Brain, Vol. 123, No. 2, 318-330,
February 2000
© 2000 Oxford University Press
Neuropsychological EEG activation in patients with epilepsy
1 Department of Psychiatry, Tohoku University School of Medicine, 2 Yaotome Clinic, 3 Faculty of Education, Tohoku University, Sendai and 4 Minami-Hanamaki National Hospital, Hanamaki, Japan
Correspondence to:
H. Matsuoka, Department of Psychiatry, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574 Sendai, Japan E-mail: mtok{at}psy.med.tohoku.ac.jp
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Abstract |
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To examine the effects of higher mental activity on the EEG, 480 Japanese patients with different types of epilepsy were subjected to potentially provocative cognitive tasking, termed `neuropsychological EEG activation' (NPA), during standard EEG recordings. NPA tasks consisted of reading, speaking, writing, written arithmetic calculation, mental arithmetic calculation and spatial construction. The NPA tasks provoked epileptic discharges in 38 patients (7.9%) and were accompanied by myoclonic seizures in 15 patients, absence seizures in eight and simple partial seizures in one. Among the cognitive tasks, mental activities mainly associated with use of the hands, i.e. writing (68.4%), written calculation (55.3%) and spatial conction (63.2%), provoked the most discharges, followed by mental calculation (7.9%) and reading (5.3%). Detailed examination of the precipitating events revealed action-programming type activities to be the most crucial in 32 out of the 38 patients (84.2%), followed by thinking type activities in four patients (10.5%). Regarding the classification of epilepsies proposed by the International League Against Epilepsy, seizure-precipitating mental activities in our series were almost exclusively (in 36 out of the 38 patients) related to idiopathic generalized epilepsies (IGEs) including juvenile myoclonic epilepsy, juvenile absence epilepsy, grand mal epilepsy on awakening and childhood absence epilepsy, and were rarely (in only two out of the 38 patients) related to temporal lobe epilepsy. In our IGE patients, the provocative effects of NPA were related to myoclonic seizures rather than absence or generalized tonic–clonic seizures. These results suggest that NPA is a useful tool for examining the relationship between cognitive function and epileptic seizures, and that the IGE patients with myoclonic seizures are vulnerable to higher mental activities requiring action-programming or thinking.
EEG activation; idiopathic generalized epilepsy; juvenile myoclonic epilepsy; neuropsychology; reflex epilepsy
CAE = childhood absence epilepsy; GMA = grand mal epilepsy on awakening; GTCS = generalized tonic–clonic seizure; IGE = idiopathic generalized epilepsy; ILAE = International League Against Epilepsy; JAE = juvenile absence epilepsy; JME = juvenile myoclonic epilepsy; NPA = neuropsychological EEG activation; TLE = temporal lobe epilepsy; WAIS-R = Wechsler Adult Intelligence Scale—Revised
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Introduction |
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A close relationship between seizures and ongoing brain activity has been stressed (Brown and Fenwick, 1989
; Fenwick and Brown, 1989) and behavioural or psychological treatment may be helpful for patients with epilepsy who are resistant to conventional drug therapy (Dahl et al., 1985, 1987). In the management of epilepsy, not only anti-epileptic drug therapy but also identification and regulation of seizure-precipitating factors are important for achieving successful treatment. Seizure-precipitating factors have varying influences upon the diverse epilepsies and epileptic syndromes because of close relationships between these factors and the underlying pathophysiological characteristics that differentiate the various forms of epilepsy. For elucidating the pathophysiology of epilepsy in any patient, it is important to know the relationship between seizure-precipitating factors and the epilepsy subtype or seizure type.
Reflex epilepsies and seizures induced by higher mental activities such as reading, calculation, speaking, writing and thinking have been described in the literature (Bickford et al., 1956; Ingvar and Nyman, 1962; Asbury and Prensky, 1963; Geschwind and Sherwin, 1967; Wilkins et al., 1982), but such triggers are considered to be uncommon. For example, standard EEG recordings at the Mayo Clinic in the USA included mental arithmetic calculation tasks, and only one patient showed an EEG effect out of patients screened in over 100 000 recordings (Wiebers et al., 1979). It has been reported, however, that various daily mental activities can facilitate or inhibit seizure occurrence beyond expectation in patients with epilepsy (Fenwick, 1998). It remains unclear how much higher mental activities have an impact on each epilepsy or seizure type, since standard EEG examination usually includes only sleep, hyperventilation, photic stimulation and opening and closing of the eyes, but not systematic cognitive tasks.
