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The visual evoked potential during development of focal epilepsy
Journal ol the Neurological Sciences, 1982, 53 : 217 224 Elsevier Biomedical Press
217
T H E VISUAL E V O K E D P O T E N T I A L D U R I N G D E V E L O P M E N T OF FOCAL EPILEPSY
A R T H U R D. ROSEN and A N N E H. REMMES
Department Of Neurolo,ev, School ql' Medicine, Stale University o f New York, Stony Brook, N Y 11794 ~U.,S'.A.) (Received 23 February, 1981) ( Revised, received 30 June, 1981 ) (Accepted 8 July, 1981)
SUMMARY
Using the intracortical hemoglobin model for focal epilepsy, changes in the visual evoked potential were evaluated during epileptogenesis in guinea pigs. The amplitude of the late components of the evoked potential exhibited a transient increase in all animals during the first few weeks and, 1½ months later, a second sustained increase was seen in 41°o . In 71'~'Jo of these this sustained increase preceded, by 1-2 weeks, photic induced focal spike activity. The late components of the visual evoked potential reflect the same excitability state which is responsible for focal epileptogenesis in visual cortex and may be useful in predicting the development of seizures following head trauma.
INTRODUCTION
Focal epilepsy may be considered to represent the altered excitability of a limited group of cortical neurons. Such a group of cells exhibit "spontaneous" epileptic activity when local conditions are optimal for such activity or require an extrinsic trigger to initiate such activity which can then be sustained by local factors. In either situation, structures which have a normal role in CNS function behave in a manner we term pathological. Of particular interest is the transition from normal to pathological behavior of the population of cells constituting the developing epileptogenic focus.
Address for reprints : Arthur D. Rosen, Department of Neurology, Health Sciences Center, Slate University of N.Y., Stony Brook, NY 11794, U,S.A. 0022-510X/82/0000-0000/$02.75 © Elsevier Biomedical Press
218 Evaluation of this functional transition presumes a relatively constant population size. The usual agents employed for establishing chronic epileptogenic foci produce significant neuronal loss at the site of application. Cobalt produces severe localized necrosis (Dow et al. 1962; Finch and Beatty 1976). Alumina cream results in significant neuronal loss and gliosis (Stercova 1966). An acute necrotic process follows injection of both tungstic acid (Black et al. 1967) and ionic iron (Witlmore et al. 1978). Freezing lesions are associated with a hemorrhagic necrosis (Rosomoff et al. 1965). The recent demonstration that free hemoglobin is an effective epileptogenic agent (Rosen and Frumin 1979) without producing significant neuronal loss surrounding the injection site, makes this agent well suited to study the changes in neuronal behavior during the development of tbcal epileptogenesis. The value of the visual evoked response (VEP) in the assessment of patients with epilepsy is controversial (Cernacek and Ciganek 1962; Broughton et al. 1969). The present study was carried out to investigate changes in the VEP during the development of focal epilepsy, under conditions where the population of cells involved in epileptogenesis remained relatively constant. The purpose of this study was to attempt to identify changes in specific components of the VEP which might prove useful in predicting the development of seizures following nonprogressive cerebral lesions. METHODS Sixteen young adult guinea pigs (225-350 g) were used in the present study. The animals were anesthetized with pentobarbital (5 mg/100 g body weight, i.p.). Using clean surgical technique, 0.6 mm holes were drilled through the skull over both occipital poles and over the posterior portion of the frontal sinus. A solution of purified bovine hemoglobin in saline (13 g/100 ml) was prepared a n d placed in a microinjection syringe fitted with a 30-gauge needle. Injection into the left striate cortex was carried out with the aid of a dissecting microscope. The needle was inserted 1.5 mm below the dura and 10 #1 of solution injected over a 2-rain period and the needle