Abstract
Migrainous headache is reported by patients with photosensitive epilepsy, whereas their relatives complain more often about headache than the relatives of patients with other types of epilepsy. We therefore investigated whether headache itself could be an epileptic symptom related to photosensitivity Four probands with headache and photosensitive epilepsy were selected. Their first-degree family members were studied using video-EEG with extensive intermittent photic stimulation and pattern stimulation. Nine of the 12 subjects (10 female and two male, mean age 30 years, range 14–46 years) proved to be photosensitive with either focal (n = 5) or generalized (n = 4) epileptiform discharges. In two subjects an ictal recording of headache occurred after visual stimulation. We found evidence that, in specific patients, headache could be an ictal sign of epilepsy. Photic stimulation during EEG recording can contribute to correct diagnosis and lead to the best care and management of the patient.
Introduction
Migraine and epilepsy are both disorders with recurrent and paroxysmal manifestations of disturbed brain function (1–3). The clinical observation that migraine and epilepsy may at times occur in the same individual could be interpreted in three ways (4): (i) migraine and epilepsy are both relatively common in the general population, so they will occur together by chance in a number of people; (ii) migraine and epilepsy may share a pathophysiological or genetic basis that would explain their coexistence; (iii) the two conditions might at times be causally related, with one leading to the other.
An apparent increase in the number of electroencephalographic (EEG) abnormalities, although usually non-specific, has been used as the main supporting evidence for a causal relationship between migraine and epilepsy (5). However, EEG investigations in assessing migraine patients have been the subject of much dispute, and nowadays most authors discourage routine EEG recording for diagnosis in migraine patients (6, 7).
Headache attacks coinciding with seizure activity (hemicrania epileptica), typically lasting seconds to minutes or sometimes hours, have been reported (1, 8); in the latter case, headache represents an isolated and single semiological manifestation of epilepsy that can even last for some days (9, 10).
The question of a possibly closer and causal relationship between migraine and epilepsy has recently arisen even more strongly with the recognition of occipital epilepsy, and especially of its subtype, photosensitive occipital epilepsy (11). It is, in general, difficult to differentiate a migraine attack from this type of epilepsy on only clinical grounds.
Publications on interictal and especially ictal EEG recordings in migraine with aura (MA) have shown rhythms like those commonly observed during an epileptic attack (1, 7, 12). Interestingly, a photoparoxysmal response (PPR) has been found in about one-third of the 43% of children with MA having EEG abnormalities, which is far more than the occurrence in a healthy population of children (1.4%) and epilepsy patients in general (5%) (13–15).
PPRs are found especially in patients with idiopathic generalized epilepsies and also in those with idiopathic partial epilepsy (photosensitive occipital epilepsy) (11). The features of the latter have much in common with migraine: (i) a high prevalence in women (female:male = 3:2), (ii) sensitivity to flickering light stimuli and striped patterns with provocation of attacks, (iii) visual aura, (iv) positive and negative ictal signs, (v) autonomic disturbances such as pallor and vomiting, and (vi) slow spreading of ictal EEG abnormalities, originating in the occipital area.
Deprez et al. (16) recently found a genetic linkage between migraine and occipito-temporal lobe epilepsy in a European multigenerational family and identified a locus on chromosome 9q21-q22. Remarkably, several observations reported in that particular family show clinical overlap of MA and epilepsy: six out of 10 patients with occipito-temporal epilepsy had a visual aura, whereas three out of 10 patients with occipito-temporal epilepsy had a history of photosensitivity and visually induced seizures (16).
All the above information prompted us to investigate whether, in families of patients with both migrainous headache and photosensitivity epilepsy, a photoparoxysmal EEG response can be regarded as an endophenotypical expression of the same underlying genes, and thus a linking pin between these two types of symptoms.