In our laboratory, a particular EEG activation protocol that we call `neuropsychological EEG activation' (NPA) (Okuma et al., 1980; Matsuoka et al., 1981), which tests for various mental activities, has been carried out as part of routine EEG examination for patients with epilepsy. To our knowledge, this is the first study in which systematic EEG activation was performed in a large number of epileptic patients. In this paper, we discuss the effects of higher mental activity on EEG discharge according to each epilepsy subtype based on the classification of epilepsies and epileptic syndromes proposed by the International League Against Epilepsy (ILAE) (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).
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Methods |
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Patients
We studied 480 patients with epilepsy (247 males and 233 females) in the EEG laboratory of the Department of Psychiatry at Tohoku University School of Medicine, after obtaining each participant's informed consent. All but 18 patients were treated with anti-epileptic drugs, and 25 patients were also given neuroleptics for psychiatric disturbances. We excluded from this study any patient who could not easily carry out the NPA tasks due to mental retardation or dementia or who did not have enough seizures in their history to confirm a seizure-precipitating factor. At the time of EEG examination, mean age and standard deviation of the sample was 26.3 ± 10.8 years (range 10–66 years). The mean duration of illness was 10.8 ± 9.5 years (range 1–59 years).
Classification of epilepsies and epileptic syndromes
Clinical information for classification of epilepsies and identification of seizure-precipitating factors was collected from each patient's medical chart and via interview with each patient by one of the authors (H.M.) at the time of EEG examination. The 480 patients were categorized according to the ILAE classification of epilepsies and epileptic syndromes (Commission on Classification and Terminology of the ILAE, 1989) based on details of the patient's previous history, family history, seizure description (age at onset, frequency, semiology, precipitating factors and drug response), ictal and interictal EEG findings, neurological and psychiatric findings, CT and/or MRI findings, and any other pertinent data.
Patients with febrile convulsions, isolated seizures, isolated status epilepticus or seizures due to metabolic or toxic events, who were categorized as having situation-related seizures under the special syndromes of the ILAE classification, were also excluded from this study. Idiopathic generalized epilepsy (IGE) patients with `seizures precipitated by specific modes of activation' were classified under the IGE subtypes other than reflex epilepsy, since some precipitating factors identified in this category were quite different from each other in the presumed mechanism (see Results). When the IGE patients showed a combination of myoclonic, absence or generalized tonic–clonic seizures (GTCSs), the predominant seizure type determined the IGE subtype. More than six GTCSs were required for a diagnosis of `epilepsy with grand mal seizures on awakening' (GMA) (Janz and Wolf, 1998).
When identifying seizure-precipitating factors from the patient's previous history, our major concern was directed towards reading, speaking, listening to music, writing, calculating, drawing and game playing, based on previous reports of reflex epilepsies induced by higher mental activities (Forster, 1977). When patients noticed more than two similar activities to be seizure-precipitating factors, we adopted the umbrella terms `hand work', which essentially required hand movement (e.g. writing, written calculation and drawing), and `thinking' (Wilkins et al., 1982), for which hand movement was non-essential (e.g. game playing, spatial tasking and mental calculation). In addition, we paid attention to `awakening' and `menstruation.' The former applied to seizures that occurred within the first hour after arousal from sleep, including daytime naps (Janz and Wolf, 1998), and the latter applied to seizures that occurred before and/or during menstruation. Lack of sleep, which often elicited seizures in many patients, was not looked at specifically in the present study, with some exceptions, because of ambiguity in the temporal relationship between the lack of sleep and seizures.
EEG recording and NPA
EEGs were recorded from 21 scalp sites, based on the international 10–20 system, using silver/silver chloride electrodes with a ground electrode at the forehead. The bandwidth was 0.5–30 Hz. After standard EEG recording including sleep activation, hyperventilation and photic stimulation, subjects sat at a desk in an electrostatically shielded chamber and performed the neuropsychological tasks.
