Do brief bursts of spike and wave activity cause a cerebral hyper- or hypoperfusion in man?

Neuroscience Letters, 127 (1991) 77 81

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© 1991 Elsevier Scientific Publishers Ireland Ltd. 0304-3940/91/$ 03.50 A DON1S 030439409100275A NSL 07791

Do brief bursts of spike and wave activity cause a cerebral hyper- or hypoperfusion in man? J/irgen K l i n g e l h 6 f e r , C h r i s t i a n Bischoff, D i r k S a n d e r , I n g o W i t t i c h a n d B a s t i a n C o n r a d Department of Neurology, Technical University of Munich, Munich (F.R.G.)

(Received4 January 1991; Revisedversion received 7 March 1991; Accepted 8 March 1991) Key words: Spikeand wave activity; Cerebral perfusion; EEG; Transcranial Doppler ultrasonography

The correlation between brain activity and cerebral blood flow velocitiesduring brief bursts of generalized spike and wave activity was analysed by simultaneous registration of the EEG and the intracranial flow patterns. The flow patterns of the middle cerebral artery were continuously recorded by means of transcranial Doppler ultrasonography using a speciallydeveloped monitoring system. A total of 25 bursts was investigated in 3 patients with spontaneous occurrence of generalized 3 Hz spike and wave activity and normal background EEG. Characteristic changes of the flow patterns were found in all cases: 3.41 + 0.98 s (n = 25) after the beginning of generalized spike and wave patterns, the flow velocitydecreased by 25.84__ 10.45% (n=25) below the 'preictal" flow velocity level. The period of flow velocity changes lasted several times longer than the phase of spike and wave activity.

The extent of cerebral blood flow change during ' a b sence' seizures is still a matter of controversy even today. With regard to the interrelationship between seizures, cerebral blood flow and brain metabolism, most of the studies using positron emission t o m o g r a p h y (PET) have been performed in interictal states [5, 7, 20]. During ictal states, mainly partial seizures and tonic-clonic seizures (grand mal) [1, 8, 9, 21, 22] could be assessed for methodological reasons: quantitative measurement of cerebral metabolic rate requires data acquisition periods of some minutes [17]. Thus, possible alterations of brain metabolism during spontaneous bursts of spike and wave activity lasting only a few seconds, can hardly be detected by means of P E T examinations. Investigations during 'absence' seizures could be performed in the exceptional case of an 'absence' status in which a decrease of glucose metabolism was observed [21]. Recently, a decrease of blood flow velocity of the middle cerebral artery (MCA) was reported to take place about 7 seconds after the appearance of the 'ictal' E E G pattern during 'absence' seizures in 2 cases [19]. We were interested in the correlation between local brain activity and regional cerebral perfusion, and approached this problem by measuring intracranial flow patterns simultaneously with the E E G recordings during

Correspondence: J. Klingelh6fer, Department of Neurology, Technical University of Munich, Mrhlstrafle 28, W-8000 Miinchen 80, F.R.G.

bursts of generalized spike and wave activity by means of transcranial Doppler ultrasonography (TCD). Three patients with spontaneous spike and wave activity were studied. Patient 1, a 19-year-old woman, had suffered from 'absence' epilepsy since the age of 9. The patient was now admitted to our department for commencement of adequate drug therapy. Before this was started, she was having dozens of 'absence' seizures every day. Patient 2, a w o m a n of 28 years, had 'absence' seizures since the age o f 8 years. Drug therapy (valproic acid) was effective but the drug level was ineffective due to non-compliance and the seizures therefore reoccurred. Patient 3, a 9-year-old boy, had a 3-month history of frequent 'absence' seizures. All three patients had no family history of epilepsy. The clinical investigations exhibited normal neurological clinical findings. In all cases, the E E G showed bursts of generalized 3 Hz spike and wave activity. The interval E E G recordings revealed no abnormalities. Using a 2 M H z pulsed Doppler device [2] (EME TC 2-64 B, F.R.G.), the intracranial flow patterns of the M C A were recorded continuously [6] and simultaneously with the E E G recordings. After identification of the M C A signal, the Doppler probe was adjusted and mechanically fixed with a specially developed probe holder attached with a tight headband. The AD-converted envelope curve of the M C A Doppler frequency spectrum was stored on hard disk of a personal computer. Additionally, each single value of mean flow velo-

