infants with West syndrome. Unfortunately, no one medical treatment gives satisfactory relief for all infants with West syndrome.
* The various medical treatment options for infants with West syndrome can be divided into 2 major groups:
o Commonly used first-line treatments (ie, ACTH, prednisone, vigabatrin, pyridoxine [vitamin B-6])
o Second-line treatments (ie, benzodiazepines, valproic acid, lamotrigine, topiramate, zonisamide)
Surgical Care:
* Focal cortical resection: In some patients, resection of a localized region can lead to freedom from seizures.
Consultations:
* Pediatric neuropsychologists can assess intellectual function and educational needs and advise on nonpharmacologic management of behavioral problems.
* Pediatric psychiatrists can advise on pharmacologic management of behavioral problems.
* Neurosurgeons can help assess whether the infant is a candidate for focal resection.
* Dietitians can assist in the institution and maintenance of the ketogenic diet.
Diet:
* The ketogenic diet has been employed successfully to treat a variety of seizure types. However, the role of the ketogenic diet in the treatment of infants with West syndrome is not defined.
Medication
The goals of treatment for infants with West syndrome are the best quality of life with no seizures, the fewest adverse effects from treatment, and the least number of medications.
Drug Category: Hormonal agents -- These agents cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
| Drug Name | Corticotropin (Acthar, ACTH) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that (i) "ACTH is probably effective for the short-term treatment of infantile spasms and in resolution of hypsarrhythmia (Level B)" and (ii) "There is insufficient evidence to recommend the optimum dosage and duration of treatment with ACTH for the treatment of infantile spasms (Level U)." A 2004 multicenter, randomized, controlled trial in the UK compared hormonal therapy (either oral prednisolone or intramuscular tetracosactide depot, a synthetic analogue of ACTH) to vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 compared to infants assigned vigabatrin (54%, p=0.043). A follow-up study demonstrated that, although hormone treatment controlled spasms better than vigabatrin initially, by age 12-14 months, both groups had similar seizure-free rates. Older studies suggest ACTH's efficacy (percentage of infants with West syndrome reaching seizure freedom) is between 50% and 67%. Associated with serious, potentially life-threatening adverse effects. Must be administered IM, which is painful to infant and unpleasant for parent to perform. Daily dosages expressed as U/d (most common), U/m2/d, or U/kg/d. Prospective single-blind study demonstrated no difference in effectiveness of high-dose, long-duration corticotropin (150 U/m2/d for 3 wk, tapering over 9 wk) versus low-dose, short-duration corticotropin (20-30 U/d for 2-6 wk, tapering over 1 wk). With respect to spasm cessation and improvement in patient's EEG; hypertension was more common with larger doses. |
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| Pediatric Dose | Not established; 5-40 U/d IM for 1-6 wk to 40-160 U/d IM for 3-12 mo suggested; some authors recommend 150 U/m2/d IM for 6 wk or 5-8 U/kg/d IM in divided doses for 2-3 wk |
| Contraindications | Documented hypersensitivity; porcine protein hypersensitivity; scleroderma; recent surgery; congestive heart failure; primary adrenal insufficiency; hypercortisolism; active herpes infection; active tuberculosis; herpes simplex ocular infection; thromboembolic disease; active serious bacterial, viral, or fungal infection |