Methods
We selected all patients with a history of photosensitivity with clear migrainous headache complaints who were admitted to the Departments of Neurology and Paediatric Neurology of the University Hospital in Rome between 2005 and 2006. Four patients met these criteria. The four probands and their first-degree family members were invited for further investigation. All the four mothers and two sisters agreed, but none of the three brothers or two fathers. Those who gave informed consent were asked in detail about any clinical symptomatology relating to epilepsy and headache, including a family history. A video-EEG recording was performed with eyes open, eyes closed, hyperventilation and photic stimulation according to the international protocol, with determination of photosensitivity ranges and use of a Grass PS 33 plus (Grass Technologies, West Warwick, RI, USA) (17).
Additional visual testing was done with black-and-white striped patterns of 2–4 cycles/degree of different sizes subtending visual angles of 10, 15, 20, 30, 40 and 60° with surrounding light on (18).
The investigations were part of a European study on visual sensitive epilepsy (‘Visual sensitivity’, MEXC-CT-2005-0242244) and were approved by the Ethical CIE of St Andrea Hospital, Rome.
Results
Clinical history, magnetic resonance imaging and video-EEG data
All the investigated probands and first-degree family members had a history of normal development after an uneventful birth. No physical or neurological abnormalities were found and magnetic resonance imaging scans were normal. Figure 1 shows the pedigrees.
Pedigrees of four Italian families with photosensitivity, epilepsy and migraine.
All subjects were recorded with a video-EEG by an experienced EEG technician.
The stimulations were given by one of the authors, while another physician was also present to observe the patient.
First family
The proband, a girl aged 15 years (1-III-1), visited our out-patient clinic because of monthly headache attacks showing clinical characteristics of migraine without aura (MoA) according to 1.1. of the International Classification of Headache Disorders, 2nd edition (ICHD-2) (19). At age 3 years she had had several febrile convulsions, and at 11 years, again during fever, she had had a short tonic seizure with loss of consciousness. However, her EEG was normal. At age 12 years she had also had complaints of paraesthesia in her right arm and right part of the tongue, with right-sided hemianopsia and aphasia for a few seconds, followed by a bad headache lasting 2 h; these headaches did not fulfil the criteria of MA (1.2) or probable MA due to the short duration of the aura (ICHD-2 criteria require that each aura symptom develops gradually over > 5 min and lasts for < 60 min) (19).
Because she complained about visual discomfort while watching television and playing videogames, she qualified for our study and, after consent, a video-EEG was recorded with special emphasis on visual stimulation. The EEG showed left temporo-occipital sharp waves spontaneously. During intermittent photic stimulation (IPS) generalized polyspikes and waves of 2 s duration could be evoked between 12 and 26 Hz, with subtle clinical signs when the discharges outlasted the stimulus train (spontaneous opening of the eyes at 24 Hz and ocular discomfort at 22 Hz). Prophylactic treatment was started with blue lenses (20).
Six months later, during a fever, she had a cluster of five focal epileptic seizures on 1 day (R-sided jerks, followed by loss of consciousness and incontinence). Prodromes were vertigo, nausea and vomiting. After taking levetiracetam 500 mg twice daily, her headache and epilepsy disappeared during a follow-up of 19 months. An EEG under medication showed some right temporo-occipital sharp waves, but no further sensitivity to IPS.
Her 44-year-old mother (1-II-2) and 14-year-old sister (1-III-2) also suffered from headache (MoA). The sister has had sensations of loss of consciousness. Video-EEGs of the sister and her 45-year-old father (1-II-1) did not show any abnormalities, but her mother showed spontaneous left temporo-occipital sharp waves. The proband's maternal aunt (1-II-3) had both headache and febrile convulsions, whereas her maternal grandmother (1-I-2) also had MoA. A third-degree family member on father's side suffered from epilepsy and had been treated with valproate (VPA) since age 15 years.
