Brain, Vol. 125, No. 9, 1960-1971,
September 2002
© 2002 Guarantors of Brain
Ictal cerebral haemodynamics of childhood epilepsy measured with near-infrared spectrophotometry
1 Department of Pediatrics and 2 Rehabilitation Medicine for the Physically Disabled, Tohoku University School of Medicine and 3 Hamamatsu Photonics KK, Hamamatsu, Japan
Correspondence to: Kazuhiro Haginoya, MD, Department of Pediatrics, Tohoku University School of Medicine 1-1, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan E-mail: khaginoya{at}ped.med.tohoku.ac.jp
Received January 28, 2002. Accepted April 9, 2002.
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Near-infrared spectrophotometry (NIRS) is a new technique that allows continuous non-invasive monitoring of tissue oxygenation and haemodynamics in the brain. We used NIRS in various types of paediatric epileptic seizures in order to understand the pathophysiology of epileptic seizures in childhood epilepsy. This study examined 15 children ranging in age from 1.5 months to 16 years (nine males and six females), with different types of epilepsy. Six series of tonic spasms and 67 isolated seizures were recorded. The results demonstrated that several pathophysiological processes exist during epileptic seizures in childhood. (i) Convulsive seizures were associated with a remarkable increase in cerebral blood volume (CBV), while absence seizures were associated with a mild decrease or no change in CBV of the frontal cortex. (ii) An initial transient decrease in CBV was observed in some types of convulsive seizures. (iii) An ictal increase in CBV changed to an ictal decrease in the course of tonic status epilepticus. (iv) There was definite heterogeneity in the CBV changes during tonic spasms in patients with West syndrome. NIRS is easily applicable to paediatric patients with epilepsy and may provide new insights into the pathophysiology of various types of epileptic seizure.
Keywords: near-infrared spectrophotometry; epilepsy; cerebral blood volume; cerebral blood flow; ictal monitoring
Abbreviations: CBF= cerebral blood flow; CBV = cerebral blood volume; CytO2 = oxidized cytochrome aa3; HbO2 = oxygenated haemoglobin; HbR = deoxygenated haemoglobin; LRE = localization-related epilepsy; PLE = parietal lobe epilepsy; NIRS = near-infrared spectrophotometry; rCBF = regional cerebral blood flow; SGT = secondary generalized tonic–clonic seizures; SPECT = single photon emission computed tomography; THb = total haemoglobin
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Introduction |
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Recent advances in neuroimaging such as PET, single photon emission computed tomography (SPECT), magnetoencephalography and magnetic resonance spectrometry have improved seizure focus localization and understanding of the pathophysiology of epileptic foci. Ictal SPECT and PET show changes in cerebral blood flow (CBF) and metabolism during epileptic seizures (Engel et al., 1982
, 1985; Bonte et al., 1983; Theodore et al., 1985; Chugani et al., 1994; Haginoya et al., 2001). Regional CBF (rCBF) and metabolism increase in the epileptogenic zone during partial seizures, but decrease interictally (Engel et al., 1982; Bonte et al., 1983; Chugani et al., 1994). However, ictal hypoperfusion of the epileptogenic zone has also been reported in some cases using SPECT. There is a controversy over the interpretation of this phenomenon. Avery and colleagues (Avery et al., 2000) reported that ictal SPECT injections made 90 s or more from seizure onset demonstrated focal areas of decreased rCBF at the epileptogenic site, while Lee and colleagues (Lee et al., 2000) reported focal ictal hypoperfusion only in cases in which the radiotracer was injected during the early ictal period. Thus, the perfusion changes of the epileptogenic zone during the peri-ictal period are not yet known exactly, since the information provided by such studies consists of static information obtained at a certain point during the peri-ictal or interictal period.
Near-infrared spectrophotometry (NIRS) is a new technique that allows continuous non-invasive monitoring of tissue oxygenation and haemodynamics in the brain. NIRS measures changes in the concentrations of oxygenated haemoglobin (HbO2), deoxygenated haemoglobin (HbR), and total haemoglobin (THb) (THb = HbO2 + HbR). Assuming a constant haematocrit, changes in THb are used as an indicator of alteration in cerebral blood volume (CBV) (Cope et al., 1988). Simultaneous NIRS and PET measurements show that the changes in THb and HbO2 correlate with changes in rCBF (Hoshi et al., 1994; Villringer et al., 1997). Several reports describe the potential of the NIRS technique for measuring haemodynamic changes related to human brain activity, including sensorimotor (Obrig et al., 1996), visual (Hoshi and Tamura, 1993), auditory (Hoshi and Tamura, 1993), cognitive (Chance et al., 1993) and language (Okada et al., 1993) activity.
