Monitoring of cortical blood flow in human epileptic foci using laser Doppler flowmetry

J Epilepsy 1993;6:145-151 © 1993 Butterworth-Heinemann

Monitoring of Cortical Blood Flow in Human Epileptic Foci Using Laser Doppler Flowmetry 1Elisabeth Ronne-Engstr6m, 1Hans Carlson, 2Sigfrid Blom, 2Roland Flink, 4Bertil Gazelius, ~Bo Sp/innare, and ~'3LarsHillered

We have used laser Doppler flowmetry (LDF) for real-time monitoring of regional cerebral blood flow (rCBF) during epileptic seizures recorded intracranially with subdural electrodes. The method was employed in six patients with medically intractable epilepsy undergoing preoperative evaluation for epilepsy surgery. rCBF was measured during 24-h video/EEG monitoring of seizures. Eleven seizures were recorded with simultaneous LDF and EEG by a combined subdural EEG electrode and laser Doppler probe. All seizures recorded on EEG were accompanied by distinct changes in rCBF. There was either an increase in blood flow up to 100% or a decrease by 30% from the basal levels. The ictal blood flow changes were similar comparing seizures within one patient, whereas striking differences were found between patients. The rCBF was also studied interictally. Different blood flow signal patterns were found correlating to the wakefulness of the patient. The LDF technique, combined with continuous EEG recording, appears to be a powerful tool for studying regional transient rCBF changes in association with focal epileptic seizure activity. Key Words: Focal epilepsy-Cerebral blood flow--Laser Doppler flowmetry--Subdural electrodes--Seizures.

Epileptic seizure activity in neurons can be defined and characterized by EEG. When studying the biochemical features of the epileptic focus, results have often been correlated to the EEG recordings. It has been difficult to find methods to measure regional cerebral blood flow (rCBF) with the same temporal and spatial resolution as EEG. Studies directly comparing rCBF and EEG changes are therefore scarce. Methods used for measuring CBF in patients with epilepsy include special thermoelectric probes for intra-

Received February 8, 1993; accepted February 12, 1993. From the Departments of 1Neurosurgery, 2Clinical Neurophysiology, and 3Clinical Chemistry, University of Uppsara, and the 4Department of Pharmacology, Karolinska Institute, Stockholm, Sweden. Address correspondence and reprint requests to Dr. E. Ronne-Engstr6m at Department of Neurosurgery, University Hospital, S 751 85 Uppsala, Sweden.

operative use (1), hydrogen clearance (2), cerebral angiography (3), and 133Xe clearance (4). Although changes in rCBF have been demonstrated with these techniques, there are limitations with respect to the spatial and temporal resolution and the relative inconvenience of some of the procedures. The introduction of computed tomography (CT) now offers methods for a noninvasive three-dimensional visualization of the brain. In functional studies, CBF and metabolism have been studied with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) (5-7). These techniques do not allow continuous measurement of CBF. Furthermore, the results from ictal studies have been ambiguous (8). Other techniques are therefore needed in order to fully understand CBF variations during seizures. The present study aimed at exploring laser Doppler flowmetry (LDF) for measurement of ictal rCBF j EPILEPSY, VOL. 6, NO. 3, 1993

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changes in the human epileptic focus. The measurements were done in patients suffering from intractable epilepsy. Laser Doppler flowmetry (9-11) is an optical technique to study relative microcirculatory blood flow. The method has been used in both animal models (12,13) and in different tissues of patients, such as the skin (14), gingiva (15), and the brain (1618). It has been shown that the LDF technique parallels autoradiographic measurements of rCBF changes in the same regions of the brain (12). Since it has been suggested that LDF also may be used for absolute rCBF measurements (17,19), we compared interictal basal LDF measurements between different patients and recordings.

Patients and M e t h o d s rCBF was measured in six patients with medically intractable complex partial seizures (CPS). The patients were evaluated before epilepsy surgery according to a routine protocol, including 24-h video/EEG monitoring with subdural electrodes, magnetic resonance imaging (MRI), CT, interictal PET with 2[18F]fluoro-2-deoxy-D-glucose (FDG), neuropsychological investigations, and intracarotid amobarbital testing of language and memory functions. Clinical data are given in Table 1. The patients' antiepileptic drugs were successively reduced during the period of