`Routine NPA' comprised reading silently and aloud, speaking, mental calculation, written calculation, writing and spatial construction. Detailed descriptions of these activities are as follows. (i) Reading silently: subjects silently read three Japanese sentences that were printed on a sheet of paper and were quoted from the Japanese version of the Binet test (Binet and Simon, 1916); (ii) reading aloud: subjects read the same sentences out loud that they had read silently; (iii) speaking: subjects described from memory what they had read silently and aloud; (iv) mental calculation: subjects responded aloud with answers to four arithmetic problems. When a calculation was difficult for the subject, an easier problem was presented; (v) written calculation: subjects responded in writing to one arithmetic problem; (vi) writing: subjects were asked to write out two Japanese sentences in phonograms (Kana) and three Japanese phrases in ideograms (Kanji); and (vii) spatial construction: subjects were instructed to draw a fish, a human face and a clock, and they performed the Block Design test using nine blocks of the Wechsler Adult Intelligence Scale—Revised (WAIS-R; Wechsler, 1981) (see Table 1 for more details). It took 10–20 min for each patient to accomplish the routine NPA.
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When the routine NPA induced epileptic discharges, reproducibility was confirmed by retrial of the same or a modified task. A `detail NPA' (Okuma et al., 1980
) was conducted on another day to identify the precipitating factor precisely. Table 2 outlines the detail NPA tasks and their respective cognitive categories, which are number-coded. A surface electromyogram (EMG) was often monitored to detect myoclonic seizures. Simultaneous video-EEG monitoring during the routine and detail NPA was utilized for later analysis.
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From the detail NPA findings, we identified three activity types related to seizure induction: hand movement independent of higher mental activity (motor activity), higher mental activity requiring hand movement (action-programming activity) and higher mental activity not requiring hand movement (thinking activity). To isolate motor activity as the seizure-inducing factor, we employed detail NPA tasks requiring no higher mental activity, i.e. finger tapping (6a in Table 2
), fine finger movement (6b) and drawing meaningless lines (6c). If a patient showed provocation of epileptic discharges during these tasks comparable with the provocation observed with writing, written calculation or spatial construction, we judged the precipitating factor to be motor activity. When motor activity was negligible, we further explored whether epileptic discharges would be triggered by action-programming activity or thinking activity. We carefully analysed the video-EEG data and employed detail NPA tasks that did not require hand movement, i.e. visualizing letters (3b in Table 2) and constructing sentences in the mind (3c) relative to writing, mental calculation (4b) relative to written calculation and mental construction of a block design illustrated in the block design test of WAIS-R (5g) relative to spatial construction. We judged the associated trigger to be action-programming activity when epileptic discharges were induced only by tasks requiring hand movement, and we judged the trigger to be thinking activity when epileptic discharges were induced by the tasks with and without hand movement. We excluded from this analysis any epileptic discharges that were induced if, during the testing, a subject was perplexed or embarrassed, since this made it difficult to identify the precipitating factor precisely.
Data analysis
To exclude the contamination of incidental discharges unrelated to activation, we defined the NPA effect operationally, based on the EEG in a state of relaxed wakefulness (including opening and closing of the eyes), i.e. the awake EEG. When no discharge was found on the awake EEG, `an NPA provocation effect' meant that one or more tasks induced paroxysmal discharges and that its reproducibility was confirmed by retrial. No discharge in the awake or NPA condition was judged as `no NPA provocation effect.' When epileptic discharges were found on the awake EEG, the activation rate was calculated for each task as follows. The number of discharges per recording time (number/minute) in each task condition that induced paroxysms was divided by the frequency (number/minute) in the awake condition. We tentatively defined the `provocative NPA effect' as above 2.0, `inhibitory NPA effect' as below 0.5, and `zero NPA effect' as between 0.5 and 2.0, according to the activation rate.
Statistical analysis
Data were subjected to a one-way ANOVA (analysis of variance) except for a simple two-group comparison to which the 
2 test or t-test was applied. Post hoc tests determined the significance of the difference between single means using Bonferroni's significance level. The criterion for statistical significance was P < 0.05.
