Impact of comorbid psychogenic non-epileptic seizures on migraine: An observational study

INTRODUCTION

Migraine is frequently associated with a variety of comorbidities. These include vascular conditions, respiratory diseases, other pain syndromes, seizures, and psychiatric conditions.^[1-3] Psychiatric comorbidities include anxiety, depression, post-traumatic stress disorders, and psychogenic non-epileptic seizures (PNES). Much information is available on the impact of psychiatric comorbidities such as anxiety and depression on migraine.^[4-6] However, there is a lack of literature regarding the impact of comorbid PNES on migraine. Although PNES is much more commonly associated with migraine (19.2% in adult migraineurs) than epileptic seizures (1% in adult migraineurs), patients as well as treating physicians are usually more concerned about epileptic seizures.^[7] Around 50–60% of PNES patients report migraine.^[8] Migraine and PNES may have a complex interplay. Frequently, PNES patients do not get the desired attention and care due to the supposed non-organicity of their symptoms,^[9] especially if they are not being treated at a specialized psychiatric facility. Several studies have shown the impact of associated chronic pain, headache, or migraine on patients with PNES.^[10-12] However, studies looking into the effect of PNES on migraine characteristics are still few [Table 1]. Our study aimed to assess the impact of PNES on headache characteristics, triggers, and associated psychiatric comorbidities in patients with migraine.

MATERIALS AND METHODS

Participants

The study was a cross-sectional and observational study. We included consecutive patients with migraine with PNES and without PNES from our neurology outdoor and indoor from June 2017 to May 2019. Migraine was diagnosed as per ICHD-3 criteria and PNES was diagnosed as per ILAE Non-epileptic Seizures Task Force criteria^[13,14] [Figure 1]. We excluded patients with a history of true seizures and a structural lesion on neuroimaging known to cause epilepsy. The Institutional Ethics Committee approved the study (Ref code: 84^th ECM IIA/P4). Written informed consent was taken from each subject before enrolment into the study.

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Figure 1:

Flow diagram of study design.

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RESULTS

Fifty-two patients with migraine with PNES and 48 patients with migraine without PNES were included in the study. Demographic and clinical characteristics are presented in [Table 1]. The median age was significantly lower in migraine with the PNES group (24 years) in comparison to migraine without the PNES group (30 years) (P < 0.001). Females outnumbered males in both groups. Median headache frequency in migraine with the PNES group (17.5/month) was significantly higher than migraine without PNES (7.5/ month) (P = 0.001). The pain was throbbing in 86.5% and non-throbbing in 13.5% of migraine with PNES, while all patients without PNES had throbbing pain (P = 0.013). Vomiting was significantly more commonly associated with migraine without PNES (P = 0.005).

All the patients with migraine with PNES had normal v-EEG. The episode of PNES was clinically established in all PNES patients. In eight patients, an attack of PNES could be induced during v-EEG and further corroborated by the caregivers. The most common semiology was swoon (67.3%), often associated with hyperventilation and clenched teeth. Other semiologies included jerking of limbs, stiffness of limbs, isolated tongue protrusion, head-banging associated with flail limb movements, and opisthotonus in different combinations.

The number of triggers was significantly more in patients with migraine without PNES (1.62 ± 1.37) when compared with migraine with PNES (1.05 ± 0.99) (P = 0.03). Apart from this, some triggers include noise (P < 0.001), patients with migraine commonly reported sun exposure (P = 0.003), and weather change (P = 0.02) without PNES. On the contrary, mental stress as a headache trigger was more common in patients with migraine with PNES (P = 0.009) [Table 2].

The median PHQ-9 score was higher in migraine with PNES (14) in comparison to migraine without PNES (9) (P = 0.03). The proportion of patients with severe depression (PHQ-9 score ≥ 20) was more in patients with migraine with PNES (P = 0.03). There was no significant difference in GAD-7 scores between the two groups. SSD was more commonly associated with migraine with PNES (75%) than migraine without PNES (39.6%) (P = 0.001) [Table 3].

DISCUSSION

Our study underscores the impact of comorbid PNES on migraine characteristics. There are few studies which highlight the impact of co morbid PNES on migraine characteristics [Table 4]. In this study, we found that PNES significantly increases headache frequency. Although both groups had a similar duration of illness, the proportion of chronic migraine was more in migraine with PNES.

In PNES patients, increased metabolism in the thalamus has been demonstrated in a positron emission tomography study.^[21] Hyperactivity of the thalamus due to comorbid PNES may cause central sensitization in these patients, leading to increasing headache episodes. Thalamic hyperactivation can also be further augmented by comorbid depression, which may contribute to the higher frequency of headaches.^[22]

We concluded that despite of increased frequency of headache episodes, patients with migraine with PNES reported a lesser number of migraine triggers in comparison to migraine without PNES. It seems very difficult for migraine patients to identify and remember the specific triggers when headache frequency is high and overwhelming. Instead, a decrease in headache frequency with treatment may result in better identification of triggers, which has been observed by other experts, too.^[23]

Although migraine with PNES patients reported an overall lesser number of migraine triggers, they reported mental stress as a headache trigger significantly more commonly than migraine without PNES. Patients with PNES usually remain in the state of hypervigilance which cause rapid hyperactivation in response to emotional cues and thus make these patients more prone to be adversely affected by mental stress.^[24] We also found SSD more common in migraine with PNES. More robust connectivity between the insula and frontoparietal cortex has been demonstrated in patients with somatization, enhancing emotions’ impact on perception, memory, and judgment capability.^[25] Comorbid somatization further makes these patients susceptible to mental stress and has higher somatosensory sensitivity. Patients having comorbid anxiety and depression may have higher stress susceptibility. Several neurobiological correlates of this increased stress susceptibility are reported such as dysregulated gene expression, impaired neurocircuitry, and dysregulation in neuroimmunoendocrine functioning.^[26] This higher stress susceptibility may lead to a pathological response to mental stress, enhanced vulnerability for PNES, and a higher propensity for migraine.^[27] Comorbid SSD and depression negatively affect the quality of life in PNES patients.^[28]

The pathophysiological connection between PNES and migraine is unknown. Hypersensitivity to visual, auditory, olfactory, and somatosensory stimuli is a well-recognized phenomenon in migraine.^[19] Although sensory hypersensitivity in PNES patients has not been studied, many experts suggest that dysfunctional tolerance to sensory arousal is one of the important pathophysiological factors. Both hyperarousal and hypoarousal responses have been shown.^[19,24] This can be the reason that the presence of PNES affects migraine differently. Patients report a higher frequency of headache episodes but say migraine-specific throbbing headaches less commonly. Anxiety, depression, somatization, neuropathic pain, and fibromyalgia are associated with migraines and PNES.^[5,29-32] The prevalence of migraine in PNES is 50–60%, much higher compared to the general population (~15%).

In addition, both conditions have common risk factors such as female gender, trauma, and childhood sexual abuse.^[29,33] All the above factors may indicate the common pathophysiological link between the two disorders. However, our study is cross-sectional, observational, and experimental studies looking into the pathophysiological connection between two conditions are lacking.

CONCLUSION

Patients with migraine with PNES suffer more frequent headaches than those without PNES. They differ in various headache triggers, mental stress being the predominant headache trigger in patients with migraine with PNES. Comorbid depression and somatization are more frequent in migraines with frequent headaches. Treating migraine with PNES requires a comprehensive approach, and including a neurologist, psychiatrist, and clinical psychologist may help improve the outcome.