Headache Patterns May Signal Surgical Success in Drug-Resistant Focal Epilepsy

For the roughly one-third of people with epilepsy whose seizures stubbornly resist every anti-seizure medication thrown at them, surgery to remove the epileptogenic focus is often the last best hope. But a question that has long hovered over the operating table is now getting a fresh answer: does the headache that so often travels alongside epilepsy change how well that surgery works? A new study from China suggests the answer is more nuanced than a simple yes or no. Having a headache, it turns out, does not by itself determine whether a patient with drug-resistant focal epilepsy will be seizure-free after surgery. But the character of that headache — whether it strikes on one side of the head, and how intensely it burns — may quietly encode information about the brain beneath it, offering clinicians an unexpected preoperative clue.

The research, published in Frontiers in Neurology, was led by a team at the First Affiliated Hospital of Zhengzhou University in Henan, China. Between April 2020 and December 2023, the investigators consecutively enrolled patients with drug-resistant focal epilepsy (DRFE) who underwent resection surgery of the epileptogenic focus, then followed them for at least one year after the operation. To qualify as drug-resistant under the criteria proposed by the International League Against Epilepsy in 2010, patients must have failed to achieve sustained seizure freedom after adequate trials of at least two appropriately selected and correctly used anti-seizure medications. Of 132 patients initially screened, 103 made it into the final analysis after exclusions for unclear epileptogenic foci, missing data, inability to describe headache reliably, or loss to follow-up. The cohort skewed young, with a median age of 24 years and a median epilepsy duration of nine years, and most patients — 76 of the 103 — had temporal lobe epilepsy.

The headline finding is deceptively simple: headache is extraordinarily common in this population, yet its mere presence does not tip the surgical scales. Among the 103 patients, 46 — 44.7 percent — had comorbid headache. That figure aligns with meta-analyses suggesting that roughly 49 percent of epilepsy patients experience headache, and that the lifetime prevalence of migraine is 52 percent higher in people with epilepsy than in those without. Within the headache group, 22 patients had migraine (21.4 percent of the full cohort), 13 had tension-type headache (12.6 percent), 9 had unclassified headache (8.7 percent), and 2 had both migraine and tension-type headache. When the researchers compared the seizure-free rate within one year after surgery between the headache and non-headache groups, the difference was not statistically significant: 78.3 percent versus 73.7 percent, with a p-value of 0.590. Headache subtypes fared no better as predictors — migraine, tension-type, and unclassified headache groups all showed seizure-free rates in the 78 to 92 percent range, none reaching statistical significance.

But the story deepens when the researchers dissected the temporal relationship between headache and seizures. Using the International Classification of Headache Disorders-3 (ICHD-3) framework, they sorted headaches into peri-ictal and interictal categories, with peri-ictal headaches further divided into preictal, ictal, and postictal phases. Preictal headache was defined as pain starting within 24 hours before a seizure and continuing into it; ictal headache occurs simultaneously with the seizure and eases markedly when it stops; postictal headache begins within 3 hours after a seizure and resolves spontaneously within 72 hours. The distribution was striking: 41 patients (39.8 percent) had peri-ictal headache, dominated overwhelmingly by the postictal type (38 patients, 36.9 percent), while only 4 had preictal headache and just 1 had ictal headache — an extreme rarity consistent with prior EEG-confirmed studies that identified ictal headache in fewer than 1 percent of epilepsy patients. Another 14 patients (13.6 percent) had interictal headache occurring independently of seizures. Notably, 10 patients — 21.7 percent of the headache group — experienced headaches in two or more temporal phases, with the coexistence of postictal and interictal headache accounting for 80 percent of these multi-phase cases. Patients with a family history of headache were significantly more likely to fall into the multi-phase category, hinting at a stronger familial predisposition.

The most eye-catching spatial finding emerged among patients with unilateral headache. Of the 46 patients with comorbid headache, 23 had pain confined to one side of the head — and in 22 of those 23 patients, a remarkable 95.7 percent, the headache side matched the side of the epileptogenic focus. This is not the first time such lateralizing value has been reported. Previous work found that among temporal lobe epilepsy patients with unilateral peri-ictal headache, 90 percent had headache ipsilateral to the focus, and comparable figures of 93.75 percent for temporal and 70 percent for extratemporal epilepsy have been documented. The consistency across studies suggests that unilateral headache is not a random symptom but a spatially anchored signal, one that points directly at the abnormal brain tissue generating the seizures.

Why would the brain produce such a geographically faithful pain signal? The answer lies in two intertwined pathophysiological mechanisms: cortical spreading depression (CSD) and activation of the trigeminovascular system (TVS). CSD is a wave of brief cortical excitation followed by prolonged suppression of neuronal activity. When the abnormal discharges generated by a localized epileptogenic focus trigger CSD, the wave can activate the trigeminovascular system, unleashing a cascade of inflammatory molecules and neurotransmitters that produce the throbbing pain of a migraine attack. Because the threshold for inducing CSD is lower than the threshold required for an outright epileptic seizure, seizures directly triggered by migraine are vanishingly rare, whereas comorbid migraine in epilepsy patients is common — and recurrent seizures in DRFE may themselves facilitate CSD, further raising migraine prevalence. Local vasodilation and reactive hyperemia at the site of the focus may also activate trigeminal sensory fibers, and electrical stimulation of cortical regions such as the anterior cingulate cortex, the entorhinal cortex, and the insula has been shown to evoke headache directly. When CSD spreads from one hemisphere to the other, bilateral headache results — which is precisely why unilateral headache may be the more diagnostically valuable pattern.

