Infantile Spasm (West Syndrome)

Background

West syndrome is a severe epilepsy syndrome composed of the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental retardation. The International League Against Epilepsy's (ILAE) revised classification and terminology of seizures and epilepsies, published in 2010, designates West syndrome as an electroclinical syndrome with onset in infancy, and epileptic spasms as a type of seizure.^[1] (See Presentation and Workup.)

West syndrome is an age-dependent expression of a damaged brain, and most patients with infantile spasms have some degree of developmental delay. The term infantile spasm has been used to describe the seizure type, the epilepsy syndrome, or both. In this article, the term infantile spasm is synonymous with West syndrome. (See Prognosis and Presentation.)

The syndrome's namesake, Dr W J West, gave the first detailed description of infantile spasms, which occurred in his own child.^[2] 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 … [T]hese 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 would not continue more than 2 or 3 minutes; he sometimes has 2, 3 or more attacks in the day."^[3]

This detailed clinical description was followed approximately 100 years later by the report of the typical interictal EEG pattern termed hypsarrhythmia. (See Workup.)

The eponym West syndrome was created in the early 1960s by Drs. Gastaut, Poirier, and Pampiglione.

Differentials

Conditions to consider in the differential diagnosis of West syndrome include the following:

• Epilepsy in children with mental retardation
• Epileptic and epileptiform encephalopathies
• Benign myoclonus of early infancy
• Myoclonic-astatic epilepsy

• References

Etiology

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 (CNS) may be important in the syndrome’s 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 (CRH), causing spasms.^[4] The clinical response to adrenocorticotropic hormone (ACTH) and glucocorticoids can be explained by the suppression of CRH production.

An existing animal model of infantile spasm may provide better insight into the pathogenesis of this disorder. The model uses a sodium channel blocker, tetrodotoxin (TTX), that is infused into the hippocampus of rodents. This infusion has produced clinical spasms in rats with electrographic findings similar to those seen in human infantile spasms.^[5]

Infantile spasms can be classified according to their suspected etiology as symptomatic, cryptogenic, or idiopathic.

Symptomatic

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. The list of etiologies can be subdivided into prenatal disorders, perinatal disorders, and postnatal disorders.

Prenatal disorders associated with infantile spasms include the following:

• Hydrocephalus
• Hydranencephaly
• Migrational disorders such as schizencephaly polymicrogyria
• Sturge-Weber syndrome
• Incontinentia pigmenti
• Tuberous sclerosis
• Trisomy 21
• Hypoxic-ischemic encephalopathy
• Congenital infections
• Trauma

Perinatal disorders giving rise to infantile spasms include the following:

• Hypoxic-ischemic encephalopathy
• Meningitis
• Encephalitis
• Trauma
• Intracranial hemorrhages

Postnatal disorders associated with infantile spasms include the following:

• Pyridoxine dependency
• Inborn errors of metabolism such as nonketotic hyperglycinemia, maple syrup urine disease, phenylketonuria, biotinidase deficiency, lysosomal disorders
• Mitochondrial encephalopathies
• Meningitis
• Encephalitis
• Trauma

Evaluating children with infantile spasms for possible tuberous sclerosis is critical, as this is the single most common disorder, accounting for 10-30% of prenatal cases of infantile spasm. 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.

Of patients with infantile spasms, 70-75% have symptomatic epilepsy; this percentage depends on the degree of sophistication of diagnostic studies. (The development of more exquisite neurodiagnostic techniques is expected to alter the relative proportion of symptomatic, cryptogenic, and idiopathic cases that has been reported.)

Cryptogenic

Patients have cryptogenic infantile spasms if no cause is identified but a cause is suspected and the epilepsy is presumed to be symptomatic.

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 patients at diagnosis, since assessment of developmental level in early infancy is difficult.

Idiopathic

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 neurologic or neuroradiologic abnormalities exist. Some investigators use the terms idiopathic and cryptogenic interchangeably. The percentage of idiopathic cases reportedly is 9-14%.

