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The mirror focus phenomenon and secondary epileptogenesis in human epilepsy
ELSEVIER
The Mirror Focus Phenomenon and Secondary Epileptogenesis in Human Epilepsy ’ Richard J. McCarthy,
2f3 Michael J. O’Connor,
and 2f4 Michael R. Sperling
Although the mirror focus and secondary epileptogenesis are described in animal models of focal epilepsy, the relevance of these phenomena to human epilepsy is controversial. We reviewed 30 patients with unilateral epileptogenie low-grade structural lesions and sought evidence of secondary epileptogenesis. Patients with evidence of mirror foci were compared with patients with unilateral discharges. The incidence of interictal mirror foci was 27%.
Location of the primary epileptogenic lesion, duration of epilepsy, age of onset of epilepsy, and postoperative seizure outcome were not affected by the presence of a mirror focus. One patient had evidence of independent secondary epileptogenesis and had had seizures arising independently from that focus of homotopic cortex contralateral to a tumor 3.75 years after excision of the primary lesion. We conclude that secondary epileptogenesis is not uncommon in
humans and that independent foci capable of generating seizures may be focus-Secondary epileptoformed. Key Words: Epilepsy-Tumor-Mirror 0 1997 by Elsevier Science Inc. All rights reserved. genesis-Outcome.
Secondary epileptogenesis encompasses a range of abnormalities that develop after the creation of a primary epileptogenic lesion in the brain in animal models of epilepsy (l-5). Interictal spikes first appear in the area of the primary lesion; in time, spikes develop in contralateral homotopic cortex. Although these spikes are initially dependent and linked temporally to spikes in the primary lesion, Received May 17,1996; accepted September 23,1996. From the ‘Department of Neurology, University of California San Francisco, San Francisco, CA; 2Comprehensive Epilepsy Center, The Graduate Hospital; 3Division of Neurosurgery, University of Pennsylvania School of Medicine; and 4Department of Neurology, Temple University School of Medicine, Philadelphia, PA, U.S.A. Address correspondence and reprint requests to Dr. Michael R. Sperling at Comprehensive Epilepsy Center, Graduate Hospital, 1 Graduate Plaza, Philadelphia, PA 19146, U.S.A. J. Epilepsy 1997;10:78-85 0 1997 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
with further passage of time spikes may develop in contralateral homotopic cortex that are not temporally linked to the discharging primary focus. These contralateral spikes, which have been termed a mirror focus, then occur asynchronously and reflect a fundamental change in the underlying excitability of that homotopic cortex. If ablation of the primary cortex is performed at this stage, the contralateral spike will ultimately disappear. However, if the primary lesion remains undisturbed, later excision of the primary lesion may not abolish the interictal spikes in homotopic cortex. The contralateral spikes may then be considered as independent, and this stage probably represents a fundamental change in the character of the secondary lesion (1). As the process progresses further, recurrent seizures may arise from that contralateral homotopic focus, which has become a fully independent cause of epilepsy in the animal. The duration of the process and
0896-6974/97/$17.00 PI1 SO896-6974(96)00077-l
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density of connections have been suggested to be the critical factors in determining whether secondary epileptogenesis will occur (1). Secondary epileptogenesis has been suggested to be relevant to human epilepsy, although this possibility has been debated (2). Nonetheless, many of the features observed in animal models of secondary epileptogenesis are also observed in humans (1). One quarter to one third of people with unilateral brain lesions and epilepsy may have bilateral interictal spike foci (1,6-Q However, this contralatera1 focus has several possible explanations. It could be due either to another primary brain abnormality related or unrelated to the obvious lesion, to brain injury directly caused by seizures (e.g., anoxia or head trauma), or secondary epileptogenesis. Given the wealth of animal data supporting secondary epileptogenesis, the amount of data bolstering the presence of such a process in humans is limited. However, the limitations in studying human epilepsy make secondary epileptogenesis difficult to document because of these potential confounding factors. Although there has been some evidence of seizures arising in the hemisphere opposite a tumor before surgery (1,8), to date only one investigator (1) has provided evidence of contralatera1 seizures that persisted long after excision of a primary epileptogenic lesion in humans. We reviewed the Graduate Hospital experience in patients with unilateral tumors and vascular malformations to seek further evidence of secondary epileptogenesis. We determined the incidence of contralateral interictal and ictal EEG foci and related their presence to risk factors suggested by previous animal work (2,3,9). Because of the enormous discrepancy regarding the incidence of secondary seizures in the literature (1,8), we also examined the frequency of seizures from the mirror focus before and after surgery and the relation between the mirror focus phenomenon and postoperative seizure relief.
