This case series demonstrates excellent efficacy of cofactor therapy (co-enzyme Q10, L-carnitine) combined with amitriptyline. Treatment responses were suboptimal in only four cases, three of which could not tolerate adequate dosages of amitriptyline, and never achieved a "therapeutic" blood level (> 80 ng/ml of amitriptyline + nortriptyline). With the removal of the fourth case of the infant with multiple gastrointestinal malformations, substantial efficacy (> 75% response) of this protocol in children and youth > age 5 years was 19/22 at the onset of treatment, and 19/19 in participants able to tolerate amitriptyline. In the author's observations, making treatment decisions contingent of the blood levels of co-enzyme Q10, carnitine and amitriptyline was very helpful in many cases, as children with sub-optimal clinical improvement always demonstrated a low level of at least one of the three agents, and increased dosing was associated with the resolution of episodes. In order to achieve these "therapeutic" blood levels and clinical efficacy, some subjects required higher-than-customary dosages, including up to 25 mg/kg/day (800 mg a day in larger subjects) of co-enzyme Q10 and 2 mg/kg/day of amitripyline. These dosages were well tolerated.
In participants under age five years, efficacy appears to be good when cofactor therapy is combined with cyproheptadine, although the number of cases reported here is small. Drug treatment varied by age in the present study and in the NASPGHAN recommendations due to expert opinion regarding low tolerability (tachycardia and increased frustration) of amitriptyline in younger children and low efficacy of cyproheptadine in older children .
Combining the 22 cases > age 5 years and 4 cases < 5 years, overall substantial efficacy (> 75% response) of this protocol was 23/26 at the start of treatment, and 23/23 of those who could tolerate the regiment.
Clinical  and molecular  data suggest that CVS in adults, in particular with the adult onset of vomiting episodes  is distinct in many ways than CVS in children. However, among the five adult cases with outcome data in the present study, all of which had the adolescent onset of vomiting episodes, two did not tolerate amitriptyline (see footnote 5 in Table 2) and in the three others episodes resolved (two with all three agents, one with amitriptyline alone). Thus, there is inadequate data in this generally-young cohort to suggest alternative management based on adult age, although there may be a higher rate of intolerance to amitriptyline in adults than in children over age 5.
The major limitation on this study is that the participants were treated on the basis of best available clinical therapy, not on a prospective clinical trial. The protocol was used as guidelines, not on a rigorous basis. For example, participants with severe disease (multiple hospitalizations) were often treated simultaneously with cofactors and medication (amitriptyline or cyproheptadine) at the first visit based on the authors' experience of frequent treatment failures on cofactors alone, while those with milder disease courses were always given a trial of cofactors alone. Some families started the therapies sequentially, and once episodes stopped or greatly diminished would elect not to treat with agents not yet attempted. A few families declined co-enzyme Q10 therapy due to costs, which unlike all the other therapies in this report was rarely covered by insurance. A small number of participants were referred to the author with partial efficacy on amitriptyline or cyproheptadine, and when episodes resolved after increasing the dosage the families chose not to start one or both cofactors. These factors contributed to the complexity of the medical regiments as listed in Table 2. However this limitation does not diminish the observations herein of very-high efficacy in general using these agents in clinical practice, either alone or in combination.
The participants in this study include cases diagnosed by the author in a primary care-like setting, tertiary care cases referred by local pediatricians and gastroenterologists, and quaternary care cases from other states that failed multiple previous attempts at therapy. Since most participants were ascertained in the latter two situations, the present cohort is a sicker, more-treatment-resistant population of CVS than is likely to be encountered by all but a few practitioners. Since the more mildly-affected participants often responded well to cofactor therapy alone, and that the side effects of the cofactors are generally much less than that of the medications [5 and author's experience], a trial of cofactor and dietary therapy alone may be warranted in most CVS patients encountered in clinical practice, with amitripyline or cyproheptidine added in refractory cases.
Many participants discontinued therapy at some point, and in most the episodes returned, later resolving again on renewed therapy. In the exceptional cases, vomiting episodes evolved into migraine headache, often at the time of puberty, and the same protocol was used successfully in migraine prophylaxis. No participants are known to be off therapy and without both vomiting episodes and migraine in the medium-term follow-up period of this study.