removed. Some leakage of the injected material was frequently seen after withdrawal of the needle. Stainless steel screws were threaded into the holes to a depth just sufficient to reach the inner table. The screws were wired to a small transistor socket which was firmly affixed to the skull with dental acrylic cement. The scalp was closed with silk sutures and the animal permitted to recover. Recordings of spontaneous cortical activity (ECoG) and visual evoked responses were made daily for 1 week, beginning on the first post-operative day, and twice weekly thereafter. Animals were maintained for periods of up to 19 weeks and then killed for histological verification of the extent of the lesions. All recording sessions were carried out on awake animals, at the same time of day (+ 1 hour) and in the same manner. ECoGs were recorded on. a Grass polygraph with a bandpass of 0.3-75 Hz and, simultaneously, on an FM tape system. Left and right occipital electrodes were referenced to a common frontal sinus electrode. Photic stimuli were presented to both eyes from a stimulator set
219 for maximum intensity and maintained at a distance of one meter. Animals were positioned to assure constant lull-field illumination. ECoGs and VEPs obtained showed no evidence of contamination with either eye movement artifact or the electroretinogram. Off-line analysis of the averaged evoked responses was carried out for 100 successive, spike free, events (2/s) using a PDP 8-e computer. Data was sampled at 2,048 Hz in the 250 ms post-stimulus period. RESULTS
Histolog~y Microscopic examination of the injection sites usually revealed a well defined intracortical lesion. This consisted of a small cavity, 0 . ~ 0 . 6 mm in diameter. involving all cortical layers but not extending to the subcortical white matter. This cavity was in communication with the subarachnoid space, presumably via the original needle tract. Scattered hemosiderin-laden macrophages were found in the cavity wall and some gliosis was evident. Surrounding neurons appeared normal in number and morphology. Fig. 1 shows a representative lesion in an animal killed 10 weeks post-operatively. Tissue processed with a ferrocyanide reaction for iron stained the material within the macrophages but failed to demonstrate any stainable iron within the neurons. In two animals, no cortical cavity could be found. In these animals the only evidence of a cortical injection were a few hemosiderin-
#
Fig. 1, Coronal section through injection site. 10-week-old lesion• Hemosiderin-laden macrophages line caxitywall. N i s s l ' s t a i n , x 100.
220 laden macrophages in the deeper cortical layers. The presence of a cavity, its size or the amount of hemosiderin, could not be correlated with observed ECoG spike activity or changes in the VEP.
Electrocortical activity Spontaneous ECoG spiking appeared during the second week in 5 animals and persisted for an averaged duration of 8.4 days tSD = 2.3 days). Spikes clearly originated from the left side, though contralateral projection was occasionally seen. Waveform and amplitude remained relatively constant from one recording session to another. Spike frequency reached a maximum of 6-40/min within ~ few days of onset and declined thereafter In 4 of the 5 animals exhibiting spontaneous spiking, photic triggered spikes could be elicited which had the same waveform and amplitude characteristics as the spontaneous spikes. In two animals which did not exhibit spontaneous spiking, spikes could be triggered by photic stimulation. In all animals with photic induced spiking, the 2 s stimuli usually elicited only 3 8 spikes and thereafter was ineffective. Three weeks post-operatively, only rare spikes were noted. In 5 animals (2 from the spontaneous spiking group, I t¥om the photic induced group and 2 from the non-spiking group) consistent photic triggered spikes could be elicited approximately 1½ months post-operatively and persisted until the animals were killed. Fig. 2 illustrates the ECoG changes tn one animal.
IDAY
1
__t Fig. 2. Serial ECoGs and corresponding averaged visual evoked potentials. Calibration for ECoG: 2 s, 300 #V. Negative up. Calibration for VEP: 50 ms. Positive up.
