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Cortical stimulation in the definition of the stimulation-induced aura zone
Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging Handbook of Clinical Neurophysiology, Vol. 3 Felix Rosenow and Hans O. Lüders (Eds.) © 2004 Elsevier B.V. All rights reserved
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CHAPTER 2.13
Cortical stimulation in the definition of the stimulation-induced aura zone Reinhard Schulz∗ Abteilung f¨ur Pr¨achirurgische Intensiv-Diagnostik, Epilepsiezentrum Bethel, Maraweg 21, D-33617 Bielefeld, Germany
1. Introduction Since the beginning of epilepsy surgery, neurologists and neurosurgeons have tried to localize the epileptogenic focus with the knowledge and the diagnostic tools of their time. Stimulation-induced auras (SIA) and seizures (SIS) have always been important in cortical localization since Fritsch and Hitzig (1870) discovered the irritability of the cortex using electrical stimulation in animals. The aura is defined as that portion of the seizure which occurs before consciousness is lost and for which memory is retained afterwards (Commission on Classification and Terminology of the International League Against Epilepsy, 1981). The SIA zone is one of several zones defining the epileptogenic zone (L¨uders and Awad, 1992; Rosenow and L¨uders, 2001). In this chapter, the role of SIA and SIS in various epochs of epilepsy surgery will be discussed, together with considerations about pathophysiologic aspects. 2. Cortical stimulation, SIA, and SIS in the beginning of epilepsy surgery In the history of epilepsy research, seizures were induced by electrical stimulation, mechanical palpation of the brain during surgery, local or systematic application of drugs, and peripheral stimulation (e.g. photic stimulation). Regarding electrical stimulation, some investigators used intermittent, faradic current, unipolar or bipolar stimulation, whereas others used galvanic, constant current stimulation. Krause favored faradic current after induction of a severe secondarily generalized tonic clonic seizure during surgery using galvanic stimulation (Krause, 1931, pp. 452–453).
∗
E-mail address: [email protected] Tel.: +49-521-144-4020; fax: +49-521-144-4562.
Foerster used a galvanic current because he judged the risk of seizures to be smaller. To monitor current intensity preoperatively, Krause used to increase the current intensity until he felt a tingling sensation when touching his tongue with the electrode; intraoperatively he held the electrodes between his bare fourth and fifth fingers. Based on their observations of cortical stimulation in dogs in 1870, Fritsch and Hitzig established a cortical theory of epilepsy as opposed to the concept of a generation of seizures by subcortical nuclei, e.g. the medulla oblongata (Taylor, 1958). In their studies, Fritsch and Hitzig stimulated the motor cortex and elicited epileptic seizures with increased stimulation intensity. They strongly influenced Jackson, who focused his studies on the semiology of unilateral motor seizures. Jackson argued that local symptoms like cloni of an arm imply a local lesion of the brain: “We may break up epilepsy proper into natural groups. If one patient’s fits always begin by vertigo, and another’s always by epigastric sensation, it follows of necessity that different parts of the nervous system are diseased in the two patients” (Jackson, cited by Taylor, 1958, p. 306). During the first decades of epilepsy research, the diagnosis of epilepsy was dependent on the occurrence of unilateral or generalized motor seizures, and so Jackson coined the term “variety of epilepsy” for seizures characterized by “dreamy states” (Jackson, cited by Taylor, 1958, p. 391). Krause (1931, pp. 103–104) used the term “petit mal” for seizures lasting only a few seconds, regardless of the semiology, including auras, tonic seizures, absences. Knowing the typical motor sequence of the cortex, Jackson classified the seizure semiology of unilateral motor seizures to draw conclusions about the anatomical site of the lesion (Jackson, cited by Taylor, 1958, pp. 116–117). Horsley (1886) reported such an inference in the discussion with Jackson about his second case of epilepsy surgery.
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In the following decades, SIA and SIS were monitored routinely during surgery. Cortex outside the central region was mostly disregarded. Wernicke (1881) also referred to Fritsch and Hitzig. Epilepsy, in his opinion, was an “obscure chapter of pathology” (“ein dunkles Gebiet der Pathologie”, p. 237). On the next page, he stated “The motor zone of the cortex is the principal organ of the epileptic convulsions. Direct or indirect stimulation of this zone is the main cause of the epileptic condition, regardless of the different etiologies.” Stimulation outside the motor cortex could also elicit a seizure because of electric short circuits (“Stromschleifen”). In his opinion, epilepsy without cloni/convulsions should rather be seen as neurosis than as epilepsy (Wernicke, 1881, p. 306). Monakow (1905) stated that Jackson-type seizures were not frequent and only occur in stimulation of circumscribed parts of the motor zone. He added that sometimes Jackson type seizures did not originate in the central region. In some of those cases, surgeons had been misled to perform a central resection in search of a small tumor (Monakow, 1905, p. 581). Cushing (1909) assumed that auras elicited by electrical stimulation of the cortex could identify the epileptogenic zone when he wrote that, in the future, it would be possible “to pick out with an electrode areas of the brain from which the sensory aura of a focal convulsion has originated” and speculated that this methodology would eventually lead toward “operative localization of subcortical irritative lesions of the immediate postcentral field.” When mentioning subcortical lesions, he was referring to lesions which could not be detected by intraoperative inspection. From 1900 to 1923, Krause performed many craniotomies and surgery on Jacksonian epilepsy. Krause found only the central motor area to be sensitive to stimulation. He sought to elicit habitual motor seizures by weak current (Krause, 1911, pp. 181, 187) and defined the “primary seizure center” (“das prim¨ar krampfende Zentrum”) which was characterized by increased irritability to SIS (Krause and Schum, 1931, pp. 454–462). He found that cortical lesions outside the primary somatosensory cortex may also cause Jackson-type seizures – the closer, the more likely (Krause and Schum, 1931, p. 499). Stimulation of the central gyrus gave him good intraoperative orientation especially in subcortical central tumors (Krause, 1911, p. 189). Krause explained the operative failures of other surgeons, proposing that they resected part of the central gyrus only regarding the semiology of the
