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Cortico-thalamic activation in generalized status epilepticus, a PET study
Clinical Neurology and Neurosurgery 110 (2008) 182–185
Case report
Cortico-thalamic activation in generalized status epilepticus, a PET study B.M. de Jong a,∗ , J.H. van de Hoeven a , J. Pruim b , J.H.J.M. Meertens c , J. van der Naalt a a
Department of Neurology, University Medical Center Groningen, University of Groningen, The Netherlands b Department of Nuclear Medicine and Molecular Imaging, UMCG, The Netherlands c Department of Anesthesiology, UMCG, The Netherlands Received 13 June 2007; received in revised form 31 August 2007; accepted 14 September 2007
Abstract In a patient with a refractory generalized convulsive status epilepticus, the ictal distribution of regional cerebral glucose was assessed with positron emission tomography (PET). Synchronized seizure activity in the EEG was associated with bilateral metabolic activation of medial sensorimotor regions, anterior cingulate cortex, striatum and thalamus. This pattern with focal cortical activation supports the concept that a cortical focus may drive epilepsy, while the thalamus mediates synchronization of neuronal activity as reflected in the EEG. © 2007 Elsevier B.V. All rights reserved. Keywords: Generalized status epilepticus; Ictal PET; FDG; Cingulate gyrus
1. Introduction The administration of anticonvulsant drugs is the corner stone of treating a status epilepticus. This may even require suppression of neuronal activity by strong sedation and consequent artificial ventilation, particularly in case of generalized seizures [1]. A situation in which synchronized cortical discharges in the electroencephalography (EEG) is only brought to normal by inducing a 48-h lasting burst-suppression EEG is not exceptional [1]. However, if a generalized status epilepticus reoccurs, even after a second period of such burst suppression, medication strategy becomes increasingly difficult. Alternative therapeutic strategies, including neurosurgery, may be considered. Moreover, one is confronted with the mystery of mechanisms underlying generalized seizures and hypersynchronization of EEG activity. In this communication, we describe the application of positron emission tomography (PET) for imaging the ictal pattern of regional increases in cerebral metabolism, in a
∗ Corresponding author at: Department of Neurology, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 361 2430; fax: +31 50 361 1707. E-mail address: [email protected] (B.M. de Jong).
0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2007.09.008
patient suffering from such a refractory generalized convulsive status epilepticus.
2. Case report The studied female patient, aged 22, had an unremarkable history. After a week of general discomfort with flue-like complaints, she was found unconscious with tonic-clonic seizures of all limbs. Head and eyes deviated to the right. She was able to localize pain stimuli, bilaterally. The seizures responded to clonazepam. Seizure reoccurrence, however, urged sedation and artificial ventilation. Initial and repeated MRI did not show specific lesions, other than a right temporal arachnoid cyst. Laboratory findings, including spinal fluid examination did not reveal a cause for the seizures. After a second period with a thiopental-induced burst-suppression EEG, propofol was still necessary for seizure suppression. Under propofol protection, the effect of various antiepileptic drugs was successively tested. At the time of the PET study, she was treated with phenytoin, levetiracetam, topiramate and acetazolamide. In order to examine whether the arachnoid cyst might provoke an epileptogenic focus, thus providing a possible
B.M. de Jong et al. / Clinical Neurology and Neurosurgery 110 (2008) 182–185
183
Fig. 1. EEG recording around the time of tracer injection (a), and two samples from the preceding 24 h (b and c). The latter show predominantly left frontocentral spike-wave discharges (b) and a stage of secondary intensification as well as spreading to both hemispheres (c). Such condition urged temporary increase of the propofol dose. The upper half of the figure shows the frontal to occipital leads over the left hemisphere, the lower half depicts the right-hemisphere recordings.
