A New Option for Intractable Pediatric Migraine?

The anti-seizure medication zonisamide significantly reduced the number of headache days per month in children with migraine, preliminary results of a retrospective study suggested.

The data showed zonisamide was effective in both patients with intractable and those with nonintractable migraine, with the strongest effect occurring after at least 2 months of use.

“Zonisamide is effective in reducing headache days for young migraine patients, and it seems to be especially effective in patients with intractable migraines, which are difficult to treat,” study investigator, Anisa F. Kelley, assistant professor, Feinberg School of Medicine, Northwestern University, Chicago, who is also an attending child neurologist, Ann & Robert H. Lurie Children’s Hospital, Chicago, told Medscape Medical News.

“I think it’s well worth a trial of this drug for these migraine patients to see if it can help reduce their headaches.”

The findings will be presented at the American Academy of Neurology (AAN) 2025 Annual Meeting in April.

Migraine Common in Children

Migraine is a relatively common neurologic disorder among children and adolescents. It’s characterized by recurrent attacks that can significantly and negatively affect quality of life.

Topiramate, which is also an anti-seizure medicine, is currently the only US Food and Drug Administration (FDA) medication approved for migraine prophylaxis in pediatric patients. However, the drug comes with “burdensome” side effects that affect alertness, appetite, and cognition, needs to be taken twice a day, said Kelley.

Although zonisamide has a similar mechanism of action as topiramate, it can be taken once daily and has a more favorable side effect profile, said Kelley. She noted that although zonisamide can also cause fatigue and appetite suppression, it is not associated with cognitive slowing or impaired concentration.

Because of its superior tolerability, Kelley said zonisamide is used off-label at her center for migraine prevention in pediatric patients. Anecdotally, she said, it appears to “work well.”

However, she added, zonisamide hasn’t been well studied as a prophylactic for migraine attacks in children. “In this study, we were hoping to help prove that what we’ve seen clinically is actually true.”

The investigators used electronic medical records to identify children diagnosed with headaches. Patient charts were then reviewed to confirm migraine diagnoses, and those affected were prescribed zonisamide. Additionally, data on headache frequency over time was collected.

The study included 256 participants treated at a single center. The children had a mean age of 15 years, and the inclusion age criteria ranged from 4-18 years. About 70% of participants were girls.

Kelley noted children “are unique” in that prepuberty, boys have more migraines than girls, whereas postpuberty, girls have more migraines.

Before starting zonisamide, study participants experienced an average of 18 HDPM. Of these, 40% had episodic migraine, whereas 60% suffered from chronic migraine.

Additionally, 28% had intractable migraine, meaning they had previously tried and failed at least two prophylactic medications, whereas 72% had nonintractable migraine, indicating they had not yet attempted at least two preventive treatments.

Researchers categorized participants based on follow-up duration: 1-2 months, 2-6 months, and 6-12 months.

Fewer Migraine Days 

Across the entire cohort, the median number of migraine days per month (HDPM) decreased from 18 to 6 at the first follow-up after initiating zonisamide (95% CI, −12 to −8.5; P < .001).

When comparing subgroups, researchers found that participants followed up within 2-6 months experienced the greatest reduction in migraine days, with a median decrease of 6 HDPM (Z, 2.18; P = .01).

Kelley noted that the findings are consistent with existing knowledge on headache prophylactic medications, which generally require at least 1-2 months to take effect before demonstrating full efficacy.

Both intractable and nonintractable migraine groups showed a significant median reduction of 6 HDPM at the first follow-up (intractable: 95% CI, −10 to −3; P < .001; nonintractable: 95% CI, −13.75 to −10; P < .001) — a finding that Kelley described as “notable.” 

Effective treatment options for patients with difficult-to-treat migraines are limited, so the fact that this drug appeared to help both intractable and nonintractable cases is a significant advance for the chronic headache population, Kelley noted.

At the first follow-up, 34% of patients changed from chronic to episodic migraine, and 4% from episodic to chronic migraine, the study found.

It’s not completely clear how anti-seizure medications work to mitigate migraine, which involves complex pathophysiology and impacts different parts of the brain. However, thecarbonic anhydrase inhibition is likely the mechanism of action that reduces the propagation of migraine, said Kelley.

“The drug stops the migraine at the source even before it becomes a full-blown migraine.”

To determine whether zonisamide or topiramate, considered the “gold standard”, is more effective at stopping the migraine, the two drugs would have to be compared head-to-head, she said.

As well, she would like to see a prospective trial carried out, rather than the retrospective trial “where we unfortunately can’t control for a lot of the variables.”

Welcome Research

Commenting on the research for Medscape Medical News, Serena Orr, MD, associate professor in the Departments of Pediatrics, Health sciences, and Clinical Neurosciences/Neurology at the University of Calgary in Calgary, Alberta, Canada, said she welcomed the study.

She noted that pediatric migraine treatment studies are always valuable, especially given the limited evidence-based pharmacological options available for young patients.

The study, she noted, adds to the conversation about potential treatment options for youth with migraine and could spur further research — ideally through randomized controlled trials.

She commended the investigators for examining differences in treatment response between patients with intractable and nonintractable migraines. She also highlighted that this is the largest study to date on zonisamide use for youth with migraines, surpassing the previous study published in 2006, which included only 12 patients.

However, since this study was observational, nonrandomized, and lacked a control group, it is impossible to determine whether zonisamide is more effective than a placebo in youth with migraines, said Orr.

She pointed out that research, including the CHAMP study, has demonstrated that placebo treatments are highly effective in pediatric migraine patients, with approximately 60%–70% experiencing a > 50% reduction in headache frequency after a few months of treatment. Without a comparator group including a placebo, it’s not possible to determine whether zonisamide provides a superior benefit, she added.

Orr also cautioned that the study’s comparison of treatment effects based on time to first follow-up is likely misleading, as patients with more severe headaches are typically followed up sooner.

In addition, she noted that the abstract does not address safety. Safety data from observational studies like this can be valuable in helping providers assess whether a treatment aligns with the “do no harm” principle, particularly when it has not yet been tested in adequate clinical trials and is being used off-label, she said.

It remains unclear how widely zonisamide is used in pediatric headache treatment, as no survey data currently provide insight into its prevalence, at least to Orr’s knowledge.

“Personally, because there’s no pediatric trial on zonisamide, I don’t use it in my practice, but I do know of some pediatric headache specialists who do use it.”

Also weighing in on the research, Carolyn Helene Goldschmidt, DO, a neurologist in Evanston, Illinois, who specializes in various neurological conditions, including migraines, said she was impressed by the findings, which demonstrated a significant reduction in HDPM in pediatric patients treated with zonisamide.

“Given the clinical success of other anti-seizure medications in migraine, the results are not overly surprising, however given the side effect profile and limitations of medications like valproic acid or Topamax, this provides an excellent alternative,” she said.

This study received support from the Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago. Kelley, Orr, and Goldschmidt reported no relevant disclosures.

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