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Jackson seizures but did not consider the results of stimulation (Krause, 1911, p. 251). In his opinion, SIS could successfully localize primary seizure centers, even without intraoperative evidence of a lesion. For example, he reported a patient with extended resection to the primary somatosensory cortex after electrical induction of a somatosensory aura (Krause and Schum, 1931, p. 457). The localization of other aura types like warmth, fear, and abdominal sensation was not known then, but Krause commented that an origin in the brainstem was not proven (Krause and Schum, 1931, pp. 498–499). 3. Cortical stimulation and SIA zone after the introduction of EEG The modern period of epilepsy surgery can be said to begin with the publication of Foerster’s experience in 1925 and his studies published together with Penfield (Foerster, 1925; Foerster and Penfield, 1925, 1930a,b). Foerster’s seminal work came together with the discovery of the EEG (Berger, 1929). Foerster and Altenburger (1935) reported intraoperative cortical EEG records of 30 patients from various regions, including an ictal EEG of the motor cortex accompanied by cloni. Gibbs et al. (1935) found spike wave complexes in absences and, in focal epilepsy, local spikes and localized EEG seizure patterns (Gibbs et al., 1936). Foerster (1925) was the first to use extensive stimulation outside the central cortex, and reported on somatosensory, auditory, olfactory, gustatory, visual SIA, and prefrontal SIS. Foerster and Penfield (1930a) reported the provocation of habitual seizures and auras by mechanical irritation and by stimulation with faradic current in a summary of 12 cases. In their stimulation studies, they carefully documented responses from the primary sensory and motor area, the occurrence of SIA and SIS, and they outlined the visible epileptogenic lesion and the borders of the resections. In 6 of 12 cases (50%), the patient’s habitual seizure or aura was elicited by electrical stimulation. In 2 patients, the cortical area with SIA or SIS was located within the epileptogenic lesion, and in 4 patients, the cortical area with SIA or SIS lay closely to the epileptogenic lesion (1 cm or less). In all 6 patients, the cortical area from which a habitual aura or seizure was elicited was resected together with complete removal of the epileptogenic lesion (Fig. 1). Apparently, Foerster assumed that the area with SIA was part of the epileptogenic zone which had to be resected to achieve freedom from seizure.
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Fig. 1. Hatched area: lesion. Dotted line: limits of resection. Small black circle (within limits of resection): flexion of left arm and left leg elicited by stimulation (6 mA). X: stimulation-induced somatosensory aura of the left body followed by turning of head and trunk to the left and generalized tonic–clonic seizure. (Adapted from Foerster and Penfield 1930a, with permission.)
An initiative to develop epilepsy surgery further was taken by Penfield after the foundation of the Montreal Neurological Institute in 1934. In a study relating the Montreal experience, intraoperative stimulation reproduced habitual auras in 44 out of 80 patients (55%) with nontumoral parietal lobe epilepsy, in 10 out of 25 patients (40%) with tumoral parietal lobe epilepsy (Salanova et al., 1995), and in 37% of 29 patients with occipital lobe epilepsy (Salanova et al., 1992). Some of the patients with SIA are illustrated in detail in Penfield’s and Jasper’s (1954) compendium “Epilepsy and the functional anatomy of the human brain”. Penfield and Jasper (1954, pp. 712–727) considered SIA to be an important criterion for delineating the limits of resection: “Electrical stimulation is the original method of initiating focal cortical epileptic discharge, and is still one of the best.” They carefully adjusted the stimulus intensity to initiate local discharges in a very restricted area of cortex: “Areas most susceptible to afterdischarge, especially if associated with the aura or onset of the patient’s seizure, indicate a hyperirritable cortex which may be the focus of spontaneous epileptic seizures.” Penfield and Jasper also commented on SIA/SIS after spread from a distant source, suggesting that the SIA/SIS zone rarely leads to false assumptions about an epileptogenic region in silent cortex: “Volleys of nerve impulses arriving in a hyperirritable area of the cortex from different distant sources may serve
to initiate epileptiform discharge in a manner similar to the direct stimulation of a hyperirritable cortex.” In one of his documented cases, they commented that “distant stimulation had its effect by means of neuronal conduction along connecting pathways.” But they mostly found a convergence of the irritative and SIA/SIS zone: In the majority of cases, however, there is a close correlation between a spike focus and the area of susceptibility to prolonged afterdischarge. There is also fairly good correspondence between the area of prolonged afterdischarge and the site from which the aura or onset of the attack was reproduced by electrical stimulation. In most cases, the SIA zone was resected. 4. Cortical stimulation and SIA zone after the introduction of brain imaging (MRI) Brain imaging has considerably changed the diagnosis of the epileptogenic lesion such that preoperative, noninvasive detection is possible in most cases, in contrast to the previous importance of EEG and, during surgery, inspection, electrocorticography, and assessment of SIA/SIS (Sperling et al., 1987; Kuzniecky et al., 1993).