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Results |
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The provocative effect of NPA tasks was observed in a total of 38 out of 480 patients (7.9%), comprising 18 of 272 patients (6.6%) without paroxysms and 20 of 208 patients (9.6%) with paroxysms on the awake EEG (Table 3
). There was no statistical difference in the percentage provocative effect between the two groups (2 = 1.45). However, NPA showed an inhibitory effect in 133 of 208 patients (63.9%) with paroxysms on the awake EEG. According to the distribution of the activation rate, which was calculated in the patients with paroxysms on the awake EEG, a conspicuous peak was found under conditions of provocative effects when the activation rate was around 30 (minimum, 6.2; maximum, 61.7). Another conspicuous peak was found under conditions of inhibitory effects when the activation rate was around 0 (minimum, 0; maximum, 0.5). Although the activation rate under the zero effect (minimum, 0.51; maximum, 1.68) was rather similar to that under the inhibitory effect, a clear discontinuity was found in the activation rates between the provocative (minimum, 6.2) and zero effect conditions (maximum, 1.68). Hereafter, the provocative effect of NPA will be mainly discussed.
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The patients showed a wide distribution of the ILAE classification (Table 4
), but neonatal and infantile epilepsies (2.1.a, 2.1.b, 2.1.c, 2.2.a, 2.2.c, 2.2.d, 2.3.1.a, 2.3.1.b, 3.1.a and 3.1.b), and some localization-related epilepsies (1.1.c, 1.2.a and 1.2.b) were not found among the patients examined. Thirty-six out of the 38 patients showing provocative NPA effects were classified as having IGE (24.7%), including one patient with childhood absence epilepsy (CAE) (7.1%), three with juvenile absence epilepsy (JAE) (16.7%), 22 with juvenile myoclonic epilepsy (JME) (46.7%), six with GMA (15.8%) and four with other generalized idiopathic epilepsies not defined above (12.9%). The remaining two patients were classified as having temporal lobe epilepsy (TLE) (1.2%) under cryptogenic localization-related epilepsies. The ANOVA for six epilepsy groups (1.1, 1.2, 1.3, 2.1, 2.3 and 3), i.e. except one group (2.2) with only one patient, showed significant provocative NPA effects [F(6,473) = 19.1, P < 0.001]. This was due exclusively to a higher rate of the effects in the IGE group (2.1) than in the other groups. The ANOVA for 19 epilepsy subtypes, i.e. except three groups (1.2.f, 2.2.b and 3.1.d) with only one patient, also showed significant provocative NPA effects [F(18,458) = 9.9, P < 0.001]. This was due to a higher rate of the effects in the JME subtype (2.1.f) than in the other subtypes, except for four subtypes (1.1.b, 1.2.e, 1.3.d and 3.1.c) with small numbers of patients. Inhibitory NPA effects were found in about half of the patients in each epilepsy subtype except for the IGE subtype, in which only two patients showed inhibitory effects. For the requisite that all or almost all (defined here as >80%) seizures be precipitated by a specific stimuli or event for a patient to be diagnosed with `reflex epilepsy', corresponding to 1.1.c, 1.2.b and 2.1.i in the ILAE classification system (Table 4), nine out of the 480 patients (1.9%) fulfilled this condition. All of them were classified as having IGE and, as noted in Methods, were assigned to IGE subtypes other than reflex epilepsies: five to JME, one to JAE and three to other IGEs not defined above. The seizure-precipitating factors were visual stimuli (flicker and/or pattern) in four patients assigned to JAE or other IGEs not defined above, and higher cognitive activities in five JME patients (writing in three, thinking and drawing in two) (Table 5).
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The 38 patients showing provocative NPA effects are shown in Table 5
with pertinent clinical and laboratory data. There were 18 males and 20 females. Mean age and standard deviation of these patients was 27.1 ± 8.6 years (range 16–51 years) and the age at onset of illness was 16.2 ± 3.8 years (range 8–28 years). A family history of epilepsy in the first-degree relatives was found in 10 out of 36 IGE patients (27.8%). Two of these patients were sisters. Various types of seizure were observed in the 38 patients: myoclonic seizure in 32 patients (84.2%), GTCS in 23 (60.5%), absence seizure in 19 (50.0%), secondary GTCS in two (5.3%), simple partial seizure in one (2.6%) and complex partial seizure in one (2.6%). Myoclonic seizures involved the arms or shoulders and often extended to the trunk or legs, especially before treatment. We did not find eyelid or orofacial myoclonias among these patients. Seizure-triggering factors inferred from the previous histories included awakening in 19 out of the 38 patients (50.0%), psychic tension and stress in 18 (47.4%), hand work in 16 (42.1%), writing in 11 (28.9%), thinking in five (13.2%), menstruation in four (20% of female patients), calculation in three (7.9%) and drawing in one (2.6%). No patient identified reading, speaking or listening to music as a trigger. Triggers identified by NPA were writing in 26 out of the 38 patients (68.4%), spatial construction in 24 (63.2%), written calculation in 21 (55.3%), mental calculation in three (7.9%) and reading aloud or silently in two (5.3%). One TLE patient (patient 37) showed non-specific psychic tension unrelated to the NPA tasks to be a trigger.