Genetics

There has been an increased understanding of the role of genetic defects in the etiology of infantile spasms, such that there are panels of genetic mutations tha are commercially available for testing. In addition to the genetic mutations in TSC1 and TSC2, which cause tuberous sclerosis, specific genetic defects have been identified in many patients with early onset of infantile spasms, including mutations in the gene ARX on the short arm of chromosome X, which is associated with a wide variety of structural brain abnormalities, and a mutation in the cyclin-dependent kinase-like protein 5 (CDKL5).

• References

Epidemiology

Occurrence in the United States

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 to be 2.5-6.0 cases per 10,000 live births. Its prevalence rate is 1.5-2.0 cases per 10,000 children aged 10 years or younger.

International occurrence

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.

Sex- and age-related demographics

Although males are affected by infantile spasm slightly more often than females, no significant gender difference is noted in infantile spasm. Ninety percent of infantile spasms begin in infants younger than 12 months. Peak onset is at age 4-6 months.^[6]

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Prognosis

The long-term overall prognosis for patients with infantile spasm is poor and is related directly to the condition’s etiology.^{[7, 8]} Infants with idiopathic infantile spasms have a better prognosis than do infants with symptomatic infantile spasms. Only 14% of infants with symptomatic West syndrome have normal or borderline-normal cognitive development, compared with 28-50% of infants with idiopathic infantile spasms. Mental retardation is severe in 70% of patients, often with psychiatric problems such as autistic features or hyperactivity.

Infrequently, spasms may persist in adulthood. It has been found that 50-70% of patients develop other seizure types and that 18-50% of patients will develop Lennox-Gastaut syndrome or some other form of symptomatic generalized epilepsy.^{[6, 9]}

Subsets of patients among the symptomatic infantile spasms group seem to have a better prognosis. A retrospective study of 17 children with trisomy 21 and infantile spasms found that 13 of 16 survivors were seizure free for more than 1 year and that 10 patients were no longer taking anticonvulsants.

A study of 15 children with neurofibromatosis type 1 and infantile spasms also reported a relatively benign seizure and cognitive outcome.

Favorable prognostic factors also include the following:

• Cryptogenic or idiopathic etiology
• Age of onset of over 4 months
• Absence of atypical spasms and partial seizures
• Absence of asymmetrical EEG abnormalities
• Short time from onset to treatment
• Early, sustained response to treatment

Infants with symptomatic infantile spasms have been shown to be at higher risk for the development of autism spectrum disorders, compared with those infants with cryptogenic or idiopathic spasms.^{[10, 11]}

Mortality

The premature death rate for infantile spasm 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 period 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.

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History

Ictal manifestations

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 of spasms may vary from a subtle head nodding to a powerful contraction of the body. Infantile spasms usually occur in clusters, often comprised of several dozen spasms, each separated by 5-30 seconds. Spasms frequently occur just before sleep or upon awakening. They can be observed during sleep, although this is rare.

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 and with extension and abduction of the limbs. Extensor spasms and asymmetrical or unilateral spasms often are associated with symptomatic cases.

Mixed spasms are the most common type, consisting of flexion of the neck and arms and extension of the legs or of flexion of the legs and 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 of 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.

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Physical Examination

General physical examination

Physical examination can be important in helping to identify specific etiologies that may have a combination of systemic and neurologic symptoms (eg, tuberous sclerosis complex). However, a patient with infantile spasms often has normal findings on general physical examination, and no pathognomonic physical findings are present in patients with infantile spasms.

Patients may exhibit moderate to severe growth delay, but this is a nonspecific finding that is more a reflection of the underlying brain injury than of a specific epilepsy syndrome.

Nonetheless, if certain abnormalities in the general physical examination are noted (eg, adenoma sebaceum, ash leaf macules), specific etiologies may be suggested.

Neurologic examination

The neurologic examination in patients with infantile spasms demonstrates abnormalities in mental status function, specifically delays in developmental milestones consistent with developmental delay or regression. However, no pathognomonic findings are present on neurologic examination in patients with infantile spasms.

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 the effect of anticonvulsant medications than of the syndrome.

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.