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Recently, SIA/SIS have mostly been elicited using subdural grid electrodes (Lesser et al., 1987; L¨uders et al., 1987). Our results of a study of a cohort of patients from Bethel, Germany are illustrative (Schulz et al., 1997). In a retrospective and prospective study of 31 patients, we evaluated the value of SIA to define the extent of the epileptogenic zone during epilepsy surgery. Invasive video and EEG monitoring with subdural grid electrodes was performed after previous noninvasive video and EEG monitoring with closely spaced electrodes according to the 10–10 system. All patients had high-resolution MRIs. After assessing the irritative zone and the EEG onset zone, cortical stimulation was carried out. The stimulation current was increased in steps of 0.5–1.0 mA, starting at 1 mA to a maximum intensity of 15 mA. Responses were regarded as SIA when: (1) the symptoms elicited by cortical stimulation were identical to the patient’s habitual aura; (2) the same aura could be elicited repeatedly; and (3) no afterdischarges occurred. Sixteen of 31 patients (52%) had SIA. The epilepsy syndromes were classified as follows: 8 frontal lobe epilepsy, 3 parieto occipital lobe epilepsy, 3 temporal lobe epilepsy, 1 perirolandic epilepsy, and 1 nonlocalizable focal epilepsy. In three patients, the habitual first subjective sign of the seizure was not an aura in the strict sense of the term but a sensation of movement of an eye, a sensation of clonic jerks on one side of the mouth, or inability to speak (aphasic seizure). SIA were elicited with 1 to 20 electrodes per patient (mean 4.8). SIA occurred upon stimulation above the epileptogenic lesion in 75% of the patients (12 out of 16), in 3 patients 1 cm from the lesion, and in 1 patient 2 cm from the lesion. The zone of SIA overlapped with the EEG seizure-onset zone in 75% of the patients (12 out of 16); in 3 patients, the EEG seizure-onset zone was 1 cm apart, and in the other patient, SIA were located on the convexity of the cortex, whereas the EEG seizure onset was on the mesial plate adjacent to the opposite limits of the lesion. Overlap of the SIA zone with the irritative zone of interictal spikes was observed in only 50% of the patients (8 out of 16). Relating surgical outcome to complete or incomplete resection of the epileptogenic lesion, the EEG seizureonset zone, SIA zone, and irritative zone of interictal spikes, we found a significant correlation of surgical outcome only with the total removal of the epileptogenic lesion (Fisher’s exact test, two-tailed P < 0.001). With complete or incomplete resection of the EEG
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seizure-onset zone, SIA zone, or irritative zone, it was not possible to predict the surgical outcome. De Salles et al. (1994) reported a small series of 12 patients with invasive diagnosis using subdural strip electrodes. Cortical stimulation was performed in 8 patients. De Salles et al. argued that confirmation with intracranial recordings was important for the final decision of resection, especially for the patient who experienced speech arrest, usual seizures and aura during cortical stimulation. Cortical stimulation confirmed the seizure focus by inducing the usual seizures or aura in 75% of the patients undergoing electrical stimulation. In France, evaluation of epilepsy patients with stereotactically placed intracerebral depth electrodes has a long tradition. Chauvel et al. (1993) reported on a series of 72 patients with mesial or lateral temporal lobe epilepsy and with frontal lobe epilepsy in whom SIA or SIS were recorded in addition to the documentation of spontaneous seizures. They found SIA/SIS to be a reliable tool in understanding the relationships between hyperexcitable zone(s) and ictal symptomatology. They summarized that hyperexcitable zones comprise a network connected by facilitated pathways which can be traced by SIA/SIS. Such knowledge could be helpful for disconnection or resection of pathways in patients in whom the total resection of the epileptogenic lesion is not possible. 5. Pathophysiology of SIA/SIS Like other zones (irritative zone of interictal sharp waves and the ictal-onset zone as defined by scalp or invasive EEG, the ictal symptomatogenic zone as defined by aura and ictal semiology, and the functional-deficit zone as defined, for example, by PET), the SIA and SIS zone may well extend beyond the epileptogenic zone (Jackson according to Taylor, 1958; Jokeit et al., 1997; Henkel et al., 2002). Kinnier Wilson (1935) presented three theories of discharge in epileptic seizures which can be helpful in explaining the generation of SIA/SIS: 1. Theory of irritation: Irritation of the cortex is followed by an aura which sets off an avalanche overwhelming adjoining centers. 2. Theory of release: Inhibitory control around a focus is lost.
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Fig. 2. Patient TN72, convexity of the left hemisphere. (Adapted from Schulz et al., 1997, with permission.)
3. Short-circuit theory: A modified release theory assumes simplification of reflex arcs through the cortex in consequence of cortical disease (traumatic, developmental, or whatever it may be), with the result that impulses reaching the brain are not, as it were, diluted by spread through association systems, but compelled to take shorter and abnormal routes; this is imagined to induce discharge. Extended irritative cortex and/or facilitated pathways can explain the induction of SIA/SIS above and in a distance from the epileptogenic lesion. Pathological neuronal connections can be assumed in malformations of cortical development like focal cortical dysplasias, around tumors (e.g. gangliogliomas), in mesial temporal sclerosis, and in ischemic and traumatic lesions. Theoretically, there are two alternative explanations for the occurrence of SIA in the absence of afterdischarges: (1) a symptomatogenic zone is stimulated directly; or (2) the stimulation activated an area outside the symptomatogenic zone which has facilitated pathways to a specific symptomatogenic zone. In the second case, the cortical area with the facilitated pathway could represent part of the epileptogenic zone. If the first hypothesis is correct, the SIA zone should have a location and size consistent with the expected location and size of the corresponding symptomatogenic area. In the Bethel study presented above, neither of these two assumptions was supported, because the SIA area was often too large and in most cases was located outside the expected functional map. If the second hypothesis is correct, we could expect a close correlation of the SIA area to the epileptogenic zone and the EEG seizure-onset zone. All the data presented here support the second hypothesis. Functional reor-
ganization as a consequence of the underlying cortical lesion may lead to a significant distortion of the normal cortical representation (Merzenich et al., 1983). Such a functional reorganization cannot be ruled out, but this possibility is not supported by the otherwise normal cortical representation in the patients of our study. However, the conclusion of a close proximity of SIA and the lesion remains the same, irrespective of whether we assume facilitated pathways indicating epileptogenicity or functional and structural reorganization within or close to the epileptogenic lesion. This conclusion is well illustrated in patient TN72 from our study (Fig. 2). The area of cortical somatosensory representation of the hand, lower, and upper arm is larger than usual. Identical somatosensory symptoms in the right upper arm (Jackson march) were elicited by stimulation from eight electrodes. This suggests the existence of a facilitated propagation to the representation of the right upper arm. In addition, a march of the aura from the upper arm into the right hand was observed on stimulation of the inferior five electrodes near the primary sensory area of the hand. This stereotyped march also supports the hypothesis of an epileptogenic, facilitated pathway. However facilitated propagation was lacking in the primary motor cortex, as no auras could be induced anterior to the central sulcus, although the lesion covered parts of the primary motor cortex. 6. Current role of SIA/SIS in epilepsy surgery A patient’s history (semiology of aura and seizure), MRI, interictal and ictal scalp EEG, neuropsychology, invasive EEG, SIA/SIS, and intraoperative ECoG are the usual methods for defining the epileptogenic zone.
