How does adrenocorticotropic hormone (ACTH) treat West syndrome in infants (3–12 months) and what is the recommended dosing regimen?

How ACTH Treats West Syndrome

Mechanism of Action

ACTH works in West syndrome by reducing glutamate/glutamine levels in the cerebral cortex, which decreases excitatory neurotransmission and modulates the glutamate-GABA cycle, thereby suppressing infantile spasms and hypsarrhythmia. 1

• ACTH therapy significantly reduces the Glx/tCr ratio (glutamine plus glutamate to creatine ratio) in the occipital cortex of West syndrome patients, as demonstrated by magnetic resonance spectroscopy studies 1
• This reduction in glutamate-glutamine cycling alters synaptic signal transduction, which directly accounts for ACTH's therapeutic effect on infantile spasms 1
• The mechanism involves modulation of the glutamate-glutamine cycle, which plays a pivotal role in synthesizing both excitatory (glutamate) and inhibitory (GABA) neurotransmitters 1

Clinical Efficacy

ACTH achieves cessation of spasms and resolution of hypsarrhythmia in approximately 76% of West syndrome patients, making it more effective than oral corticosteroids and comparable to vigabatrin. 2, 3

• At the end of ACTH therapy, 76% of patients show excellent seizure control, 17% show good effect, and only 7% show poor response 3
• EEG improvement occurs in 93% of patients (38% excellent, 55% good response) 3
• ACTH demonstrates superior efficacy compared to oral corticosteroids for cessation of spasms 2
• When compared to vigabatrin, ACTH shows improved outcomes in achieving spasm cessation 2

Recommended Dosing Regimen

Low-dose ACTH (0.005-0.032 mg/kg daily, equivalent to 0.2-1.28 IU/kg) for 2 weeks followed by dose tapering is as effective as high-dose regimens while minimizing serious adverse effects. 4, 2, 3

Standard Short-Term Protocol

• Daily ACTH injections for 2 weeks at low doses (0.005-0.032 mg/kg or 0.2-1.28 IU/kg) 4, 3
• Followed by gradual dose tapering over subsequent weeks 4
• Total treatment duration typically 2-4 weeks for initial therapy 4
• Low-dose regimens produce equivalent efficacy to high-dose protocols (daily doses up to 150 IU) 2, 3

Long-Term Protocol for Relapsed Cases

• For patients with relapsed or intractable West syndrome, long-term ACTH (LT-ACTH) may be considered 5
• LT-ACTH consists of 11-28 days of daily injections (median 16 days) followed by 3-22 months of weekly injections (median 10 months) 5
• The nonrelapse rate at 24 months after daily injections is estimated at 60.6% with this approach 5
• This extended protocol is reserved for patients who have failed conventional ACTH treatment (81% of LT-ACTH patients had prior conventional ACTH) 5

Adverse Effects and Safety Considerations

Serious adverse effects including intracranial hemorrhage, brain atrophy, Cushing syndrome, infection, hypertension, and weight gain correlate directly with ACTH dosage, making low-dose short-term therapy essential for safety. 2, 3

• The severity of adverse effects correlates with total ACTH dosage 3
• Brain volume loss severity correlates with both daily dosage and total dosage 3
• Short-term therapy (2 weeks) is specifically recommended to reduce adverse event risk 4, 2
• Common adverse effects include height stagnation, hypertension, and irritability 5
• Lethal adverse events have not been reported with low-dose protocols 5

Long-Term Outcomes

At long-term follow-up, 52% of ACTH-treated patients achieve seizure freedom, though only 6% have normal cognitive development, with 51% experiencing severe mental retardation. 3

• Seizure prognosis: 52% seizure-free, 48% continue to have seizures 3
• Cognitive outcomes: 6% normal development, 16% mild mental retardation, 27% moderate mental retardation, 51% severe mental retardation 3
• Initial ACTH effects on seizures and long-term outcomes are not dose-dependent within the low-dose range 3
• Early diagnosis and shorter lag time to treatment are essential for optimal outcomes 4

Clinical Pitfalls

• Do not delay ACTH initiation—early treatment is critical for neurodevelopmental outcomes 4
• Avoid high-dose regimens when low-dose protocols provide equivalent efficacy with better safety profiles 2, 3
• Do not extend treatment duration beyond necessary—prolonged therapy increases risk of brain atrophy and other serious complications 3
• Vigabatrin-related retinal toxicity occurs in 21-34% of infants, most frequently when treatment exceeds 6 months, making ACTH a safer first-line option for many patients 4
• Studies are limited by small sample sizes, inconsistent dosage regimens, and use of different ACTH products (synthetic vs. natural), making direct comparisons difficult 2