Barbara Chmielewska, Krzysztof Turowski
Migraine-triggering epileptic seizures - migralepsy
Chair and Department of Neurological Nursing,
Medical University of Lublin
Katedra i Zakład Pielęgniarstwa Neurologicznego,
Uniwersytet Medyczny w Lublinie
Barbara Chmielewska, Krzysztof Turowski
Migraine-triggering epileptic seizures – migralepsy
Migrenopochodne napady padaczkowe – migralepsja
The coexistence of migraine and epilepsy has been a subject of interest for more than a century and has intrigued prominent neurologists. The clinically based hypothesis that there are several links between both conditions dates back to the 19th century. Jackson discussed the spectrum of these disorders and analyzed their relationship. Conversely, Gowers, after detailed clinical analysis of cases gave a migraine a place in the borderland of epilepsy and concluded that any relationship was rare, indirect and frequently constituted a source of errors because a distinction of these two diseases can be a challenge. Furthermore, he stressed two crucial symptoms that are discriminative: 1. visual symptoms (short in epilepsy, long in migraine), and 2. intensity of headache (severe pain in migraine, moderate in epileptic postictal headache). In the monograph “The border-land of epilepsy. Faints, vagal attacks, vertigo, migraine, sleep symptoms, and their treatment” published in 1907 Gowers kept a list of cases, which seemed to be in the border-land of epilepsy (“near it, but not of it”). Gowers stated that: ”many were so placed by their features and character; others because they had given rise to an erroneous diagnosis”. He concluded that “some surprise may be felt that migraine is given a place in the borderland of epilepsy, but the position is justified by many relations, and among them the fact that the two maladies are sometimes mistaken, and more often their distinction is difficult”. His concept of the co-occurrence of migraine and epilepsy within the life-time includes three possibilities: 1. overlap at some point in life expectancy, 2. in parallel throughout the life, 3. mutually exclusive illnesses occur in separate periods of life. Migralepsy is an old term deriving from migraine (migra-) and epilepsy (-lepsy) [1]. It has been used for the first time by Lennox and Lennox to describe in their three patients a condition wherein “ophthalmic migraine with perhaps nausea and vomiting was followed by symptoms characteristic of epilepsy”. After describing further cases the term migralepsy was reintroduced in the nineties by Marks and Ehrenberg [2]. Migralepsy represents a concept in which two separate disorders occur in succession. Recently,migralepsy as such appears in the headache classifications and not in the epilepsy classifications. The term migralepsy or migraine-triggered seizures is currently included in the International Classification of Headache Disorders, Second Edition (ICHD-II) in section 1.5.5 (“Migraine. Complications of migraine. Migraine-triggered seizure”) as a complication of migraine. The description states that migralepsy means a seizure triggered by a migraine. According to ICHD-II the diagnosis of migralepsy is based on the fulfillment of two criteria: 1. migraine fulfilling criteria for migraine with aura and 2. a seizure fulfilling diagnostic criteria for one type of epileptic attack (according to the International League Against Epilepsy (ILAE) classification) occurring during or within 1 h after a migraine aura. It is worth stressing that migralepsy is not included in the current seizure classification or in the more recent recommendations of the ILAE Commission on Classification and Treminology of seizures and epilepsies [3,4].
Prevalence of migralepsy
Migralepsy is a rare disease. There have been about 60 cases of possible migralepsy described in children and adults. A recent Embase search found 31 reviews (half of them with case description) in the last thirteen years. The prevalence of epilepsy is higher in headache patients than in the normal population. However direct indices of prevalence are not known. Comorbidity studies have shown the prevalence of migraine in 7-26 % among epilepsy patients, and prevalence of epilepsy between 1 and 17% among migraine patients. About 1.6-2.0% patients with migraine-like or tension headache simultaneously complain of seizures [5].
Clinical characteristics
Migralepsy is usually under diagnosed due to its clinical rarity. Clinical diagnosis of migralepsy requires that there is a temporal relationship between the migraine aura and a seizure event within an hour; epileptic seizure arise during a pre-established migraine attack. However most reported cases of migralepsy are complicated. Both disorders can present with episodic, overlapping constellations of headaches, sensory, motor and cognition symptoms. Both are phenotypically heterogenous. The diagnosis in the majority of previously published cases is uncertain and debatable. Most common complains, signs and symptoms of migralepsy are presented in cited below clinical descriptions.