There was no patient in whom the precipitating factor was judged to be motor activity rather than higher mental activity. Action-programming was critical for the induction of epileptic discharges in 32 out of the 38 patients (84.2%), among whom five patients (patients 1–5) showed the precipitating factor to be restricted to linguistic activity (i.e. writing). The remaining 27 patients were affected by varying action-programming factors. In four patients the precipitating factor was thinking, predominantly the spatial task in three patients and the linguistic task in one patient. The diagnosis of reflex epilepsy based on the patient's history (patients 1–3, 17 and 22) was also confirmed by NPA. Patients 1–3, in whom, according to their histories, seizures were precipitated exclusively by writing, were also diagnosed with writing-induced or graphogenic epilepsy (Asbury and Prensky, 1963) by NPA. Although one patient (patient 17) claimed that his habitual seizures were induced by playing games, mental calculation and drawing pictures, the detail NPA revealed the non-linguistic thinking activity of mental construction and mental calculation to induce myoclonic seizures. Patient 22 was diagnosed with thinking epilepsy (Wilkins et al., 1982) by NPA as well by his history; linguistic activity was mainly involved.
The 38 patients were taking anti-epileptic drugs as shown in Table 5. Although mild head injury before the onset of illness was noted in four patients (10.5%), it was aetiologically insignificant because it was not accompanied by loss of consciousness or MRI abnormality. Febrile convulsion in infancy was found in five patients (13.2%). There were patients with stutter, depression and phobia. Patient 36 was born prematurely but without developmental abnormality. Neurological examinations in all patients were normal. Brain CT and/or MRI scans obtained in 32 out of the 38 patients were also normal.
Interictal EEGs of the 38 patients showed paroxysmal discharges characteristic of each epileptic syndrome. The IGE patients had diffuse bilaterally synchronous polyspike- or spike-and-wave discharges and discharges that were sometimes confined to frontocentral or centroparietal regions (Fig. 1). Generalized bursts of spike-and-wave discharges were determined to be 3 Hz in CAE and >3 Hz in the other IGE subtypes. Polyspikes or polyspike-and-wave discharges were prevailing in JME. Background activity was normal except in three out of 36 IGE patients (patients 16, 27 and 34), who showed excessive intermingled theta activity. Two TLE patients showed focal spikes, spike-and-wave discharges and slow waves over the right temporal region with normal background activity.
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) or the subjective experience of thinking arrest (right tracings). Rt. EMG: EMG from the right wrist. Recording electrodes were referred to the ipsilateral earlobes.NPA induced myoclonic seizures in 15 patients, absence seizures in eight patients and simple partial seizures in one patient. Myoclonic seizures, which were accompanied by paroxysms similar to the interictal discharges, were mainly induced by action-programming and thinking. They usually involved the arms or shoulders, either symmetrically or asymmetrically, and rarely extended to the trunk or legs. Similarly, NPA induced absence seizures, which were accompanied by spike-and-wave discharges of 3 Hz or greater, and lasted for <10 s (usually 3–5 s). During these seizures, the patients were motionless and unresponsive without overt automatism. Simple partial seizures were an autonomic manifestation causing a burning visceral sensation that started in the epigastric region and spread to the throat without alteration of consciousness. They were accompanied by recruiting rhythm from theta to delta activity like sharp waves over the right temporal region and frequently recurred in one patient when under psychic strain (patient 37).
Table 6 indicates the relationship between the NPA effect and seizure type in a total of the 146 IGE patients. According to combinations of myoclonic seizure, absence seizure and GTCS, which are usually observed in IGE, the IGE patients were divided into seven groups, as shown in Table 6. The four groups comprising patients with myoclonic seizure showed higher provocative NPA effect rates (minimum, 36.8%; maximum, 50.0%) than the others (minimum, 0.0%; maximum, 7.7%). The ANOVA for the seven groups showed a significant provocative NPA effect [F(6,139) = 5.0, P < 0.001]. This was due to higher rates of the effect in the groups of myoclonic seizure only, myoclonic seizure with GTCS, and myoclonic seizure with absence seizure and GTCS, than in the group of absence seizure with GTCS. Small sample size may cause insignificant effects in the groups of myoclonic seizure with absence seizure, GTCS only or absence seizure only.