indication for neurosurgical treatment, regional uptake of 18Fluor Deoxyglucose (FDG) was assessed with PET. This study was performed 3 weeks after seizure onset. FDG was injected intravenously (185 MBq), 30 min before scanning. Before injection, propofol was stopped, which led to generalized convulsive seizures again. These were particularly observed around 10 min before and 3 min after tracer injection. EEG recording demonstrated the epileptic genesis (Fig. 1). The latter showed synchronized spike-wave discharges with subtle signs of a left frontocentral maximum. Within 10 min after tracer injection, propofol was restarted and the patient was scanned while being ventilated (Siemens ECAT Exact HR + camera, axial field of view 15 cm). A static measurement was thus performed (one time frame, no arterial blood sampling). This implied that only the distribution of relative tracer uptake was obtained, an absolute glucose metabolic rate was not measured. The obtained image of regionally distributed FDG uptake did not show enhanced activity bordering the arachnoid cyst. However, the bilateral pattern, with left-hemisphere dominance, indicated the activation of coherent circuitry, which was cortically distributed over medial sensorimotor regions, extending into the anterior cingulate cortex, while it subcortically comprised striatum and thalamus (Fig. 2). Cortical metabolism outside these enhanced foci of activation was low, hardly beyond that of the white matter. The result of the PET measurement did not change the treat-
ment strategy. During the following weeks, propofol dose was gradually reduced while EEG activity slowly normalized. Six weeks after seizure onset, our patient was extubated. With classical antiepileptic drugs she remained free from seizures. Following a period of slowness in thought and clumsy movements, recovery was with only mild behavioral complaints.
3. Discussion Although EEG synchronization of spike-wave activity may suggest a cortical spread from the frontocentral focus, the metabolic pattern demonstrated a rather isolated cortical region subsequently activating basal ganglia and the thalamus. This profile is consistent with the explanation that rhythmicity of a cortical focus drives the thalamus [2,3]. The latter has widely distributed connections with virtually all cortical regions, thus providing the condition for cortical synchronization [4]. Apparently such synchronization does not necessarily imply generalized neuronal hyperactivation in all cortical regions. This can be inferred from the relatively low metabolic status outside the activated regions. Indeed, the ictal metabolic pattern in our patient is consistent with the clinically interictal pattern of both regional activations and deactivations that have been shown with fMRI [5]; during generalized epileptic discharges in the EEG, acti-
184
B.M. de Jong et al. / Clinical Neurology and Neurosurgery 110 (2008) 182–185
Fig. 2. Distribution of cerebral metabolism during generalized convulsive seizures. Uptake of FDG is relative to the focus of maximal uptake (scale 0–100). Relative increases of metabolism are seen in the locations labeled by the numbers 1–4. In the upper row, transversal sections are depicted, with the most superior slice on the left side. The middle and lower rows show coronal and sagital sections, respectively. (1) Medial sensorimotor cortex (supplementary motor area), (2) anterior cingulate cortex, (3) thalamus, (4) putamen, (5) arachnoid cyst; (R) right side of the brain, (L) left, (ant) anterior.
vations were seen in thalamus and medial frontal cortex, together with deactivations in lateral prefrontal and parietal cortices. In the present report, we demonstrated a distinct pattern of regional cerebral metabolism during generalized convulsive seizures. In absence seizures, which are generalized but nonconvulsive [6], ictal functional imaging has been extensively described before, and revealed both increases and decreases of global cortical metabolism [7,8]. In addition, increased thalamus perfusion was regarded to reflect a role in the propagation of the absence seizures [9]. It has further been reported that generalized absence seizures may also originate from a frontal focus [10]. Although we did not see enhanced FDG uptake around the arachnoid cyst, we are reluctant to draw the absolute conclusion that the cyst did not provoke epilepsy. An epileptic focus that gives rise to partial seizures generally shows increased local cerebral metabolism during such seizures, while interictal metabolism is reduced [7,11,12].
In our patient, one might, e.g. consider the possibility that a repeated alteration between short local bursts and a subsequent hypometabolic interval resulted in a summed focal FDG uptake which is similar to that of the surrounding cortex. On the other hand, the correspondence between the left frontocentral maximum of intermittent epileptic discharges in the EEG, and a predominantly left frontomedial increase of tracer uptake indicates that the distribution of metabolic activity indeed included the effect of epileptic activity. The present patient study thus provided unique data that may improve the understanding of mechanisms involved in generalized epilepsy. Our data support the idea that the thalamus plays a role in seizure propagation [5]. Whether the anterior cingulate gyrus similarly contributes to such seizure propagation remains to be further elucidated. Although the PET findings did not have direct clinical consequences, the strategy of obtaining an ictal measurement for the detection of a possible epileptic focus appeared to be feasible.