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were excluded because of possible confounding epilepsy risk factors such as head trauma with loss of consciousness, childhood febrile convulsions, encephalitis, meningitis, perinatal complications, or central nervous system irradiation. These patients were excluded so that no other possible reasons would exist for epilepsy in this population. One additional patient was excluded because all his preoperative scalp EEGs were interpreted at an outside hospital and not reviewed at our institution. All patients had focal unilateral pathology on preoperative magnetic resonance imaging (MRI).
EEG Recording All patients had scalp EEG recorded with lo-20 system and sphenoidal electrodes (10). Eighteen subjects underwent prolonged ambulatory or inpatient video-EEG monitoring, and 12 had only outpatient interictal EEG recording. Inpatient monitoring was performed with a 16-21 channel Telefactor Corporation system (Conshohoken, PA) with automated spike and seizure detection or continuous paper write-out. Random interictal samples also were recorded. Ambulatory recording was obtained with a 16-channel system (Digitrace, Boston, MA) with automatic spike and seizure detection and random time samples. EEGs from all patients were examined in wakefulness and sleep. All EEGs were read by board-certified electroencephalographers. Outside EEG reports were not considered for the study. Results of intracranial monitoring were not considered in the study. All EEGs were examined for interictal spike and sharp waves. These were considered present only if they were observed more than once during EEG recording. Seizures were recorded before surgery in 11 patients. The remainder underwent surgery based on interictal EEG findings, MRI, and the neurologic history and examination.
Surgery, Surgical Pathology, and Outcome Methods Patients Fifty patients with intractable partial epilepsy underwent surgical resection of unilateral intracerebra1 tumors or vascular malformations between 1986 and 1993 at the Graduate Hospital in Philadelphia. Thirty patients were eligible for the present review, and 20 were excluded. Nineteen patients
The same neurosurgeon (M.J.0) performed all operations. Patients with temporal lobe lesions underwent anterior temporal lobectomies with the tumor or vascular malformation included in the margins. Patients with extratemporal tumors had their tumors excised along with a margin of adjacent tissue. All specimens were reviewed by a neuropathologist. The histopathology of tissue from patients with persistent postoperative seizures were also reviewed by a second neuropathologist (Dr. J EPILEPSY, VOL. 10, NO. 2, 1997
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Lucy Rorke) to verify diagnoses. Postoperative seizure outcome was determined in each patient at the time of most recent examination. Subjects were classified as either being seizure-free (class I); having fewer than three seizures a year or only nocturnal seizures (class II); having 80% reduction in seizures (class III); or having less than 80% reduction in seizures (class IV) (11).
Data Analysis Based on the preoperative interictal EEG, subjects were divided into three groups: (a) patients with spikes or sharp waves observed ipsilateral to the region of brain containing the tumor (unilateral interictal epileptiform discharge [IED] group); (b) patients with spikes or sharp waves recorded ipsilatera1 to the tumor and in contralateral cortex (bilateral IED group); and (c) patients without spikes or sharp waves. t-Tests were used to compare the length of follow-up and the average number of days of continuous monitoring were compared between the bilateral and unilateral IED groups, and Fisher’s exact test was used to compare differences in tumor location between the two groups. Differences between the two groups in age of seizure onset and duration of epilepsy before surgery were compared by f tests. In assessment of effect of IED on postoperative seizure outcome, patients were considered seizure-free or not seizure-free.