Case 1. 22 year-old woman, at the age 12 began having 2-3 min episodes of fluorescent-colored flashing, black spots and squiggly lines. At the age 13, visual symptoms began to be followed by bi-frontal headaches. At the age 15 she experienced the first convulsion in context of worsened headache after left visual field scintillations. This latter phenomenon was followed by loss of vision. Over next four years, she had 1-2 seizures per year preceded by identical visual aura. Seizures were in relation with menses. She has not had family history of epilepsy but many maternal relatives suffered from migraine [6].
Case 2. 23-year-old women with a history of migraine attacks but not epilepsy referred to the epilepsy out-patients clinic because of reappearance of generalized tonic-clonic seizures. She also had either family history of epilepsy or migraine. At 13 years of age she began having very rare episodes of headaches preceded by visual aura lasting no longer than an hour with clinical features of migraine with aura. At 15 years she began having episodes of myoclonic jerks sometimes with generalized tonic-clonic seizures or absence. Her disorder was diagnosed as juvenile myoclonic epilepsy. The interictal EEG showed generalized, synchronous polispike-and-waves discharges (typical for juvenile myoclonic epilepsy) with a photoparoxysmal response. Treatment with valproate reduced seizures, so she decided to finish it. Three years after drug withdrawal seizures reappeared. Her neurological examination was normal, as well as routine laboratory analyses, cerebrospinal fluid examination and brain magnetic resonance imaging with FLAIR and post-gadolinium sequences. Continuous video EEG recorded one typical episode of her migraine attack lasting several minutes followed by tonic-clonic seizure lasting 60 s. Ictal EEG showed bilateral 2-3 Hz delta waves over the fronto-temporal regions lasting 6 s and followed by a generalized spike and polyspikes (3-4 Hz) lasting 10 s, with return to the slow background activity. She was started with topiramate and she obtained freedom both from seizures and migraine [7].
Case 3. A 20-year female with history of migraine for 7 years and epilepsy for 4 years was presented in epilepsy center with complaints of exacerbation of migraine with 4-5 seizures attacks per week. She had been given increasing doses of drugs combination but no relief was achieved. She had no family history of migraines and seizures; birth and development had been normal. At the age of 13 years she began to have regular attacks of migraine with aura as well as without aura and without associated precipitating or exacerbating factors. Headache was severe, throbbing, bi-frontal and temporal with nausea, lasting for several hours and occasionally it was triggered by catamenial component. During and between attacks treatment with different symptomatic analgesic and anti-migraineous drugs was unsuccessful. At the age of 16 years she developed her first convulsion attack. CT scan of brain was normal. EEG showed diffuse fast beta rhythm without abnormal activity. At time of exacerbation MRI scanning was found to be normal. She has been instructed to withdraw all her pervious medications and prescribed topiramate at low dose of 25 mg and carbamazepine 200 mg. Patient had migraine and epileptic relief in one weeks time and there after continued for 3 months. Patient was reported to be absolutely free from migralepsy [8].
Sances, at al reviewed all potential migralepsy cases published up to 2008. Assessing clinical and diagnostic characteristics they found as much as 62% of patients with migraine with aura, while 26% who presented basiliar or without aura type of migraine. A half of patients suffered from generalized tonic-clonic seizures, 24% had partial and 20% mixed-partial and generalized tonic-clonic seizures. Interictal EEG showed localized and generalized abnormalities, respectively in 34 and 28% of patients but it was often normal - in one third of patients. Unfortunately, ictal EEG was rarely available in 32% of cases and was mostly abnormal - in 28% of these registrations. Any type of brain imaging was performed in two third of cases and was normal in a half but shown structural or transient alterations in 20%. In conclusion the analysis stressed that only 4% of these cases actually met current ICHD-II criteria for migraine-triggered seizures, while 28% were questionable for the nature of epileptic seizures and 38% were uncertain [9]. Verotti, et al. reviewed the records of 4600 children with epilepsy and selected 16 cases (0,3%) of migraine with or without aura- triggering seizures within 1 hour of the migraine attacks; 75% were female [10]. 31% of patients had primary generalized epilepsy and among them 80% had tonic-clonic seizures. 69% had complex partial seizures with occipital or temporo-parieto-occipital lobe focus in about three quarters of cases. Symptoms during migraine consisted of nausea, vomiting, abdominal pain, dizziness and photophobia in 50% of patients. In addition, 56% of patients felt other visual symptoms during migraine, e.g. scotoma, loss of visual field and elementary or complex visual hallucinations. The interictal EEG revealed epileptiform complexes in 87% patients with partial seizures during migraine. Ictal EEG recordings during migraine revealed spike-and-wave complexes in 56% of patients, while only a quarter of them had generalized epilepsy (and generalized interictal EEG discharges). The MRI was nonspecifically abnormal in 25% of patients including differentiated organic lesions (gliosis, altered neuronal migration or hydrocephalus) [10].
