Regional cerebral blood flow and kainic acid-induced focal limbic seizures in cats

260

Epilepsy Res., 2 ( ISXX) 260-26X Elaevirr

ERS 00168

Regional cerebral blood flow and kainic acid-induced focal limbic seizures in cats

Kenichi Makino, Tatsuya Tanaka and Yukichi Yonemasu L)eparmenl

of Neurosurgery,

(Received

18 May 1987: revised received

k’f~y words: Kainic acid: Regional

An experimental ccrehral

Immediately mained

limbic seizure was induced

blood flow (rCBF)

the seizure.

of continuous

creased

to 140% of the baseline

During

limbic seizure in which spike discharges

turned to baseline

value.

values in the primary

where seizure propagation During

the interictal

rCBF

spikes,

almost

clearance

method

(RA)

Measurement

about

2-fold in the left amygdala

to the left hippocampus

and left sensorimotor

cortex

spike discharges

intermittently

of regional

clearance

(LH),

method. (LA) and re-

rCBF in the LH in-

(LCx) it remained

to the LCx, rCBF in the LA, RA, LCx and LH increased

stage in which interictal

appeared

unchanged.

to 220%,

130%.

in the LA, rCBF re-

foci.

simultaneously

and returned

in the primary

Hydrogen

by means of the hydrogen

rCBF increased

spikes were transmitted

propagated

and secondary

were observed, stage.

multiple

multiple

24 July 19X7)

of kainic acid into the left amygdala.

cortex was performed

but in the right amygdala

In the interictal

The results show that rCBF increased

blood flow; Limbic seizure;

and cerebral

When continuous

12O“iand 190%. respectively.

cerebral

8 July 1987; accepted

in cats by microinjection

in the limbic structure

after the development

so during

Asahikawa Medical College, Asahikawa 078-I I (Japan)

with the development

to baseline

of the seizure in the primary

focus and the areas

value once the seizure had disappeared.

focus was only slightly

increased

in spite of persistence

of interictal

spike dis-

charges.

INTRODUCTION There is a close relationship between functional activity in cerebral structures and regional cerebral blood flow (rCBF). It is well known that rCBF of the epileptic focus increases during focal cortical seizuresl?.15.“.2j.‘h. However, the relationship between rCBF of deeply located epileptic foci in limbic structures and electroencephalographic seizure activity has (‘orre~pondmce Neurosurgery.

IO: Dr. Asahikawa

Tatsuya Medical

Tanaka.

Department

College,

Asahikawa

117X-lI. Japan.

NQO-1211/88/$03.5fJ@)

1988 Elsevier

Science Publishers

of

not been well studied. Moreover, rCBF changes in the areas where seizure propagation is seen on EEG have still not been determined. We have reported that local application of a small amount of kainic acid (KA) into limbic structures produced a localized epileptic focus and secondary limbic status in cats”2.“4. In the present study, focal amygdaloid status was elicited by a microinjection of KA unilaterally into the amygdala in an acute preparation. The rCBF in the left amygdala and the area where electrographic seizure propagation was observed, i.e., the right amygdala, left hippocampus and left sensorimotor cortex, were measured by means of the

B.V. (Biomedical

Division)

261

hydrogen clearance method under concurrent monitoring by eIectroencephalogram. rCBF in each region during the baseline, ictal and interictal periods was serially recorded and analyzed. MATERIAL