Second family
The 21-year-old proband (2-II-2) had had a febrile seizure at age 10 years. From 13 years old she had had seizures without fever, occurring especially in the morning when the light came through the Venetian blinds. She was successfully treated with VPA 500 mg. At ages 18 and 19 years she had again had two generalized tonic clonic seizures (GTCS), the first with head rotation to the right, the second with sudden loss of consciousness and no lateralizing signs. After increasing VPA to 700 mg she had became seizure-free. She has unspecified complaints about headache that did not fit any of the internationally coded headache types (19). Her video-EEG (700 mg VPA, 64 mg/l) showed bilateral spikes and polyspike waves over the frontal regions on a regular background. Her reaction to IPS was normal with symmetrical driving responses. Pattern stimulation utilized a 40-cm diameter size, with horizontal orientation of the stripes. This produced sharp and slow waves of high amplitude, lasting for 2s; after stimulation with vertical orientation of the stripes, slow waves were seen in both occipital regions lasting for 18 s. She complained of headache exactly time-locked to the evoked discharges (Fig. 2). During the attack no movement of the neck was detected by the observers or later by the video.
The proband 2-II-2 complained of headache exactly time-locked to these evoked discharges after stimulation with vertical striped patterns.
Since age 15 years, her 16-year-old sister (2-II-3) had suffered monthly from vertigo, then loss of vision for a few minutes, followed by headache for the rest of the day, which fulfilled MA criteria in ICHD-2. The EEG showed sharp waves over the right temporo-occipital regions, spontaneously and especially during IPS between 12 and 25 Hz. During IPS she complained of headache. The same complaints occurred during pattern stimulation (15° with vertical orientation of the stripes). During stimulation with patterns of 30° and vertical orientation, she had nausea for 3 min and 20 s. Further stimulation was then stopped.
The 45-year-old mother (2-I-2) started having seizures at 15 years old, with head deviation lasting for a few seconds. The EEG showed generalized PPRs. The seizures disappeared with VPA 500 mg. Since age 35 years she had experienced massive jerks in her body when she was in front of a computer or driving in a car under trees. She also complained about weekly headaches, starting on the left side of the head and spreading subsequently to other areas, without phono/photophobia or vomiting, with bilateral pain of pressing quality that did not worsen with routine physical activity, lasting 1–24 h (frequent tension-type headache, 2.2).
The video-EEG (VPA 500 mg; 67 mg/l) showed sharp waves over the left temporo-occipital region, with some spreading to the right homologous region. Her photosensitivity range was 6–60 Hz with generalized spikes and waves originating in the left temporo-occipital region and outlasting the stimulus. No clinical signs were noted.
Third family
The proband (3-III-1), a girl aged 14 years, complained of dizziness and MoA. A previous EEG, at 11 years of age, showed no spontaneous epileptiform activity (EA), but a PPR at 10 Hz. A 24-h EEG recording in that period showed generalized EA while awake. The recent video-EEG showed right temporal spikes and waves, both spreading to all regions spontaneously, during hyperventilation, and IPS with a range of 15–25 Hz with eyes closed.
Her 42-year-old mother (3-II-2) had had visual sensitive epilepsy since 10 years old. Her seizures, six in total, were generalized with vertigo as an initial sign. Three of the seizures occurred in front of the television (while changing channels and being close to the screen) and one seizure in a discotheque. Postictally she had difficulty speaking. Between the age of 10 and 15 years, she had taken carbamazepine 400 mg twice daily without any beneficial effect. She had learned to avoid provocative stimuli. EEGs (IPS not performed) were normal at age 22 years. Subsequent EEGs at age 23, 34 and 36 years showed generalized EA with high voltage, slow and sharp waves. During the video-EEG she showed PPRs with a range of 15–20 Hz, maximally with eyes closed. Her father (43 years of age) suffered from MoA between the ages of 27 and 35 years, with phonophobia and photophobia, nausea and vomiting. His mother and one of his brothers also suffered from MoA. The father did not consent to having an EEG made.