| Interactions | Avoid vaccines and immunizations during therapy Amphotericin B can decrease response; acetazolamide or other carbonic anhydrase inhibitors can cause hypernatremia, hypocalcemia, hypokalemia, and edema; diuretics can reduce natriuretic and diuretic effects; potassium-depleting diuretics can cause hypokalemia; phenytoin, barbiturates, and rifampin can decrease effects; estrogens can potentiate effects; salicylates or NSAIDs can cause GI ulceration; can reduce growth response to growth hormone (somatropin); warfarin can decrease anticoagulation response |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Avoid vaccines and immunizations during therapy Because of increased risk of infection, hypertension, hypertrophic cardiomyopathy, and electrolyte disturbances, careful and frequent clinical and laboratory monitoring of patient is essential Caution in Cushing disease, hypertension, hypokalemia, hypernatremia, diverticulitis, ulcerative colitis or intestinal anastomosis, renal disease, diabetes mellitus, hypothyroidism, hepatic disease |
| Drug Name | Prednisone (Deltasone, Orasone, Meticorten) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence that oral corticosteroids are effective in the treatment of infantile spasms (Level U)." Few comparative studies between ACTH and prednisone have been performed; one double-blind, placebo-controlled, crossover study demonstrated no difference between low-dose ACTH (20-30 U/d) and prednisone (2 mg/kg/d), while second prospective, randomized, single-blinded study demonstrated high-dose ACTH at 150 U/m2/d was superior to prednisone (2 mg/kg/d) in suppressing clinical spasms and hypsarrhythmic EEG in infants with infantile spasms. A 2004 multicenter, randomized, controlled trial in the UK compared hormonal therapy (either oral prednisolone or intramuscular tetracosactide depot, a synthetic analogue of ACTH) to vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 compared to infants assigned vigabatrin (54%, p=0.043). A follow-up study demonstrated that, although hormone treatment controlled spasms better than vigabatrin initially, by age 12-14 months, both groups had similar seizure-free rates. |
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| Pediatric Dose | 2 mg/kg/d PO for 2-4 wk |
| Contraindications | Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease |
| Interactions | Barbiturates, phenytoin, rifabutin, and rifampin can increase metabolism of prednisone; hyperthyroidism can increase metabolism of prednisone; hypothyroidism can decrease metabolism of prednisone; isoproterenol in patients with asthma can increase risk of cardiac toxicity, clinical deterioration, myocardial infarction, congestive heart failure, and death |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Prolonged therapy can affect metabolic, GI, neurologic/behavioral, dermatologic, and endocrine systems; metabolic adverse events can include (but are not limited to) fluid retention and electrolyte disturbances (eg, hypernatremia, hypokalemia, hypokalemic metabolic alkalosis, hypocalcemia), edema, hypertension, and hyperglycemia GI adverse events can include nausea, vomiting, abdominal pain, anorexia, diarrhea, constipation, gastritis, esophageal ulceration, weight loss, and delayed growth Neurological and behavioral adverse events reported during prolonged administration can include headache, insomnia, restlessness, mood lability, anxiety, personality changes, and psychosis Visual adverse events may include exophthalmos, retinopathy, posterior subcapsular cataracts, and ocular hypertension Dermatological adverse events reported during therapy can include skin atrophy, diaphoresis, impaired wound healing, facial erythema, hirsutism, ecchymosis, and easy bruising Endocrinological adverse events from prolonged use include hypercorticism and physiologic dependence Idiosyncratic reactions include pancreatitis and dermatological hypersensitivity reactions (allergic dermatitis, angioedema, urticaria); avoid vaccination with live-virus vaccines; avoid abrupt discontinuation if patient has been on long-term therapy Caution in congestive heart failure, hypertension, glaucoma, GI disease, diverticulitis, intestinal anastomosis, hepatic disease, hypoalbuminemia, peptic ulcer disease, renal disease, osteoporosis, diabetes mellitus, hypothyroidism, coagulopathy or thromboembolic disease, or potential impending GI perforation |
Drug Category: Anticonvulsants -- These agents are used to manage severe muscle spasms.