221 No obvious behavioral manifestations of seizure activity were observed in any of the animals.
l'i~ual evoked potential The waveform of the averaged VEP was similar in all animals. In general form it consisted of 2-4 biphasic oscillations in the first 125 ms after the stimulus (early components) followed by 1 2 slower biphasic oscillations in the next 125 ms (late components). The most readily identifiable early component was a positive wave with a peak at 50 55 ms, while the most consistent late component was a negative wave with a peak at 150 175 ms. Serial measurements were made of the amplitude of these components in all animals. Measurements were made from baseline to peak and expressed as percentage change from the amplitude of that component on the first post-operative day. The averaged VEP recorded from the right occipital area, had a maximum amplitude change for either component, of less than 40";>. The relatively constant nature of this response verified uniformity of stimulus presentation and .justified the longitudinal comparison of simultaneously recorded responses from the left occipital area, where significant cyclical changes in both early and late components were found. Evaluation of the averaged VEP revealed that in 5 animals the early component was diminished in amplitude in the first 5 days post-operatively, with a return to normal over the next 1-2 weeks. In 9 animals the early component increased in amplitude, reaching maximum in 6 days (SD = 4.5 days) and declining to normal over the next 2 weeks. In the remaining 2 animals, no significant early component change was seen. In every animal there was an increase in amplitude of the late component of the left VEP, with maximum amplitudes reached in 9.5 days (SD = 3.0 days). The amplitude was quite variable thereafter but declined gradually over several weeks. In 7 animals a second increase in amplitude of the
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Fig. 3. Same animal as thai in Fig. 2. Serial amplitude changes in VEP recorded from left and rieht occipital regions. Component plotted is thelate negativc wave with a peak at 150 175 ms after photic stimulation. Insert shows VEP from left side at 9 days with baseline to peak measurement indicated.
222
Fig. 4. Single photic induced spike beginning after evoked cortical potential Stimulus at ot~set of trace. Calibration: 50 ms, 125/~V. Positive up.
VEP late component was seen. The average time to occurrence of this second increase was 49 days (SD = 18.9 days) and it persisted until the animal was killed. A typical example of the changes in the VEP late component is shown in Fig. 3. All 5 of the animals which manifest delayed photic induced ECoG spikes exhibited the second increase in VEP late component amplitude with the VEP change preceding the ECoG spiking by 1-2 weeks. Two of the 7 animals who developed a second increase in the VEP late component never had ECoG spikes. Examination of individual photic induced spikes on a fast time line (Fig. 4) demonstrated a biphasic wave beginning 90-125 ms after the stimulus and lasting approximately 75 ms. The peak amplitude was usually 140-160 ms alter the stimulus and was of a polarity opposite that of the late component of the VEP expected to be seen at that time. DISCUSSION
Significant differences in the frequency and duration of focal spike activity following intracortical hemoglobin injection were found in the present study compared with a recent report (Rosen and Frumin 1979L Inasmuch as the injection technique and histopathology were identical in both studies, we can only conclude that the difference is related to the species of animal used. The previous study, with an 89",~, incidence of persistent focal spikes, was carried oul on young adull rats while the present study, using young adult guinea pigs, yielded an incidence of early transient focal spikes of 44°~j, and of late persistent focal spikes of 31",,. Species differences for seizure susceptibility is well documented [Wilder e~ al. 1968: Ward 1972) and must be taken into account when assessing the usefulness of any model of epilepsy. For the purpose of the present study, the hemoglobin-guinea pig model proved quite satisfactory. The precise cellular basis for the VEP is largely hypothetical but it is generally accepted that the response reflects synchronous afferent and efferent fiber activity as well as summated post-synaptic potentials of cortical neurons (Creutzfeldt and