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is shown in Fig. 1 (patient 1; burst 4). During the first seconds of generalized spike and wave activity a slight increase of enddiastolic flow velocity could be observed; 4.5 s after the onset of the spike and wave activity, the MFV began to decrease and reached the lowest value 3.8 s later which was 19.8% below the 'preictal' MFV level.

city (MFV) derived during one heart cycle was calculated by means of a computer-aided integration procedure. In all recorded 25 bursts of generalized spike and wave activity of the 3 patients, MCA flow patterns showed similar characteristic changes. An exemplary recording

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Fig. 1. Blood flow velocity of the middle cerebral artery (MCA) during a burst of generalized spike and wave activity. Simultaneous recordings of EEG, ECG, envelope curve of the MCA Doppler frequency spectrum, and normalized mean flow velocity determined from consecutive heart cycles. Blood flow velocity began to decrease 4.5 s after the onset of the first spike and wave patterns.

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After disappearance of spike and wave patterns, MFV increased reaching the 'preictal' level, e.g. after 12.7 s (Fig. 2A; patient 1, burst 6) and 16.5 s respectively (Fig. 2B; patient 3, burst 2). Such a characteristic development of cerebral blood flow velocities was found in all recorded bursts, showing: (1) a latency of some seconds between the onset of generalized spike and wave activity and the onset of blood flow velocity decrease, (2) a period of blood flow velocity decrease, (3) a period of reduced blood flow velocity, (4) a period of blood flow velocity increase, and (5) a possible overshoot (increase of blood flow velocity slightly over the 'preictal' value). To elucidate the dynamics of'ictal' blood flow velocity changes, the MFV values during the 25 bursts of the 3 patients were averaged (Table I) and drawn true to scale in Fig. 3. The duration of the recorded 25 bursts varied from about 2 s to about 16 s. The exact duration of the bursts (mean values and standard deviation) of the 3 patients could not be calculated because the offset of the spike and wave patterns of the separate EEG channels ensues at different times (cf. Figs. 1 and 2). On an average, the period of MFV changes, i.e. MFV decrease, duration of the reduced MFV, and period of MFV increase, lasted several times longer than the phase of spike and wave activity. After the increase period, a small overshoot was recognized in 9 of 25 bursts. It might be argued that the blood flow velocity recorded by means of TCD does not reflect volume flow [13]. However, the relationship between blood flow velocity and blood volume within the large basal intracranial

arteries is linear as long as alterations of the cerebral vascular bed are restricted to the small cortical resistance vessels. Recent studies confirmed that the intra-individual changes in blood flow velocity during TCD examination correspond directly to changes in volume flow [3, 12, 15]. Even if the relationship between volume flow and flow velocity is considered critically, the decrease in

TABLE I MEAN VALUES AND STANDARD DEVIATIONS OF MEAN FLOW VELOCITY (MFV) D U R I N G BURSTS OF GENERALIZED SPIKE AND WAVE ACTIVITY Patient 1 Patient 2 Patient 3 Number of bursts of spike and wave activity Approx. duration of the burst(s) Latency(s)* Duration of MFV decrease(s) Duration of reduced MFV(s) Duration of MFV increase(s) Decrease of MFV (%) Number of MFV overshoots

11 2-14 3.26 _+0.74 5.97 _+3.29 6.31 _+2.79 7.31 -t-4.19 22.74 _+8.21 7

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Fig. 3. Characteristic mean flow velocity changes during a burst of generalized spike and wave activity. Values of the different velocity stages were drawn true to scale according to the overall average of Table I. The black arrow indicates the onset of generalized spike and wave activity.

