Tuesday, November 28, 2017

Response to second treatment after initial failed treatment of infantile spasms

Knupp KG, Leister E, Coryell J, Nickels KC, Ryan N, Juarez-Colunga E, Gaillard WD, Mytinger JR, Berg AT, Millichap J, Nordli DR Jr, Joshi S, Shellhaas RA, Loddenkemper T, Dlugos D, Wirrell E, Sullivan J, Hartman AL, Kossoff EH, Grinspan ZM, Hamikawa L; Pediatric Epilepsy Research Consortium. Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort. Epilepsia. 2016 Nov;57(11):1834-1842.

Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome.
The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ACTH] or oral corticosteroids), vigabatrin, or "other." Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi-square tests and multivariable logistic regression models.
One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040).
Greater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

Notwithstanding the non-randomized design and observational nature of this study, a large number of children were studied, so some useful conclusions can be drawn:

Standard treatments (ACTH, steroids, and VGB) are superior to nonstandard treatments and should be the preferred initial treatment for infantile spasms;

Hormonal treatments (ACTH, oral steroids) are superior to VGB except in children with TS for whom VGB is clearly more effective. Response to ACTH was higher than for VGB and also somewhat higher than oral steroids. Similar findings emerged from the UKISS trial favoring hormonal treatments over VGB after 14 days of treatment although this difference was not evident at 14 months. Infants with cryptogenic etiology receiving hormonal treatment had higher developmental scores than those receiving VGB;

The NISC studies were not sufficiently powered to detect differences between various nonstandard treatments. Published reports suggest that some therapies (ketogenic diet, valproate, topiramate) may be more effective than others such as phenobarbital, oxcarbazepine, or pyridoxine (at least in North America);

Response to a second standard treatment with different mechanism of action was superior to response to a second treatment with a similar mechanism of action.

A shorter time (<4 weeks) to starting standard treatment is associated with a higher response to the second therapy, suggesting that the window for optimal seizure control starts to close somewhere between 4 and 8 weeks after spasm onset.

An interesting open-label trial published earlier this year by the International Collaborative Infantile Spasms Study (ICISS) recruited 766 children with infantile spasms from 102 hospitals in 5 countries. The 377 children who met inclusion criteria (reasons for exclusion were not recorded) were randomly assigned 1:1 to receive either hormonal therapy alone or hormonal therapy with VGB. Cessation of spasms occurred in 133/186 (72%) of those assigned to a combination of hormonal treatments with VGB versus 108/91(57%) of those receiving hormonal treatment alone (p=0.002). Infants receiving combination therapy also had a significantly shorter time to cessation of spasms (p<0.001). These results indicate that some infants clearly respond better to combination therapy than to hormone treatment alone. given the urgency of fully controlling spasms, combination treatment may be ideal as response rates dropped in those initiating treatment greater than 2 months after spasm onset. A limitation of this study was the large proportion of infants who were excluded from the study and the failure to randomize the type of hormonal treatment used. (parents could choose between tetracosactide depot or prednisolone). However, the group receiving tetracosactide had greater electroclinical response than the prednisolone group. These results need to be replicated before tetracosactide can be recommended over prednisolone.

Oral steroids are a reasonable option in certain situations (socioeconomic, parental educational level and choice) but doses greater than or equal to 2 mg/kg/day are needed. A 2012 review of available data concluded that the efficacy of high-dose corticosteroids was similar to low-dose ACTH and inferior to high-dose ACTH.


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