AND METHODS

Fifteen adult cats, weighing 2.5-3.5 kg, were used in this study. All cats were initially anesthetized with intraperitoneal administration of pentobarbital (35 mg/kg) and mounted in the stereotaxic apparatus. Mild anesthesia was continued by periodic intravenous administration of pentobarbital (usually 1.0 mg/kg/h) in order to relieve the painful stimuli under continuous monitoring of cortical electroencephalography. The depth of anesthesia was monitored carefully, ensuring that spindle waves were present in the cortical electroencephalogram. Local anesthesia (1% xylocaine) was also applied to the painful areas. Polyethylene catheters were passed through the femoral artery and femoral vein to allow continuous measurement of arterial blood pressure and drug administration, respectively. Arterial blood pressure was recorded via a strain gauge by EEG, electrocardiogram and respiratory curve on a polygraph. Samples of arterial blood were taken for measurements of arterial blood gases and pH. Tracheostomy and intubation were carried out, and then the cats were paralyzed with pancuronium bromide (0.25 mgikglh). Artificial ventilation was initiated in order to maintain pC0, at 30-35 mm Hg, and p0, 80-100 mm Hg. Core body temperature was monitored using a rectal thermometer, and a normal temperature maintained by means of a small heating blanket. Before fitting a stereotaxic ear-bar, 2% xyloCaine gel was applied to the bilateral external auditory meatus for local anesthesia. After fixation of the cat’s head in a stereotaxic device, stainless screw electrodes were placed over bilateral anterior sigmoid gyri so that they touched the dura mater. A stainless screw electrode was placed over the frontal sinus for an indifferent electrode. These electrodes were utilized for cortical EEG monitoring. Three bipolar needle electrodes were stereotaxically placed into both lateral nuclei of the amygdala (LA, RA) and the left dorsal hippo-

campus (LH) for deep EEG monitoring, and 4 platinum needle electrodes were stereotaxically placed into LA, RA, LH and left sensorimotor cortex (LCx) for the measurement of rCBF, according to the atlas of Jasper and Ajmone Marsan16. The positions of the electrodes in the LA, RA and LH were confirmed by the appearance of injury potentials upon insertion of these bipolar and platinum needle electrodes under concurrent monitoring by EEG. The hydrogen clearance method, utilizing the saturation clearance method, was used to measure rCBF. The tips of the platinum needle electrodes were 0.3 mm in diameter and 1 mm in length. A polarization potential of about +lOO mV was applied to the electrode. Hydrogen was administered to the animal via the respirator (5-10% Hz in air), with additional 0, to maintain the 0, level at about 20% in the inspired air. Hydrogen inhalation was continued until saturation of the brain tissue with hydrogen was obtained. The hydrogen concentration of the brain tissue was monitored via the electrodes on a recorder. The saturation and clearance curves were thus studied. The rapidity of the hydrogen clearance is a measure of rCBF in the small brain area where the tip of the platinum needle electrode is located. The rCBF measured from the initial slope over a period of 2 min is calculated by the following equation’.“’ fBF

=

A ’ 69-3ml/l00 T l/2

gimin

where A is the tissue blood partition coefficient = 1, T,,2 is the time taken for H, concentration to decay to l/2. The H, saturation and clearance procedures were repeated at least 3 times in order to obtain baseline values before kainic acid (KA) injection. After measurement of baseline rCBF, an injection needle was inserted stereotaxically into LA, and KA solution (2 pg of KG in 2 ,~l of phosphate buffer, 0.2 mol at pH 7.4) was injected at a rate of 1 pllmin. Polygraph monitoring followed. The electro-clinical changes after microinjection of kainic acid to the left amygdala have been studied and reported precisely by Tanaka et al.j4. In the present experiment, the changes after microinjection of kainic acid were conventionally di-

lxx -

L/-j

ECG

.u-A..~--

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.,

-..

LLII.I

.._...

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I..

._

_-

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I

I_..._ ,.., ._;. _

-

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263

LCX RCX

LA RA LH ECG Besp BP 30 set Fig. 3. Polygraph recordings 180 min after kainic acid injection (2pcg) into the left amygdala. A limbic status was observed (stage III). For abbreviations see legend to Fig. 1.

LCX-

ycu~~cw.*-~w~

LH

I

f-L

ECG~

,

Resp’

Fig. 4. Polygraph recordings 12 h after kainic acid injection (2pg) into left amygdala (inter-ictal phase; stage IV). For abbreviations see legend to Fig. 1.

264 TABLE

I

Physiological

parameters

Values are means

before and after kainic

t S.D. MABP

= mean arterial

acid injection

blood pressure;

BT = body temperature;

pH, PO,, HCO,

= arterial

blood gas analy-

sis. Control

MABP (mm Hg) BT (“C)

107 + 17 37.4 + 0.4

Stage I

104?