M C A flow velocities briefly after the appearance of generalized spike and wave bursts in any case argues against an increase in cerebral blood flow during the 'ictal' phase. Sanada et al. [19] describe a similar observation in 2 cases. They recorded a decrease in blood flow velocity appearing 7-9 s after the onset of the spike and wave activity. So far, we do not have any satisfactory explanation for this discrepancy with respect to our results. However, it is absolutely necessary for the exact determination of the latency between the onset of spike and wave activity and the onset of blood flow velocity decrease that the T C D signals were recorded continuously and simultaneously with the E E G recordings. Various explanations can be discussed with regard to the decrease in blood flow velocity. Changes of M C A flow velocities may be a consequence of vegetative (cardio-vascular) reactions induced by bursts of spike and wave activity. The simultaneously recorded electrocardiogram (ECG) showed only slight changes in heart rate (e.g. patient 1: increase in heart rate by 3.4-5.5% in 4 bursts, no changes in 2 bursts, and a decrease by 1.76.8% in 5 bursts) during the spike and wave activity, which could only have little effect on the M C A flow velocity decrease in our results. Decreasing blood flow velocities might also be the result of a reduction of the partial pressure of CO,, for example following hyperventilation [18, 23]. None of the 3 patients changed his breathing rhythm perceptibly during the whole E E G recording. Suppression of respiration is expected to be more likely during bursts of spike and wave activity [16] with the consequence of increasing pCO2 and increasing M C A flow velocity [18, 23]. Therefore, the observed M C A flow velocity decrease is not likely to be the result of respiration changes. To our

knowledge, there exists no report of a drop in blood pressure which would be sufficient to reduce M C A flow velocity to the extent shown in our results. A final appraisal with regard to the influence of blood pressure on the observed blood flow changes requires further investigations with continuous measurement of blood pressure [4]. Gibbs propounded the hypothesis with respect to physiological mechanisms of the spike and wave patterns that each spike potential is followed by a resting phase of 0.3 s in the form of a slow wave component. This evidently serves to enable functional recovery and a new convulsive discharge [10]. With regard to the physiological mechanism of the spike and wave patterns, Gloor also discussed that 'during spike and wave discharges a large number of neurons oscillate between short periods of excitation, corresponding to the spike, and longer periods of inhibition, corresponding to the slow wave component of the spike and wave complex' [11]. Assuming that a brief excitation of neuronal activity occurs during the short ( < 100 ms) 'spike-period' and that there is an inhibition of neuronal activity during the 'wave-period" the duration of which is several times longer (200 500 ms), a temporal predominance (or a net effect) of reduced cerebral neuronal activity during a single spike and wave complex might be expected. Enhanced neuronal activity increases cerebral blood flow; reduced neuronal activity decreases it [6, 14]. Therefore, the assumption of a reduced cerebral neuronal activity during spike and wave activity suggests a reduction of cerebral blood flow which is reflected by the decrease in M C A flow velocity. Our findings enable new approaches for studying the coupling mechanisms between generalized seizures and cerebral perfusion by analysis of intracranial flow patterns. We thank Dr. Christoph Arit for help with computer programming. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 220).

1 Alavi, A., Dann, R., Chawluk, J., Alavi, J., Kushner, M. and Reivich, M., Positron emission tomography imaging of regional cerebral glucose metabolism, Semin. Nucl. Med., 16 (1986) 2 34. 2 Aaslid, R., Markwalder, T.M. and Nornes, H., Noninvasivetranscranial Doppler ultrasound recording of flow velocityin basal cerebral arteries, J. Neurosurg., 57 (1982) 769-774. 3 Bishop, C.C.R., Powell, S., Rutt, D. and Brouse, N.L., Transcranial Doppler measurement of middle cerebral artery blood flow velocity: A validation study, Stroke, 17 (1986) 913 915. 4 Bochmer, R.D., Continuous, real-time, noninvasive monitor of blood pressure: Penaz methodology applied to the finger, J. Clin. Monit., 3 (1987) 282-287. 5 Chugani, H.T., Shewmon, D.A., Peacock, W.J., Shields, W.D., Maziotta, J.C. and Phelps, M.E., Surgical treatment of intractable neonatal-onset seizures: the role of positron emission tomograpy, Neurology, 38 (1988) 1178-1188.