B.M. de Jong et al. / Clinical Neurology and Neurosurgery 110 (2008) 182–185
References [1] Bleck TP. Refractory status epilepticus. Curr Opin Crit Care 2005; 11:117–20. [2] Steriade M. Impact of network activities on neuronal properties in corticothalamic systems. J Neurophysiol 2001;86:1–39. [3] Meeren HK, Pijn JP, Van Luijtelaar EL, Coenen AM, Lopes da Silva FH. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J Neurosci 2002;22:1480–95. [4] McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 2001;63:815–46. [5] Gotman J, Grova C, Bagshaw A, Kobayashi E, Aghakhani Y, Dubeau F. Generalized epileptic discharges show thalamocortical activation and suspension of the default state of the brain. Proc Natl Acad Sci USA 2005;102:15236–40. [6] Holmes GL, McKeever M, Adamson M. Absence seizures in children: clinical and electroencephalographic features. Ann Neurol 1987;21:268–73.
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[7] Chugani HT, Rintahaka PJ, Shewmon DA. Ictal patterns of cerebral glucose utilization in children with epilepsy. Epilepsia 1994;35:813– 22. [8] Theodore WH, Brooks R, Margolin R, Patronas N, Sato S, Porter RJ, et al. Positron emission tomography in generalized seizures. Neurology 1985;35:684–90. [9] Prevett MC, Duncan JS, Jones T, Fish DR, Brooks DJ. Demonstration of thalamic activation during typical absence seizures using H2(15)O and PET. Neurology 1995;45:1396–402. [10] Millan E, Abou-Khalil B, Delbeke D, Konrad P. Frontal localization of absence seizures demonstrated by ictal positron emission tomography. Epilepsy Behav 2001;2:54–60. [11] Engel J, Kuhl DE, Phelps ME, Rausch R, Nuwer M. Local cerebral metabolism during partial seizures. Neurology 1983;33:400–13. [12] Henry TR, Votaw JR. The role of positron emission tomography with [18F]fluorodeoxyglucose in the evaluation of the epilepsies. Neuroimag Clin N Am 2004;14:517–35.
Case report
Cortico-thalamic activation in generalized status epilepticus, a PET study B.M. de Jong a,∗ , J.H. van de Hoeven a , J. Pruim b , J.H.J.M. Meertens c , J. van der Naalt a a
Department of Neurology, University Medical Center Groningen, University of Groningen, The Netherlands b Department of Nuclear Medicine and Molecular Imaging, UMCG, The Netherlands c Department of Anesthesiology, UMCG, The Netherlands Received 13 June 2007; received in revised form 31 August 2007; accepted 14 September 2007
Abstract In a patient with a refractory generalized convulsive status epilepticus, the ictal distribution of regional cerebral glucose was assessed with positron emission tomography (PET). Synchronized seizure activity in the EEG was associated with bilateral metabolic activation of medial sensorimotor regions, anterior cingulate cortex, striatum and thalamus. This pattern with focal cortical activation supports the concept that a cortical focus may drive epilepsy, while the thalamus mediates synchronization of neuronal activity as reflected in the EEG. © 2007 Elsevier B.V. All rights reserved. Keywords: Generalized status epilepticus; Ictal PET; FDG; Cingulate gyrus
1. Introduction The administration of anticonvulsant drugs is the corner stone of treating a status epilepticus. This may even require suppression of neuronal activity by strong sedation and consequent artificial ventilation, particularly in case of generalized seizures [1]. A situation in which synchronized cortical discharges in the electroencephalography (EEG) is only brought to normal by inducing a 48-h lasting burst-suppression EEG is not exceptional [1]. However, if a generalized status epilepticus reoccurs, even after a second period of such burst suppression, medication strategy becomes increasingly difficult. Alternative therapeutic strategies, including neurosurgery, may be considered. Moreover, one is confronted with the mystery of mechanisms underlying generalized seizures and hypersynchronization of EEG activity. In this communication, we describe the application of positron emission tomography (PET) for imaging the ictal pattern of regional increases in cerebral metabolism, in a
∗ Corresponding author at: Department of Neurology, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 361 2430; fax: +31 50 361 1707. E-mail address: [email protected] (B.M. de Jong).