Dermatologic examination

Use a Wood lamp to examine the skin. Tuberous sclerosis is the single most common recognizable cause of infantile spasms. 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 a light complexion.

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Approach Considerations

Evaluating children with infantile spasms for possible tuberous sclerosis is critical, as this is the single most common disorder, accounting for 10-30% of prenatal cases of infantile spasm. 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. Two-thirds of patients with tuberous sclerosis have a de novo mutation.

Lab studies

Prior to initiating therapy, consider obtaining some or all of the following laboratory studies:

• Complete blood count (CBC) with differential, liver panel, renal panel with electrolytes and glucose, calcium, magnesium, phosphorus, and urinalysis with microscopic examination
• Metabolic workup, including glucose, liver panel, serum lactate and pyruvate, plasma ammonia, serum and urine amino acids, urine organic acids, and serum biotinidase
• Blood, urine, and cerebrospinal fluid cultures if an infection is suspected
• Cerebrospinal fluid analysis for cell count, glucose, protein, bacterial and viral culture, lactate, pyruvate, and amino acids

Lumbar puncture

In young infants with early onset of infantile spasms, consider a lumbar puncture as part of a full sepsis workup to look for signs of meningitis.

In older infants in whom no clear signs of infection are present, a lumbar puncture is useful in evaluating metabolic causes of infantile spasms, such as nonketotic hyperglycinemia.

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CT Scanning and MRI

About 70-80% of patients have abnormal findings on neuroimaging studies. Magnetic resonance imaging (MRI) of the brain provides a more detailed evaluation than does computed tomography (CT) scanning of the brain. 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 scanning

Structural brain anomalies such as hydrocephalus, hydranencephaly, schizencephaly, and agenesis of the corpus callosum can be recognized easily by CT scans.In addition, cerebral calcifications can be observed in patients with tuberous sclerosis or congenital infections. However, unless CT is indicated to assess for an acute process, MRI is preferred due to greater detail and lack of radiation exposure.

MRI

MRI scans are superior to CT scans in detecting areas of cortical dysgenesis, disorders of neuronal migration, or disorders of myelination.

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Electroencephalography

Always perform an EEG in patients with suspected infantile spasms, since the diagnosis depends on the presence of specific EEG findings.^[12]

If possible, obtain prolonged video-EEG telemetry to record waking and sleeping 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. If there are no interictal abnormalities, prolonged video-EEG to catch the events of concern would also assist in differentiating them from other movements such as benign myoclonus of infancy.

Interictal electroencephalogram

Hypsarrhythmia (seen in the image below) is the characteristic interictal EEG pattern. It consists of chaotic, high- to extremely high–voltage, polymorphic delta and theta rhythms with superimposed multifocal spikes and wave discharges. Multiple variations of this pattern are possible, including focal or asymmetrical hypsarrhythmia.

View Image

Mountainous, chaotic, disorganized rhythms with superimposed multifocal spikes demonstrating hypsarrhythmia in a boy aged 8 months with infantile spas....

In a study of 77 patients with infantile spasms, unilateral hypsarrhythmia and asymmetrical ictal EEG changes during spasms often occurred together and correlated with focal or asymmetrical cerebral lesions on imaging studies. Patients with symmetrical hypsarrhythmia and infantile spasms rarely had focal or asymmetrical cerebral lesions on imaging studies (most had structural diffuse brain lesions), and overall they had better chances for a normal outcome.

In a study of 26 patients with infantile spasms, 6 patients (23%) had asymmetrical 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 infantile spasms who are candidates for focal cortical resections.

Ictal electroencephalogram

Eleven different types of ictal patterns have been identified in patients with infantile spasms. 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.No close correlation exists between the type of seizure and the EEG pattern.

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Approach Considerations

The goals of treatment for infants with infantile spasms are the best quality of life (with no seizures), the fewest adverse effects from treatment, and the lowest number of medications.

Medications such as ACTH, oral corticosteroids, vigabatrin, and conventional antiepileptic drugs (AEDs) have all been used for infantile spasms. Unfortunately, no single medical treatment gives satisfactory relief for all infants with infantile spasms, and what is considered the best approach for treatment has been a debated and evolving topic.

