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Changes in cerebral blood flow velocities during childhood absence seizures
ELSEVIER
Changes in Cerebral Blood Flow Velocities During Childhood Absence Seizures R o b e r t o D e S i m o n e , M D * * , M a u r o Silvestrini, M D * * , M a r i a G r a z i a M a r c i a n i , M D * * , a n d P a o l o C u r a t o l o , M D **
A simultaneous recording of mean flow velocity in the right middle cerebral artery by transcranial Doppler ultrasonography and electroencephalographic activity was performed in 5 children with multiple daily typical absence seizures. Twenty-eight absence episodes were recorded. Mean flow velocity increased gradually a few seconds before the clinical and electroencephalographic manifestations of each seizure and reached the maximum values (range of increase: 25.5-42.8% with respect to baseline) within 2-3 seconds from their onset. This increase was then followed by a fast reduction in flow velocity, with the lowest levels (range of decrease: 30.8-44.0% with respect to baseline) recorded within 4-6 seconds from the end of each absence seizure. These findings suggest that changes in cerebral blood flow and activity are quite complex during absence seizures and that they do not fully correlate with clinical and electroencephalographic manifestations. © 1998 by Elsevier Science Inc. All rights reserved. De Simone R, Silvestrini M, Marciani MG, Curatolo P. Changes in cerebral blood flow velocities during childhood absence seizures. Pediatr Neurol 1998; 18:132-135.
Introduction Studies of cerebral blood flow (CBF) and metabolism with positron emission tomography (PET) have added valuable information to our knowledge of the human epilepsies [1]. The most interesting data refer to the possibility of identifying regions of interictal cerebral dysfunction, usually revealed as hypometabolism and hypoperfusion, which could have practical implications from a diagnostic, as well as a therapeutic, point of view [2,3]. The possibility of using PET to study changes in cerebral activity during the ictal phase of epilepsy is rather
From the Clinics of *Neurology and ~Pediatric Neurology; Tor Vergata; University of Rome; and *IRCCS S. Lucia; Rome, Italy.
132
PEDIATRIC NEUROLOGY
Vol. 18 No. 2
limited. The short half-life of positron emitting isotopes greatly restricts investigation time. With the exception of those times when seizures occur fortuitously either during or soon after tracer injection, PET can study only provoked seizures. Moreover, with this technique, time resolution is low and a few minutes are required to detect changes in CBF and metabolism. The fact that metabolic and flussimetric data are not available at the same time as when clinical observation and electroencephalographic (EEG) recording are made prevents us from knowing the exact temporal sequence of changes in cerebral activity, including during the postictal phase. Therefore, pathophysiologic interest in these studies seems limited. The introduction of single photon emission computed tomography (SPECT) in the study of epilepsy is of some advantage because the isotopes used have a relatively long half-life. This, even with a lower spatial resolution, makes the technique more appropriate than PET for studying the ictal phase of epilepsy [4]. However, changes in regional CBF can be recorded with SPECT only for events lasting at least 10 s. This temporal resolution is not completely satisfactory when the clinical situation is evolving quickly and continuously, as it does in the case of an epileptic seizure. Transcranial Doppler ultrasonography (TCD) is a noninvasive technique that makes it possible to assess instantaneous changes in blood flow velocity in the large cerebral arteries that have been found to correlate reliably with changes in CBF [5,6]. The major disadvantage of TCD is its low spatial resolution. Changes in CBF investigated with this technique refer to the distribution territory of a large intracranial vessel. However, the possibility of having instantaneous information makes TCD particularly useful to monitor changes in cerebral functional status during rapid clinical events. In this study, we aimed to obtain information about changes in cerebral hemodynamics during spontaneous
Communication should be addressed to: Dr. Silvestrini; Clinica Neurologica; Universita' di Roma Tor Vergata; Ospedale S. Eugenio; P.le dell'Umanesimo 10; 00144; Roma, Italy. Received April 11, 1997; accepted July 22, 1997.
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(97)00165-3 • 0887-8994/98/$19.00
absence seizures and the interictal and postictal period by continuous r e c o r d i n g o f the intracerebral f l o w v e l o c i t y with T C D simultaneous with the E E G m o n i t o r i n g o f cerebral activity.