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Successful epilepsy surgery primarily depends on the complete resection of the lesion as determined by postoperative MRI. With increasing imaging quality, the importance of intracranial stimulation has been reduced, and noninvasive monitoring is sufficient in most patients. High-resolution MRI today often detects epileptogenic lesions, in contrast with the experience of Cushing (1909), who hoped to find invisible, subcortical lesions by SIA/SIS. Convergence of all obtained data should be sought in spite of today’s wide spectrum of methodologies. The localization of SIA and SIS will be considered as an index of epileptogenicity – in modern epilepsy surgery as in earlier times – in cases in which invasive monitoring with subdural electrodes is necessary. References ¨ Berger, H (1929) Uber das Elektroenkephalogramm des Menschen. Arch. Psychiat. Nervenkr., 87: 527–570. Chauvel, P, Landr´e, E, Trottier, S, Vignel, JP, Biraben, A, Devaux, B and Bancaud, J (1993) Electrical stimulation with intracerebral electrodes to evoke seizures. In: O Devinsky, A Beric and M Dogali (Eds.), Electrical and Magnetic Stimulation of the Brain and Spinal Cord. Adv. Neurol., 63: 115–121. Commission on Classification and Terminology of the International League Against Epilepsy (1981) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia, 22: 489–501. Cushing, H (1909) A note upon the faradic stimulation of the postcentral gyrus in conscious patients. Brain, 32: 44–53. De Salles, AA, Swartz, BE, Lee, TT and Delgado-Escueta, AV (1994) Subdural recording and electrical stimulation for cortical mapping and induction of usual seizures. Stereotact. Func. Neurosurg., 62: 226–231. Foerster, O (1925) Zur Pathogenese und chirurgischen Behandlung der Epilepsie. Zentralbl. Chir., 52: 531–548. Foerster, O and Altenburger, H (1935) Elektrobiologische Vorg¨ange an der menschlichen Hirnrinde. Dtsch. Z. Nervenheilk., 135: 277–288. Foerster, O and Penfield, W (1930a) Der Narbenzug am und im Gehirn bei traumatischer Epilepsie in seiner Bedeutung f¨ur das Zustandekommen der Anf¨alle und die therapeutische Bek¨ampfung derselben. Z. Ges. Neurol., 125: 475–572. Foerster, O and Penfield, W (1930b) The structural basis of traumatic epilepsy and results of radical operation. Brain, 53: 99–119. ¨ Fritsch, G and Hitzig, E (1870) Uber die elektrische Erregbarkeit des Grosshirns. Arch. Anat. Physiol. Wiss. Med., 300–332.
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Gibbs, FA, Davis, H and Lennox, WG (1935) The electroencephalogram in epilepsy and in impaired states of consciousness. Arch. Neurol. Psychiatry, 34: 1133– 1148. Gibbs, FA, Lennox, WG and Gibbs, EL (1936) The electro-encephalogram in diagnosis and in localization of epileptic seizures. Arch. Neurol. Psychiatry, 36: 1225– 1235. Henkel, A, Noachtar, S, Pf¨ander, M and L¨uders, HO (2002) The localizing value of the abdominal aura and its evolution. Neurology, 58: 271–276. Horsley, V (1886) Brain-surgery. Br. Med. J., 2: 670–675. Jokeit, H, Seitz, RJ, Markowitsch, HJ, Neumann, N, Witte, OW and Ebner, A (1997) Prefrontal asymmetric interictal glucose hypometabolism and cognitive impairment in patients with temporal lobe epilepsy. Brain, 120: 2283–2294. Kinnier Wilson, SA (1935) The epilepsies. In: O Bumke and O Foerster (Eds.), Handbuch der Neurologie, Band 17: Spezielle Neurologie 9. Erkrankungen des R¨uckenmarks und Gehirns 7. Epilepsie, Narkolepsie, Spasmophilie, Migr¨ane, vasomotorisch-trophische Erkrankungen, neuroasthenische Reaktion, Organneurosen. Springer, Berlin, pp. 1–87. Krause, F (1911) Chirurgie des Gehirns und R¨uckenmarks. Band 2. Urban and Schwarzenberg, Berlin. Krause, F and Schum, H (1931) Die epileptischen Erkrankungen. 1. und 2. H¨alfte. In: F Krause (Ed.), Die spezielle Chirurgie der Gehirnkrankheiten. Enke, Stuttgart. Kuzniecky, RI, Cascino, GD, Palmini, A, Jack, CR, Berkovic, SF, Jackson, GD and McCarthy, G (1993) Structural neuroimaging. In: J. Engel (Ed.), Surgical Treatment of the Epilepsies, 2nd edn. Raven Press, New York, pp. 197–209. Lesser, RP, L¨uders, H, Klem, G, Dinner, DS, Morris, HH, Hahn, JF and Wyllie, E (1987) Extraoperative cortical functional localization in patients with epilepsy. J. Clin. Neurophysiol., 4: 27–53. L¨uders, HO and Awad, I (1992) Conceptual considerations. In: HO L¨uders (Ed.), Epilepsy Surgery. Raven Press, New York, pp. 51–62. L¨uders, H, Lesser, RP, Dinner, DS, Morris, HH, Hahn, JF, Friedman, L, Skipper, G, Wyllie, E and Friedman, D (1987) Commentary: Chronic intracranial recording and stimulation with subdural electrodes. In: J Engel (Ed.) Surgical Treatment of the Epilepsies. Raven Press, New York, pp. 297–321. Merzenich, MM, Kaas, JH, Wall, JT, Sur, M, Nelson, RJ and Felleman, DJ (1983) Progression of change following median nerve section in the cortical representation of the hand in areas 3b and 1 in adult owl and squirrel monkeys. Neuroscience, 10: 639–665. Monakow, C v (1905) Gehirnpathologie. 2. Auflage. In: H Nothnagel (Ed.), Spezielle Pathologie und Therapie. H¨alder, Vienna.