In 2007, an expert survey concluded that 1-3 trials of monotherapy should be implemented before considering epilepsy surgery. In patients with tuberous sclerosis or symptomatic infantile spasms, vigabatrin was the drug of choice.^{[13, 14]} Publications regarding specific treatments are reviewed in the Medication section, however, findings from a multicenter prospective database of infants with new diagnosis of infantile spasms compared "standard therapy" with ACTH, oral steroids, or vigabatrin to all other medications and found that 46% of patients treated with standard therapy had remission of spasms and resolution of hypsarrhythmia sustained at 3 months after initiation of the treatment, versus 9% of patients treated with "nonstandard" therapy.^[15]

Focal cortical resection

In some patients, resection of a localized region can lead to freedom from seizures.

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Diet

The ketogenic diet has been used successfully to treat a variety of seizure types. Studies have shown that it can be considered for the medical management of infantile spasms.^[16]

A 2006 retrospective study showed that the ketogenic diet in a ratio of 4:1 was effective in a small patient population with intractable infantile spasm previously treated with combinations of vigabatrin, topiramate, other AEDs, or prednisolone. A greater than 90% reduction in seizures was seen in 63% of children, and 40% were seizure free at 6 months. Side effects, including gastrointestinal disturbance, infection, and renal stones, were transient.^[17]

One center prospectively followed 104 patients with infantile spasms, treated with the ketogenic diet; these patients included both patients with new onset infantile spasms and those that were unsuccessfully treated with other therapies. Of the total patients, 37% became spasm-free for at least 6 months within a median 2.4 months of starting the ketogenic diet, and 64% had a greater than 50% improvement in spasms.^[18]

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Consultations

Consultations with the following specialists can be beneficial:

• 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 to assess whether the infant is a candidate for focal resection
• Dietitians - Can assist in the institution and maintenance of the ketogenic diet
• Cardiologists - Can be consulted at the initiation of therapy with ACTH or steroids; they can look for potential side effects of these therapies, evaluating cardiac function (by looking for signs of hypertrophic cardiomyopathy) and aiding in the management of hypertension

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Medication Summary

The goals of treatment for infants with infantile spasms are the best quality of life (with no seizures), the fewest adverse effects from treatment, and the lowest number of medications.

Commonly used first-line treatments for infants with infantile spasms include the following:

• ACTH^{[19, 20, 21, 22, 23]}
• Vigabatrin^{[20, 24, 25, 26, 27, 28, 29]}
• Prednisone
• Pyridoxine (vitamin B-6)^{[30, 31, 32, 33]}

Second-line treatments include the following:

• Benzodiazepines
• Valproic acid
• Lamotrigine^{[34, 35]}
• Topiramate^{[36, 37]}
• Zonisamide^{[38, 39]}
• Levetiracetam^[40]

Complications

Complications of infantile spasms include dose-related, idiosyncratic, or long-term adverse effects from medications, including death. For example, valproate is associated with hepatotoxicity and pancreatitis, which are idiosyncratic effects. Lamotrigine can cause 2 other idiosyncratic effects; specifically, Steven-Johnson syndrome and toxic epidermal necrolysis.

A retrospective review of 130 patients with infantile spasm found that patients treated with ACTH experienced a significant short-term weight gain and an increase in systolic and diastolic blood pressures, compared with patients on other AED therapies. There was no difference between the groups with respect to hospitalizations, infections, or onset of new seizure types. Medication changes secondary to persistent or recurrent infantile spasms were seen in 40% of patients treated with ACTH and in 51% of patients treated with other AEDs.^[41]

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Corticotropin (Acthar, ACTH)

• Dosing, Interactions, etc.

Clinical Context:  A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that (1) "ACTH is probably effective for the short-term treatment of infantile spasms and in resolution of hypsarrhythmia (Level B)" and (2) "[t]here is insufficient evidence to recommend the optimum dosage and duration of treatment with ACTH for the treatment of infantile spasms (Level U)."