223 Kuhnt 1967). The earliest components are associated with the arrival of specific afferent input and the later components with postsynaptic excitatory and inhibitory mechanisms. In this study the most prominent and consistent changes in the VEP during epileptogenesis were in the late components, reflecting abnormalities in cortical elements rather than in the thalamocortical projection. If the epileptogenic agent used produced significant cell death, those changes would have been overshadowed by a marked attenuation of the VEP (Finch and Beatty 1976). Comparable late component amplitude increases have been reported in human photosensitive epilepsy (Broughton et al. 1969) and although exceptions to this have been described (Cernacek and Ciganek 1962) these probably reflect a difference in the underlying pathological process. In the present study, the abrupt appearance of spikes of constant amplitude and waveform suggests that a critical number of neuronal elements is necessary for epileptogenesis. This view is substantiated by the recent demonstration of a minimal volume of cortical tissue necessary to maintain paroxysmal activity (Reichenthal and Hocherman 1977). Although it appears that the VEP late coinponent amplitude reflects the same excitability phenomenon which is responsible for ECoG spikes, the suggestion that the early spikes in photo-sensitive epilepsy are augmented late components of the VEP (Hishkawa et al. 1967) is not supported by the present study. The polarity difference between the spike and the VEP indicate generation by different cortical elements. The relative preservation of the evoked response during electrical seizures in striate cortex (Vastola and Rosen 1960) is additional evidence supporting this view. Histopathologically, the lesions produced by intracortical injection of hemoglobin are very similar to those seen in post-traumatic epilepsy (Payan et al. 1970). In a large series of patients with head trauma (Evans 1963), early seizures occurred in 30". of those with intracranial hematoma and in 7". of those without hematoma. Patients with very early post-traumatic seizures were not especially predisposed to the development of late epilepsy. A parallel situation exists in the present study where the presence of ECoG spikes in the early post-operative period was not a useful predictor of recurrent epileptogenic activity, having a rate of 57", for lidse positives and 22<'o ti)r false negatives. The late components of the VEP. on the other hand. were increased in every animal with delayed ECoG spikes and therefore had only a 2t)",, false positive and 0",, t:alse negative rate. Those animals with increased VEP late components but without observed ECoG spiking might not have been followed for an adequate period of time. The present study suggests that serial evaluation of the evoked cortical response would prove useful in assessing patients at risk for development of a seizure disorder liHlowing head trauma. In addition to the visual evoked response. auditory and somatosensory responses would be expected to provide further information concerning the potential for epileptogenesis in that they reflect excitability changes in a larger cortical area.