| Drug Name | Vigabatrin -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that (i) "Vigabatrin is possibly effective for short-term treatment of infantile spasms (Level C, Class III and IV evidence)." (ii) "Vigabatrin is also possibly effective for short-term treatment of infantile spasms in majority of children with tuberous sclerosis (Level C, Class III and IV evidence)." (iii) "Serious concerns about retinal toxicity in adults suggest that serial ophthalmologic screening is required in patients on vigabatrin. However, data are insufficient to make recommendations regarding the frequency or type of screening that would be of value in reducing the prevalence of this complication in children (Level U, Class IV studies)." Not approved by FDA in US, but available in many countries worldwide. Multiple studies (both open label and double blind) have reported some effectiveness in stopping seizures in infants with West syndrome, especially when caused by tuberous sclerosis. A 2004 multicenter, randomized, controlled trial in the UK compared hormonal therapy (either oral prednisolone or intramuscular tetracosactide depot, a synthetic analogue of ACTH) to vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 compared to infants assigned vigabatrin (54%, p=0.043). A follow-up study demonstrated that, although hormone treatment controlled spasms better than vigabatrin initially, by age 12-14 months, both groups had similar seizure-free rates. |
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| Pediatric Dose | Initial dose: 40 mg/kg/d in 2 divided doses Maintenance doses: 40-150 mg/kg/d |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Precautions | Dose-dependent adverse effects include hyperactivity, agitation, sedation, depression, psychosis, drowsiness, insomnia, facial edema, ataxia, nausea and/or vomiting, stupor, and somnolence; idiosyncratic reactions include visual field constriction; may exacerbate myoclonic and absence seizures in some patients; long-term reactions (ie, cumulative adverse effects) include weight gain; lower doses in patients with renal dysfunction |
Drug Category: Benzodiazepines -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend benzodiazepines for the treatment of infantile spasms (Level U, Class III and IV evidence)."
By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.
| Drug Name | Clonazepam (Klonopin) -- Considered second-line AED therapy against spasms associated with West syndrome. Adverse effects and development of tolerance limit usefulness over time. Nitrazepam and clobazam not approved by FDA in US but are available in many countries worldwide. |
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| Pediatric Dose | Maintenance dose: 0.01-0.2 mg/kg/d PO |
| Contraindications | Documented hypersensitivity; significant liver disease; acute narrow-angle glaucoma |
| Interactions | Decreases plasma levels of phenytoin, phenobarbital, and carbamazepine; potentiates CNS depression induced by other anticonvulsants and alcohol; may reduce renal clearance of digoxin; cimetidine and erythromycin decrease clearance |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Dose-dependent adverse effects include hyperactivity, sedation, drooling, incoordination, drowsiness, ataxia, fatigue, confusion, vertigo, dizziness, amnesic effect, and encephalopathy; considered least-sedating benzodiazepine; long-term (cumulative) adverse effects include tolerance and dependence; considered to have longest time to development of tolerance; adjust dose or discontinue therapy in presence of renal or liver function impairment, since metabolism occurs in liver and metabolites are excreted in urine |
Drug Category: Anticonvulsants -- These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
| Drug Name | Valproic acid (Depakote, Depakene, Depacon) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend valproic acid for treatment of infantile spasms (Level U, Class III and IV evidence)." Considered effective second-line AED therapy against spasms associated with West syndrome. |
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| Pediatric Dose | Initial dose: 10-15 mg/kg/d PO divided bid/tid Titration: 5-10 mg/kg/d increments at weekly intervals until therapeutic effect achieved or toxic effects occur Maintenance dose: 15-60 mg/kg/d PO |
| Contraindications | Documented hypersensitivity; history of hepatotoxicity or pancreatitis (patients at high risk for hepatotoxicity include <2 y, multiple concomitant AEDs including phenobarbital, underlying metabolic disease such as defect in fatty acid oxidation, and developmental delay) |
| Interactions | Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce levels; in children, salicylates decrease protein binding and metabolism of valproate; may result in variable changes of carbamazepine concentrations, with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; may displace warfarin from protein binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Dose-dependent adverse effects include asthenia, nausea, vomiting, somnolence, tremor, and dizziness; less common adverse effects include thrombocytopenia and parotid swelling; idiosyncratic reactions include hepatotoxicity and pancreatitis; long-term (cumulative) adverse effects include hair loss and weight gain |