However, there have been few reports in the literature of the application of NIRS to epileptic seizures (Steinhoff et al., 1996; Watanabe et al., 1998; Adelson et al., 1999). Recently, Watanabe and colleagues applied multichannel NIRS monitoring to measure bemegride-induced ictal changes in CBV in 10 patients with temporal lobe epilepsy and two patients with parietal lobe epilepsy (PLE) (Watanabe et al., 1998). The patients showed an ictal increase in CBV on the side of the epileptic focus and it was concluded that NIRS is one of the most reliable techniques for focus diagnosis. We used NIRS to examine various types of paediatric epileptic seizure in order to understand the pathophysiology of epileptic seizures in childhood epilepsy.
Patients and methods
This study examined 15 children, ranging in age from 1.5 months to 16 years (nine males and six females) with different types of epilepsy as listed in Table 1. Informed consent was obtained from the parents before each NIRS study. In total, six series of tonic spasms and 67 isolated seizures were recorded with NIRS. Tonic seizures were recorded in five patients [neonatal onset localization-related epilepsy (LRE), startle epilepsy, Lennox–Gastaut syndrome, secondary generalized epilepsy and West syndrome]. An asymmetrical generalized clonic seizure was observed in one patient with severe myoclonic epilepsy in infancy. Secondary generalized tonic–clonic seizures (SGT) and focal motor seizures were recorded in patients with LRE. We studied four patients with West syndrome who had hypsarrhythmia and typical tonic spasms with cluster formation. In three of these patients, we recorded tonic spasms; in the fourth, we recorded a brief tonic seizure that coexisted with tonic spasms. An epileptic spasm was recorded in one patient with band heterotopia. Complex partial seizures were recorded in four patients with neonatal onset LRE, PLE and band heterotopia. Absence seizures were monitored in two patients.
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The NIRS system (NIRO300, Hamamatsu Photonics KK, Hamamatsu, Japan) used in this study produces light at four wavelengths (776, 810, 848 and 913 nm). The design and features of this device have been described previously (Suzuki et al., 1999
). Light at each frequency is transmitted in sequential pulses by a fibre-optic cable (optode) to the patient’s forehead. The transmitting and receiving optodes are placed 4 cm apart on the patient’s forehead to detect haemodynamic changes in the frontal cortex. The difference between the transmitted and received light intensities at each wavelength is used to determine the optical density change at each wavelength. A computer converts the changes in optical density into changes in cerebral HbO2, HbR, and concentration of oxidized cytochrome aa3 (CytO2) expressed in micromoles (µM). We did not include the CytO2 data in this study because the in vivo spectrum and physiological meaning of changes in the redox state of cytochrome oxidase remain controversial (Cooper et al., 1994). The THb was calculated as the sum of HbO2 and HbR, and was used as a measure of CBV. Changes in HbO2, HbR and THb from an arbitrary zero were measured continuously from the pre-ictal through the post-ictal period in spontaneously occurring seizures. Measurements were made every 0.5 s. We applied a differential path length factor of 4.0 in patients less than 3 years of age (Benaron et al., 1990; van der Zee et al., 1992; Cooper et al., 1996) and 5.9 in patients older than 3 years of age (van der Zee et al., 1992). The optical path length was set by multiplying the interoptode distance by differential path length factor. An EEG was also recorded simultaneously in all but two patients (Cases 6 and 13). In the two exceptions, ictal EEGs were recorded separately within 2 days of the NIRS study. To avoid movement artifacts, the patient’s head was held to reduce movement as much as possible during seizures. Ictal records with extensive motion artifacts and unstable baseline levels were excluded from the analysis. Using t-tests, we compared sampling data for the ictal period with a pre-ictal period with the same amount of data as the ictal period. Significance was established at P < 0.05. |
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Generalized tonic–clonic seizure, tonic seizure, clonic seizure, focal motor seizure (Cases 1–7)
The NIRS, ictal and interictal EEG, and neuroimaging studies are summarized in Table 1. The ictal NIRS classification is summarized in Table 2. Out of seven cases with convulsive seizures (which included SGT, tonic seizures, brief tonic seizures, asymmetrical generalized clonic seizures and focal motor seizures), an increase in THb, HbO2 and HbR was observed in five cases (Fig. 1). An increase in THb and HbO2 with no change in HbR was observed in one case, and a decrease in THb and HbO2 with no change in HbR was observed in another. In Case 6 (with tonic status epilepticus), THb and HbO2 increased early in the seizures and as in the other cases with convulsive seizures. However, both values gradually attenuated and then decreased in the later period (Fig. 2A–C). In four out of seven cases with convulsive seizures (Fig. 1) and in one with an epileptic spasm (Fig. 4B), a transient decrease in all three parameters was observed at the onset of the seizure. The duration of the transient decrease ranged from 2 to 12 s.