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Penfield, W and Jasper, H (1954) Epilepsy and the functional anatomy of the human brain. Little, Brown and Co., Boston. Rosenow, F and L¨uders, H (2001) Presurgical evaluation of epilepsy. Brain, 124: 1683–1700. Salanova, V, Andermann, F, Olivier, A, Rasmussen, T and Quesney, LF (1992) Occipital lobe epilepsy: Electroclinical manifestations, electrocorticography, cortical stimulation and outcome in 42 patients treated between 1930 and 1991. Brain, 115: 1655–1680. Salanova, V, Andermann, F, Rasmussen, T, Olivier, A and Quesney, LF (1995) Parietal lobe epilepsy: clinical manifestations and outcome in 82 patients treated surgically between 1929 and 1988. Brain, 118: 607–627.
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Schulz, R, L¨uders, HO, Tuxhorn, I, Ebner, A, Holthausen, H, Hoppe, M, Noachtar, S, Pannek, H, May, T and Wolf, P (1997) Localization of epileptic auras induced on stimulation by subdural electrodes. Epilepsia, 38: 1321– 1329. Sperling, MR, Sutherling, WW and Nuwer, MR (1987) New techniques for evaluating patients for epilepsy surgery. In: J Engel (Ed.), Surgical Treatment of the Epilepsies. Raven Press, New York, pp. 235–257. Taylor, J (Ed.) (1958) Selected writings of John Hughlings Jackson. Volume 1: On Epilepsy and Epileptiform Convulsions. Staples Press, London. Wernicke, C (1881) Lehrbuch der Gehirnkrankheiten. Band 1. Fischer, Kassel.
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CHAPTER 2.13
Cortical stimulation in the definition of the stimulation-induced aura zone Reinhard Schulz∗ Abteilung f¨ur Pr¨achirurgische Intensiv-Diagnostik, Epilepsiezentrum Bethel, Maraweg 21, D-33617 Bielefeld, Germany
1. Introduction Since the beginning of epilepsy surgery, neurologists and neurosurgeons have tried to localize the epileptogenic focus with the knowledge and the diagnostic tools of their time. Stimulation-induced auras (SIA) and seizures (SIS) have always been important in cortical localization since Fritsch and Hitzig (1870) discovered the irritability of the cortex using electrical stimulation in animals. The aura is defined as that portion of the seizure which occurs before consciousness is lost and for which memory is retained afterwards (Commission on Classification and Terminology of the International League Against Epilepsy, 1981). The SIA zone is one of several zones defining the epileptogenic zone (L¨uders and Awad, 1992; Rosenow and L¨uders, 2001). In this chapter, the role of SIA and SIS in various epochs of epilepsy surgery will be discussed, together with considerations about pathophysiologic aspects. 2. Cortical stimulation, SIA, and SIS in the beginning of epilepsy surgery In the history of epilepsy research, seizures were induced by electrical stimulation, mechanical palpation of the brain during surgery, local or systematic application of drugs, and peripheral stimulation (e.g. photic stimulation). Regarding electrical stimulation, some investigators used intermittent, faradic current, unipolar or bipolar stimulation, whereas others used galvanic, constant current stimulation. Krause favored faradic current after induction of a severe secondarily generalized tonic clonic seizure during surgery using galvanic stimulation (Krause, 1931, pp. 452–453).
∗
E-mail address: [email protected] Tel.: +49-521-144-4020; fax: +49-521-144-4562.
Foerster used a galvanic current because he judged the risk of seizures to be smaller. To monitor current intensity preoperatively, Krause used to increase the current intensity until he felt a tingling sensation when touching his tongue with the electrode; intraoperatively he held the electrodes between his bare fourth and fifth fingers. Based on their observations of cortical stimulation in dogs in 1870, Fritsch and Hitzig established a cortical theory of epilepsy as opposed to the concept of a generation of seizures by subcortical nuclei, e.g. the medulla oblongata (Taylor, 1958). In their studies, Fritsch and Hitzig stimulated the motor cortex and elicited epileptic seizures with increased stimulation intensity. They strongly influenced Jackson, who focused his studies on the semiology of unilateral motor seizures. Jackson argued that local symptoms like cloni of an arm imply a local lesion of the brain: “We may break up epilepsy proper into natural groups. If one patient’s fits always begin by vertigo, and another’s always by epigastric sensation, it follows of necessity that different parts of the nervous system are diseased in the two patients” (Jackson, cited by Taylor, 1958, p. 306). During the first decades of epilepsy research, the diagnosis of epilepsy was dependent on the occurrence of unilateral or generalized motor seizures, and so Jackson coined the term “variety of epilepsy” for seizures characterized by “dreamy states” (Jackson, cited by Taylor, 1958, p. 391). Krause (1931, pp. 103–104) used the term “petit mal” for seizures lasting only a few seconds, regardless of the semiology, including auras, tonic seizures, absences. Knowing the typical motor sequence of the cortex, Jackson classified the seizure semiology of unilateral motor seizures to draw conclusions about the anatomical site of the lesion (Jackson, cited by Taylor, 1958, pp. 116–117). Horsley (1886) reported such an inference in the discussion with Jackson about his second case of epilepsy surgery.
