Infantile Spasm (West Syndrome) 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 lowest number of medications. In 2007, an expert survey concluded that 1-3 trials of monotherapy should be implemented before considering epilepsy surgery.

Commonly used first-line treatments for infants with West syndrome include the following:

• ACTH^{[17, 18, 19, 20, 21]}
• Prednisone
• Vigabatrin^{[18, 22, 23, 24, 25, 26]}
• Pyridoxine (vitamin B-6)^{[27, 28, 29, 30]}

Second-line treatments include the following:

• Benzodiazepines
• Valproic acid
• Lamotrigine^{[31, 32]}
• Topiramate^{[33, 34]}
• Zonisamide^{[35, 36]}
• Levetiracetam^[37]

Complications

Complications of West syndrome 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.^[38]

Class Summary

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

Corticotropin (Acthar, ACTH)

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%).^[39]

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.^[40]

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.

Prednisone

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%).^[39]

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.^[40]

Class Summary

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

Vigabatrin (Sabril)

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.^[41] 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)."^[42]

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%).^[39]

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.^[40]

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.

Topiramate (Topamax)

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)."^[42]

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.

Levetiracetam (Keppra, Keppra XR)

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.

Valproic acid (Depakote, Depakene, Depacon)

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)."

Lamotrigine (Lamictal)

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.

Zonisamide (Zonegran)

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)."

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)."^[42]

Clonazepam (Klonopin)

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.

Class Summary

These agents are essential for normal metabolic processes.

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

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)."