0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2007.09.008
patient suffering from such a refractory generalized convulsive status epilepticus.
2. Case report The studied female patient, aged 22, had an unremarkable history. After a week of general discomfort with flue-like complaints, she was found unconscious with tonic-clonic seizures of all limbs. Head and eyes deviated to the right. She was able to localize pain stimuli, bilaterally. The seizures responded to clonazepam. Seizure reoccurrence, however, urged sedation and artificial ventilation. Initial and repeated MRI did not show specific lesions, other than a right temporal arachnoid cyst. Laboratory findings, including spinal fluid examination did not reveal a cause for the seizures. After a second period with a thiopental-induced burst-suppression EEG, propofol was still necessary for seizure suppression. Under propofol protection, the effect of various antiepileptic drugs was successively tested. At the time of the PET study, she was treated with phenytoin, levetiracetam, topiramate and acetazolamide. In order to examine whether the arachnoid cyst might provoke an epileptogenic focus, thus providing a possible
B.M. de Jong et al. / Clinical Neurology and Neurosurgery 110 (2008) 182–185
183
Fig. 1. EEG recording around the time of tracer injection (a), and two samples from the preceding 24 h (b and c). The latter show predominantly left frontocentral spike-wave discharges (b) and a stage of secondary intensification as well as spreading to both hemispheres (c). Such condition urged temporary increase of the propofol dose. The upper half of the figure shows the frontal to occipital leads over the left hemisphere, the lower half depicts the right-hemisphere recordings.
indication for neurosurgical treatment, regional uptake of 18Fluor Deoxyglucose (FDG) was assessed with PET. This study was performed 3 weeks after seizure onset. FDG was injected intravenously (185 MBq), 30 min before scanning. Before injection, propofol was stopped, which led to generalized convulsive seizures again. These were particularly observed around 10 min before and 3 min after tracer injection. EEG recording demonstrated the epileptic genesis (Fig. 1). The latter showed synchronized spike-wave discharges with subtle signs of a left frontocentral maximum. Within 10 min after tracer injection, propofol was restarted and the patient was scanned while being ventilated (Siemens ECAT Exact HR + camera, axial field of view 15 cm). A static measurement was thus performed (one time frame, no arterial blood sampling). This implied that only the distribution of relative tracer uptake was obtained, an absolute glucose metabolic rate was not measured. The obtained image of regionally distributed FDG uptake did not show enhanced activity bordering the arachnoid cyst. However, the bilateral pattern, with left-hemisphere dominance, indicated the activation of coherent circuitry, which was cortically distributed over medial sensorimotor regions, extending into the anterior cingulate cortex, while it subcortically comprised striatum and thalamus (Fig. 2). Cortical metabolism outside these enhanced foci of activation was low, hardly beyond that of the white matter. The result of the PET measurement did not change the treat-
ment strategy. During the following weeks, propofol dose was gradually reduced while EEG activity slowly normalized. Six weeks after seizure onset, our patient was extubated. With classical antiepileptic drugs she remained free from seizures. Following a period of slowness in thought and clumsy movements, recovery was with only mild behavioral complaints.
3. Discussion Although EEG synchronization of spike-wave activity may suggest a cortical spread from the frontocentral focus, the metabolic pattern demonstrated a rather isolated cortical region subsequently activating basal ganglia and the thalamus. This profile is consistent with the explanation that rhythmicity of a cortical focus drives the thalamus [2,3]. The latter has widely distributed connections with virtually all cortical regions, thus providing the condition for cortical synchronization [4]. Apparently such synchronization does not necessarily imply generalized neuronal hyperactivation in all cortical regions. This can be inferred from the relatively low metabolic status outside the activated regions. Indeed, the ictal metabolic pattern in our patient is consistent with the clinically interictal pattern of both regional activations and deactivations that have been shown with fMRI [5]; during generalized epileptic discharges in the EEG, acti-
184
B.M. de Jong et al. / Clinical Neurology and Neurosurgery 110 (2008) 182–185
Fig. 2. Distribution of cerebral metabolism during generalized convulsive seizures. Uptake of FDG is relative to the focus of maximal uptake (scale 0–100). Relative increases of metabolism are seen in the locations labeled by the numbers 1–4. In the upper row, transversal sections are depicted, with the most superior slice on the left side. The middle and lower rows show coronal and sagital sections, respectively. (1) Medial sensorimotor cortex (supplementary motor area), (2) anterior cingulate cortex, (3) thalamus, (4) putamen, (5) arachnoid cyst; (R) right side of the brain, (L) left, (ant) anterior.