Table 1. Patients

video/EEG monitoring. Blood flow was measured in periods of up to 8 h/day during the continuous video/ EEG monitoring session. Blood flow was measured with two laser Doppler perfusion monitors, the Periflux PF 3 and PF 2b (Perimed AB, Stockholm, Sweden). The principles are described by Bonner and Nossal (20). In short, the helium-neon laser light is led to the surface of the brain by a flexible optical fiber. The light is scattered in the brain tissue, and, when striking moving objects, such as blood cells, the frequency of the light is shifted according to the Doppler effect. When the light hits static objects, it is unshifted. Part of the light, composed of a mixture of different wavelengths, is backscattered through the brain tissue, picked up by the optical fiber, and fed back to the photodetectors. The detected light is converted into an output flux signal value, proportional to the flow of blood cells. In this study, a flexible single optical fiber (PF 319: 02 120, with a diameter of 0.5 mm) for bidirectional light guidance was attached to the distal end of a Wyler subdural strip electrode (Ad-Tech Medical Instrument Corp., Racine, WI, U.S.A.) (Fig. 1). The fiber was connected via a multifiber PF 318 master probe to the Periflux monitor. The flux signal values were expressed as perfusion units (PL0, where I PU corresponds to 10 mV and relates to a physical motility standard. The PU flux signal value and the total amount of

Patient data

Seizures° Neuroimaging

Age No.

(years)

Start (years of age)

1

24

7

CPS

Left temporal lobe

Left ventricle slightly dilated

Normal

2

25

7

CPS

Right temporal lobe

Normal

Normal

3

30

11

CPS

Normal

Normal

4

33

30

CPS

Normal

5

46

25

CPS

Right temporal lobe Both temporal lobes, left dominating Left temporal lobe

Gliosis, left medial temporal lobe Normal

6

49

0

CPS

Type

aComplex partial seizures. I46

]EPILEPSY, VOL. 6, NO. 3, 1993

EEG focus

Both temporal lobes, right dominating

CT

Small calcification, right temporal lobe Normal

MRI

Gliosis, left uncus

PET (FDG) Hypometabolism, left temporal lobe Hypometabolism, right temporal lobe Normal Hypometabolism, left temporal lobe Hypometabolism, left temporal lobe Not performed

CORTICAL BLOOD FLOW MEASUREMENTS

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frontal probe. The remaining three patients had one probe each, placed subtemporally on the side of the presumed focus. The measurements were made both day and night. During the recordings, the patients were allowed to move around in the vicinity of the bed. The connection between the patient and the Periflux monitor was arranged so that it would disconnect if the patient tried to walk away during seizures or in states of postictal confusion. The degree of movement artifacts varied. Some patients could move around on the floor without any artifacts, whereas in others small movements of the head gave rise to artifacts. The development of movement artifacts was probably due to the status of the connector between the masterprobe and the single fiber on the subdural electrode/probe. Intracranial movements of the electrode/probe is highly unlikely, owing to the fixation procedure used. When the seizure monitoring was completed, the electrodes were extracted in local anesthesia. No complications of bleeding, infection, or cerebrospinal fluid leakage occurred. The study was approved by the local ethics committee, and the patients gave their informed consent to participate.

A

Figure 1. The flexible optical single fiber (A) is attached to the subdural electrode (B). The probe end (C) is close to the distal electrode.

backscattered light (total backscatter, TB) were continuously recorded on a two-channel pen recorder (ABB SE 120, Goertz A.G., Austria). The recordings were made with the time constant set to 1.5. The interictal basal flux signal levels were determined by calculating the mean flux signal value of three randomly chosen 10-min periods during each recording session. These basal levels were used to calculate the relative flux value changes during seizures. The subdural electrodes were handled according to clinical routine and implanted during general anesthesia. Usually, four subdural strip electrodes were implanted. One or two of these was equipped with the custom-made single-fiber laser Doppler probe. The localization of the electrode/probe was determined from postoperative x-ray examination of the skull. Flux signal levels were monitored for altogether 250 h. The recording periods varied from 2 to 19 days. Measurements were made both during wakefulness and normal sleep. Two patients were monitored with two subtemporal probes, one on each side. One patient was monitored with a subtemporal probe on the same side as the focus and an ipsilateral sub-

Results

Interictal Recordings H u x Levels

The interictal absolute flux values (PU) are shown in Fig. 2. The flux values varied over a wide range, both between different measurements in the same pa-

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Figure 2. Interictal basal flux levels in perfusion units (PU) plotted for each recording session (c.f. "Methods"). Patients 1-6 (c.f. Table 1). Probe placements were subtemporal (ST) or frontal (F), and the side was either ipsilateral (i) or contralateral (co) to the seizure onset region.

