Neuroscience Letters, 127 (1991) 77 81 © 1991 Elsevier Scientific Publishers Ireland Ltd. 0304-3940/91/$ 03.50 A DON1S 030439409100275A

NSL 07791

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

J / i rgen Kl inge lh6fe r , Chr i s t i an Bischoff, D i r k Sander , I n g o Wi t t i ch and Bas t i an C o n r a d

Department of Neurology, Technical University of Munich, Munich (F.R.G.)

(Received 4 January 1991; Revised version received 7 March 1991; Accepted 8 March 1991)

Key words: Spike and wave activity; Cerebral perfusion; EEG; Transcranial Doppler ultrasonography

The correlation between brain activity and cerebral blood flow velocities during 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 specially developed 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 velocity decreased 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 ' ab - sence' seizures is still a matter of controversy even today. With regard to the interrelationship between seizures, ce- rebral blood flow and brain metabolism, most of the studies using positron emission tomography (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 method- ological reasons: quantitative measurement of cerebral metabolic rate requires data acquisition periods of some minutes [17]. Thus, possible alterations of brain metabol- ism during spontaneous bursts of spike and wave activi- ty lasting only a few seconds, can hardly be detected by means of PET examinations. Investigations during 'ab- sence' 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 ' EEG 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 EEG 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 ul trasonography (TCD). Three patients with spontaneous spike and wave activ-

ity 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 com- mencement of adequate drug therapy. Before this was started, she was having dozens of 'absence' seizures every day. Patient 2, a woman of 28 years, had 'absence' seizures since the age of 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 fre- quent 'absence' seizures. All three patients had no family history of epilepsy. The clinical investigations exhibited normal neurological clinical findings. In all cases, the EEG showed bursts of generalized 3 Hz spike and wave activity. The interval EEG recordings revealed no abnormalities.

Using a 2 MHz pulsed Doppler device [2] (EME TC 2-64 B, F.R.G.), the intracranial flow patterns of the MCA were recorded continuously [6] and simulta- neously with the EEG recordings. After identification of the MCA signal, the Doppler probe was adjusted and mechanically fixed with a specially developed probe holder attached with a tight headband. The AD-con- verted envelope curve of the MCA Doppler frequency spectrum was stored on hard disk of a personal com- puter. Additionally, each single value of mean flow velo-

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city (MFV) derived during one heart cycle was calcu- lated by means of a computer-aided integration proce- dure.

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

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.

EEG

F 8 - F 4

F 4 I F z

F z - F 3

F 3 - F 7

T 4 - C 4

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C 4 - C z

C z - C 3

C 3 - T 3

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P4" Pz

Pz" P3

P3" T5

A 2 - C z

A 1 - C z

ECG

.,oo o o ::

40

:E

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i ®--= I I Time ls l

3 s

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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E 100 o o

4 o

® ~ - - 15 t

o3 e ~ 0.5 90 120 210 240 Time [s]

Fig. 2. Envelope curves of the MCA Doppler frequency spectrum (I) and normalized mean flow velocity (II) determined from consecutive heart cycles during 2 (A,B) bursts of generalized spike and wave activity. The duration of the spike and wave activity is illustrated by means of a bar (the full line characterizes the period of generalized spike and wave activity; the dotted line characterizes the period in course of which the offset

of the spike and wave patterns of the separate EEG channels ensues at different times).

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 peri- od 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 aver- age, the period of MFV changes, i.e. MFV decrease, duration of the reduced MFV, and period of MFV in- crease, 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 velo- city and blood volume within the large basal intracranial

arteries is linear as long as alterations of the cerebral vas- cular bed are restricted to the small cortical resistance vessels. Recent studies confirmed that the intra-indivi- dual changes in blood flow velocity during TCD examin- ation 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) DURING BURSTS OF GENERAL- IZED SPIKE AND WAVE ACTIVITY

Patient 1 Patient 2 Patient 3 Total

Number of bursts of spike and wave activity Approx. duration of the burst(s) 2-14 4-16 3-16 2-16 Latency(s)* 3.26 3.77 3.11 3.41

_+0.74 _+ 1.15 _+0.99 +0.98 Duration of MFV 5.97 9.54 6.35 7.28 decrease(s) _+3.29 _ + 6 . 7 0 +4.01 +6.82 Duration of reduced 6.31 5.54 6.01 6.25 MFV(s) _+2.79 _+4.55 _+ 3.99 + 3.75 Duration of MFV 7.31 12.63 13.98 11.88 increase(s) -t-4.19 _ + 6 . 5 1 _+4.67 -t-5.01 Decrease of MFV 22.74 26.89 25.11 25.84 (%) _+8.21 _+11.30 _+11.43 _+10.45 Number of MFV 7 1 1 9 overshoots

11 10 4 25

*Latency(s) between onset of generalized spike and wave activity and

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sp~

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11

t 0

0,9

0.8

0 7

0 6

0

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1 katen¢~ Decrease 1 I pe r i od [ I I I

O v e r s h o o t

I pe r i od I

R e d u c t i o n I pe r i od I I i

10 20 30 40 50

T ime [sl

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 Ta- ble I. The black arrow indicates the onset of generalized spike and

wave activity.

MCA 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 ac- tivity. So far, we do not have any satisfactory explana- tion for this discrepancy with respect to our results. However, it is absolutely necessary for the exact determin- ation of the latency between the onset of spike and wave activity and the onset of blood flow velocity decrease that the TCD signals were recorded continuously and

simultaneously with the EEG recordings. Various explanations can be discussed with regard to

the decrease in blood flow velocity. Changes of MCA flow velocities may be a consequence of vegetative (car- dio-vascular) reactions induced by bursts of spike and wave activity. The simultaneously recorded electrocar- diogram (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 1.7- 6.8% in 5 bursts) during the spike and wave activity, which could only have little effect on the MCA flow velo-

city decrease in our results. Decreasing blood flow velocities might also be the re-

sult 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 dur- ing the whole EEG 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 MCA flow velocity [18, 23]. There- fore, the observed MCA 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 MCA 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 in- vestigations 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 evi- dently serves to enable functional recovery and a new convulsive discharge [10]. With regard to the physiologi- cal 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 per- iods of inhibition, corresponding to the slow wave com- ponent 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 neuro- nal activity increases cerebral blood flow; reduced neuro- nal activity decreases it [6, 14]. Therefore, the assump- tion 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 MCA flow velo- city. 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).

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