Patients and Methods Five children (I boy, 4 girls) aged 6 to 12 years with multiple daily typical absence seizures, based on clinical and EEG data, according to the classification of the International League against Epilepsy [7], were included in the study. Neurologic examination was normal; no child was under therapy. Informed consent was obtained from both parents and children. A recording of mean flow velocity (MFV) in the right middle cerebral artery by means of a MultidopX/TCD 7 (DWL Elektronische Systeme GmbH, Sipplingen, Germany) TCD instrument and of EEG activity by means of an eight-channel electroencephalograph (Vega 10, Esaote Biomedica, Florence, Italy) was performed for a mean period of 75 rain. One dual 2-MHz transducer, fitted on a headband and placed on the temporal bone window, was used to obtain a continuous measurement of flow velocity. The Doppler spectra were recorded for the entire period of each study. EEG results were recorded according to the international 10 to 20 system with collodium electrodes. No movements or other automatic activity were observed during our evaluation. Clinical and electric events were marked on the Doppler tracing by clicking on a computer mouse. Because each recorded seizure was of a different duration and MFV changes bad no univocal direction during the different recorded periods, it was not possible to perform an analysis of the difference in flow velocity among preictal, ictal, and postictal phases of each absence seizure. Therefore, we were limited to providing a qualitative description of the flow changes and of their correlation with the clinical and EEG findings. The percentage of MFV maximum increase or decrease refers to a single cardiac cycle and is calculated with respect to a basal value referring to a l-rain period recorded at a distance of at least 5 rain from a previous or a following absence. Data for statistical analysis consisted of the values (expressed in cm/s) of basal MFV and of maximum increase and decrease of MFV. A one-way analysis of variance with basal mean values, and values of maximum increase and decrease of MFV as repeated measures was used.
Results During our evaluation, a total o f 28 absence seizures w e r e observed. D u r a t i o n o f clinical and E E G findings during seizures ranged f r o m 5-7.5 seconds (mean +_ S.D., 6.28 -+ 0.9). No changes in respiratory activity or heart rate w e r e observed. T h e increase in f l o w velocity was gradual; it started 5-10 seconds b e f o r e onset o f the absence and reached the m a x i m u m level with respect to baseline within 2-3 seconds f r o m the onset of clinical and electric changes (range of percentage increase, 25.5-42.8%). T h i s increase was f o l l o w e d by an abrupt decrease in f l o w v e l o c i t y that started during the absence and reached the m i n i m u m value within 4-6 seconds f r o m the end of the crisis (range of percentage decrease, 30,8-44.0). The t i m e course of this last p h e n o m e n o n was quite short. In fact, the return to baseline levels occurred within about 15-20 seconds. Figure 1 depicts the f l o w v e l o c i t y pattern during one o f the recorded absences and the relative E E G finding. T h e values of m a x i m u m decrease of M F V w e r e significantly higher than basal M F V values (79.0 + 7.5 vs 53.7 + 7.8, P < 0.0001). A significant difference (P < 0.0001) was
Figure 1. Top: Flow velocity pattern in a middle cerebral artery during a typical absence seizure lasting 6 s. Baseline values were 42.5 cm/s; the maximum increase occurred 2 s after the onset of the seizure: 54.0 cl~s" (+27,5%). The increase of flow velocity was gradual and started about 5 s befi)re the e!ectroencephalographic and clinical changes. Values of flow velocity deereased during the final part of the absence seizure and reached the minimum value 4 s after its end: 28 cnu's (-34.1%). A return to values similar to baseline occurred in about 15 s. Bottom: Relative eleetroencephalographic f n d i n g showing a sequence of bilateral spikeand-wave complexes for 6 s.
also detected b e t w e e n values (33.6 +_ 5.6) and basal ones.