| Drug Name | Lamotrigine (Lamictal) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend lamotrigine for the treatment of infantile spasms (Level U, Class III and IV evidence)." Lamotrigine inhibits release of glutamate and inhibits voltage-sensitive sodium channels, leading to stabilization of neuronal membrane. Effectiveness in West syndrome has been investigated in open-label studies with promising results. Initial dose, maintenance dose, titration intervals, and titration increments depend on concomitant medications. |
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| Pediatric Dose | Combination with AEDs that induce hepatic CYP-450 enzyme system WITHOUT valproate Initial starting dose: 0.6 mg/kg/d PO for 2 wk; 1.2 mg/kg/d for wk 3-4; 5-15 mg/kg/d thereafter; after week 4, dosage increment not to exceed 1.2 mg/kg/d q1-2wk until maintenance dose achieved; maximum daily dose is 400 mg/d Combination WITH valproate with or without other AEDs that induce hepatic CYP-450 enzyme system Initial starting dose: 0.15 mg/kg/d PO for 2 wk; 0.3 mg/kg/d for weeks 3-4; 1-5 mg/kg/d thereafter; after week 4, dosage increment not to exceed 0.3 mg/kg/d q1-2wk until maintenance dose achieved; usual maximum daily dose is 200 mg/d |
| Contraindications | Documented hypersensitivity; history of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis; erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis |
| Interactions | Affected by concomitant AEDs; when used in conjunction with medications that induce hepatic CYP-450 microsomal enzymes (eg, phenobarbital, carbamazepine, phenytoin), clearance enhanced; conversely, when used in conjunction with medications that inhibit hepatic CYP-450 microsomal enzymes (eg, valproate), clearance diminished; lower starting doses, slow titration rate (ie, 2-wk or greater intervals between dosage increases), and smaller increments are needed |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Dose-dependent adverse effects include ataxia, diplopia, dizziness, headache, nausea, and somnolence; idiosyncratic reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis; no long-term (cumulative) adverse effects noted to date Risk factors for associated severe dermatologic reactions include younger age (children more than adults), co-medication with valproic acid, rapid rate of titration, and high starting dose; give careful attention to initial starting dose, titration rate, and co-medications; prompt evaluation of any rash is prudent and imperative; approximately 10-12% of patients develop non–life-threatening rash that usually resolves rapidly upon withdrawal and occasionally without changing dosage |
| Drug Name | Topiramate (Topamax) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend topiramate for the treatment of infantile spasms (Level U, Class III and IV evidence)." Topiramate is a sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have state-dependent sodium channel blocking action, potentiates inhibitory activity of neurotransmitter GABA. May block glutamate activity. Effectiveness in West syndrome has been investigated in one open-label study with promising results. |
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| Adult Dose | Initial starting dose: 2-3 mg/kg/d PO; increment of 2-3 mg/kg q3-4d Maintenance dose: 15-20 mg/kg/d PO |
| Pediatric Dose | Initial starting dose: 2-3 mg/kg/d PO; increment of 2-3 mg/kg q3-4d Maintenance dose: 15-20 mg/kg/d PO |
| Contraindications | Documented hypersensitivity |
| Interactions | May increase phenytoin plasma levels; may decrease valproate plasma levels; phenytoin and carbamazepine decrease levels |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Dose-dependent adverse effects include irritability, ataxia, dizziness, fatigue, nausea, somnolence, psychomotor slowing, concentration, constipation, and speech problems; if CNS adverse effects occur, reduce concomitant AEDs, slow titration, or reduce dose; no idiosyncratic reactions noted; oligohidrosis and nephrolithiasis reported |
| Drug Name | Zonisamide (Zonegran) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend zonisamide for the treatment of infantile spasms (Level U, Class III and IV evidence)." Effectiveness in West syndrome has been investigated in 5 open-label studies with promising results. |
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| Pediatric Dose | Initial dose: 1-2 mg/kg/d PO; increase 1-2 mg/kg/d q2wk Maintenance dose: 8-12 mg/kg/d PO |
| Contraindications | Documented hypersensitivity |
| Interactions | Phenytoin, phenobarbital, carbamazepine, and valproate decrease half-life; no effect on steady-state plasma concentrations of other AEDs |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Dose-dependent adverse effects include headache, anorexia, nausea, dizziness, ataxia, paresthesia, difficulty concentrating, irritability, and somnolence; idiosyncratic reactions include severe rash (Stevens-Johnson syndrome, toxic epidermal necrolysis) with reporting rate of 46 per million patient-years of exposure; oligohidrosis and nephrolithiasis reported |
