Introduction and Epidemiology

Epilepsy and headache are common paroxysmal disorders frequently encountered by neurologists in both inpatient and outpatient settings and may account for up to 20% of all visits to neurologists [1]. Both are complex, chronic disorders with heterogenous etiologies and typically require long-term management. Migraine affects about 12% of the general population [2], while epilepsy affects about 1% [3]. Additionally, the two conditions are comorbid, co-occurring more than would be expected by chance. Patients with epilepsy are 2.4 times more likely to have comorbid migraine compared with the general population [4]. Migraine with aura is three times more common in children with epilepsy compared to the general population [5]. Patients with epilepsy have more disabling headaches and a high prevalence of medication overuse headache. In one study, most epilepsy patients (83.2%) reported having headaches of some kind [6••]. Migraine is common in patients with benign, partial, and generalized epilepsy syndromes and is often unaddressed in these patients [7]. Conversely, in migraineurs, particularly females, there is an increased risk of developing subsequent epilepsy [8].

Clinical Features

Migraine and epilepsy share some clinical features including discrete phases of premonitory [9], aura, ictal, and post-ictal phases. While typically easy to distinguish, occasionally, the symptoms of migraine aura and those of an aura associated with a seizure can be similar. While in epilepsy, aura represents a focal seizure and in migraine, it represents excitation followed by cortical spreading depression, they are both cortical processes often presenting with positive phenomenon. In migraine, however, these positive phenomenon can be followed by negative phenomenon, which is not typically seen in seizures, although negative motor phenomenon, such as a Todd’s paresis, are well described in the post-ictal state of a focal seizure. Most commonly, migraine aura will last for minutes to an hour, usually accompanied by a typical headache and epileptic auras are more brief, lasting seconds to minutes, although there are certainly outliers in both cases [10]. Migraine auras that include complex sensory, aphasic, or motor symptoms, such as those that occur in patients with hemiplegic migraine or brainstem aura, can be very difficult to distinguish from epilepsy according to symptoms alone. Additionally, both migraine and epilepsy share multiple common triggers such as sleep deprivation, female hormone fluctuations, visual stimulation, and alcohol [11, 12].

Pathophysiology

The similarities in clinical features and presence of positive cortical symptoms may lead one to infer that cortical hyper-excitability is the underlying mechanisms in both disorders, but there appears to be some important differences. The positive symptoms in migraine can be followed by negative symptoms, the latter of which is attributed to cortical spreading depression, while the preceding excitation is likely responsible for the positive symptoms. Seizure propagation is dependent on synaptic transmission and involves glutamate acting at AMPA receptors while cortical spreading depression that occurs with migraine aura is slower, independent of synaptic transmission, and linked to NMDA glutamate receptors [13].

Furthermore, the episodic nature of both migraine and epilepsy is suggestive of ion channel dysfunction. Channelopathies have been proposed as a common link between the two, specifically the Na+/K+ ATPase ion channel [14]. Whether this channel dysfunction is primary or secondary to another process is unclear. Furthermore, inherited channelopathies may present with migraine, seizures, or both. These will be discussed further below.

Mitochondrial dysfunction has also been suggested as a possible etiology for both epilepsy and migraine, an etiology that is supported by the common co-occurrence of both migraine and seizures in many mitochondrial disorders [15••].

Genetic Disorders Manifesting with Migraine and Epilepsy

Mitochondrial Disease

Mitochondrial dysfunction has been speculated to play a part in migraine pathophysiology. Known mitochondrial disorders, caused by mutations in mitochondrial genes or nuclear genes regulating mitochondrial function, may present with both migraine and epilepsy and often both concurrently [15••]. There have been cases of migraine with aura-triggered seizures in mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) [16]. Other known mitochondrial diseases presenting with both seizures and migraine include myoclonic epilepsy with ragged red fibers, Leber’s hereditary optic neuropathy, and POLG1 mutations, among others [17]. MELAS [18] and POLG1 [19] in particular have a predilection for the occipital lobes. The occipital predilection of CNS involvement with these disorders may explain their association with migraine visual auras, while the oxidative damage due to these disorders might be responsible for the seizures.

It may be that there are yet-to-be-discovered, less deleterious mutations, associated with comorbid epilepsy and migraine. In addition, there are treatments which are speculated to affect mitochondrial function, which are effective in both conditions, such as topiramate and magnesium, suggesting a common underlying process. The episodic nature and environmental triggers found in both migraine and epilepsy in and of itself suggest a defect in energy metabolism as is seen in mitochondrial disorders.