of maximum
decrease
Discussion T h e h a l l m a r k o f a t y p i c a l a b s e n c e s e i z u r e is the s u p p r e s s i o n o f m e n t a l f u n c t i o n to the p o i n t w h e r e r e s p o n s i v e n e s s , a w a r e n e s s , and m e m o r y are lost. T h e pathophysiology of childhood absence epilepsy remains u n c l e a r . R e c e n t f i n d i n g s h a v e p o s t u l a t e d that the prim a r y d i s t u r b a n c e is an a b n o r m a l e x c i t a b i l i t y o f the c o r t e x that interacts w i t h t h a l a m u s and b r a i n s t e m reticular s u b s t a n c e to p r o d u c e the c h a r a c t e r i s t i c ictal pattern. C o r t i c a l i n v o l v e m e n t in the d i s c h a r g e is also p r o v e d by i n c r e a s e d g l u c o s e m e t a b o l i s m , as i n d i c a t e d in P E T studies [1,8]. O u r results s u g g e s t that d u r i n g the o c c u r r e n c e o f a t y p i c a l a b s e n c e s e i z u r e , h e m o d y n a m i c cerebral c h a n g e s h a v e a p a r t i c u l a r pattern in t i m e that d o e s not f u l l y c o r r e l a t e w i t h the c l i n i c a l and E E G f i n d i n g s .
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The interpretation of these CBF changes requires a brief explanation of the functional significance of TCD. Because flow velocity in the large cerebral arteries is directly related to the diameter of the small resistance vessels [9], an increase in cerebral metabolism associated with neuronal activity causes an increase in flow velocity in the proximal portion of the artery by promoting a dilatation of the precapillary bed. On the contrary, a reduction in neural activity causes a reduction in flow velocity with the opposite mechanism [10]. Previous studies with emission tomography techniques described increased cerebral activity during absence [8]. This increase seems confirmed in our study in which more detailed information about the temporal course of changes in cerebral activity is provided. Moreover, the reduction in flow velocity at the end of the seizure adds another detail not described in PET and SPECT studies. The limited temporal resolution of these techniques can account for this apparent contrast because we recorded a reduction in flow velocity that is too short to be revealed with PET or even with SPECT. From a pathophysiologic point of view the most interesting finding that emerged from the present study is that changes in CBF appear to last longer than the clinical and EEG alterations of an absence seizure. Even if the TCD information can only suggest the occurrence of changes in cerebral functional activity, our data provide some insights into the metabolic functional status connected with an epileptic discharge. It seems that the increase in cerebral activation is a gradual phenomenon that starts and develops progressively toward a level at which a seizure occurs. This hyperactivity is then followed by a period of hypoactivity that starts during the final part of the seizure and goes on for some seconds after its end. This dual pattern of cerebral activity could result from the function of two major neurotransmission systems that regulate each other within the involved thalamocortical circuitry. The modulation of thalamocortical rhythmicity is mediated by 3,-aminobutyric acid-ergic interneurons within the cerebral cortex [1 1]. Identification of the exact functional mechanisms in this very intricate network is difficult. Our data suggest a diphasic pattern of the ground metabolic modifications. Thus the absence seizure does not seem to be provoked by the activation of a single neurotransmission pathway but rather by the excitatory and inhibitory action of several systems. The TCD pattern of increase and decrease of cerebral flow velocity suggests the existence of a feedback system that starts after the onset of the generalized discharge. The possibility that changes of MFV are mediated by neurogenic factors seems to be reasonably excluded by their time course. In particular the time interval between the onset of the electric discharge and the decrease of MFV is expected to be shorter if the latter was due to changes in vascular diameter mediated by neurogenic factors [ 12]. Our findings do not confirm the results of previous TCD studies in which a reduction in flow velocity was found
134 PEDIATRICNEUROLOGY Vol. 18 No. 2
during the ictal period of absences [13,14]. The reason fl)r this finding opposite to that described in the present study is not easy to determine. It is possible that the contrast is related to differences in the sensitivity of the equipment used in the recording of flow velocity or in the time intervals considered. In tact, as shown in our study, the hemodynamic changes before, during, and after a spontaneous absence happen very quickly, and the possibility of documenting them can be managed only with a system that has the maximum degree of temporal resolution. For the same reason, the hemodynamic values may be different based on the length of the time considered for calculating MFV. In particular, as shown in Figure I, MFV values are opposite to interictal values within the time period when electrical discharges occur. Then, if we consider the entire duration of the absence seizure, MFV may also seem reduced; but if we consider values for more limited periods of time, we can appreciate fully the true nature and quality of the changes. Our findings are consistent with those of experimental studies in which the reduction of CBF was delayed by some seconds, compared with the beginning of the spike-and-wave discharges [15]. For all of these reasons, we believe that our approach provides exact indications on cerebral flow changes. This is also confirmed by the reproducibility of our hemodynamic findings in every recorded seizure. In conclusion, our results suggest that TCD can provide useful information about seizure pathophysiology. The limited regional resolution of this technique prevents any possibility of alternative employment to PET or SPECT to study particular aspects, such as the localization of areas of cerebral dysfunction. On the other hand, the high temporal resolution that permits having instantaneous information makes the use of TCD superior to any other technique of CBF investigation in the evaluation of the time course of rapidly evolving clinical and functional events. The recent efforts to improve this technique in order to permit simultaneous measurements of blood flow changes in different cerebral arteries deserves further attention for future possible use of TCD in the study of epilepsy.