81 6 Conrad, B. and Klingelhrfer, J., Dynamics of regional cerebral blood flow for various visual stimuli, Exp. Brain Res. 77 (1989) 437-441. 7 Dasheiff, R.M., Rosenbeck, J., Matthews, C., Nickles, R.J., Koeppe, R.A., Hutchins, G.D., Ramirez, L. and Dickinson, L.V., Epilepsy surgery improves regional glucose metabolism on PET scan. A case report, J. Neurol. 234 (1987) 283-288. 8 Engel, J., Jr., Kuhl, D.E. and Phelps, M.E., Patterns of the human local cerebral glucose metabolism during epileptic seizures, Science, 218 (1982) 64~6. 9 Engel, J., Jr., Kuhl, D.E. and Phelps, M.E., Local cerebral metabolism during partial seizures, Neurology, 33 (1983) 400-413. 10 Gibbs, F.A., Der gegenw/irtige Stand der kliniscben Elektrencephalographie, Arch. Psychiat. Nervenkr., 183 (1949) 2-11. I1 Gloor, P., Generalized epilepsy with bilateral synchronous spike and wave discharge. New findings concerning its physiological mechanisms, Electroencephalogr. Clin. Neurophysiol., Suppl. 34 (1978) 245-249. 12 Kirkham, F.J., Padayachee, T.S., Parsons, S., Seargeant, L.S., House, F.R. and Gosling, R.G., Transcranial measurement of blood velocities in the basal cerebral arteries using pulsed Doppler ultrasound: Velocity as an index of flow, Ultrasound. Med. Biol., 12 (1986) 15-21. 13 Kontos, A.A., Validity of cerebral arterial blood flow calculations from velocity measurements, Stroke, 20 (1989) 1-3. 14 Lassen, N.A., Control of cerebral circulation in health and disease, Circ. Res., 34 (1974) 749-760. 15 Lindegaard, K.F., Lundar, T., Wiberg, J., Sjoberg, D., Aaslid, R. and Nornes, H., Variations in middle cerebral artery blood flow investigated with noninvasive transcranial blood velocity measurements, Stroke, 18 (1987) 1025-1030.

16 Mirsky, A.F. and van Buren, J.M., On the nature of the 'absence' in centrencephalic epilepsy: A study of some behavioral, electroencephalographic and autonomic factors, Electroencephalogr. Clin. Neurophysiol., 18 (1965) 334-348. 17 Raichle, M.E., Herscovitch, P., Mintum, M.A., Martin, W.R.W. and Powers, W., Dynamic measurements of local blood flow and metabolism in the study of higher cortical function in humans with positron emission tomography, Ann. Neurol., 15 (1984) 548-549. 18 Ringelstein, E.B., Sievers, C., Ecker, S., Schneider, P.A., Otis, S.M., Noninvasive assessment of CO2-induced cerebral vasomotor response in normal individuals and patients with internal carotid artery occlusions, Stroke, 19 (1988) 963-969. 19 Sanada, S., Murakami, N. and Ohtahara, S., Changes in blood flow of the middle cerebral artery during absence seizures, Pediatr. Neurol., 4 (1988) 158-161. 20 Theodore, W.H., Newmark, M.E. and Sato, S., 18F-Fluorodesoxyglucose positron emission tomography in refractory complex partial seizures, Ann. Neurol., 14 (1983) 429-437. 21 Theodore, W.H., Brooks, R., Sato, S., Patronas, N., Margolin, R., Di Chiro, G. and Porter, R.J., The role of positron emission tomography in the evaluation of seizure disorders, Ann. Neurol., Suppl. 15 (1984) 176-179. 22 Theodore, W., The role of Fluorodesoxyglucose-Positron Emission Tomography in the evaluation of seizure disorders, Sem. Neurol., 9 (1989) 301-306. 23 Widder, B., Paulat, K., Hackspacher, J. and Mayr, E., Transcranial Doppler CO2-test for the detection of hemodynamically critical carotid artery stenoses and occlusions, Eur. Arch. Psychiat. Neurol. Sci., 236 (1986) 162-168.