Definitions of the levels of the recommendations (A, B, C, U) and classification of the evidence (Class I-IV) are provided at the end of the "Major Recommendations" field.
Are Other Forms of Corticosteroids as Effective as Adrenocorticotropic Hormone (ACTH) for Treatment of Infantile Spasms?
Data are insufficient regarding the equivalence of other corticosteroids to ACTH (Class III and IV evidence).
The evidence is insufficient to recommend the use of prednisolone, dexamethasone, and methylprednisolone as being as effective as ACTH for short-term treatment of infantile spasms (Level U).
Are Low-Dose ACTH Regimens Effective for Short-term Treatment of Infantile Spasms?
A Class I study showed similar efficacy between low-dose (20–30 IU) and high-dose (150 IU/m2) natural ACTH, and a Class II study using the same low-dose natural ACTH showed clinical and electroencephalographic (EEG) response rates of >40%. The evidence suggests that low-dose ACTH is probably as effective as high-dose ACTH for short-term treatment of infantile spasms (Class I and II evidence).
Low-dose ACTH should be considered as an alternative to high-dose ACTH for treatment of infantile spasms (Level B).
Is ACTH More Effective Than Vigabatrin (VGB) for Short-term Treatment of Infantile Spasms?
Two Class III studies (1 from the 2004 parameter and a later study) demonstrated that ACTH is more effective than VGB for short-term treatment of children with infantile spasms (excluding those with tuberous sclerosis complex [TSC]). A small Class III study and a Class IV study found no difference in short-term outcome between ACTH and VGB.
ACTH (Level B) or VGB (Level C) may be offered for short-term treatment of infantile spasms. Evidence suggests that ACTH may be offered over VGB (Level C).
What Other Agents Are as Effective as ACTH for Treatment of Infantile Spasms?
Data from previously reviewed and updated evidence are insufficient to determine whether valproic acid (VPA), vitamin B6, nitrazepam (NZP), levetiracetam (LEV), zonisamide (ZNS), topiramate (TPM), the ketogenic diet, sulthiame, or other novel therapies (e.g., intravenous immunoglobulin [IVIg], thyrotropin-releasing hormone [TRH]) are effective in the treatment of infantile spasms (Class III and IV evidence). A single Class III study showed better outcome for combination therapy with ACTH and magnesium sulfate (MgSO4).
The evidence is insufficient to recommend other therapies (VPA, vitamin B6, NZP, LEV, ZNS, TPM, the ketogenic diet, or novel/combination therapies) for treatment of infantile spasms (Level U).
Does Successful Early Treatment of Infantile Spasms Lead to Long-term Improvement of Neurodevelopmental Outcomes or Decreased Incidence of Epilepsy?
A Class II study showed that hormonal therapy (ACTH or prednisolone) relative to VGB therapy leads to better neurodevelopmental outcome in children with cryptogenic spasms. One previous Class III study and 1 newer Class II study showed that shorter lag time to treatment improves long-term cognitive outcomes.
- Hormonal therapy (ACTH or prednisolone) may be considered for use in preference to VGB in infants with cryptogenic infantile spasms, to possibly improve developmental outcome (Level C).
- A shorter lag time to treatment of infantile spasms with either hormonal therapy or VGB may be considered to improve long-term cognitive outcomes (Level C).
Classification of Recommendations
Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)
Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)
Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).
Classification of Evidence for Therapeutic Intervention
Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required:
- Concealed allocation
- Primary outcome(s) clearly defined
- Exclusion/inclusion criteria clearly defined
- Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
- For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*
- The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
- The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
- The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
- The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.
Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**
Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.
*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).