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Complex partial seizure (Cases 7–10)
Because the optodes are placed on the patient’s forehead, this method only detects changes in the frontal cortex. This was demonstrated to be true in Cases 7 and 8, which had complex partial seizures. A hypomotor seizure originating from the left parietal to occipital area in Case 7 and an electrical seizure originating from the left parietal area in Case 8 (Fig. 3B), whose ictal SPECT showed hyperperfusion of the right parietal lobe, did not produce any change in the NIRS parameters before propagation of the epileptic activity from the focus. Case 9, however, whose optodes were placed on the right forehead, showed an ictal increase in THb and HbO2. The ictal SPECT in Case 9 showed hyperperfusion of the right frontal to parietal areas. A patient with band heterotopia had a complex partial seizure and an epileptic spasm. The ictal EEG failed to localize the seizure focus; however, our preliminary magnetoencephalography study showed a dipole location in the parietal inner heterotopic layer. Both types of attack elicited an ictal increase in THb and HbO2 in the frontal lobe, where the optodes were placed (Fig. 4). These results differ from those for other patients with complex partial seizures (Cases 7 and 8), suggesting that seizure propagation in band heterotopia differs from that in other types of LRE.
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Absence seizure (Cases 11 and 12)
In absence seizures, observed in two patients, one patient showed no substantial changes in the three parameters, which were reproducibly recognized. However, another patient with atypical absence showed a small, but significant, decrease in THb and HbO2, while HbR increased during all the five seizures examined (Fig. 5). These two patients also showed frequent generalized spike-wave bursts on EEG without absence seizures, during which no changes in NIRS parameters were observed.
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Tonic spasms (Cases 13–15)
One of three patients with West syndrome showed a remarkable increase in all three parameters during spasms (Fig. 6), while the remaining two patients showed no substantial changes. The ictal EEG showed generalized irregular polyspike-waves in Case 13, generalized fast waves in Case 14 and generalized delta waves in Case 15. The clinical difference between Case 13, and Cases 14 and 15 seems to be the strength of the spasms. Very strong contractions of the extremities were observed in Case 13, while the other two patients had very mild spasms. In Case 13, we immobilized the patient’s head during spasms to eliminate motion artifact. Hypsarrhythmia that appeared continuously during periods of wakefulness and periodically during sleep did not produce any changes in the three parameters.
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CBV changes during seizures and NIRS
Based on the current understanding of the coupling of neuronal activation and CBF, it is widely accepted that localized activation of neuronal populations leads to a fast, localized increase in blood flow in a restricted cortical area (Villringer and Dirnagl, 1995
). An increase in THb can be induced by either an increase in rCBF, which is usually associated with an increase in HbO2, or by obstruction of the cerebral venous return, such as with crying, which is usually associated with an increase in HbR (Brazy, 1988) or by a combination of these factors. In a human activation study of adults using NIRS, researchers demonstrated a decrease in HbR with increases in both HbO2 and THb in the area of activation (Chance et al., 1993; Hoshi and Tamura, 1993; Okada et al., 1993; Obrig et al., 1996). This was interpreted as an increase in cerebral blood supply exceeding the increase in neuronal oxygen consumption responsible for the production of deoxyhaemoglobin (Malonek and Grinvald, 1996; Obrig et al., 1996). In the activated area of animal brains, oxygen consumption causes an early (<3 s) increase in HbR and then a reactive increase in regional perfusion, which occurs >1 s after the increase in HbR. This results in a rise in HbO2 and a decrease in HbR due to washout (Malonek and Grinvald, 1996; Malonek et al., 1997). The relative contribution of oxygen consumption and blood supply determines whether HbR increases or decreases. Contrary to the activation study of adults, photic stimulation of early infants revealed concomitant increases in HbR and HbO2 in the occipital lobe, which were demonstrated using NIRS (Meek et al., 1998) and functional MRI (Yamada et al., 2000). These findings suggest that maturation of the brain affects neuronal oxygen consumption and cerebral blood supply. As in activation studies, focal seizures elicit an increase in rCBF in the seizure focus by decreasing cerebrovascular resistance, which is mediated by local tissue changes, such as changes in nitric oxide (Iadecola, 1992), pH and CO2 (Lassen, 1968) and adenosine (Berne et al., 1974). However, the propagation of seizure activity to subcortical systems induces mass excitation of the sympatho-adrenal axis (Doba et al., 1975) and brain stem centres affecting autoregulation (Langfitt and Kassell, 1968; Reis, 1984), resulting in a remarkable change in CBF (Meldrum and Nilsson, 1976). Although our method is limited, in that it only measures changes in THb, HbO2 and HbR in the frontal cortex, the results demonstrate that several pathophysiological processes exist during epileptic seizures in childhood.
