Topiramate might not be helpful in achieving a more efficient clinical trial endpoint than placebo in preventing migraine in patients less than 18 years of age.

Migraine is one of the most popular causes of a headache prevalent in pediatric neurology patients. It affects about 5-10% of children at various stages of life. It impairs daily life activities of patients like presence in school, social events, and friendship. Also, it disturbs the family harmony and self-esteem of the individual. The onset of migraine occurs in 7.2 years in boys and 10.9 years in girls and increases with age. The diagnostic criteria for migraine headache has emerged over time, and modern classification criteria include frequency as a criterion. Episodic headaches is defined as headache occurring up to 14 days per month, while chronic migraine refers to the persistence of headache without aura for at least 15 days per month and at least 3 consecutive months without medication overuse (ICHD-II). There always exists a diversity of symptoms, so diagnostic criteria for migraine in children needs to be refined further. A variety of prophylactic treatments are available to reduce the severity of headaches. Topiramate is an antiepileptic drug that exhibits favorable efficacy and safety in children and adults with epilepsy. It has been approved for preventing migraine in adults in Europe since 2003 and the United States since 2004. The mechanism of action of Topiramate in migraine is still unknown, but it was found to be related with influence on pain transmission in the trigeminocervical complex and the third-order neurons in the ventroposteromedial thalamus. Several studies have reported the efficacy of Topiramate in pediatric populations with severe headache and migraine, but a study conducted by Scott W et al determined that there were no significant differences between Topiramate and placebo in the prevention of migraine.

Rationale behind the research:

There is lack of clarity regarding the efficacy of Topiramate in the pediatric population. So, a meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the effectiveness of Topiramate in migraine prevention in patients aged below 18 years.

Objective:

To assess the currently published data about the efficacy of Topiramate for migraine prevention in patients aged below 18 years.

Outcome measures

• Primary outcomes: Relative reduction in the number of headache days of 50% or more in the comparison of the 28-day baseline period with the last 28 days
• Secondary outcomes: Headache days and PedMIDAS scores

Study outcomes

Primary outcomes:

• There were no notable differences between the Topiramate and placebo groups regarding the numbers of patients experiencing a ≥ 50% relative reduction in headache frequency (n=465, RR=1.26, 95% CI=[0.94, 1.67], Z =1.55, P = 0.12) (Fig. 1)

Secondary outcomes:

• There was no considerable difference found in mean headache days between the Topiramate and placebo groups (n = 465, MD = −0.77, 95% CI = [−2.31, 0.76], Z = 0.99, P = 0.32)
• There were significant differences in the mean PedMIDAS score between the two groups (n = 205, MD = −9.02, 95% CI = [−17.34, −0.70], Z = 2.13, P = 0.03)

Figure 1: Reduction in headache frequency

In this meta-analysis, the efficacy of Topiramate in comparison with placebo for the prevention of migraines in patients aged below 18 years was examined. As indicated by IHS guidelines, the reduction in the total number of headache attacks in a 28-day period or the proportion of patients with a higher than 50% relative reduction in headache frequency defines the efficacy of Topiramate in comparison with placebo in the prevention of migraine in patients aged <18 years. The first finding of the study indicates that there were no significant differences between Topiramate and placebo group in reducing 50% headache frequency and reduced mean headache days in a 28-day period.  Three explanations were made for these possible outcomes: 1) High response rate to placebo in children and younger patients (age-related response 30-70%). 2) Difficult to monitor headache changes in children aged 8-12 years due to the incorrect interpretation made by parents. 3) Patients with either episodic or chronic migraine were included which may influence the results of the meta-analysis. The second finding of the study indicated a decrease in PedMIDAS scores on administration with Topiramate. This contradicts that headache-related disability can be alleviated by Topiramate administration. Mean PedMIDAS scores in both the Topiramate group and the placebo group decreased between baseline and endpoint, and the fact that only two trials used this tool as a trial assessment may be the cause of the heterogeneity.

It was evaluated that Topiramate has various side effects which may be serious and life-threatening as compared to placebo. The various adverse effects reported in previous studies were metabolic acidosis, renal calculi, nervous system effects, such as fatigue or somnolence, dizziness, cognitive disorder or aphasia. Other adverse effects reported in this meta-analysis were changes in visual acuity, including visual field deficits, acute myopia, and secondary closed-angle glaucoma. Topiramate also increases the psychomotor reaction times and sometimes suicidal behavior and ideation in some patients. Overall, it was concluded that pathomechanism of migraine is not entirely understood, the choice of medication for personalized therapy tailored to each patient needs to be made cautiously.