224 REFERENCES Black, R, G., J. Abraham and A.A. Ward, Jr. (1967) The preparation of tungstic acid gel and its use in the production of experimental epilepsy, Epilepsia (Amst.), 8: 58-63. Brougbton, R., K.H. Meier-Ewart and M. Ebe (1969) Evoked visual, somatosensory and retinal potentials in photosensitive epilepsy, Electroenceph. clin. Neurophysiol., 27: 373-386. Cernacek, J. and L. Ciganek (1962) The cortical electroencephalographic response to light stimulation in epilepsy, Epilepsia (Amst.), 3: 304-314. Creutzfeldt, O. D, and U. Kuhnt (1967) The visual evoked potential --- Physiological, development and clinical aspects, Electroenceph. clin. Neurophysiol., Suppl. 26: 2%41. Dow, R.S., A. Fernandez-Guardiota and E. Manni (1%2) The production of experimenlal cobalt epilepsy in the rat, Electroenceph. clin. Neurophysiol., 14: 399--407. Evans, J.H. (1963) The significance of early post-traumatic epilepsy, Neurology (Mmneap.), 13: 207-212. Finch, D. M. and J. Beatty (1976) Visual evoked potentials during the development of a spiking cobalt focus in rat neocortex, Electroeneeph. clin. Neurophysiol., 41:137-152. Hishkawa, J., J. Yamamoto, E. Furuya. Y. Yamada, K. Miyazaki and Z. Kaneko (t967) Photosensitive epilepsy - - Relationships between the visual evoked response and the epileptilbrm discharges induced by intermittent photic stimulation, Elcctroenceph. olin. Neurophysiol.. 23 : 320 334. Payan, H., M. Toga and M. Berard-Badier (1970) The pathology of post-traumatic epilepsies. Epilepsia (Amst.), l I : 81-94. Reichenthal, E. and S. Hocherman (1977) The critical cortical area for development ¢~f penicillininduced epilepsy, Electroenceph. clin. Neurophysiol., 42: 248--251. Rosen, A. D. and N.V. Frumin (1979) Focal epileptogenesis after intracortical hemoglobin injection. Exp. Neurol., 66: 277-284. Rosomoff, H. L., R.A. Clasen, R. Hartstock and J. Bebin (1965) Brain reaction to experimental injury after hypothermia, Arch. Neurol. (Chic.), 13 : 337-345. Stercova, A. (1966) Dynamics of neurohistological changes in an epileptogenic focus produced by alumina cream in the rat. In : Z. Servit (Ed.), Comparative and Cellular Patho-physiolo~,~v o1' Epilepsl, Excerpta Medica, Amsterdam, pp. 247-257. Vastola, E. F. and A. Rosen (1960)Effect ot seizures in visual cortex on response to geniculate stimulation. Amer. J. Physiol., 199: 683-687. Ward, A.A., Jr (1972) Topical convul~nt metals. In: D.P. Purpura, J.K. Penry, I).B. Tower, D. M. Woodbury and R. D. Walter (Eds.); Experimental Models of Epilep,yv, Raven Pressl New York, NY, pp. 13~35. Wilder, B.J., R.L. King and R.P. Schmidt (1968) Comparative study of secondary epileptogenesis, Epilepsia (Amst.), 9: 275-289. Willmore, L.J., G.W. Sypert and J.B. Munson (1978) Recurrent seizures induced by cortical iron injection A model of post-traumatic epilepsy, Ann. Neurot., 4: 309-336.
217
T H E VISUAL E V O K E D P O T E N T I A L D U R I N G D E V E L O P M E N T OF FOCAL EPILEPSY
A R T H U R D. ROSEN and A N N E H. REMMES
Department Of Neurolo,ev, School ql' Medicine, Stale University o f New York, Stony Brook, N Y 11794 ~U.,S'.A.) (Received 23 February, 1981) ( Revised, received 30 June, 1981 ) (Accepted 8 July, 1981)
SUMMARY
Using the intracortical hemoglobin model for focal epilepsy, changes in the visual evoked potential were evaluated during epileptogenesis in guinea pigs. The amplitude of the late components of the evoked potential exhibited a transient increase in all animals during the first few weeks and, 1½ months later, a second sustained increase was seen in 41°o . In 71'~'Jo of these this sustained increase preceded, by 1-2 weeks, photic induced focal spike activity. The late components of the visual evoked potential reflect the same excitability state which is responsible for focal epileptogenesis in visual cortex and may be useful in predicting the development of seizures following head trauma.
INTRODUCTION
Focal epilepsy may be considered to represent the altered excitability of a limited group of cortical neurons. Such a group of cells exhibit "spontaneous" epileptic activity when local conditions are optimal for such activity or require an extrinsic trigger to initiate such activity which can then be sustained by local factors. In either situation, structures which have a normal role in CNS function behave in a manner we term pathological. Of particular interest is the transition from normal to pathological behavior of the population of cells constituting the developing epileptogenic focus.
