Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

all patients

1st line – hormonal therapy plus vigabatrin

1st line – vigabatrin

2nd line – optimise therapy or switch to alternative therapy

2nd line – ketogenic diet

2nd line – alternative anticonvulsant

3rd line – pyridoxine or pyridoxal phosphate

4th line – surgery

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ONGOING
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all patients
1st line – 

hormonal therapy plus vigabatrin

The 2022 UK National Institute for Health and Care Excellence guideline on infantile spasms recommends combination therapy with high-dose oral prednisolone and vigabatrin as first-line treatment for infantile spasms that are not due to tuberous sclerosis, unless the child is at high risk of corticosteroid-related adverse effects.[26]​ This decision is based on evidence from the International Collaborative Infantile Spasms Study (ICISS) trial suggesting that first-line treatment combining corticosteroids with vigabatrin is more effective than either corticosteroids or vigabatrin alone in stopping spasms.[42]

Adrenocorticotrophic hormone (ACTH) plus vigabatrin is an alternative option. Synthetic ACTH is known as tetracosactide (or tetracosactrin) and is the preferred form of ACTH in the UK. Natural ACTH (corticotropin) may not be available in some countries. There is no general agreement regarding the optimum dosage of ACTH.[46] While no definitive trial has determined superiority of low- or high-dose ACTH in management of infantile spasms, low-dose therapy may be preferable owing to its comparative efficacy and reduced risk of adverse effects.​

In view of the adverse effects from hormonal therapy (including hypertension; hyperglycaemia; increased susceptibility to infections, particularly varicella; increased appetite; weight gain; irritability; gastric irritation; and altered sleep-wake pattern), clinical assessment, including measurement of blood pressure and urinalysis for glycosuria, should be performed both before and regularly during the course of hormonal treatment. The adverse effects of long-term corticosteroid therapy may be avoided by limiting the length of treatment, and short-term adverse effects are fully reversible. A proton-pump inhibitor may be considered for gastric irritation prophylaxis in patients on long-term corticosteroid therapy.

Primary options

prednisolone: consult specialist for guidance on dose

and

vigabatrin: consult specialist for guidance on dose

Secondary options

tetracosactide: consult specialist for guidance on dose

or

corticotropin: consult specialist for guidance on dose

-- AND --

vigabatrin: consult specialist for guidance on dose

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all patients
1st line – 

vigabatrin

Vigabatrin is advocated as first-line treatment in infants with spasms and tuberous sclerosis.[13][27][51] 

In the UK, vigabatrin monotherapy is a first-line treatment for infantile spasms in children at high risk of corticosteroid-related adverse effects and in those who have spasms due to tuberous sclerosis.[26]

Following initial response, treatment should be continued for 6-12 months, with appropriate monitoring. If there is no response by 12 weeks of treatment, vigabatrin should be discontinued.[76]

Commonly observed adverse effects of vigabatrin include lethargy, irritability, sleeping and feeding difficulties, constipation, and hypotonia.[55][56][57][58] 

Vigabatrin-associated visual field defects are well recognised and generally considered to be irreversible. They have a prevalence varying from 10% to 40%, but are thought to be related to age at treatment and dosage.[38] The prevalence of vigabatrin-induced retinal damage in patients treated for less than 6 months has been found to be low, at 5.3%.[60]​ Visual fields should be assessed before treatment with vigabatrin, but this should not delay initiation of treatment.

Reports have emerged of magnetic resonance imaging brain signal changes in children receiving vigabatrin for infantile spasms. These changes, vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), which are dose-dependent, predominantly affect the basal ganglia, thalamus, dentate, and brainstem.[62][63]​​​ Risk factors for the development of VABAM may include age younger than 11 months and higher vigabatrin dose.[64]​ They are of unknown clinical significance and usually resolve when therapy is discontinued.[41][62]

Primary options

vigabatrin: consult specialist for guidance on dose

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2nd line – 

optimise therapy or switch to alternative therapy

Following initial spasm cessation, approximately 64% of those initially treated with vigabatrin and 60% of those randomised to receive hormonal treatments subsequently relapsed.[27][46][65][66] 

There are no controlled trial data to support evidence-based therapy decisions when first-line treatment fails to stop spasms. Decisions can be based on expert opinion and experience, which should be guided and supervised by a tertiary paediatric neurologist experienced in the care of these children.[26]​

Consideration should be given to optimising the therapeutic dosages of chosen medications and a trial of alternative first-line agents. A trial of hormonal therapy should be considered in those who fail to respond to vigabatrin, and vigabatrin considered in those who fail to respond to hormonal therapy. The specific needs and characteristics of the individual child and carers should be considered.

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all patients
2nd line – 

ketogenic diet

The UK National Institute for Health and Care Excellence (NICE) guideline on infantile spasms suggests considering a ketogenic diet (KD) as a second-line monotherapy or as an add-on treatment.[26]

The ketogenic diet (KD) is a high-fat, low-carbohydrate, and normal protein diet. The most common types of KD are the classic KD (4:1 or 3:1 fat to non-fat ratio), the medium-chain triglyceride (MCT) diet, the modified Atkins diet, and the low-glycaemic index treatment diet.[69] Literature is lacking qualitative studies on effects of KD in infantile spasms.

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2nd line – 

alternative anticonvulsant

Options include a wide range of anticonvulsants.[26][67] These include levetiracetam, nitrazepam (other benzodiazepines can be considered), valproic acid (caution is required in those with suspected mitochondrial disease), or topiramate.

A randomised controlled trial in 50 patients compared topiramate with nitrazepam as first-line drugs in the treatment of infantile spasms.[68]​ Cessation of spasms occurred in 12 (48%) infants in the topiramate group and 4 (16%) in the nitrazepam group. 

Primary options

levetiracetam: consult specialist for guidance on dose

OR

nitrazepam: consult specialist for guidance on dose

OR

valproic acid: consult specialist for guidance on dose

OR

topiramate: consult specialist for guidance on dose

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all patients
3rd line – 

pyridoxine or pyridoxal phosphate

Pyridoxine treatment should be considered in patients who are refractory to first-line treatment and in whom pyridoxine dependent epilepsy (PDE) has not been excluded.[72][73]​​ It is favoured as a first-line treatment modality in Japan. Evidence from uncontrolled prospective studies indicates that the response rate is similar to the predicted spontaneous remission rate.[41]

Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency has rarely been reported as the cause of infantile spasms. Pyridoxal 5'-phosphate-dependent epilepsy is caused by changes or mutations in the PNPO gene. This is a potentially treatable condition, and pyridoxal phosphate (the active form of pyridoxine) should be considered in the treatment of infantile spasms not responding to first-line treatments.[74]

Primary options

pyridoxine: 100 mg orally once daily

OR

pyridoxal phosphate: consult specialist for guidance on dose

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4th line – 

surgery

Evaluation for epilepsy surgery should be considered in those with atypical, asymmetrical spasms, or other suggestions of focality in seizure semiology, supported by lesional identification on neuroimaging and localisation on electroencephalogram (EEG). Criteria for selecting patients for surgical evaluation include the following: infantile spasms refractory to medical management; focal EEG abnormalities; focal abnormality on neuroimaging (e.g., magnetic resonance imaging or positron emission tomography); no evidence of metabolic or degenerative disease. The likely severity of any post-surgical neurological deficit must also be carefully considered.[38][75]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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