Inherited Channelopathies

Ion channel dysfunction is widely speculated as a potential etiology for migraine and epilepsy. While defective channels have not been clearly identified in most cases, there are several, well-described genetic disorders of ion channels that lead to a clinical phenotype of migraine, epilepsy, or both. Perhaps the most well-described examples are those of the familial hemiplegic migraine classification. The CACNA1A gene which encodes a calcium channel protein is defective in familial hemiplegic migraine (FHM) type 1 as well as several other episodic disorders. Additionally, there have been many cases of seizures and epilepsy reported with mutations in the CACNA1A gene [20]. The ATP1A2 gene, a sodium/potassium ATPase, when defective is responsible for FHM type 2. There are also several reports of seizures or epilepsy from mutations in this gene, sometimes concomitant with migraines [21]. Lastly, and perhaps most importantly is the SCN1A gene, which encodes a voltage-gated sodium channel. Mutations in this gene are responsible for FHM3 and several other neurological disorders. Epilepsy syndromes such as severe myoclonic epilepsy of infancy (Dravet’s Syndrome) and generalized epilepsy with febrile seizures plus (GEFS+) are also known to be caused by mutations in this gene [22]. There are several other identified candidate genes whose association with headache and epilepsy will likely be clarified in the near future [23]. The mechanisms by which these gene mutations lead to migraine and epilepsy are complex an incompletely understood. One possible mechanism is the dysfunctional ion channel leading to altered neuronal resting potentials increasing the susceptibility to cortical spreading depression and epileptic discharges [21]. Alternatively, altered calcium levels from dysfunctional channels are thought to affect the function of mitochondria which leads to a deficit in energy metabolism leading to the paroxysmal symptoms [15••].

Classification

There are separate authorities which classify headache disorders and epilepsy syndromes. The International Headache Society (IHS) Classification Committee publishes the International Classification of Headache Disorders (ICHD) and the International League Against Epilepsy (ILAE) Commission on Classification and Terminology publishes criteria for epilepsy. While the ICHD 3 beta recognizes the comorbidity of headaches and seizures by classifying the headaches as either primary (as the cause of the seizure) or secondary (as the consequence of a seizure), the ILAE’s current classification make no mention of the comorbidity between epilepsy and headaches [24]. Of note, the 2001 iteration of the ILAE classification included “cephalic aura” as a non-motor, sensory manifestation of epileptic aura, although this has since been removed [25]. A common method for describing the association between headaches and seizures is to describe when the headache arises with respect to the seizure (peri-ictal and post-ictal; peri-ictal is further subclassified into pre-ictal, ictal, and post-ictal headaches). Each of these patterns is discussed below. For a list of common terms used in these cases, refer to Table 1.

Table 1 Terms that have been used as descriptors for peri-ictal headaches
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Peri-Ictal Headaches

Pre-Ictal Headaches

Pre-ictal headaches are those that occur prior to the development of a seizure. Pre-ictal headaches likely encompass several discrete clinical entities and the timing of the headache relative to the seizure may not suggest any particular underlying diagnosis. Pre-ictal headache also includes the nebulous term “migralepsy,” a term that has been in the literature for many years but refers to varying clinical phenomena [26]. Currently, the ICHD 3 beta classifies migraine aura-triggered seizure (1.4.4) as a complication of migraine. It is defined as a seizure occurring in a patient with a known diagnosis of migraine with aura during or within 1 h of an attack of migraine with aura. It also notes that this entity is sometimes referred to as migralepsy [27]. Migraine with visual aura and occipital lobe epilepsy do share some clinical features (see Table 2) and for this reason, the diagnosis of migraine aura-triggered seizure should only be made after it is determined that the aura is not part of the seizure itself.

Table 2 Clinical features differentiating migraine with visual aura from occipital epilepsy
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There are also multiple reports of headaches occurring prior to the onset of a seizure in known epilepsy conditions, such as focal occipital lobe epilepsy and benign occipital epilepsy of childhood [28]. In many of these reports, EEG data was not collected prior to the seizure, the presence of the headache was based on patient report, or the characteristics of the headaches were not described. As such, it is difficult to determine whether these were truly pre-ictal headaches or an epiphenomenon of the seizure.

Seizures following migraine without aura attacks have also been reported in the literature. The duration of migraine headaches in these cases ranged from hours to days (i.e., status migrainosus) [29,30,31]. Seizures following migraine without aura attacks are not separately classified within existing diagnostic classification systems. Patients with epilepsy may report a headache as an “aura” to their seizure. However, a recent study of 831 patients with epilepsy found that only 6 patients reported headache as an “aura,” suggesting this is a rare occurrence. Three of these six patients also had ictal headache [32].

Ictal Headaches

Ictal headaches are the least common form of headache related to seizures and encompass two discrete entities, ictal epileptic headache (IEH) and hemicrania epileptica [33]. Hemicrania epileptica is defined in the ICHD-3 beta as a secondary headache disorder (7.6.1) occurring during a seizure, located ipsilateral to the epileptic discharge, and resolving following the seizure. Thus, the definition infers that hemicrania epileptica occurs exclusively in patients with focal epilepsy. By contrast, IEH is described in the literature but is not classified in the ICHD-3 beta. It has been described as a headache as the sole manifestation of an epileptic seizure [34]. Reports of IEH describe headaches as the sole manifestation of both generalized and focal epilepsies and many different EEG patterns have been observed during the headache [35•] including non-convulsive status epilepticus [36].