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Figure 3. Flux signal pattern during sleep and wakefulness. Time bar, 1 rain. tient and between different patients. There were no systematic changes of interictal flux values day to day, but there was a tendency for the mean flux value to be higher during sleep than w h e n the patient was awake.

The flux signal pattern in awake alert patients differed from that monitored during sleep (Fig. 3). The most obvious difference was that the 5-8 cycle/min wave had lower amplitudes during sleep than in the awake state.

Flux Signal Pattern The flux signal showed rhythmic variations with three different frequencies: (a) synchronous with the heartbeats, which could only be observed w h e n the speed of the p e n recorder was increased; (b) I cycle/ min; and (c) 5-8 cycles/min. These rhythmic values could be recorded from all the regions investigated, i.e., in subtemporal and frontal regions. During interictal conditions, there was no difference in flux signal pattern between the focus and remote cortical regions. The patterns were detected in fully awake, alert patients. Thus, the rhythmic variations appear to be a widespread cortical microcirculatory p h e n o m e n o n occurring during normal physiological conditions.

Table 2.

Peri-ictal Recordings Flux Levels In 4 patients, a total of 11 seizures were monitored with simultaneous video/EEG recording and LDF (Table 2). Nine blood flow recordings during seizures were of good quality, whereas two had m o v e m e n t artifacts and could not be evaluated. All the seizures recorded with simultaneous EEG and LDF were associated with marked changes of blood flow. Typical examples are shown in Fig. 4. In two patients (Nos. 1 and 2), increases of blood flow with 70-100% were seen (Fig. 4 A and B). The blood flow changed in close association to the EEG-

Electrophysiological characteristics of the seizures recorded with laser Doppler flowmetry

Patient no.

Duration(s)

Seizure onset region

Interhemispheric propagation time(s)

Time from EEG onset to symptoms(s)

1 1 1 2 3 3 3 3 3 3 6a

118 143 127 100 45 120 120 130 160 150 --

Subtemporally left side Subtemporally left side Subtemporally left side SubtemporaUy right side Subtemporally right side Subtemporally right side Subtemporally right side Subtemporally right side Subtemporally right side Subtemporally right side Subtemporally right side

28 25 20 20 Unilateral Unilateral Unilateral Unilateral 12 Unilateral --

20 20 20 10 Subclinical Subclinical Subclinical Not recorded on video 34 Not recorded on video Not recorded on video

rFhe patient disconnected the LDF probe and the video/EEG monitor during this seizure. 148 I P_~PILEPSY,VOL. 6, NO. 3, 1993

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Hgure 4. Relativefluxlevels during seizures in three different patients. A: Patient 1. B" Patient 2. Cand D" Patient 3. Solid lines represent measurements from the seizure onset region, whereas dotted lines are from the contralateral side (c.f. Table 2). Duration of seizures are indicated by horizontal bar and time marks given for every minute. The seizure in (C) was strictly unilateral, whereas the seizure in (D) spread to the contralateral side.

recorded seizures and returned toward the interictal flow values shortly after termination of the seizures. In one patient (No. 2), the blood flow elevation started 4 min before the start of seizure activity on the subdural E]~G recording (Fig. 4B). Patient No.'3 was recorded with bilateral probes. An ipsilateral 30% decrease of blood flow was found when the seizure activity was unilateral (Fig. 4C), whereas the flow on the contralateral side remained unchanged. In seizures spreading to the other side (Fig. 4D), the ipsilateral decrease in blood flow was followed by a contralateral increase in blood flow within seconds after the propagation to the contralateral side.

changes in the slow rhythmic variations (1 cycle/ min).

Discussion CBF and metabolism have been estimated previously by 133Xe clearance, SPECT, and PET in epilepsy patients (21). These methods do not provide detailed information about dynamic changes of rCBF during seizures. To our knowledge, this is the first report on LDF monitoring of the rCBF peri- and interictaUy in epilepsy patients. A preliminary report has been published in abstract form (22).