Differentiation
The mentioned reviewshave shown that there is the high prevalence of purely epileptic disorders among cases reported as migralepsy. Detailed analysis of Lennox and Lennox cases of migralepsy also revealed that two of three were in fact symptomatic and idiopathic occipital epilepsies with visual hallucinations [9]. Occipital epilepsies represent 5% of partial epilepsies. Headache or visual symptoms can be the epileptic aura of a seizure in occipital lobe epilepsy.Distinction between migraine visual auras and occipital lobe seizures aura must be kept in mind when evaluating attacks suggestive of migralepsy. According to Panayiotopoulos migraine visual aura starts as a flickering, uncolored, zigzag line in the center of the visual field, progressing over 4-30 min toward the periphery of one hemi-field. It is often followed by scotoma. Total duration of aura is about 60 min. Contrary, ictal elementary visual hallucinations of occipital lobe epilepsies develop rapidly (seconds), and they are colored, circular and brief (2 min). They appear in the periphery of a temporal hemi-field, widen during seizure and move horizontally toward the contralateral side (tab.1)[11]. However visual symptoms may be mixed or simply blurred vision, followed by headache and vomiting as in migraine attack. Furthermore headache itself can be exclusive ictal epileptic phenomenon. Some epilepsy syndromes such as childhood benign epilepsy with occipital paroxysms (focal cryptogenic or symptomatic epilepsies) and childhood benign epilepsy with centro-temporal spikes (benign rolandic epilepsy) ought to be differentiated from migralepsy in which seizures are triggered by migraine aura. Both are primary migraine-epilepsy syndromes with features of both migraine and epilepsy without a specific underlying cause. Benign rolandic epilepsy is characterized by unilateral somatosensory or motor seizures and centro-temporal spikes. Among symptoms are speech arrest, pooling of saliva with preservation of consciousness; secondary generalization may also occur. The seizures respond well to anticonvulsant medication and disappear by age 15. An association with migraine has been reported; migraine was presented much higher in patients with centro-temporal epilepsy and higher in patients with absence epilepsy than in patients with any other partial epilepsy or in cases without epilepsy. The association may be a part of the co-morbidity of migraine with all forms of epilepsy [12]. Benign epilepsy of childhood with occipital paroxysm is a rare disorder characterized by a partial seizure with visual symptoms, followed by postictal migraine and occipital spikes on EEG. It has features of both epilepsy and migraine. The visual symptoms include amaurosis, elementary or complex visual hallucinations or illusions often followed by colonic, complex partial or secondary generalized tonic-clonic seizures, following by migraine-like headaches in about 40% of patients. The interictal EEG is characterized by normal background activity and occipital biphasic spike high-voltage discharges. They disappear with eye opening and reappear after eye closure. Occipital spikes are not specific for occipital epilepsies; they have been reported in people with migraine, in myoclonic, absence and photosensitive epilepsies and in healthy children under 4 years [13].