One study found that after approximately 2 weeks, hormonal therapy provided better relief from spasm than did vigabatrin. The 2004 multicenter, randomized, controlled trial compared hormonal therapy (either oral prednisolone or intramuscular [IM] tetracosactide depot, a synthetic analogue of ACTH) with vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 than did infants assigned vigabatrin (54%).^[42]

However, a follow-up study demonstrated that, although hormonal treatment initially controlled spasms better than vigabatrin did, by age 12-14 months, infants in the hormonal and vigabatrin groups had similar seizure-free rates.^[43]

Older studies have suggested that ACTH's efficacy (percentage of infants with West syndrome reaching seizure freedom) is between 50% and 67%.

Corticotropin is associated with serious, potentially life-threatening adverse effects. It must be administered intramuscularly, and such injections are painful for the infant to receive and are unpleasant for the parent to perform.

A prospective, single-blind study demonstrated no difference in effectiveness between high-dose, long-duration corticotropin (150 U/m2/day for 3 wk, tapering over 9 wk) and low-dose, short-duration corticotropin (20-30 U/day for 2-6 wk, tapering over 1 wk with respect to spasm cessation and improvement in the patient's EEG. Hypertension was more common with larger doses.

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Prednisone

• Dosing, Interactions, etc.

Clinical Context:  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/day) and prednisone (2 mg/kg/day). However, a prospective, randomized, single-blinded study demonstrated high-dose ACTH at 150 U/m2/day to be superior to prednisone (2 mg/kg/day) in suppressing clinical spasms and hypsarrhythmic EEG in infants with infantile spasms.

One study found that after approximately 2 weeks, hormonal therapy provided better relief from spasm than did vigabatrin. The 2004 multicenter, randomized, controlled trial compared hormonal therapy (either oral prednisolone or IM tetracosactide depot) with vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 than did infants assigned vigabatrin (54%).^[42]

However, a follow-up study demonstrated that, although hormonal treatment initially controlled spasms better than vigabatrin did, by age 12-14 months, infants in the hormonal and vigabatrin groups had similar seizure-free rates.^[43]

Findings from a multicenter prospective database of infants with new diagnosis of infantile spasms compared “standard therapy” with ACTH, oral steroids, or vigabatrin to all other medications, and found that 55% of patients treated with ACTH had remission of spasms and resolution of hypsarrhythmia sustained at 3 months after initiation of the treatment, compared to 39% treated with oral steroids, 36% treated with vigabatrin, and 9% of patients treated with “nonstandard” therapy.^[15]

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Class Summary

These agents cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

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Vigabatrin (Sabril)

• Dosing, Interactions, etc.

Clinical Context:  Vigabatrin (Sabril)

Vigabatrin is indicated as monotherapy for children aged 1 month to 2 year with infantile spasms. Its precise mechanism of action is unknown. The drug is a selective, irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T). GABA-T metabolizes GABA, an inhibitory neurotransmitter, thereby increasing CNS GABA levels. Vigabatrin use must be weighed against the risk of permanent vision loss.^[44] Vigabatrin was approved by the US Food and Drug Administration (FDA) in August 2009. It is available only from a restricted access program.

A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that (1) "[v]igabatrin is possibly effective for short-term treatment of infantile spasms (Level C, Class III and IV evidence)," (2) "[v]igabatrin 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)," and (3) "[s]erious 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)."^[45]

Multiple studies (open label and double blind) have reported that vigabatrin showed some effectiveness in stopping seizures in infants with West syndrome, especially when caused by tuberous sclerosis.

One study found that after approximately 2 weeks, corticosteroid therapy provided better relief from spasm than did vigabatrin. The 2004 multicenter, randomized, controlled trial compared corticosteroid therapy (either oral prednisolone or intramuscular tetracosactide depot) with vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 than did infants assigned vigabatrin (54%).^[42]

However, a follow-up study demonstrated that, although corticosteroid treatment initially controlled spasms better than vigabatrin did, by age 12-14 months, infants in the corticosteroid and vigabatrin groups had similar seizure-free rates.^[43]

In a total of 12 studies, 4 of which were randomized, controlled trials carried out between 1990 and 2005, the percentage of spasm freedom with vigabatrin ranged from 11-78%. The response rate was influenced by the etiology of the spasms. Vigabatrin was most effective in patients with tuberous sclerosis and other symptomatic etiologies.