Address for reprints : Arthur D. Rosen, Department of Neurology, Health Sciences Center, Slate University of N.Y., Stony Brook, NY 11794, U,S.A. 0022-510X/82/0000-0000/$02.75 © Elsevier Biomedical Press
218 Evaluation of this functional transition presumes a relatively constant population size. The usual agents employed for establishing chronic epileptogenic foci produce significant neuronal loss at the site of application. Cobalt produces severe localized necrosis (Dow et al. 1962; Finch and Beatty 1976). Alumina cream results in significant neuronal loss and gliosis (Stercova 1966). An acute necrotic process follows injection of both tungstic acid (Black et al. 1967) and ionic iron (Witlmore et al. 1978). Freezing lesions are associated with a hemorrhagic necrosis (Rosomoff et al. 1965). The recent demonstration that free hemoglobin is an effective epileptogenic agent (Rosen and Frumin 1979) without producing significant neuronal loss surrounding the injection site, makes this agent well suited to study the changes in neuronal behavior during the development of tbcal epileptogenesis. The value of the visual evoked response (VEP) in the assessment of patients with epilepsy is controversial (Cernacek and Ciganek 1962; Broughton et al. 1969). The present study was carried out to investigate changes in the VEP during the development of focal epilepsy, under conditions where the population of cells involved in epileptogenesis remained relatively constant. The purpose of this study was to attempt to identify changes in specific components of the VEP which might prove useful in predicting the development of seizures following nonprogressive cerebral lesions. METHODS Sixteen young adult guinea pigs (225-350 g) were used in the present study. The animals were anesthetized with pentobarbital (5 mg/100 g body weight, i.p.). Using clean surgical technique, 0.6 mm holes were drilled through the skull over both occipital poles and over the posterior portion of the frontal sinus. A solution of purified bovine hemoglobin in saline (13 g/100 ml) was prepared a n d placed in a microinjection syringe fitted with a 30-gauge needle. Injection into the left striate cortex was carried out with the aid of a dissecting microscope. The needle was inserted 1.5 mm below the dura and 10 #1 of solution injected over a 2-rain period and the needle removed. Some leakage of the injected material was frequently seen after withdrawal of the needle. Stainless steel screws were threaded into the holes to a depth just sufficient to reach the inner table. The screws were wired to a small transistor socket which was firmly affixed to the skull with dental acrylic cement. The scalp was closed with silk sutures and the animal permitted to recover. Recordings of spontaneous cortical activity (ECoG) and visual evoked responses were made daily for 1 week, beginning on the first post-operative day, and twice weekly thereafter. Animals were maintained for periods of up to 19 weeks and then killed for histological verification of the extent of the lesions. All recording sessions were carried out on awake animals, at the same time of day (+ 1 hour) and in the same manner. ECoGs were recorded on. a Grass polygraph with a bandpass of 0.3-75 Hz and, simultaneously, on an FM tape system. Left and right occipital electrodes were referenced to a common frontal sinus electrode. Photic stimuli were presented to both eyes from a stimulator set
219 for maximum intensity and maintained at a distance of one meter. Animals were positioned to assure constant lull-field illumination. ECoGs and VEPs obtained showed no evidence of contamination with either eye movement artifact or the electroretinogram. Off-line analysis of the averaged evoked responses was carried out for 100 successive, spike free, events (2/s) using a PDP 8-e computer. Data was sampled at 2,048 Hz in the 250 ms post-stimulus period. RESULTS
Histolog~y Microscopic examination of the injection sites usually revealed a well defined intracortical lesion. This consisted of a small cavity, 0 . ~ 0 . 6 mm in diameter. involving all cortical layers but not extending to the subcortical white matter. This cavity was in communication with the subarachnoid space, presumably via the original needle tract. Scattered hemosiderin-laden macrophages were found in the cavity wall and some gliosis was evident. Surrounding neurons appeared normal in number and morphology. Fig. 1 shows a representative lesion in an animal killed 10 weeks post-operatively. Tissue processed with a ferrocyanide reaction for iron stained the material within the macrophages but failed to demonstrate any stainable iron within the neurons. In two animals, no cortical cavity could be found. In these animals the only evidence of a cortical injection were a few hemosiderin-
#
Fig. 1, Coronal section through injection site. 10-week-old lesion• Hemosiderin-laden macrophages line caxitywall. N i s s l ' s t a i n , x 100.
220 laden macrophages in the deeper cortical layers. The presence of a cavity, its size or the amount of hemosiderin, could not be correlated with observed ECoG spike activity or changes in the VEP.