vations were seen in thalamus and medial frontal cortex, together with deactivations in lateral prefrontal and parietal cortices. In the present report, we demonstrated a distinct pattern of regional cerebral metabolism during generalized convulsive seizures. In absence seizures, which are generalized but nonconvulsive [6], ictal functional imaging has been extensively described before, and revealed both increases and decreases of global cortical metabolism [7,8]. In addition, increased thalamus perfusion was regarded to reflect a role in the propagation of the absence seizures [9]. It has further been reported that generalized absence seizures may also originate from a frontal focus [10]. Although we did not see enhanced FDG uptake around the arachnoid cyst, we are reluctant to draw the absolute conclusion that the cyst did not provoke epilepsy. An epileptic focus that gives rise to partial seizures generally shows increased local cerebral metabolism during such seizures, while interictal metabolism is reduced [7,11,12].
In our patient, one might, e.g. consider the possibility that a repeated alteration between short local bursts and a subsequent hypometabolic interval resulted in a summed focal FDG uptake which is similar to that of the surrounding cortex. On the other hand, the correspondence between the left frontocentral maximum of intermittent epileptic discharges in the EEG, and a predominantly left frontomedial increase of tracer uptake indicates that the distribution of metabolic activity indeed included the effect of epileptic activity. The present patient study thus provided unique data that may improve the understanding of mechanisms involved in generalized epilepsy. Our data support the idea that the thalamus plays a role in seizure propagation [5]. Whether the anterior cingulate gyrus similarly contributes to such seizure propagation remains to be further elucidated. Although the PET findings did not have direct clinical consequences, the strategy of obtaining an ictal measurement for the detection of a possible epileptic focus appeared to be feasible.
B.M. de Jong et al. / Clinical Neurology and Neurosurgery 110 (2008) 182–185
References [1] Bleck TP. Refractory status epilepticus. Curr Opin Crit Care 2005; 11:117–20. [2] Steriade M. Impact of network activities on neuronal properties in corticothalamic systems. J Neurophysiol 2001;86:1–39. [3] Meeren HK, Pijn JP, Van Luijtelaar EL, Coenen AM, Lopes da Silva FH. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J Neurosci 2002;22:1480–95. [4] McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 2001;63:815–46. [5] Gotman J, Grova C, Bagshaw A, Kobayashi E, Aghakhani Y, Dubeau F. Generalized epileptic discharges show thalamocortical activation and suspension of the default state of the brain. Proc Natl Acad Sci USA 2005;102:15236–40. [6] Holmes GL, McKeever M, Adamson M. Absence seizures in children: clinical and electroencephalographic features. Ann Neurol 1987;21:268–73.
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[7] Chugani HT, Rintahaka PJ, Shewmon DA. Ictal patterns of cerebral glucose utilization in children with epilepsy. Epilepsia 1994;35:813– 22. [8] Theodore WH, Brooks R, Margolin R, Patronas N, Sato S, Porter RJ, et al. Positron emission tomography in generalized seizures. Neurology 1985;35:684–90. [9] Prevett MC, Duncan JS, Jones T, Fish DR, Brooks DJ. Demonstration of thalamic activation during typical absence seizures using H2(15)O and PET. Neurology 1995;45:1396–402. [10] Millan E, Abou-Khalil B, Delbeke D, Konrad P. Frontal localization of absence seizures demonstrated by ictal positron emission tomography. Epilepsy Behav 2001;2:54–60. [11] Engel J, Kuhl DE, Phelps ME, Rausch R, Nuwer M. Local cerebral metabolism during partial seizures. Neurology 1983;33:400–13. [12] Henry TR, Votaw JR. The role of positron emission tomography with [18F]fluorodeoxyglucose in the evaluation of the epilepsies. Neuroimag Clin N Am 2004;14:517–35.