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We analysed the pertinent data of the JME patients because they showed the highest provocative NPA effect rate among the patients of various epilepsy types. Table 7
shows clinical and laboratory data characterizing our JME patients with and without provocative NPA effects. There were no statistical differences between these patients except with respect to precipitating factors noted in the case histories: JME patients showing provocative NPA effects showed a higher rate in response to provocative mental activity (2 = 27.1, P < 0.001).
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Discussion |
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The present results show that higher mental activities can precipitate generalized spike-and-wave discharges, which may be accompanied by myoclonic or absence seizures. This was true almost exclusively in the patients with IGE out of the various epilepsies and epileptic syndromes we looked at. Mental activities had zero or inhibitory influence on epileptic discharges in the other epilepsies except in TLE (two patients) (Table 4
). We confirmed the precipitating effects of routine NPA by retrials and the detail NPA, precluding the possibility of chance occurrences. Within the IGE group, the precipitating effect of NPA was observed most frequently among JME patients (46.7%) followed by JAE patients (16.7%), GMA patients (15.8%) and CAE patients (7.1%). Since these four epileptic syndromes overlap in their manifestations and the boundaries between them are obscure, there may be a nosologic relationship between these IGE subtypes (Janz, 1990; Reutens and Berkovic, 1995). Seizure susceptibility to higher mental activities in IGE revealed by the present study suggests a pathophysiological similarity between syndromes. As mentioned earlier, we did not adopt the `epilepsies with seizures precipitated by specific modes of activation' subtype in the ILAE classification system and classified patients manifesting these seizures into the other IGE subtypes according to their clinical characteristics. We found five patients whose seizures occurred almost exclusively under a particular higher mental activity condition confirmed by NPA (writing in three patients, thinking in two patients) and all five of these patients were classified under JME. Therefore, some of the `epilepsies with seizures precipitated by specific modes of activation' would be a subtype of JME.
Concerning seizure distribution in IGE, the effect of NPA on EEG discharges was closely related to having myoclonic seizures (Table 6). This necessarily coincided with the higher rate of provocative effects of NPA in JME. The pathophysiology underlying myoclonic seizure will be critical for determining seizure susceptibility to higher mental activities. It is pointed out that JME seizures are often precipitated by emotional stress, anxiety, expectation, thinking, decision making or concentration, in addition to physiological factors such as sleep deprivation, awakening and fatigue, and that a combination of these precipitating factors is usual in patients with JME. For example, Panayiotopoulos and colleagues reported that mental concentration precipitated seizures in 22.8% of their JME patients, and stress and expectation in 12.3% (Panayiotopoulos et al., 1994). Penry and colleagues reported that seizures in JME were exacerbated by stress (100%), strong emotion (96 %) and chronic anxiety (70%) (Penry et al., 1989). These psychological factors might be linked to a specific mental activity; nevertheless, JME patients who have shown a specific mental activity to be a seizure-precipitating factor have been considered merely part of the entire JME group (Inoue et al., 1994; Panayiotopoulos et al., 1994). However, most of the reported findings were not confirmed by a special EEG activation procedure but rather were based on the patients' subjective experiences. Patients with JME may mistakenly identify seizure-precipitating factors, especially when the circumstances of seizure occurrence are complex and some of them are not even aware of having myoclonic seizures (Delgado-Escueta and Enrile-Bacsal, 1984; Panayiotopoulos et al., 1994). Indeed, some patients in the present study did not realize the precise precipitating factors until NPA tasking was carried out. Without this, many myoclonic seizures induced by higher mental activities would have been overlooked.