(i) Convulsive seizures were associated with a remarkable increase in CBV, while absence seizures were associated with a mild decrease or no change in the CBV of the frontal cortex.
(ii) Initial transient decreases in CBV and HbR were observed in some types of convulsive seizures.
(iii) An ictal increase in CBV changed to an ictal decrease in the course of tonic status epilepticus.
(iv) There was definite heterogeneity in the CBV changes during tonic spasms in patients with West syndrome. Simultaneous ictal SPECT may be of help in verifying the efficacy of ictal NIRS recording more precisely.
NIRS findings during convulsive seizures
The ictal NIRS of convulsive seizures demonstrated that there were different patterns of ictal haemodynamics among patients. It is still unclear whether these differences reflect different patterns of propagation of seizure activity from the seizure focus or differences in neuronal activity in the frontal cortex during seizures. The patterns included: (i) increases in THb and HbO2 associated with an increase in HbR; (ii) increases in THb and HbO2 without a change in HbR and (iii) decreases in THb and HbO2 without a change in HbR. The increases in HbO2 and THb could be caused by an increase in rCBF in the frontal cortex. On the other hand, an increase in HbR could be interpreted in two ways: either tissue oxygen consumption during seizures is much greater than that during activation studies, so that the reactive increase in cerebral blood supply is insufficient to wash out the deoxyhaemoglobin; or increased impedance of cerebral venous return during the seizure causes the increase. Both factors may be relevant, especially the former in infancy, according to the results of an activation study (Meek et al., 1998). Moreover, it is notable that the increase in rCBF was much greater than that seen in activation studies (Sakatani et al., 1999). Contrary to previous cases, the ictal decrease in CBV was seen in an infant with West syndrome during a brief tonic seizure. This may reflect the steal phenomenon caused by an epileptic focus located outside the frontal cortex. The steal phenomenon was recently demonstrated (Hollo et al., 2001) using subtraction SPECT in infants with occipital lobe epilepsy; concomitant ictal hypoperfusion was observed around the hyperperfused occipital area or the extra-occipital area when radiotracer was injected during the early ictal period.
In four out of seven cases with convulsive seizures and in one with an epileptic spasm, transient decreases lasting a few seconds were observed in all three parameters at the onset of a seizure. This probably reflected a decrease in CBV, together with a decrease in oxygen consumption. Surprisingly, in Case 1, there was an initial decrease of CBV lasting 12 s after the appearance of the generalized convulsion. A transient decrease in CBV has been observed using NIRS in seizures evoked by transcerebral electroshock in experimental animals (Kreisman et al., 1983) and in the seizures associated with electroconvulsive therapy in man (Saito et al., 1995). Experimental studies have shown that electrical stimulation of a complex nucleus of the dorsal pons can reduce rCBF by vasoconstriction, with or without parallel changes in metabolism (Reis, 1984). The propagation of seizure activity in these areas may cause a transient decrease in CBF, as recorded in the current study. A few seconds later, the mass excitation of the sympatho-adrenal axis leads to a remarkable increase in CBF (Doba et al., 1975). Alternatively, the transient steal phenomenon may redistribute CBV in accordance with the neuronal demand of the epileptogenic zone outside the frontal lobe as demonstrated using SPECT (Hollo et al., 2001).