Stage II

Stage 111

Sroge IL’

18

107 i- 14

IO’) k IX

to.5 k 10

37.5 i- 0.3

37.5 t 0.3

37.5 i 0.3

37.2 z!z0.3

PH

7.40 f 0.07

7.39 t 0.08

7.40 k 0.07

7.40 f 0.08

7.3’) f 0.08

PO, (mm Hg)

01.7 _+ 13.x

X7.5 + 10.0

NY.6 _t 10.4

87.7 t 10.7

87.7-t

PCO, (mm Hg) HCO, (mEq/l)

33.6 f 3.2

33.2 + 3.5

33.1 t 2.4

33.3 + 3.5

33.4 i 3.5

21.8 * 3.7

21.1 23.1

21.1 i- 3.5

21.6 + 4.2

21.1 i- 3.J

vided into 4 stages, from stage I to stage IV. Between 1 and 20 min after KA injection, continuous multiple spikes appeared in the injected site of LA (stage I, Fig. 1). Forty to 120 min later, continuous multiple spikes propagated to LH (stage II, Fig. 2). Two to 5 h later, limbic seizure occurred (stage III, Fig. 3). Seizure propagation extended to LH. RA and occasionally to LCx. These limbic seizures lasted S-10 h and interictal discharge appeared afterwards (stage IV, Fig. 4). Measurement of rCBF was repeated at least 3 times during each stage. In stage III, the duration of each epileptiform activity in LA, LH and LCx was anything up to 1 min. In this special stage, the hydrogen clearance examination started before the beginning of each seizure. Then clearance curves became bi-exponential and accelerated after seizure development. We calculated rCBF with these accelerated clearance curves. Three cats died at the end of the experiment because of heart failure and problems with ventilation, and 3 cats were sacrificed before stage IV because limbic status epilepticus had not ceased within 15 h of kainic acid injection. Stage I was missed in one cat because its duration was too short to allow measurement of rCBF. Fifteen hours after kainic acid injection. all cats were sacrificed by intravenous administration of potassium chloride under deep pentobarbital anesthesia. Normal saline infusion via the left cardiac ventricle was followed by 10%~ formalin solution for fixation. After fixation, the brain was embedded in paraffin and processed for light microscopic examination. The sections were stained

IS.8

with hematoxylin-eosin and cresyl violet. Histological changes were evaluated, and careful checks of the electrode positions confirmed correct placement of electrode tips. Values are recorded as mean * S.D. A paired t test is used to assess significance of differences between rCBF in various stages and between experimental animals and controls. RESULTS Arterial blood pressure, body temperature and blood gas analyses during the experimental period are summarized in Table I. No significant changes in these parameters were noted in the various stages. Results of regional cerebral blood flow measurement are summarized in Table Il. In the table state prior to injection, rCBF of LA, RA, LCx and LH were 20.7 + 6.4, 21.1 * 6.1. 44.1 i 9.8, 24.1 + 10.5 ml/100 gimin, respectively. KA injection into the left amygdala resulted in continuous multiple spikes in the injected site of LA (stage I). The rCBF of LA, RA, LCx and LH changed to 21096, 100%. 100%. 100% of the baseline values, respectively. The rCBF of LA increased to approximately twice the baseline value (P < 0.0001); rCBF of RA, LCx and LH did not change. After the propagation of continuous multiple spikes to LH (stage II). rCBF of LA, RA, LCx and LH changed to 190%, 100%. 1100/c,, 140%’ of the baseline values, respectively. The rCBF of LA remained about twice the baseline value (P < O.OOOl), and rCBF of LH where the continuous multiple spikes propagated increased

265 TABLE

II

Regional cerebral

bloodflow(mll100 glmin) before and after kainic acid injection into the left amygdala (2~g)

Values are means + S.D. N = number

Symbols indicate significance

of change from the baseline value (paired

I test).