That mechanistic logic dovetails with the study’s subgroup analysis, which is where the clinical payoff emerges. Among the 46 patients with comorbid headache, the researchers compared those who were seizure-free within one year after surgery against those who still had seizures. Univariate analysis revealed that unilateral headache was significantly more frequent in the seizure-free group — 58.3 percent versus 20.0 percent, p = 0.032 — and that the mean preoperative visual analogue scale (VAS) score, a 0-to-10 measure of headache intensity, was significantly lower in the seizure-free group: 5.50 ± 2.171 versus 7.60 ± 1.578, p = 0.007. When these variables were entered into a multivariate binary logistic regression, unilateral headache remained independently associated with higher odds of seizure freedom (OR = 1.854, 95% CI 1.112–3.092, p = 0.018), while a higher preoperative VAS score was independently associated with lower odds (OR = 0.136, 95% CI 0.020–0.923, p = 0.041). The interpretation offered by the authors is that unilateral headache may reflect a more localized epileptogenic network — one that surgery can more cleanly excise — whereas intense headache, as indexed by a high VAS score, may signal stronger trigeminovascular activation by CSD, with CSD-induced cerebral ischemia, hypoxia, and energy metabolism disorders contributing to broader brain cell damage and poorer surgical outcomes.

The study also painted a demographic portrait of who develops comorbid headache in DRFE. Compared with the non-headache group, the headache group had a significantly higher proportion of female patients (56.5 percent versus 35.1 percent, p = 0.030), a significantly higher rate of family history of headache (15.2 percent versus 0.0 percent, p = 0.003), and a significantly higher preoperative seizure frequency, with half of the headache group experiencing seizures at least once per week versus 24.6 percent of the non-headache group (p = 0.027). The female predominance is consistent with the generally higher susceptibility to headache in women, possibly linked to hormonal fluctuations during the postpartum period and late luteal phase that affect serotonergic and GABAergic activity. The familial clustering points to shared genetic susceptibility — genes such as CACNA1A, ATP1A2, and SCN1A have been implicated in both conditions — though the study did not find a significant association between family history of epilepsy and comorbid headache. The link with frequent seizures echoes prior findings that patients with recurrent seizures are more likely to develop headache, likely because each seizure can trigger postictal pain through the same CSD-trigeminovascular pathway.

During follow-up, the researchers also tracked what happened to the headaches themselves after surgery. Among the 41 patients with peri-ictal headache who were seizure-free within one year, the peri-ictal headache resolved — a satisfying consequence of removing the seizure generator. Among patients with interictal headache, the picture depended on temporal sequence: when epilepsy onset preceded headache onset, the headache resolved after surgery in most cases, but when headache onset preceded epilepsy onset, the headache showed no significant improvement. This pattern reinforces the idea that seizure-driven headache is surgically curable, while headache with an independent origin may follow its own course regardless of the operation.

The authors are careful to frame these findings within their limits. This was a single-center study with a modest sample size, so selection bias cannot be ruled out and multi-center replication is needed. The one-year follow-up captures only short-term outcomes, and long-term data consistently show that the proportion of patients remaining seizure-free declines over time — among patients seizure-free at the end of the first postoperative year, the annual probability of recurrence is 5.6 percent between years 1 and 5, dropping to 4.2 percent beyond year 5. In pediatric epilepsy surgery, seizure freedom within the first year raises the chance of long-term remission to 87 percent, underscoring why even short-term success matters. The study also did not systematically control for the types and durations of anti-seizure medications patients took preoperatively, and headache classification inevitably depended on patient recall, introducing potential recall bias. Still, the practical message stands: headache itself should not discourage DRFE patients from surgery, but a detailed preoperative inquiry into headache characteristics — laterality and intensity in particular — has genuine guiding value for individualized treatment decisions. In a field where roughly 70 million people worldwide live with epilepsy and comorbid headache is sometimes more disabling than the seizures themselves, teaching clinicians to read the headache as a clinical signal may be one of the quiet advances to emerge from this work.

Subject of Research: The relationship between comorbid headache characteristics and short-term surgical outcomes in drug-resistant focal epilepsy

Article Title: The impact of comorbid headache on surgical outcomes in drug-resistant focal epilepsy

Article References: Cheng, W., Shi, A., Du, M., Ma, Y., Wang, Y., Jiao, H., Geng, J., Lian, Y., Tian, Y., & Lian, X. (2026). The impact of comorbid headache on surgical outcomes in drug-resistant focal epilepsy. Frontiers in Neurology, 17, Article 1964217. https://doi.org/10.3389/fneur.2026.1964217

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1964217

Keywords: epilepsy, headache, migraine, epilepsy surgery, drug-resistant focal epilepsy, cortical spreading depression, trigeminovascular system, neurology, impact, comorbid, surgical, outcomes