References
[l] Wieser HG. PET and SPECT in epilepsy. Eur Neurol 1994; 34(Suppl 1):58-62. [2] Stefam H, Pawlik G, Bocher-SchwarzHG, et al. Functional and morphological abnormalities in temporal lobe epilepsy: A comparisonof interictal and ictal EEG, CT, MRI, SPECT, and PET. J Neurol 1987; 234:377-84. [3] Hajek M, Antonini A, Leenders KL, Wieser HG. Mesiobasal versus lateral temporal lobe epilepsy: Metabolic differences in the temporal lobe shown by interictal t~F-FDGpositron emission tomography. Neurology 1993;43:79-86. [4] Newton MR, Austin MC, Chan JG, McKay WJ, Rowe CC, Berkovic SF. Ictal SPECT using ~mTc-HMPAO: Methods for rapid preparation and optimal deployment of tracer during spontaneous seizures. J Nucl Med 1993;34:666-70. [5] Aaslid R, Markwalder TH, Nornes H. Noninvasive transcranial
Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982;57:769-74. [6] Kontos HA. Validity of cerebral arterial blood flow calculations from velocity measurements. Stroke 1989;20:1-3. [7] Commission on Classification and Terminology of the Internation League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99. [8] Engel Jr J, Lubens P, Kuhl DE, Phelps M. Local cerebral metabolic rate for glucose during petit real absences. Ann Neurol 1985;17:121-8. [9] ltuber P, Handa J. Effect of contrast material, hypercapnia, hyperventilation, hypertonic glucose and papaverine on the diameter of the cerebral arteries. Invest Radiol 1967;2:17-32. [10] Raichle ME, Grubb RL, Gado MH, Eichling JO, Ter-Pogossian MM. Correlation between regional blood flow and oxidative metabolism. Arch Neurol 1976;33:523-6.
[11] Snead 1II OC. Basic mechanisms of generalized absence seizures. Ann Neurol 1995;37:146-57. [12] Langfitt TW, Kassell NF. Cerebral vasodilation produced by brainstem stimulation: Neurogenic control vs autoregulation. Am J Physiol 1968;215:90-7. [13] Bode H. Intracranial blood flow velocities during seizures and generalized epileptic discharges. Eur J Pediatr 1992;151:706-9. [14] Nehlig A, Vergnes M, Waydelich R, et al. Absence seizures induce a decrease in cerebral blood flow: Human and animal data. J Cereb Blood Flow Metab 1996;16:147-55. [15] Nehlig A, Vergnes M, Hirsch E, Marescaux C. Brain metabolism and blood flow in models of generalized idiopathic epilepsies in rodents. In: Malafosse A, Genton P, Hirsch E, Marescaux C, Broglin D, Bernasconi R, eds, Idiopathic generalized epilepsies: Clinical, experimental and genetic aspects. London: John Libbey & Company, 1994: 169-76.
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Changes in Cerebral Blood Flow Velocities During Childhood Absence Seizures R o b e r t o D e S i m o n e , M D * * , M a u r o Silvestrini, M D * * , M a r i a G r a z i a M a r c i a n i , M D * * , a n d P a o l o C u r a t o l o , M D **
A simultaneous recording of mean flow velocity in the right middle cerebral artery by transcranial Doppler ultrasonography and electroencephalographic activity was performed in 5 children with multiple daily typical absence seizures. Twenty-eight absence episodes were recorded. Mean flow velocity increased gradually a few seconds before the clinical and electroencephalographic manifestations of each seizure and reached the maximum values (range of increase: 25.5-42.8% with respect to baseline) within 2-3 seconds from their onset. This increase was then followed by a fast reduction in flow velocity, with the lowest levels (range of decrease: 30.8-44.0% with respect to baseline) recorded within 4-6 seconds from the end of each absence seizure. These findings suggest that changes in cerebral blood flow and activity are quite complex during absence seizures and that they do not fully correlate with clinical and electroencephalographic manifestations. © 1998 by Elsevier Science Inc. All rights reserved. De Simone R, Silvestrini M, Marciani MG, Curatolo P. Changes in cerebral blood flow velocities during childhood absence seizures. Pediatr Neurol 1998; 18:132-135.