EEG and neuroimaging contribution to study the association between migraine and epilepsy
EEG abnormalities can be similar in migraine and occipital epilepsy. Both interictal and ictal EEG abnormalities in patients with migraine comprise symmetrical high voltage theta bursts over the temporo-occipital areas. Patients with epileptic visual symptoms may show similar abnormalities. However patients with ictal autonomic manifestation or from a deep epileptic focus may not show epileptiform spikes or spike and wave activity and scalp EEG might only record theta/delta waves, reflecting the subcortical abnormalities. Prolonged 24-h video EEG recordings seems to be more useful in assessment headache/epilepsy patients. It was shown in migralepsy subjects that during migraine aura, burnst of spike activity may resemble the ictal EEG during an epileptic seizure although their sequence may be different. EEG does not show the usual temporal evolution with progressive increase and declines in the frequency and amplitude of rhythmic, repetitive epileptiform activity, typical of ictal EEG during epileptic fit. EEG during migraine aura shows variable course with both disturbed and completely normal activity despite the persistence of clinical symptoms [2, 14]. The interictal EEG in published migralepsy cases was rarely normal in one third of patients but displayed localized (34%) or generalized (28%) abnormalities in majority of them. They were characterized by spikes, sharp waves or spike-wave complexes in the temporal or occipital lobe. Simultaneously an EEG during the migraine attack was not available in the majority of cases (15). In cases of migralepsy, most EEG recordings showed a diffuse, irregular, high voltage, theta-delta activity during the episodes. These abnormalities were transient and disappeared at the long-term follow-up. Although an EEG abnormalities are expected, they would be irrelevant in the differential diagnosis. Only ictal EEG recordings performed in migraine-epileptic patients to demonstrate the underlying pathogenic mechanism of these episodes have the meanings. Sporadically, in about 6% of patients with migralepsy neuroimaging studies showed transient reversible brain abnormalities in MRI. These alterations were explained as a consequence of blood-brain damage resulting in brain edema persisting for days while disappeared [16].
Pathophysiology
Migraine and epilepsy share similar pathophysiological mechanisms. However, the exact phenomenon of migraine-induced seizures are still undefined. The hypothesis of excessive paroxysmal hyperexcitability of neocortical cells as a triggering pathological process underlying the onset of both disease have been extensively studied. It is associated with the phenomenon of cortical spreading depression during headache and hypersynchronous activity during epileptic fit. Cortical spreading depression (CSD) is believed to be the connecting point between migraine and epilepsy. CSD, a mechanisms of profound cellular depolarization is responsible for migraine aura and is a trigger for the headache pain in migraine. In turn, cellular hyperexcitability is associated with localized epileptiform discharges. Hyperexcitability is an initial event preceding cortical spreading depression. CSD is characterized by a slowly propagating neuronal depolarization followed by neural suppression. This initial phase means transient loss of membrane ionic gradients and surge of extracellular potassium, neurotransmitters and intracellular calcium and it is associated with an increase in regional cerebral blood flow, contrary to the reduced circulatory during the next phase [15]. The CSD causes the activation of the trigeminovascular system (TVS) at the cortical level and initiates release of inflammatory mediators and neurotransmitters, which result in pain during the migraine attack. The threshold required for the onset of CSD seems to be lower than that of hyperexcitation required for the epileptic seizures onset and propagation. Independently, the cortical excitation treshold in migraineurs is lower than in healthy subjects, thereby favoring the occurrence of seizures. This lower cortical excitation threshold might be due to several condition, such as disturbances in electrolyte metabolism, mitochondrial defects or ion channelopathies. The onset of CSD and that of the epileptic seizure may facilitate each other. The triggering causes may be environmental or individual, and among others also some of them are genetically determined. Also, recurrent seizures might predispose to CSD, thereby increasing the occurrence of peri-ictal migraine-like headache. Changes in the composition of extracellular fluid such as an elevation of glutamate and potassium ionsduring CSD results in hyperexcitability and in lowering threshold for seizures. Altered metabolisms of such neurotransmitters as glutamate, serotonine and dopamine as well as impaired ion channels play an importand role in both disorders [17,18]. Glutamate is a critical mediator of the hyperexcitability in both focal seizures and migraine. Ionotropic glutamate receptors play roles in both migraine and epilepsy with NMDA receptors critical to cortical spreading depression of particular importance on migraine. Candidates for drug therapy include NMDA, GluK1 and GluR5 antagonists. In experiments memantine inhibited CSD and was effective in migraine prophylaxis. In focal epilepsy, seizure generation and spread is mediated by synaptically released glutamate acting on AMPA receptors. Triggering of CSD depends on NMDA receptors and spread does not require synaptic transmission [18].