NPA results revealed that myoclonic seizures in JME were frequently precipitated not only by sleep deprivation and awakening, which are emphasized in many reports (e.g. Janz, 1990; Reutens and Berkovic, 1995), but also by higher mental activities. Our particular interest in higher mental activities might have caused a bias towards atypical patients in our JME sample, but both JME subgroups (with and without provocative effects of NPA) showed similar clinical features, including seizure type and seizure-precipitating factor in their previous histories, apart from mental activity as a trigger (Table 7). This suggests that NPA effects had no obvious influence upon the manifestations of JME and that there was not a close relationship between provocative higher mental activities and precipitating physiological factors such as sleep deprivation, awakening and menstruation. Since the patients showing provocative NPA effects had a marginally, but not significantly (P < 0.1), higher rate of absence seizure, further study in a larger sample is needed to confirm the present results.
Myoclonic seizures in JME are predominant over the upper extremities and shoulders, and are even confined to this area with asymmetry in mild cases. This can lead to a misdiagnosis of partial seizure (Canevini et al., 1992; Lancman et al., 1994; Panayiotopoulos et al., 1994). Careful investigation of the patients' previous histories (Table 5) disclosed that mental activities associated with use of the hands often provoked myoclonic seizures of the upper extremities. NPA findings confirmed that activities such as writing, written calculation and spatial construction frequently provoked epileptic discharges and myoclonic seizures. This may contrast well with the jaw jerking characteristic of reading epilepsy (Bickford et al., 1956; Commission on Classification and Terminology of the ILAE, 1989). Since the epileptic discharges usually preceded the hand movements related to a specific task, according to the visual inspection of the video-EEG monitor during NPA tasking, the seizure-precipitating factor was assumed to be action-programming and/or thinking prior to hand movement. Further analysis of the temporal relationship between mental activity and epileptic discharge will be important to elucidate the seizure-precipitating mechanism.
Epileptic discharges in IGE induced by NPA were quite similar to those that appeared spontaneously. They consisted of diffuse and symmetric spike-wave or polyspike-wave complexes, but were sometimes concomitant with bilateral spike-wave complexes that predominated over the central electrode site both with and without lateral asymmetry. Such a focality or asymmetry has been noted in JME (Matsuoka, 1990; Aliberti et al., 1994; Lancman et al., 1994; Andermann et al., 1998) and might be associated with the pathophysiology of myoclonic seizure in the upper extremities (Matsuoka, 1989). Aird and colleagues (Aird et al., 1984) speculated that epileptic myoclonus might be caused by a thalamo-rolandic projection system pathology with reference to the thalamocortical mechanism involved in the absence seizure (Gloor, 1979; Gloor et al., 1990).
Reflex epilepsy induced by thinking and spatial tasks (Wilkins et al., 1982; Goossens et al., 1990; Andermann et al., 1998) has been described as a rather homogeneous IGE syndrome. Generalized seizures in this syndrome are activated by thinking or decision making, which is common to calculation, card and board games, and spatial tasks, and neuropsychological analysis of the stimuli points to parietal cortical participation in seizure induction (Wilkins et al., 1982; Goossens et al., 1990; Andermann et al., 1998). The clinical profile of the condition is suggestive of JME or JAE. In the present study, four IGE patients (three JME and one GMA) showed susceptibility to thinking activity without action-programming activity and may have a pathophysiology similar to the reflex epilepsy induced by thinking and spatial tasks. Writing, which was confirmed to be the major precipitating factor in the patients showing provocative NPA effects, has not been identified as a trigger in the form of reflex epilepsy, and action-programming activity associated with use of the hands is little emphasized (Andermann et al., 1998). Therefore, it is likely that IGE seizures induced by higher mental activity consist of at least two forms: seizures induced by thinking and spatial tasks, and seizures induced by writing, written calculation or drawing requiring action-programming activity. These two forms would either show distinct mechanisms of seizure induction or represent two ends of a pathophysiological continuum.
Inoue and colleagues reported patients with reflex epilepsy in whom myoclonic seizures mainly involving the arms were precipitated by a non-linguistic praxic activity accompanied by calculation, game playing, writing, drawing, construction or copying. They stressed `a combination of complicated processes of thinking (decision-making) along with voluntary motor activities (including ideation of voluntary acts) involving the fingers and arms' as the seizure-induction mechanism (Inoue et al., 1989, 1992, 1994). In contrast with the reflex epilepsy induced by thinking and spatial tasks (Wilkins et al., 1982; Goossens et al., 1990; Andermann et al., 1998), they listed writing as one of the major precipitating factors and emphasized requisite hand movement in seizure induction, factors that were quite similar to our action-programming activity provocations. Based on the NPA tasking results and detail analysis of habitual seizures, we confirmed precipitating factors to be action-programming activity in 32 out of the 36 patients with IGE, linguistic activity alone in five, both linguistic and non-linguistic activity in 20, and non-linguistic activity alone in seven. Therefore, the mechanism of action-programming seizure induction would have two forms related to linguistic and non-linguistic activities as each end in a pathophysiological continuum. This is supported by the induced spike activity in a patient reported by Hasegawa and colleagues that predominated over the dominant central EEG site with letter writing and over the non-dominant parietocentral EEG site with spatial construction (Hasegawa et al., 1981).