Introduction Studies of cerebral blood flow (CBF) and metabolism with positron emission tomography (PET) have added valuable information to our knowledge of the human epilepsies [1]. The most interesting data refer to the possibility of identifying regions of interictal cerebral dysfunction, usually revealed as hypometabolism and hypoperfusion, which could have practical implications from a diagnostic, as well as a therapeutic, point of view [2,3]. The possibility of using PET to study changes in cerebral activity during the ictal phase of epilepsy is rather
From the Clinics of *Neurology and ~Pediatric Neurology; Tor Vergata; University of Rome; and *IRCCS S. Lucia; Rome, Italy.
132
PEDIATRIC NEUROLOGY
Vol. 18 No. 2
limited. The short half-life of positron emitting isotopes greatly restricts investigation time. With the exception of those times when seizures occur fortuitously either during or soon after tracer injection, PET can study only provoked seizures. Moreover, with this technique, time resolution is low and a few minutes are required to detect changes in CBF and metabolism. The fact that metabolic and flussimetric data are not available at the same time as when clinical observation and electroencephalographic (EEG) recording are made prevents us from knowing the exact temporal sequence of changes in cerebral activity, including during the postictal phase. Therefore, pathophysiologic interest in these studies seems limited. The introduction of single photon emission computed tomography (SPECT) in the study of epilepsy is of some advantage because the isotopes used have a relatively long half-life. This, even with a lower spatial resolution, makes the technique more appropriate than PET for studying the ictal phase of epilepsy [4]. However, changes in regional CBF can be recorded with SPECT only for events lasting at least 10 s. This temporal resolution is not completely satisfactory when the clinical situation is evolving quickly and continuously, as it does in the case of an epileptic seizure. Transcranial Doppler ultrasonography (TCD) is a noninvasive technique that makes it possible to assess instantaneous changes in blood flow velocity in the large cerebral arteries that have been found to correlate reliably with changes in CBF [5,6]. The major disadvantage of TCD is its low spatial resolution. Changes in CBF investigated with this technique refer to the distribution territory of a large intracranial vessel. However, the possibility of having instantaneous information makes TCD particularly useful to monitor changes in cerebral functional status during rapid clinical events. In this study, we aimed to obtain information about changes in cerebral hemodynamics during spontaneous
Communication should be addressed to: Dr. Silvestrini; Clinica Neurologica; Universita' di Roma Tor Vergata; Ospedale S. Eugenio; P.le dell'Umanesimo 10; 00144; Roma, Italy. Received April 11, 1997; accepted July 22, 1997.
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(97)00165-3 • 0887-8994/98/$19.00
absence seizures and the interictal and postictal period by continuous r e c o r d i n g o f the intracerebral f l o w v e l o c i t y with T C D simultaneous with the E E G m o n i t o r i n g o f cerebral activity.