Vigabatrin is not recommended for patients with nonketotic hyperglycinemia. The increase in GABA from vigabatrin, coupled with increased glycine, enhances the epileptic encephalopathy in these patients.

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Topiramate (Topamax)

• Dosing, Interactions, etc.

Clinical Context:  Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity that may have state-dependent sodium channel blocking action, may potentiate the inhibitory activity of the neurotransmitter GABA, and may block glutamate activity.

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)."^[45]

A 2005 open-label trial of topiramate in 15 infants with infantile spasms demonstrated clinical effectiveness at doses of up to 27 mg/kg/day. The median seizure rate reduction in the first 2 months of treatment was 41%. Twenty percent of patients were seizure free, and 33% had a greater than 50% reduction in seizures. Other small study series have shown that 88% of patients had a more than 50% seizure reduction in spasms with topiramate.

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Levetiracetam (Keppra, Keppra XR)

• Dosing, Interactions, etc.

Clinical Context:  Levetiracetam's mechanism of action is the inhibition of N-type calcium channels, the modulation of GABA and glycine receptors, and binding to SVA2 protein.

An open-label trial of 5 infants with new-onset, cryptogenic infantile spasms showed levetiracetam to be clinically effective. Two children became seizure free, while 2 others showed a minimum of 50% reduction in seizures. The dose ranged from 30-60 mg/kg/day.

In an open-label trial of 7 children (including 5 with symptomatic infantile spasms) treated with 20-80 mg/kg/day of levetiracetam, all responded to therapy. Two patients had a greater than 75% reduction in spasms and 1 had complete cessation of spasms.

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Valproic acid (Depakote, Depakene, Depacon)

• Dosing, Interactions, etc.

Clinical Context:  Valproic acid is considered an effective second-line AED therapy against spasms associated with West syndrome.

However, 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)."

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Lamotrigine (Lamictal)

• Dosing, Interactions, etc.

Clinical Context:  Lamotrigine inhibits the release of glutamate and also inhibits voltage-sensitive sodium channels, leading to stabilization of the neuronal membrane. Its effectiveness in West syndrome has been investigated in open-label studies with promising results.

Even so, 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)."

The drug's initial dose, maintenance dose, titration intervals, and titration increments depend on concomitant medications.

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Zonisamide (Zonegran)

• Dosing, Interactions, etc.

Clinical Context:  The effectiveness of zonisamide as a treatment for West syndrome has been investigated in 5 open-label studies, with promising results.

Nonetheless, 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)."

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Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

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Clonazepam (Klonopin)

• Dosing, Interactions, etc.

Clinical Context:  Clonazepam is considered a second-line AED therapy against spasms associated with West syndrome. However, adverse effects and the development of tolerance limit the drug's usefulness over time. Nitrazepam and clobazam are not approved by the FDA but are available in many countries worldwide.

• References

Class Summary

By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

However, 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)."^[45]

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Pyridoxine (vitamin B-6; Aminoxin, Pyri-500)

• Dosing, Interactions, etc.

Clinical Context:  Two distinct treatment situations exist in which pyridoxine is used in patients with West syndrome.

First is intravenous (IV) administration during diagnostic EEG to assess whether the patient's seizures and EEG abnormalities are related to pyridoxine deficiency. In this approach, administer 50-100 mg IV during a diagnostic EEG; if dramatic improvement is noted in the EEG, the patient is believed to have pyridoxine-dependent seizures.

Second is long-term oral administration. The effectiveness of long-term, oral, high-dose pyridoxine in West syndrome has been investigated in multiple open-label studies, with promising results. Most patients who respond to long-term, oral, high-dose pyridoxine do so within 1-2 weeks of initiation.

However, a 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend pyridoxine for the treatment of infantile spasms (Level U, Class III and IV evidence)."

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Class Summary

These agents are essential for normal metabolic processes.

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