Control (N = 17)

Stage I (N = 13)

Stage II (N = 14)

Stage III (N = 12)

Stage IV (N = II)

LA

20.7 + 6.4

42.8 f 15.0**

39.5 + 12.5**

43.9 + 16.4**

23.0 + 6.5

RA

21.1 f 6.1

21.0 + 7.3

21.6 + 7.7

26.7 + 6.9*

19.1 xk4.9

LCX

44.1 + 9.8

45.3 f 11.8

48.4 + 9.8

56.8 + 11.9*

38.5 rt 10.6

LH

24.1 + 10.5

24.1 f 11.4

34.9 f 15.6*

41.7 f 9.2**

24.0 + 8.1

*P < 0.001. **P<0.0001.

significantly (P < 0.001). During limbic seizures (stage III), rCBF of LA, RA, LCx and LH increased to 220% (P < O.OOOl), 130% (P < O.OOl), 120% (P < 0.001) and 190% (P < 0.0001) of the baseline values, respectively. The increment of rCBF in LA was significantly higher than that of RA and LCx, but there was no significant difference between the increment in rCBF of LA and that of LH. During the interictal phase (stage IV), rCBF of LA, RA, LCx and LH returned to llO%, 90%, 90%, 100% of the baseline values, respectively. These values do not indicate any significant changes compared to the baseline rCBF. DISCUSSION Kainic acid, a potent analogue of glutamate, has neurotoxic and neuro-excitatory effects22’30. Systemic administration of kainic acid causes many neurological symptoms including seizures7,23. Recently, microinjections of kainic acid into the limbit nuclei have been studied and reported as a possible model of human temporal lobe epilepsg. 25.32.33. Tanaka et a1.34 reported an experimental model of limbic status and secondarily generalized seizure following microinjection of kainic acid into the amygdala in non-anesthetized and freely moving cats. In non-anesthetized cats, continuous multiple spikes appeared in the injected site of the amygdala, l-10 min following kainic acid injection. At first, the amplitude of the spikes was very low and augmented gradually. The first limbic seizure was triggered 30-90 min after injection. These limbic seizures lasted 5-S h and were fol-

lowed by the appearance of interictal discharges. In our experiment under pentobarbital anesthesia, the course after microinjection of kainic acid was quite similar, but slowly progressive compared with non-anesthetized cats. The hydrogen clearance method is widely used in regional cerebral blood flow studies. For measurement of intercompartmental diffusion, the errors are greatest when the electrode is within 2 mm of another tissue compartment”‘. In this experiment, we measured regional blood flow of amygdala, hippocampus and cerebral cortex. The smallest region of the three is the amygdala, its diameter being about 5 mm. The platinum needle electrode is sited at the center. However, the diameter of our electrode (0.3 mm) is larger than that (0.075 mm) of Halsey et al.“‘. We must take into account that the diffusion effect of the present study is somewhat larger than that found by Halsey et al. In the present study, rCBF was measured in kainic acid-induced limbic seizures by means of the hydrogen clearance method. In stages 1.11 and IV, stable hydrogen clearance curves were observed. But during stage III, each seizure lasted only 20-40 set and the seizure recurred frequently with an interval of lo-50 sec. Therefore, bi-exponential curves were analyzed and rCBF value was calculated with concurrent monitoring of electroencephalogram. Consequently, the rCBF measured during this special stage is not representative of the rCBF occurring during the seizure. Because the hydrogen clearance method is unable to analyze repeating brief seizures within a period of 2 min, further investigations should be carried out in