In the ILAE classification of epilepsies and epileptic syndromes, primary reading epilepsy takes its place as the only syndrome among reflex epilepsies. Higher mental activities other than reading may also be triggers in some patients with reading epilepsy (Wolf, 1992; Radhakrishnan et al., 1995; Koutroumanidis et al., 1998). Geschwind and Sherwin described a case of language-induced epilepsy in which seizures were precipitated by three language functions: speaking, writing and reading (Geschwind and Sherwin, 1967). These made us expect reading to trigger seizure activity in the patients with epilepsy induced by writing, calculation or spatial construction. However, reading aloud and silently were less provocative (5.3% of patients) than the other mental activities and none of our patients were diagnosed with reading epilepsy. Although the typical reading-provoked jaw or orofacial jerk may spread to the upper limbs in myoclonic reading epilepsy (Radhakrishnan et al., 1995; Koutroumanidis et al., 1998), no jaw jerk was observed when NPA induced the myoclonic seizures of the arms in our series. Spikes or spike-waves in the dominant parietotemporal region characteristic of primary reading epilepsy of the ILAE classification were not found in the patients whose EEG discharges were precipitated by writing. Therefore, we speculate that reading epilepsy would be distinct in its clinical and pathophysiological features from epilepsy induced by mental activity associated with use of the hands, even if some overlap exists.
The total NPA screening was carried out within 10–20 min because of clinical limitations in routine EEG examination. Since prolonged reading is usually necessary to induce seizures in reading epilepsy (Ramani, 1998), the rarity of `reading' as a precipitating factor in the present study might stem simply from the activation method. However, we failed to find any suggestion of reading epilepsy in our series despite our great interest in reflex epilepsy. This rarity might be characteristic of Japanese patients (Inoue et al., 1992; Wolf, 1992). If so, we must consider ethnic variation as noted in at least one genetic study of JME (Sander et al., 1997) or linguistic features specific to the Japanese written languages (Wolf, 1992; Sakurai et al., 1997). To clarify this question, NPA tasking should be applied in other languages to different sample groups of different racial backgrounds.
Only two patients with localization-related epilepsy showed NPA provocation. One of them showed epigastric discomfort and clouded consciousness under stress, and non-specific psychic tension unrelated to the NPA tasks which precipitated rhythmic waves over the non-dominant temporal area with symptoms. The other patient, showing spontaneous complex partial seizures, was unaware of any specific precipitating factor, and NPA reading precipitated spike-wave discharges over the non-dominant temporal area but without symptoms. This patient cannot be diagnosed with primary reading epilepsy of the ILAE classification because of no clinical correlation with EEG findings. These two TLE patients could have a unique discharge-precipitating pathophysiology, since mental activity showed a zero or inhibitory effect on EEG discharge in almost all patients with localization-related epilepsies.
The provocative effect of NPA was mainly discussed in the present study because the activation rate employed (see Results) easily drew a sharp line between the provocative and the zero or inhibitory effects. In order to use NPA results in the management of epilepsy, such as behavioural or psychological treatment (Dahl et al., 1985, 1987), further study is required to clear clinical correlation of the inhibitory NPA effect.
The present study had some limitations, as follows. The epileptic patients examined were recruited from the University Hospital to which intractable patients are usually referred. This hospital has a separate paediatric epilepsy unit. In addition, the patients had the ability to perform the neuropsychological tasks. Therefore, our sample had a potential bias with respect to disease severity, age distribution and intellectual capability. Although duration of disease and drug treatments were uncontrolled in the present study, these factors seemed to be non-essential to our findings.
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We thank Dr T. Okuma and Dr T. Hasegawa for their help in various aspects of this project.
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Received April 21, 1999. Revised August 6, 1999. Accepted August 23, 1999.
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