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In the following decades, SIA and SIS were monitored routinely during surgery. Cortex outside the central region was mostly disregarded. Wernicke (1881) also referred to Fritsch and Hitzig. Epilepsy, in his opinion, was an “obscure chapter of pathology” (“ein dunkles Gebiet der Pathologie”, p. 237). On the next page, he stated “The motor zone of the cortex is the principal organ of the epileptic convulsions. Direct or indirect stimulation of this zone is the main cause of the epileptic condition, regardless of the different etiologies.” Stimulation outside the motor cortex could also elicit a seizure because of electric short circuits (“Stromschleifen”). In his opinion, epilepsy without cloni/convulsions should rather be seen as neurosis than as epilepsy (Wernicke, 1881, p. 306). Monakow (1905) stated that Jackson-type seizures were not frequent and only occur in stimulation of circumscribed parts of the motor zone. He added that sometimes Jackson type seizures did not originate in the central region. In some of those cases, surgeons had been misled to perform a central resection in search of a small tumor (Monakow, 1905, p. 581). Cushing (1909) assumed that auras elicited by electrical stimulation of the cortex could identify the epileptogenic zone when he wrote that, in the future, it would be possible “to pick out with an electrode areas of the brain from which the sensory aura of a focal convulsion has originated” and speculated that this methodology would eventually lead toward “operative localization of subcortical irritative lesions of the immediate postcentral field.” When mentioning subcortical lesions, he was referring to lesions which could not be detected by intraoperative inspection. From 1900 to 1923, Krause performed many craniotomies and surgery on Jacksonian epilepsy. Krause found only the central motor area to be sensitive to stimulation. He sought to elicit habitual motor seizures by weak current (Krause, 1911, pp. 181, 187) and defined the “primary seizure center” (“das prim¨ar krampfende Zentrum”) which was characterized by increased irritability to SIS (Krause and Schum, 1931, pp. 454–462). He found that cortical lesions outside the primary somatosensory cortex may also cause Jackson-type seizures – the closer, the more likely (Krause and Schum, 1931, p. 499). Stimulation of the central gyrus gave him good intraoperative orientation especially in subcortical central tumors (Krause, 1911, p. 189). Krause explained the operative failures of other surgeons, proposing that they resected part of the central gyrus only regarding the semiology of the
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Jackson seizures but did not consider the results of stimulation (Krause, 1911, p. 251). In his opinion, SIS could successfully localize primary seizure centers, even without intraoperative evidence of a lesion. For example, he reported a patient with extended resection to the primary somatosensory cortex after electrical induction of a somatosensory aura (Krause and Schum, 1931, p. 457). The localization of other aura types like warmth, fear, and abdominal sensation was not known then, but Krause commented that an origin in the brainstem was not proven (Krause and Schum, 1931, pp. 498–499). 3. Cortical stimulation and SIA zone after the introduction of EEG The modern period of epilepsy surgery can be said to begin with the publication of Foerster’s experience in 1925 and his studies published together with Penfield (Foerster, 1925; Foerster and Penfield, 1925, 1930a,b). Foerster’s seminal work came together with the discovery of the EEG (Berger, 1929). Foerster and Altenburger (1935) reported intraoperative cortical EEG records of 30 patients from various regions, including an ictal EEG of the motor cortex accompanied by cloni. Gibbs et al. (1935) found spike wave complexes in absences and, in focal epilepsy, local spikes and localized EEG seizure patterns (Gibbs et al., 1936). Foerster (1925) was the first to use extensive stimulation outside the central cortex, and reported on somatosensory, auditory, olfactory, gustatory, visual SIA, and prefrontal SIS. Foerster and Penfield (1930a) reported the provocation of habitual seizures and auras by mechanical irritation and by stimulation with faradic current in a summary of 12 cases. In their stimulation studies, they carefully documented responses from the primary sensory and motor area, the occurrence of SIA and SIS, and they outlined the visible epileptogenic lesion and the borders of the resections. In 6 of 12 cases (50%), the patient’s habitual seizure or aura was elicited by electrical stimulation. In 2 patients, the cortical area with SIA or SIS was located within the epileptogenic lesion, and in 4 patients, the cortical area with SIA or SIS lay closely to the epileptogenic lesion (1 cm or less). In all 6 patients, the cortical area from which a habitual aura or seizure was elicited was resected together with complete removal of the epileptogenic lesion (Fig. 1). Apparently, Foerster assumed that the area with SIA was part of the epileptogenic zone which had to be resected to achieve freedom from seizure.
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Fig. 1. Hatched area: lesion. Dotted line: limits of resection. Small black circle (within limits of resection): flexion of left arm and left leg elicited by stimulation (6 mA). X: stimulation-induced somatosensory aura of the left body followed by turning of head and trunk to the left and generalized tonic–clonic seizure. (Adapted from Foerster and Penfield 1930a, with permission.)