order to measure true rCBF during such a brief seizure. The value of baseline rCBF in the cortex in our experiment is lower than that published in other report?‘. Our experiment was carried out under mild pentobarbital anesthesia, which probably explains the low perfusion of the cortex in the present study. Functional activity in the local cerebral tissue is closely coupled to local energy metabolism, and rCBF normally varies in direct proportion to the rate of glucose metabolism’” and cerebral oxygen c~~~lsurnption~~.It is well known that regional cerebral metabolism and regional cerebral blood flow increase tremendously during seizure, due to the excessive functional neuronal activity”.“~“.‘h. This relationship between rCBF and seizure is amply investigated, particularly in focal cortical epilepsy. In clinical studies, utilizing the “jXe clearance methodi4,“’ and single photon emission tomography’.‘“. an increase of rCBF in the epileptic focus has been demonstrated during the ictal state. Kuhl et al. “, using PECT. showed that cerebral blood perfusion of epileptic focus increased during the ictal state; but the extent of the increase was smaller than that of the increase in regional cerebral metabolism of the focus. In an experimental study, increases in rCBF and regional cerebral metabolism were reported in the penicillin-induced epileptic focush.‘i.75~ic’.Heiss et al.” demonstrated that the increase in focal flow was significantly correlated with the change in firing rate of the neurons. As far as we are aware, there has been no report which demonstrates a relationship between rCBF and seizure activity of a deeply situated focus. The present study is the first experiment to demonstrate changes of rCBF in the region w-here seizures propagated from the focus under concurrent monitoring by EEG. In this experiment. rCBF of the left amygdala, the primary focus, increased to about twice the control value with the development of multiple spikes. This finding is in accordance with that of previous reports of focal cortical seizures4.i4.1”.2y. The experiment further showed that rCBF of the region where seizures propagated increased simultaneously with the propagation of the paroxysmal epileptiform

events. During limbic status epilepticus. the increase of rCBF in RA and LCx was smaller than that of the epileptic focus. Interestingly. electroencephalographic epileptic activities in these areas were less prominent than in the primary focus. On the other hand, there was no difference between the extent of increase in rCBF of the left hippocampus and that of the left amygdala. The spike discharges of the left hippocampus were as intense as those of the left amygdala. This showed that the extent of increase in rCBF was similar in areas ot similar spike discharge intensity, whichever area was the primary focus or the area where the seizure propagated. Accordingly one can state that the area with a marked increase in rCBF during seizure is not always the site of the epileptic focus. In human cases, Engel et al.” dem~?nstrated that an ictal pattern reflected the spread of epileptic discharge to those brain areas involved in the ictal behavior and was not reliable for identifying the site of ictal origin by PECT study. Our results support this observation. The change in rCBF and cerebral metabolism of the epileptic focus during interictat state has been a matter of controversy. Using “C-deoxyglucose audoradiography in penicillin-induced cortical focal seizures in rats, Collinsi demonstrated that glucose metabolism was increased with interictal spikes. Baldy-Moulinier et al.’ reported that interictal neuronal hyperactivities were accompanied by an increase in cerebral metab~~lism and cerebral blood flow. The hyperperfusion during the interictal state was demonstrated by Hougaartl ct al.” and Sakai et al.“‘. On the other hand. there have been some reports which demonstrated hypometnbolism and hypoperfusion during the intcrictal phase, however. most of these were human studiesj.“.‘~.‘X.“.Kuhl ct al, I7 dein~~nstrated a decrease in local cerebral metabolic rate of glucose during the interictal state and a slight decrease in cerebral perfusion in a human study. In the explanation of the discrepancy in these reports, Kuhl en~ph~~sized the variability of cerebral metabolism and perfusion during interictal state in these human and exl~erimental epileptic foci. The interictal state was related to the difference in numbers of neuronal elements participating in the generation of interictal spike activity in these very different types of ep-

267 ileptic foci. In penicillin-induced seizures, over 90% of cortical neurons participated in the interictal spike discharge*‘, whereas extremely few elements were involved in generating interictal spikes in the epileptic focus in humans”. In our experiment, rCBF of the epileptic focus (left amygdala) increased slightly but not significantly during the interictal phase (stage IV) in spite of frequent interictal discharges occurring in EEG. This finding is of relevance to the observations made in human epileptic focus by Kuhl et

al.“. Further metabolic study of this kainic acidinduced limbic seizure should be made, in order to clarify the relationship between rCBF and metabolism of the epileptogenic focus during the interictal period.

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seizures

in

47 (1975) Xi -96.

Effect of blood pressure in nonischemic lX(lYhX)h13-621.

ccrchral

on blood

flow m is.

cortex.

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