Fourth family
The proband, a 14-year-old girl (4-II-1), had had three epileptic attacks with loss of consciousness since age 13 years. During the first seizure she was on a merry-go-round with flickering white and coloured lights. The second attack occurred at 14 years old in the evening, without any recorded visual provocation. Two months later she had her third seizure while awake. The latter two seizures occurred after a period of sleep deprivation.
She also complained of MoA. The headache attacks (three to four per month, starting at age 6 years) were without aura and with unilateral eye pain, phono/photophobia and vomiting. Her first EEG showed generalized polyspikes and waves and, in addition, a massive myoclonus during IPS at 25 Hz. She was then started on 500 mg VPA daily. During the video-EEG (500 mg VPA) occipital and generalized spike- and polyspike waves were recorded during IPS exclusively and were accompanied by eyelid myoclonia. Her photosensitivity range was 12–30 Hz maximally with eyes closed (Fig. 3A). In the following 8 months no further MoA or epileptic attacks were reported.
Intermittent photic stimulation-evoked discharges in the fourth nuclear family. They all show a generalized photoparoxysmal response (PPR) with differences in the type of response. The maximal response per patient has been chosen. A: the proband 4-II-1 showing a generalized PPR at 25 Hz in the eyes-open condition. B: her mother 4-I-2 showing a generalized PPR at 23 Hz in the eyes-closed condition. C: her father 4-I-1 showing a generalized PPR at 10 Hz in the eyes-closed condition.
During the video-EEG, her 43-year-old mother (4-I-2) showed spontaneous sharp and slow waves, as well as PPRs, both localized (occipital area) and generalized, without any accompanying clinical signs or symptoms. The photosensitivity range was 20–30 Hz, maximally with eyes closed (Fig. 3B).
In the video-EEG her 46-year-old father (4-I-1) showed focal and generalized polyspikes and waves, without any clinical signs or symptoms, spontaneously as well as during IPS. His photosensitivity range was 10–50 Hz maximally with eyes closure (Fig. 3C).
Summary
Of the 12 investigated subjects (belonging to four families), five had both headache and epilepsy, three had headache and one had epilepsy. Three were treated with antiepileptic medication. Epileptic manifestations in the EEG were correlated with headache complaints during extensive photic or pattern stimulation in two subjects. Nine of the 12 showed a PPR. See Table 1 for details.
Clinical and EEG data of families studied
IPS, Intermittent photic stimulation; PPR, photoparoxysmal response; MoA, migraine without aura; MA, migraine with aura; FTTH, frequent tension-type headache; G, generalization; VSE, visually sensitive epilepsy; VPA, valproate; L, left; R, right; P, poly; S, spike; W, wave.
The probands are shown in italics.
Discussion
In our four families, headache appeared to be related not only to epilepsy but especially to photosensitivity (a history of visually induced seizures and/or a PPR in the EEG).
Subjects belonging to the second family had ictal headache as the only symptom of epileptic EEG abnormalities and evoked by visual stimuli.
There are obviously more possible explanations of this phenomenon, including that this might have been the result of prolonged exposure to visual stimuli and that the relationship with the 2 s paroxysmal spike and slow-wave activity might have been coincidental. However, in our proband of the second family (2-II-2) headache was exactly time-locked to the epileptiform discharges: the complaints started at the beginning of the discharges and stopped exactly at the end.
The medication (700 mg of VPA) may have been the reason for the discharges remaining clearly occipital.
A headache attack as the sole manifestation of a seizure is not clearly included in either the ICHD or the International Classification of Epilepsy (19, 21). It would be helpful to develop new terminology for such cases (22). We suggest introducing the term ‘ictal headache’ and to reserve it for any type of headache associated with ictal epileptiform EEG abnormalities. In particular, patients with migrainous features and complaining of visual stimuli might suffer from ictal headache and deserve to be investigated by EEG.