CBV changes during status epilepticus
Status epilepticus leads to neuronal cell damage that is localized to selectively vulnerable regions, chiefly the cerebral cortex, cerebellum and hippocampus (Meldrum and Brierley, 1973). Experimental studies have revealed that there is a mismatch between rCBF and the metabolic rate in these vulnerable areas (Meldrum and Nilsson, 1976; Siesjo et al., 1983). In studies by Kreisman and colleagues (Kreisman et al., 1981, 1983), early seizures were accompanied by increases in CBV, arterial blood pressure, cortical oxygen pressure and CytO2 pressure, indicating that oxygen supply was adequate to meet the metabolic demand of the seizures. However, these variables failed to increase during subsequent seizures, resulting in decreases in CBV, cortical oxygen pressure and CytO2, as occur in cerebral hypoxia (Kreisman et al., 1981, 1983). In Case 6, a patient with tonic status epilepticus, CBV increased early in the seizure as in the other cases with convulsive seizures; however, the CBV increase gradually attenuated and then decreased later in the seizure. These findings suggest that there is a transition from sufficient to insufficient cerebral oxygen supply during recurrent seizures, although we did not evaluate cortical oxygen pressure or CytO2. Continuous monitoring with NIRS during status epilepticus may provide useful information on its deleterious effects.
CBV changes during absence seizures
The ictal changes in cerebral metabolism and CBF during absence seizures are still controversial. A study using H215O-PET, in which the data acquisition time was improved to 
30 s, showed a 14.9% mean global increase in CBF associated with a relatively higher increase in the thalamus during absence seizures (Prevett et al., 1995). On the other hand, researchers using transcranial Doppler sonography and laser Doppler flowmetry observed a decrease in CBF during human absence seizures and in the genetic absence epilepsy rat (Sanada et al., 1988; Klingelhofer et al., 1991; Bode, 1992; Nehlig et al., 1996). In our study, one patient showed no substantial changes in CBV, while another showed a mild decrease in CBV during absence seizures. Gloor (1978) suggested that generalized spike-waves represent an abnormal response of cortical neurones to afferent thalamocortical projection; short periods of increased cortical excitation corresponding to the EEG spike are followed by a longer period of cortical inhibition, corresponding to the wave component. According to this hypothesis, CBF may decrease due to reduced cerebral neuronal activity during absence seizures when the duration of inhibition of neuronal activity exceeds that of excitation, or may show no change when inhibition and excitation of neuronal activity are balanced.
CBV changes during tonic spasms of West syndrome
Despite extensive work by many investigators, the pathophysiology of West syndrome is still elusive. We have reported ictal SPECT studies of West syndrome, in which we found two clear ictal SPECT patterns: (i) focal cortical hyperperfusion; and (ii) a diffuse pattern that probably included patients with diffuse hyperperfusion and those with no changes (Haginoya et al., 2001). As one explanation of these heterogeneous ictal SPECT findings, we propose that the tonic spasms of West syndrome do not involve a single neurophysiological process, and that West syndrome is divided into subgroups defined by the origin of the spasms. In one group, the spasms originate in the cortical hemisphere (Gaily et al., 1995), while in other groups they originate in other structures such as the brainstem (Haginoya et al., 2001). In the current study, one of three patients with West syndrome showed a remarkable increase in all three parameters (THb, HbO2 and HbR concentrations) during spasms. Interestingly, the changes developed shortly before the onset of spasms. Since the ictal EEG changes preceded the clinical onset of spasms in this patient by 60–70 s, we believe that the changes in the NIRS parameters shortly before the onset of spasms reflect neuronal activity associated with ictal EEG. It needs to be clarified whether differences in ictal NIRS patterns reflect differences in the neurophysiological or propagating processes as suggested in our SPECT study (Haginoya et al., 2001). Brain stem involvement might cause a phasic increase in CBV associated with each spasm, since cerebral vasodilation produced by brainstem stimulation has been described (Langfitt et al., 1968; Reis, 1984). Alternatively, ictal EEG may help to explain the heterogeneity of ictal NIRS; a patient with no changes on NIRS monitoring showed fast waves predominantly over the bilateral parieto-occipital areas during spasms. If the ictal perfusion changes are restricted to those regions, it is reasonable that NIRS optodes placed on the forehead would not detect changes in the frontal area. It is important to study more patients with West syndrome in order to clarify ictal change during NIRS monitoring.
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