Patients and Methods Five children (I boy, 4 girls) aged 6 to 12 years with multiple daily typical absence seizures, based on clinical and EEG data, according to the classification of the International League against Epilepsy [7], were included in the study. Neurologic examination was normal; no child was under therapy. Informed consent was obtained from both parents and children. A recording of mean flow velocity (MFV) in the right middle cerebral artery by means of a MultidopX/TCD 7 (DWL Elektronische Systeme GmbH, Sipplingen, Germany) TCD instrument and of EEG activity by means of an eight-channel electroencephalograph (Vega 10, Esaote Biomedica, Florence, Italy) was performed for a mean period of 75 rain. One dual 2-MHz transducer, fitted on a headband and placed on the temporal bone window, was used to obtain a continuous measurement of flow velocity. The Doppler spectra were recorded for the entire period of each study. EEG results were recorded according to the international 10 to 20 system with collodium electrodes. No movements or other automatic activity were observed during our evaluation. Clinical and electric events were marked on the Doppler tracing by clicking on a computer mouse. Because each recorded seizure was of a different duration and MFV changes bad no univocal direction during the different recorded periods, it was not possible to perform an analysis of the difference in flow velocity among preictal, ictal, and postictal phases of each absence seizure. Therefore, we were limited to providing a qualitative description of the flow changes and of their correlation with the clinical and EEG findings. The percentage of MFV maximum increase or decrease refers to a single cardiac cycle and is calculated with respect to a basal value referring to a l-rain period recorded at a distance of at least 5 rain from a previous or a following absence. Data for statistical analysis consisted of the values (expressed in cm/s) of basal MFV and of maximum increase and decrease of MFV. A one-way analysis of variance with basal mean values, and values of maximum increase and decrease of MFV as repeated measures was used.
Results During our evaluation, a total o f 28 absence seizures w e r e observed. D u r a t i o n o f clinical and E E G findings during seizures ranged f r o m 5-7.5 seconds (mean +_ S.D., 6.28 -+ 0.9). No changes in respiratory activity or heart rate w e r e observed. T h e increase in f l o w velocity was gradual; it started 5-10 seconds b e f o r e onset o f the absence and reached the m a x i m u m level with respect to baseline within 2-3 seconds f r o m the onset of clinical and electric changes (range of percentage increase, 25.5-42.8%). T h i s increase was f o l l o w e d by an abrupt decrease in f l o w v e l o c i t y that started during the absence and reached the m i n i m u m value within 4-6 seconds f r o m the end of the crisis (range of percentage decrease, 30,8-44.0). The t i m e course of this last p h e n o m e n o n was quite short. In fact, the return to baseline levels occurred within about 15-20 seconds. Figure 1 depicts the f l o w v e l o c i t y pattern during one o f the recorded absences and the relative E E G finding. T h e values of m a x i m u m decrease of M F V w e r e significantly higher than basal M F V values (79.0 + 7.5 vs 53.7 + 7.8, P < 0.0001). A significant difference (P < 0.0001) was
Figure 1. Top: Flow velocity pattern in a middle cerebral artery during a typical absence seizure lasting 6 s. Baseline values were 42.5 cm/s; the maximum increase occurred 2 s after the onset of the seizure: 54.0 cl~s" (+27,5%). The increase of flow velocity was gradual and started about 5 s befi)re the e!ectroencephalographic and clinical changes. Values of flow velocity deereased during the final part of the absence seizure and reached the minimum value 4 s after its end: 28 cnu's (-34.1%). A return to values similar to baseline occurred in about 15 s. Bottom: Relative eleetroencephalographic f n d i n g showing a sequence of bilateral spikeand-wave complexes for 6 s.
also detected b e t w e e n values (33.6 +_ 5.6) and basal ones.
of maximum
decrease
Discussion T h e h a l l m a r k o f a t y p i c a l a b s e n c e s e i z u r e is the s u p p r e s s i o n o f m e n t a l f u n c t i o n to the p o i n t w h e r e r e s p o n s i v e n e s s , a w a r e n e s s , and m e m o r y are lost. T h e pathophysiology of childhood absence epilepsy remains u n c l e a r . R e c e n t f i n d i n g s h a v e p o s t u l a t e d that the prim a r y d i s t u r b a n c e is an a b n o r m a l e x c i t a b i l i t y o f the c o r t e x that interacts w i t h t h a l a m u s and b r a i n s t e m reticular s u b s t a n c e to p r o d u c e the c h a r a c t e r i s t i c ictal pattern. C o r t i c a l i n v o l v e m e n t in the d i s c h a r g e is also p r o v e d by i n c r e a s e d g l u c o s e m e t a b o l i s m , as i n d i c a t e d in P E T studies [1,8]. O u r results s u g g e s t that d u r i n g the o c c u r r e n c e o f a t y p i c a l a b s e n c e s e i z u r e , h e m o d y n a m i c cerebral c h a n g e s h a v e a p a r t i c u l a r pattern in t i m e that d o e s not f u l l y c o r r e l a t e w i t h the c l i n i c a l and E E G f i n d i n g s .