An initiative to develop epilepsy surgery further was taken by Penfield after the foundation of the Montreal Neurological Institute in 1934. In a study relating the Montreal experience, intraoperative stimulation reproduced habitual auras in 44 out of 80 patients (55%) with nontumoral parietal lobe epilepsy, in 10 out of 25 patients (40%) with tumoral parietal lobe epilepsy (Salanova et al., 1995), and in 37% of 29 patients with occipital lobe epilepsy (Salanova et al., 1992). Some of the patients with SIA are illustrated in detail in Penfield’s and Jasper’s (1954) compendium “Epilepsy and the functional anatomy of the human brain”. Penfield and Jasper (1954, pp. 712–727) considered SIA to be an important criterion for delineating the limits of resection: “Electrical stimulation is the original method of initiating focal cortical epileptic discharge, and is still one of the best.” They carefully adjusted the stimulus intensity to initiate local discharges in a very restricted area of cortex: “Areas most susceptible to afterdischarge, especially if associated with the aura or onset of the patient’s seizure, indicate a hyperirritable cortex which may be the focus of spontaneous epileptic seizures.” Penfield and Jasper also commented on SIA/SIS after spread from a distant source, suggesting that the SIA/SIS zone rarely leads to false assumptions about an epileptogenic region in silent cortex: “Volleys of nerve impulses arriving in a hyperirritable area of the cortex from different distant sources may serve
to initiate epileptiform discharge in a manner similar to the direct stimulation of a hyperirritable cortex.” In one of his documented cases, they commented that “distant stimulation had its effect by means of neuronal conduction along connecting pathways.” But they mostly found a convergence of the irritative and SIA/SIS zone: In the majority of cases, however, there is a close correlation between a spike focus and the area of susceptibility to prolonged afterdischarge. There is also fairly good correspondence between the area of prolonged afterdischarge and the site from which the aura or onset of the attack was reproduced by electrical stimulation. In most cases, the SIA zone was resected. 4. Cortical stimulation and SIA zone after the introduction of brain imaging (MRI) Brain imaging has considerably changed the diagnosis of the epileptogenic lesion such that preoperative, noninvasive detection is possible in most cases, in contrast to the previous importance of EEG and, during surgery, inspection, electrocorticography, and assessment of SIA/SIS (Sperling et al., 1987; Kuzniecky et al., 1993).
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Recently, SIA/SIS have mostly been elicited using subdural grid electrodes (Lesser et al., 1987; L¨uders et al., 1987). Our results of a study of a cohort of patients from Bethel, Germany are illustrative (Schulz et al., 1997). In a retrospective and prospective study of 31 patients, we evaluated the value of SIA to define the extent of the epileptogenic zone during epilepsy surgery. Invasive video and EEG monitoring with subdural grid electrodes was performed after previous noninvasive video and EEG monitoring with closely spaced electrodes according to the 10–10 system. All patients had high-resolution MRIs. After assessing the irritative zone and the EEG onset zone, cortical stimulation was carried out. The stimulation current was increased in steps of 0.5–1.0 mA, starting at 1 mA to a maximum intensity of 15 mA. Responses were regarded as SIA when: (1) the symptoms elicited by cortical stimulation were identical to the patient’s habitual aura; (2) the same aura could be elicited repeatedly; and (3) no afterdischarges occurred. Sixteen of 31 patients (52%) had SIA. The epilepsy syndromes were classified as follows: 8 frontal lobe epilepsy, 3 parieto occipital lobe epilepsy, 3 temporal lobe epilepsy, 1 perirolandic epilepsy, and 1 nonlocalizable focal epilepsy. In three patients, the habitual first subjective sign of the seizure was not an aura in the strict sense of the term but a sensation of movement of an eye, a sensation of clonic jerks on one side of the mouth, or inability to speak (aphasic seizure). SIA were elicited with 1 to 20 electrodes per patient (mean 4.8). SIA occurred upon stimulation above the epileptogenic lesion in 75% of the patients (12 out of 16), in 3 patients 1 cm from the lesion, and in 1 patient 2 cm from the lesion. The zone of SIA overlapped with the EEG seizure-onset zone in 75% of the patients (12 out of 16); in 3 patients, the EEG seizure-onset zone was 1 cm apart, and in the other patient, SIA were located on the convexity of the cortex, whereas the EEG seizure onset was on the mesial plate adjacent to the opposite limits of the lesion. Overlap of the SIA zone with the irritative zone of interictal spikes was observed in only 50% of the patients (8 out of 16). Relating surgical outcome to complete or incomplete resection of the epileptogenic lesion, the EEG seizureonset zone, SIA zone, and irritative zone of interictal spikes, we found a significant correlation of surgical outcome only with the total removal of the epileptogenic lesion (Fisher’s exact test, two-tailed P < 0.001). With complete or incomplete resection of the EEG
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seizure-onset zone, SIA zone, or irritative zone, it was not possible to predict the surgical outcome. De Salles et al. (1994) reported a small series of 12 patients with invasive diagnosis using subdural strip electrodes. Cortical stimulation was performed in 8 patients. De Salles et al. argued that confirmation with intracranial recordings was important for the final decision of resection, especially for the patient who experienced speech arrest, usual seizures and aura during cortical stimulation. Cortical stimulation confirmed the seizure focus by inducing the usual seizures or aura in 75% of the patients undergoing electrical stimulation. In France, evaluation of epilepsy patients with stereotactically placed intracerebral depth electrodes has a long tradition. Chauvel et al. (1993) reported on a series of 72 patients with mesial or lateral temporal lobe epilepsy and with frontal lobe epilepsy in whom SIA or SIS were recorded in addition to the documentation of spontaneous seizures. They found SIA/SIS to be a reliable tool in understanding the relationships between hyperexcitable zone(s) and ictal symptomatology. They summarized that hyperexcitable zones comprise a network connected by facilitated pathways which can be traced by SIA/SIS. Such knowledge could be helpful for disconnection or resection of pathways in patients in whom the total resection of the epileptogenic lesion is not possible. 5. Pathophysiology of SIA/SIS Like other zones (irritative zone of interictal sharp waves and the ictal-onset zone as defined by scalp or invasive EEG, the ictal symptomatogenic zone as defined by aura and ictal semiology, and the functional-deficit zone as defined, for example, by PET), the SIA and SIS zone may well extend beyond the epileptogenic zone (Jackson according to Taylor, 1958; Jokeit et al., 1997; Henkel et al., 2002). Kinnier Wilson (1935) presented three theories of discharge in epileptic seizures which can be helpful in explaining the generation of SIA/SIS: 1. Theory of irritation: Irritation of the cortex is followed by an aura which sets off an avalanche overwhelming adjoining centers. 2. Theory of release: Inhibitory control around a focus is lost.