Post-Ictal Headaches

Currently, post-ictal headaches are classified in the ICHD-3 beta as a secondary headache disorder (7.6.2). While the actual prevalence varies widely among studies, it is clear that post-ictal headaches are the most common type of peri-ictal headache in people with epilepsy. The current classification for post-ictal headaches requires that a headache begin within 3 h of a seizure and resolve within 72 h of the seizure. Many patients with post-ictal headaches also report having inter-ictal headaches, although a recent Dutch study reports that as many as 11% of children report only post-ictal headaches [37••]. A Japanese study in 2002 studying patients with various types of epilepsy revealed that post-ictal headache was more likely to occur after a generalized tonic-clonic seizure compared with focal seizures and more common in occipital lobe epilepsy compared to temporal lobe and frontal lobe epilepsy [38].

Inter-Ictal Headaches

Inter-ictal headaches are those that occur between episodes of seizure without a time-locked association. Approximately 24% of patients with epilepsy have comorbid migraine [39]. Most of these are likely inter-ictal. The rate of tension-type headache does not appear to differ from the general population [6••], but likely also accounts for a large amount of the inter-ictal headaches experienced by patients with epilepsy due to its high prevalence. When there is an absence of a clear time-locked association between a headache and a seizure, the classification becomes much simpler; the primary headache disorder and the underlying epilepsy disorder are classified individually and the patient is said to carry both diagnoses. Therefore, “inter-ictal headache” is a descriptive term and not a diagnosis.

Headache and Non-epileptic Seizures

While the relationship between headache and psychogenic non-epileptic seizures (PNES) is less clear from a biological perspective, there appears to be an important relationship between the two. There are characteristics of headache that are more common in PNES patients as compared with epilepsy patients. Ictal pain, while rare in an EMU setting, is most commonly associated with PNES as opposed to epilepsy [40]. Additionally, pre-ictal headaches are a relatively common occurrence in patients with PNES. A recent study demonstrated that the presence of chronic pain and a history of head trauma are good predictors of PNES in an EMU setting [41]. Additionally, more than 70% of PNES patients have some form of chronic pain. When pain of any kind is present during a seizure, the most likely etiology for the seizure is PNES [40]. Migraines are a stronger predictor for PNES with comorbid epilepsy than they are for PNES alone [41]. Additionally, it has been reported that patients with PNES report more frequent, longer duration, and more severe headaches compared with epilepsy patients. [42] Compared to patients with epilepsy, they also report more non-visual aura symptoms [42].

The nature of the relationship between headache and PNES remains unclear. It may be that the presence of pain disorders in a susceptible person leads to the functional neurological disorder as a coping mechanism. It may also be that the described pain is part of the overall functional syndrome. Regardless of the cause of the relationship, it is an important one with regards to treatment. Patients with comorbid PNES and headache should have non-medication approaches instituted early as part of their treatment plan. Patients with PNES who are diagnosed and treated early present to the emergency department less often [43•], perhaps a reflection of their somatic symptoms being under better control.

Treatment Considerations

The treatment of epilepsy is largely aimed at prophylaxis while the treatment of headache involves abortive strategies with preventive treatments when the headaches are high frequency, prolonged duration, unresponsive to abortive strategies, and/or associated with significant disability. One of the major similarities in treatment of epilepsy and migraine is the effectiveness of certain anti-epileptic medications. There is, of course, significant heterogeneity in both migraine and epilepsy, and this underlying heterogeneity must be taken into account when choosing a treatment agent. In appropriate patients, it may be pertinent for topiramate [44] or valproic acid, which are FDA approved for migraine prophylaxis to be first-line treatment when both epilepsy and migraine are present in one patient. Other anti-epileptic drugs have varying levels of evidence for treating migraine, including zonisamide [45], levetiracetam [46], gabapentin [47], and pregabalin [48].

In epilepsy patients who have comorbid migraine, it is important for patients to have a plan for aborting their migraine attacks. Studies reveal that headaches in epilepsy patients often go untreated, even in monitored settings. It has been reported that simple measures such as over-the-counter NSAIDs may reduce pain in up to 75% of patients, but are often not administered [48]. In fact, one study found that peri-ictal headaches were often reported as more severe and disabling, but were only treated 50% of the time [49]. It has also been reported that migraine-specific abortive agents such as sumatriptan are effective in treating post-ictal headaches [50]. Screening patients with epilepsy for headaches would presumably lead to earlier diagnosis and treatment and ultimately to reduced headache burden.

Conclusions

Both headache and epilepsy represent a complex group of heterogeneous disorders that are commonly comorbid. There are several proposed shared pathophysiologic mechanisms. Classification is complex, evolving, and currently based on phenomenology. ICHD 3 beta recognizes migraine aura triggered seizure, hemicrania epileptica, and post-ictal headache. Ictal headaches are rare, and when present should raise suspicion for PNES. The comorbidity of headache and epilepsy needs to be better recognized in clinical practice so that clinicians recommend treatments that address both disorders.