De Simone et al: Cerebral Hemodynamics During Absences
133
The interpretation of these CBF changes requires a brief explanation of the functional significance of TCD. Because flow velocity in the large cerebral arteries is directly related to the diameter of the small resistance vessels [9], an increase in cerebral metabolism associated with neuronal activity causes an increase in flow velocity in the proximal portion of the artery by promoting a dilatation of the precapillary bed. On the contrary, a reduction in neural activity causes a reduction in flow velocity with the opposite mechanism [10]. Previous studies with emission tomography techniques described increased cerebral activity during absence [8]. This increase seems confirmed in our study in which more detailed information about the temporal course of changes in cerebral activity is provided. Moreover, the reduction in flow velocity at the end of the seizure adds another detail not described in PET and SPECT studies. The limited temporal resolution of these techniques can account for this apparent contrast because we recorded a reduction in flow velocity that is too short to be revealed with PET or even with SPECT. From a pathophysiologic point of view the most interesting finding that emerged from the present study is that changes in CBF appear to last longer than the clinical and EEG alterations of an absence seizure. Even if the TCD information can only suggest the occurrence of changes in cerebral functional activity, our data provide some insights into the metabolic functional status connected with an epileptic discharge. It seems that the increase in cerebral activation is a gradual phenomenon that starts and develops progressively toward a level at which a seizure occurs. This hyperactivity is then followed by a period of hypoactivity that starts during the final part of the seizure and goes on for some seconds after its end. This dual pattern of cerebral activity could result from the function of two major neurotransmission systems that regulate each other within the involved thalamocortical circuitry. The modulation of thalamocortical rhythmicity is mediated by 3,-aminobutyric acid-ergic interneurons within the cerebral cortex [1 1]. Identification of the exact functional mechanisms in this very intricate network is difficult. Our data suggest a diphasic pattern of the ground metabolic modifications. Thus the absence seizure does not seem to be provoked by the activation of a single neurotransmission pathway but rather by the excitatory and inhibitory action of several systems. The TCD pattern of increase and decrease of cerebral flow velocity suggests the existence of a feedback system that starts after the onset of the generalized discharge. The possibility that changes of MFV are mediated by neurogenic factors seems to be reasonably excluded by their time course. In particular the time interval between the onset of the electric discharge and the decrease of MFV is expected to be shorter if the latter was due to changes in vascular diameter mediated by neurogenic factors [ 12]. Our findings do not confirm the results of previous TCD studies in which a reduction in flow velocity was found
134 PEDIATRICNEUROLOGY Vol. 18 No. 2
during the ictal period of absences [13,14]. The reason fl)r this finding opposite to that described in the present study is not easy to determine. It is possible that the contrast is related to differences in the sensitivity of the equipment used in the recording of flow velocity or in the time intervals considered. In tact, as shown in our study, the hemodynamic changes before, during, and after a spontaneous absence happen very quickly, and the possibility of documenting them can be managed only with a system that has the maximum degree of temporal resolution. For the same reason, the hemodynamic values may be different based on the length of the time considered for calculating MFV. In particular, as shown in Figure I, MFV values are opposite to interictal values within the time period when electrical discharges occur. Then, if we consider the entire duration of the absence seizure, MFV may also seem reduced; but if we consider values for more limited periods of time, we can appreciate fully the true nature and quality of the changes. Our findings are consistent with those of experimental studies in which the reduction of CBF was delayed by some seconds, compared with the beginning of the spike-and-wave discharges [15]. For all of these reasons, we believe that our approach provides exact indications on cerebral flow changes. This is also confirmed by the reproducibility of our hemodynamic findings in every recorded seizure. In conclusion, our results suggest that TCD can provide useful information about seizure pathophysiology. The limited regional resolution of this technique prevents any possibility of alternative employment to PET or SPECT to study particular aspects, such as the localization of areas of cerebral dysfunction. On the other hand, the high temporal resolution that permits having instantaneous information makes the use of TCD superior to any other technique of CBF investigation in the evaluation of the time course of rapidly evolving clinical and functional events. The recent efforts to improve this technique in order to permit simultaneous measurements of blood flow changes in different cerebral arteries deserves further attention for future possible use of TCD in the study of epilepsy.
References
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