Electrocortical activity Spontaneous ECoG spiking appeared during the second week in 5 animals and persisted for an averaged duration of 8.4 days tSD = 2.3 days). Spikes clearly originated from the left side, though contralateral projection was occasionally seen. Waveform and amplitude remained relatively constant from one recording session to another. Spike frequency reached a maximum of 6-40/min within ~ few days of onset and declined thereafter In 4 of the 5 animals exhibiting spontaneous spiking, photic triggered spikes could be elicited which had the same waveform and amplitude characteristics as the spontaneous spikes. In two animals which did not exhibit spontaneous spiking, spikes could be triggered by photic stimulation. In all animals with photic induced spiking, the 2 s stimuli usually elicited only 3 8 spikes and thereafter was ineffective. Three weeks post-operatively, only rare spikes were noted. In 5 animals (2 from the spontaneous spiking group, I t¥om the photic induced group and 2 from the non-spiking group) consistent photic triggered spikes could be elicited approximately 1½ months post-operatively and persisted until the animals were killed. Fig. 2 illustrates the ECoG changes tn one animal.
IDAY
1
__t Fig. 2. Serial ECoGs and corresponding averaged visual evoked potentials. Calibration for ECoG: 2 s, 300 #V. Negative up. Calibration for VEP: 50 ms. Positive up.
221 No obvious behavioral manifestations of seizure activity were observed in any of the animals.
l'i~ual evoked potential The waveform of the averaged VEP was similar in all animals. In general form it consisted of 2-4 biphasic oscillations in the first 125 ms after the stimulus (early components) followed by 1 2 slower biphasic oscillations in the next 125 ms (late components). The most readily identifiable early component was a positive wave with a peak at 50 55 ms, while the most consistent late component was a negative wave with a peak at 150 175 ms. Serial measurements were made of the amplitude of these components in all animals. Measurements were made from baseline to peak and expressed as percentage change from the amplitude of that component on the first post-operative day. The averaged VEP recorded from the right occipital area, had a maximum amplitude change for either component, of less than 40";>. The relatively constant nature of this response verified uniformity of stimulus presentation and .justified the longitudinal comparison of simultaneously recorded responses from the left occipital area, where significant cyclical changes in both early and late components were found. Evaluation of the averaged VEP revealed that in 5 animals the early component was diminished in amplitude in the first 5 days post-operatively, with a return to normal over the next 1-2 weeks. In 9 animals the early component increased in amplitude, reaching maximum in 6 days (SD = 4.5 days) and declining to normal over the next 2 weeks. In the remaining 2 animals, no significant early component change was seen. In every animal there was an increase in amplitude of the late component of the left VEP, with maximum amplitudes reached in 9.5 days (SD = 3.0 days). The amplitude was quite variable thereafter but declined gradually over several weeks. In 7 animals a second increase in amplitude of the
+35O #
+300
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o +250 _ _ ~ . _ "
g u
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+150
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0
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+100 +50
•
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/
o
/r
i
/
RIGHT ~,.I
./'\/" •
\--%.~
50 0
rO
20
,30
,40
50 60 Days
70
80
90
I00
PI0
Fig. 3. Same animal as thai in Fig. 2. Serial amplitude changes in VEP recorded from left and rieht occipital regions. Component plotted is thelate negativc wave with a peak at 150 175 ms after photic stimulation. Insert shows VEP from left side at 9 days with baseline to peak measurement indicated.
222
Fig. 4. Single photic induced spike beginning after evoked cortical potential Stimulus at ot~set of trace. Calibration: 50 ms, 125/~V. Positive up.