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Fig. 2. Patient TN72, convexity of the left hemisphere. (Adapted from Schulz et al., 1997, with permission.)
3. Short-circuit theory: A modified release theory assumes simplification of reflex arcs through the cortex in consequence of cortical disease (traumatic, developmental, or whatever it may be), with the result that impulses reaching the brain are not, as it were, diluted by spread through association systems, but compelled to take shorter and abnormal routes; this is imagined to induce discharge. Extended irritative cortex and/or facilitated pathways can explain the induction of SIA/SIS above and in a distance from the epileptogenic lesion. Pathological neuronal connections can be assumed in malformations of cortical development like focal cortical dysplasias, around tumors (e.g. gangliogliomas), in mesial temporal sclerosis, and in ischemic and traumatic lesions. Theoretically, there are two alternative explanations for the occurrence of SIA in the absence of afterdischarges: (1) a symptomatogenic zone is stimulated directly; or (2) the stimulation activated an area outside the symptomatogenic zone which has facilitated pathways to a specific symptomatogenic zone. In the second case, the cortical area with the facilitated pathway could represent part of the epileptogenic zone. If the first hypothesis is correct, the SIA zone should have a location and size consistent with the expected location and size of the corresponding symptomatogenic area. In the Bethel study presented above, neither of these two assumptions was supported, because the SIA area was often too large and in most cases was located outside the expected functional map. If the second hypothesis is correct, we could expect a close correlation of the SIA area to the epileptogenic zone and the EEG seizure-onset zone. All the data presented here support the second hypothesis. Functional reor-
ganization as a consequence of the underlying cortical lesion may lead to a significant distortion of the normal cortical representation (Merzenich et al., 1983). Such a functional reorganization cannot be ruled out, but this possibility is not supported by the otherwise normal cortical representation in the patients of our study. However, the conclusion of a close proximity of SIA and the lesion remains the same, irrespective of whether we assume facilitated pathways indicating epileptogenicity or functional and structural reorganization within or close to the epileptogenic lesion. This conclusion is well illustrated in patient TN72 from our study (Fig. 2). The area of cortical somatosensory representation of the hand, lower, and upper arm is larger than usual. Identical somatosensory symptoms in the right upper arm (Jackson march) were elicited by stimulation from eight electrodes. This suggests the existence of a facilitated propagation to the representation of the right upper arm. In addition, a march of the aura from the upper arm into the right hand was observed on stimulation of the inferior five electrodes near the primary sensory area of the hand. This stereotyped march also supports the hypothesis of an epileptogenic, facilitated pathway. However facilitated propagation was lacking in the primary motor cortex, as no auras could be induced anterior to the central sulcus, although the lesion covered parts of the primary motor cortex. 6. Current role of SIA/SIS in epilepsy surgery A patient’s history (semiology of aura and seizure), MRI, interictal and ictal scalp EEG, neuropsychology, invasive EEG, SIA/SIS, and intraoperative ECoG are the usual methods for defining the epileptogenic zone.
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Successful epilepsy surgery primarily depends on the complete resection of the lesion as determined by postoperative MRI. With increasing imaging quality, the importance of intracranial stimulation has been reduced, and noninvasive monitoring is sufficient in most patients. High-resolution MRI today often detects epileptogenic lesions, in contrast with the experience of Cushing (1909), who hoped to find invisible, subcortical lesions by SIA/SIS. Convergence of all obtained data should be sought in spite of today’s wide spectrum of methodologies. The localization of SIA and SIS will be considered as an index of epileptogenicity – in modern epilepsy surgery as in earlier times – in cases in which invasive monitoring with subdural electrodes is necessary. References ¨ Berger, H (1929) Uber das Elektroenkephalogramm des Menschen. Arch. Psychiat. Nervenkr., 87: 527–570. Chauvel, P, Landr´e, E, Trottier, S, Vignel, JP, Biraben, A, Devaux, B and Bancaud, J (1993) Electrical stimulation with intracerebral electrodes to evoke seizures. In: O Devinsky, A Beric and M Dogali (Eds.), Electrical and Magnetic Stimulation of the Brain and Spinal Cord. Adv. Neurol., 63: 115–121. Commission on Classification and Terminology of the International League Against Epilepsy (1981) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia, 22: 489–501. Cushing, H (1909) A note upon the faradic stimulation of the postcentral gyrus in conscious patients. Brain, 32: 44–53. De Salles, AA, Swartz, BE, Lee, TT and Delgado-Escueta, AV (1994) Subdural recording and electrical stimulation for cortical mapping and induction of usual seizures. Stereotact. Func. Neurosurg., 62: 226–231. Foerster, O (1925) Zur Pathogenese und chirurgischen Behandlung der Epilepsie. Zentralbl. Chir., 52: 531–548. Foerster, O and Altenburger, H (1935) Elektrobiologische Vorg¨ange an der menschlichen Hirnrinde. Dtsch. Z. Nervenheilk., 135: 277–288. Foerster, O and Penfield, W (1930a) Der Narbenzug am und im Gehirn bei traumatischer Epilepsie in seiner Bedeutung f¨ur das Zustandekommen der Anf¨alle und die therapeutische Bek¨ampfung derselben. Z. Ges. Neurol., 125: 475–572. Foerster, O and Penfield, W (1930b) The structural basis of traumatic epilepsy and results of radical operation. Brain, 53: 99–119. ¨ Fritsch, G and Hitzig, E (1870) Uber die elektrische Erregbarkeit des Grosshirns. Arch. Anat. Physiol. Wiss. Med., 300–332.
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