Lennox suggested in 1960 that migraine may be an autonomic epilepsy, and later publications with ictal EEG recordings in patients with MA, MoA and basilar migraine have indeed shown rhythms like those commonly observed during an epileptic attack (1, 7, 12, 23, 24). The occipital lobe epilepsies are undoubtedly the most associated with autonomic signs and symptoms. The close association between migraine and idiopathic benign childhood epilepsy and especially with the occipital lobe epilepsies has been well described (11, 25–27). In patients with this type of epilepsy, it is known that differentiation from migraine is difficult, since both have visual aura followed by headache and other autonomic symptoms. In both diseases, the visual aura preceding the cephalalgia can be elicited by bright and flashing lights, and may be positive (flicker scotoma, hallucinations) or negative (temporary loss of vision) in nature.
Recently we have observed a 14-year-old photosensitive girl whose first GTCS was preceded and followed by a status migrainosus for 3 days. Standard analgesic therapy did not help, but the headache disappeared after intravenous administration of 10 mg diazepam (DZP). Continuous EEG recording showed suppression of the epileptiform discharges over the right occipital region 7 min after the DZP injection, while the headache resolved 3 min later. The migraine status was provoked by prolonged television viewing (a new, large-screen television) and visiting an exhibition with much colour and contrast (9).
A similar story was found in a Dutch boy aged 19 years (unpublished): since age 4 he had had headache attacks with vomiting about once a month, fulfilling MoA diagnostic criteria. At age 12 years he lost consciousness in front of the television, and his photosensitivity was confirmed in an EEG showing generalized EA during IPS (range 6–50 Hz), striped patterns and watching television (at ≤ 2 m distance). Treatment with phenobarbitone (60 mg) as well as VPA (600–1100 mg) was successful for both MoA and the episodes of loss of consciousness. During an attempt to withdraw the VPA medication at age 17 years, first the headache complaints returned, then increased in intensity and were followed by a GTCS while watching television. Both his parents had a history of sensitivity to strong lights, with the mother having migraine (or, in retrospect, possibly occipital photosensitive epilepsy).
These patients' histories show many similarities with a 25-year-old girl described in 1966 by Barolin (28). He remarked on the importance of performing EEGs with IPS in patients with migraine and syncopal faints (28, 29). Another sign of headache/migraine being of epileptic origin is the fact that, in our families, all patients given antiepileptic therapy had complete remission of headache attacks and seizures.
Several recent studies have indicated that at least some forms of migraine and epilepsy share the same underlying neuropathophysiology (30), e.g. due to impairment of Na+-K+ ATPase pump (31, 32). Changes in neurotransmitter concentrations could also play a role in both symptoms (2, 33), whereas in progressive myoclonus epilepsy the mechanisms of visual sensitivity have been related to a deficit in dopaminergic transmission, because apomorphine was able to abolish the PPRs (34).
Even though this was a preliminary study, it has shown clearly that it is important to record EEGs with extensive photic stimulation in all patients with migraine belonging to a family in which epilepsy and, in particular, photosensitivity is present. A proper diagnosis can help in giving advice about preventive non-pharmacological treatment (coloured glasses) as well as antiepileptic drugs (AEDs). Although nowadays many AEDs are proven to be effective for migraine, the duration of treatment differs substantially (35). Premature withdrawal of AED therapy can expose patients such as those described here to an unnecessary risk of having tonic clonic seizures.
Finally, headache can be not only the sole manifestation of epilepsy in patients without other clear epileptic seizures, but also the sole residual sign in patients who are being treated for epilepsy. This should be borne in mind when declaring epileptic patients with photosensitivity and history of migraine headaches ‘seizure free’.
Footnotes
Acknowledgements
This work was supported by Marie Curie Grant MEXC-CT-2005-24224: Visual Sensitivity. We would like to thank, in particular, Jackie Senior for editing the manuscript and our technicians Antonio Lucci, Eugenio Grassi and Daniela De Santis.