VEP late component was seen. The average time to occurrence of this second increase was 49 days (SD = 18.9 days) and it persisted until the animal was killed. A typical example of the changes in the VEP late component is shown in Fig. 3. All 5 of the animals which manifest delayed photic induced ECoG spikes exhibited the second increase in VEP late component amplitude with the VEP change preceding the ECoG spiking by 1-2 weeks. Two of the 7 animals who developed a second increase in the VEP late component never had ECoG spikes. Examination of individual photic induced spikes on a fast time line (Fig. 4) demonstrated a biphasic wave beginning 90-125 ms after the stimulus and lasting approximately 75 ms. The peak amplitude was usually 140-160 ms alter the stimulus and was of a polarity opposite that of the late component of the VEP expected to be seen at that time. DISCUSSION
Significant differences in the frequency and duration of focal spike activity following intracortical hemoglobin injection were found in the present study compared with a recent report (Rosen and Frumin 1979L Inasmuch as the injection technique and histopathology were identical in both studies, we can only conclude that the difference is related to the species of animal used. The previous study, with an 89",~, incidence of persistent focal spikes, was carried oul on young adull rats while the present study, using young adult guinea pigs, yielded an incidence of early transient focal spikes of 44°~j, and of late persistent focal spikes of 31",,. Species differences for seizure susceptibility is well documented [Wilder e~ al. 1968: Ward 1972) and must be taken into account when assessing the usefulness of any model of epilepsy. For the purpose of the present study, the hemoglobin-guinea pig model proved quite satisfactory. The precise cellular basis for the VEP is largely hypothetical but it is generally accepted that the response reflects synchronous afferent and efferent fiber activity as well as summated post-synaptic potentials of cortical neurons (Creutzfeldt and
223 Kuhnt 1967). The earliest components are associated with the arrival of specific afferent input and the later components with postsynaptic excitatory and inhibitory mechanisms. In this study the most prominent and consistent changes in the VEP during epileptogenesis were in the late components, reflecting abnormalities in cortical elements rather than in the thalamocortical projection. If the epileptogenic agent used produced significant cell death, those changes would have been overshadowed by a marked attenuation of the VEP (Finch and Beatty 1976). Comparable late component amplitude increases have been reported in human photosensitive epilepsy (Broughton et al. 1969) and although exceptions to this have been described (Cernacek and Ciganek 1962) these probably reflect a difference in the underlying pathological process. In the present study, the abrupt appearance of spikes of constant amplitude and waveform suggests that a critical number of neuronal elements is necessary for epileptogenesis. This view is substantiated by the recent demonstration of a minimal volume of cortical tissue necessary to maintain paroxysmal activity (Reichenthal and Hocherman 1977). Although it appears that the VEP late coinponent amplitude reflects the same excitability phenomenon which is responsible for ECoG spikes, the suggestion that the early spikes in photo-sensitive epilepsy are augmented late components of the VEP (Hishkawa et al. 1967) is not supported by the present study. The polarity difference between the spike and the VEP indicate generation by different cortical elements. The relative preservation of the evoked response during electrical seizures in striate cortex (Vastola and Rosen 1960) is additional evidence supporting this view. Histopathologically, the lesions produced by intracortical injection of hemoglobin are very similar to those seen in post-traumatic epilepsy (Payan et al. 1970). In a large series of patients with head trauma (Evans 1963), early seizures occurred in 30". of those with intracranial hematoma and in 7". of those without hematoma. Patients with very early post-traumatic seizures were not especially predisposed to the development of late epilepsy. A parallel situation exists in the present study where the presence of ECoG spikes in the early post-operative period was not a useful predictor of recurrent epileptogenic activity, having a rate of 57", for lidse positives and 22<'o ti)r false negatives. The late components of the VEP. on the other hand. were increased in every animal with delayed ECoG spikes and therefore had only a 2t)",, false positive and 0",, t:alse negative rate. Those animals with increased VEP late components but without observed ECoG spiking might not have been followed for an adequate period of time. The present study suggests that serial evaluation of the evoked cortical response would prove useful in assessing patients at risk for development of a seizure disorder liHlowing head trauma. In addition to the visual evoked response. auditory and somatosensory responses would be expected to provide further information concerning the potential for epileptogenesis in that they reflect excitability changes in a larger cortical area.
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