Headache in People With Epilepsy: Diagnosis and Clinical Management
Summary by Epilepsy Canada Volunteer Mehrshad Hanafimosalman
Article published in Nature Reviews Neurology
Published in Nature Reviews Neurology by researchers in Montreal, Canada, the Netherlands, the UK, and Germany, this study reviews over 260 research articles published during the period 2015-2020 that provide insights into the associations between headache and epilepsy, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. It also discusses the current best practice for the management of headaches co-occurring with epilepsy and highlights future challenges for this area of research. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden.
Epidemiological evidence.
Headaches, especially migraine, and epilepsy frequently co-exist in the same individual. In a meta-analysis of population-based studies of migraine in people with epilepsy published between 1996 and 2012, the lifetime migraine prevalence was 52% greater in people with epilepsy than in individuals without epilepsy. In recent studies published between 2014 and 2019, up to 79% of individuals with epilepsy reported experiencing headaches. Women with epilepsy tended to report migraine more often than men with epilepsy.
Diagnosis, classification and pathophysiology.
Headaches that co-occur with epilepsy can be classified according to their temporal relationship to seizure.
Interictal headaches occur >24h before and >72h after epileptic seizures. General brain hyperexcitability in people with epilepsy might, even in the absence of seizures, lower the activation thresholds of brain regions that are part of the trigeminovascular system (major pain-signalling pathway), resulting in interictal headaches. In migraine, effects of exogenous triggers such as light or stress, food or sleep deprivation, and systemic fluctuations in sex hormones have been hypothesized to contribute to attack initiation via the dysregulation of cortical and (hypo)thalamic pathway.
Peri-ictal headaches, including migraine, occur shortly before (pre-ictal), during (ictal) or just after (post-ictal) an epileptic seizure and can present a diagnostic challenge (see Figure 1 below). Here is a summary of the three types of peri-ictal headaches:
1. Pre-ictal headaches occur <24h before a seizure and last until seizure onset. These pre-ictal headaches occur in 1-10% of people with epilepsy and are migraine-like in 30-60% of these individuals. At the subcortical level, pre-ictal hyperexcitability can affect central autonomic circuits, including hypothalamic and brainstem areas, and projections to the limbic system. Given the involvement of these areas in the development of head pain, pre-ictal hyperexcitability in these regions could be hypothesized to elicit head pain before the development of widespread seizure activity
2. Ictal epileptic headaches develop simultaneously with onset of the partial seizure. Persistent ictal epileptic headache can occur in non-convulsive status epilepticus, and in some individuals the headache only resolves after intravenous administration of anti-seizure medication. Ictal epileptic headache was identified in just five people in a retrospective review of 8,800 video-EEG recordings of 4,800 individuals with epilepsy. A case series identified a multitude of EEG patterns in ictal epileptic headache, suggesting that this form of headache is associated with different seizure types and localizations. As was suggested for pre-ictal headache, the mechanisms underlying ictal epileptic headache might also involve inflammatory changes caused by enhanced network excitability during seizures. However, in ictal epileptic headache, the timing of events triggering the trigeminovascular system occurs in parallel to the expression of symptomatic seizures and epileptiform EEG bursts.
3. A post-ictal headache is defined as a headache caused by an epileptic seizure, occurring <3h after the end of the seizure event and remitting spontaneously <72h after seizure termination. Evidence indicates that post-ictal headache occurs in <45% of individuals with epilepsy, making it the most common type of peri-ictal headache. In ~50% of individuals with post-ictal headache, the headache is migraine-like. The results of a meta- analysis published in 2019 indicated that of individuals with epilepsy, one third experience post-ictal headache and 16% experience post-ictal migraine. Interestingly, in people with focal epilepsy, post-ictal headache is more common in those with occipital epilepsy than in those with epilepsy originating in the frontal or temporal lobes. On the basis of evidence from preclinical studies, activation of meningeal nociceptive fibres (part of trigeminovascular system) due to excessive neuronal network activation during seizures could lead to perception of headache by thalamocortical activation within 10–30min, in line with a post-ictal phenomenon. Seizures can also yield post-ictal hypoperfusion (reduced blood flow), leading to hypoxia, which might be sufficient to trigger headache mechanisms as occurs in hypoxia-induced migraine attacks.
Figure 1 | The timing of pre-ictal, ictal and post-ictal headaches in relation to the seizure.
Clinical management.
The results of a cross-sectional study indicated that ~50% of individuals with headache and epilepsy report the headaches as severe. Headaches linked to epilepsy negatively affect quality of life. A study at an epilepsy clinic found that depression and anxiety were linked to the presence of headache. Post-ictal headaches, in particular, were associated with depression and suicidality. A survey study found that neurologists underestimate the occurrence of headache among individuals with epilepsy, suggesting that increased awareness among neurologists of the association between epilepsy and headache is required. Interictal and peri-ictal headaches that the individual reports as moderate or intense, once correctly diagnosed, should be treated with analgesics. If migraine is diagnosed concomitantly with epilepsy or vice versa, an anti-seizure medication that also has proven efficacy for migraine (e.g., topiramate and valproate) should be prescribed whenever possible to avoid polypharmacy and possible drug–drug interactions.
Paradoxically, headaches are a common (>10%) adverse effect of anti-seizure medication, and are most often associated with carbamazepine, phenytoin, lamotrigine and levetiracetam. Individuals with drug-resistant focal epilepsy can benefit from a resection of the epileptic focus; 34–74% become seizure-free following the procedure. However, in one study, 12% of participants who underwent the procedure subsequently developed chronic headaches, which persisted for >1 year after surgery.
Activation of the trigeminovascular system seems to be associated with the increased release of CGRP from C-fibres in the trigeminal ganglion. Upon its release, CGRP binds to its receptor on Aδ-fibres, leading to pain perception. Although still in clinical trials, CGRP-inhibiting drugs hold particular promise for individuals with difficult-to-treat migraine, who have high unmet needs and few treatment options.
Cannabidiol has received considerable media attention after a case report indicated that it can reduce seizure frequency in individuals with epilepsy. One trial to assess the effect of cannabis on migraine is ongoing and another is planned.
Clinical trials have found non-invasive stimulation of the trigeminal nerve to be moderately effective for acute migraine treatment and prevention.
Conclusion.
Headaches and epilepsy are not separate disease entities but seem to be symptoms of altered neuronal network excitability. The results of studies published in the past 5 years have confirmed that headache, especially migraine, often co-occurs with epilepsy. Highlighting this overlap during neurological and medical training should help neurologists and general physicians be more attentive to the association between headaches and epilepsy. The gap between headache and epilepsy classifications highlights the need for closer collaboration between specialists, within departments and between professional bodies such as the International League Against Epilepsy (ILAE) and International Headache Society.