Interictal Observations Hux Signal Pattern The 5-8 cycle/min rhythmic variations observed during the interictal state continued during the seizures, but their amplitudes decreased by about 50%. The seizures recorded were too short to observe any

It has been claimed that the LDF method could be used for measuring the absolute CBF after calibration procedures (17,19) or that the absolute flux levels monitored from day to day may be related to the clinical status of patients following severe head injury (18). In the present investigation, the basal interictal J EPILEPSY, VOL. 6, NO. 3, 1993

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F~RONNE-ENGSTROM ET AL.

flux levels recorded in repeated sessions under similar conditions in the same patient varied more than 10 times. Such variations were seen in all the regions investigated, i.e., also in nonepileptogenic regions. There were also large interindividual variations of the absolute basal flux signal levels. Thus, our results argue against systematic variations of basal interictal flux signal levels relating to the clinical status of the patient. The flux recordings made in awake, conscious patients or during sleep revealed three types of rhythmic variations in flux signal pattern, partly corresponding to variations described earlier in patients during general anesthesia (16). The 5-8 cycle/min variations had a lower amplitude during sleep. These variations correspond to the low-frequency rhythmic variations (LFRV) described by Fasano et al. (16), which were found to be reduced by the administration of anesthestic drugs. Furthermore, we observed a rhythmic variation of 1-2 cycles/min, which has not been described earlier. The biological significance of these flux signal patterns is not yet known.

Peri-Ictal Observations

PET and SPECT investigations are at present used preoperatively in epilepsy patients in order to visualize the epileptic region. With these techniques, it has been shown that an epileptic region often has a decreased blood flow and metabolism interictally (6). PET investigations show that seizure activity often is accompanied by signs of increased blood flow and metabolism (8,23). However, these functional neuroimaging techniques have also revealed other patterns of metabolism and CBF changes in patients with focal epilepsy. A normal interictal blood flow in the focus (as defined by EEG) may occur in combination with an altered blood flow in other parts of the brain (23). The blood flow may also be elevated on the contralateral side of the focus during the seizure activity (23). In this investigation, all the seizures recorded simultaneously with EEG and LFD were associated with distinct blood flow changes. In two patients, an elevation of the blood flow of up to two times the basal levelwas seen. In one patient, a moderate decrease of the ipsilateral blood flow was recorded. Using ictal PET and SPECT techniques for CBF estimations, it has also been shown that there may be an ictal hypoperfusion. Due to the restrictions of time resolution with these techniques, it has been argued that these "ictal hypoperfusions" may instead reflect a postictal ~50 J EPILEPSY, VOL. 6, NO. 3, 1993

depression. The present LDF results support that ictal hypoperfusion may occur in certain patients. Thus, it seems likely that individual epileptic loci are different with respect to blood flow changes. Some methodological aspects should be considered in relation to the ictal hypoperfusion as seen with LDF. The small region where rCBF is measured may not be representative for the entire focus. The laser Doppler probe may have been placed in the border or outside the onset region for the seizures where the blood flow could be reduced by a steal phenomenon. This is not a likely explanation for the present results, since the LDF probes were located at the electrodes in which the seizure activity was first recorded, suggesting a close spatial correlation between the site of the flow measurements and the onset region of the epileptic activity. Video monitoring and the clinical features also supported the EEG recordings. It is known that generalized seizures could change the systemic blood pressure (24,25). However, since LDF recordings made simultaneously in different areas of the brain during seizures were different, it appears that local mechanisms, rather than possible systemic blood pressure alterations, are responsible for the changes in rCBF during seizures. LDF yields measurements with a high temporal resolution compared to PET and SPECT techniques. This study shows that the rCBF changes are closely related to the period with epileptic activity. The rCBF changes returned to basal level within minutes after the seizures had terminated. No evidence of rCBF changes corresponding to postictal depression of the EEG was found. In one of the patients, the blood flow increased 3-4 min before the seizure onset on EEG. There were no clinical manifestations of seizures before the onset of epileptic activity on the EEG, which started in the electrode closest to the laser Doppler probe. It has for long been known that the EEG activity may shift character before the actual seizure onset (26). The present data suggest that preseizure rCBF changes may also occur. In conclusion, our findings using LDF combined with subdural electrode EEG monitoring support the concept of different rCBF changes in individual epileptic foci, which may help to explain the previous ambiguous findings with functional neuroimaging techniques, as noted. The two methods in combination appear to be a powerful tool for studying the temporal characteristics of rCBF changes in the human epileptic focus.

Acknowledgment: This study was supported by the Margarethemmet Foundation, the Ulf Lundahl Foundation, and Swedish Medical Research Council project number B92-14X-09482-02A.

CORTICAL BLOOD FLOW MEASUREMENTS

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