Results Of 30 patients, 17 were females and 13 were males. Age at operation was 13-63 years (mean 32 + 12 years). Age of epilepsy onset was 3-55 years (mean 20 ? 11 years). Duration of epilepsy before operation was 2-34 years (mean 12 + 8 years). Tumor types included ganglioglioma (n = 12), vascular malformation (n = 7), astrocytoma (n = 6), dermoid cyst (n = l), epidermoid cyst (n = 1), hamartoma (n = l), oligodendroglioma (n = l), and subependymoma (n = 1). At the time of most recent postoperative follow-up, 26 patients had class I, 2 had class II, 1 had class III, and 1 had class IV seizure outcome. Sixteen patients had unilateral IEDs on their preoperative scalp interictal EEGs, 8 patients had bilateral IEDs, and 6 patients had no IEDs on their preoperative interictal EEGs. Patients in the unilateral and bilateral IED groups had similar follow-up duration and intensity of EEG evaluation. All pa80 J EPILEPSY, VOL. 10, NO. 2, 1997
tients with unilateral IEDs had spikes in the region of the structural lesion. All contralateral spikes in the scalp EEG were homotopic. Table 1 summarizes findings for patients with unilateral and bilateral IEDs. There were no significant differences between tumor types or location between the two groups. Age of onset of epilepsy and duration of epilepsy before surgery were similar in the two groups as well. Moreover, there was no difference in postoperative seizure outcome between the two groups, as patients with either unilateral or bilateral IEDs had similar postoperative seizure-free rates.
Preoperative EEG Findings Scalp EEG demonstrated preoperative seizures in 62% (5/8) of the bilateral IED group and 38% (6/16) of the unilateral IED group. All the preoperative seizures arose from the area of the brain involved by tumor, with two exceptions. One patient in the bilateral IED group had seizure onset obscured by muscle artifact, so that no localization could be as-
Table 1.
Parameter Mean duration of follow-up, range (mo) Mean no. of days of continuous EEG monitoring bw) Tumor type Ganglioglioma Arteriovenous malformation Astrocytoma Epidermoid cyst Hamartoma Oligodendroglioma Subependymoma Tumor location Temporal Frontal Parietal Mean age at onset of epilepsy (range) (in years) Mean duration of epilepsy, yr (range) No. of seizure-free patients after surgery (%) Postoperative seizure class I II III IV
Unilateral IED group (n = 16)
Bilateral IED group (n = 8)
40 + 19 (10-73) 2+3 (O-8)
50 f 33 (7-94) 3*3 (O-7)
13 1 2 20+11 (3-38) 12+7 (2-30) 15 (94%)
5 3 0 21 f 15 (7-55) 12 + 7 (2-24) 6 (75%)
15 1 0 0
6 0 1 1
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certained. Another patient in the bilateral IED group had seizures that appeared to localize in cortex contralateral to the tumor on scalp EEG. Intracranial recording later showed that the scalp EEG was misleading, and all seizures had onset in the area of brain involved by tumor. This patient has been seizure-free postoperatively.
Postoperative EEG Findings Patients with Unilateral
IEDs Before Surgery
Postoperative routine outpatient EEG recordings were available in 10 of the 16 patients in the preoperative unilateral IED group. Nine of these patients had no postoperative IEDs, including the 1 patient with class II outcome. One patient had IEDs ipsilateral to the site of surgical resection; this patient is seizure-free 42 months postoperatively. Patients with Bilateral
IEDs Before Surgery
Postoperative EEGs were available in 6 of the 8 patients in the bilateral IED group. None of the 4 seizure-free patients with EEGs had postoperative IEDs. One patient with class III seizure outcome had 1 outpatient day and 18 inpatient days of monitoring after surgery that showed spikes in the area of surgical excision as well as one seizure that was not clearly localized. One patient with class IV outcome had four outpatient EEGs and inpatient monitoring on two occasions. These showed spikes and seizures arising from homologous cortex contralatera1 to the site of surgical resection as well as rare spikes from the site of surgical resection and were recorded 14 months and 3.67 years after resection of the primary tumor. Further detail is provided in the following case history.
Case His tory A 33-year-old right-handed man was evaluated for intractable epilepsy. Despite normal birth and development, no history of head trauma, and a negative family history of epilepsy, complex partial seizures (OS) had onset at age 7 years and were refractory to 11 anti-epileptic drugs (AEDs) over the years. A cystic mass lesion in the right frontal lobe was biopsied when he was 10 years old and was interpreted as showing gliosis and inflammation. At the time of surgical evaluation, he had three seizure types: (a) generalized tonic-clonic seizures (GTCs) which began with left arm fencing posture,
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lasted 15-20 s, and were followed by 1 h of postictal fatigue; (b) CPS with 2 min of staring and unresponsiveness, and (c) rare drop attacks during which he would drop to the floor for a second and then immediately arise. He had one to two tonicclonic seizures a day and one to two CPS a week. He did well in school until onset of his epilepsy. According to his parents, his intellectual abilities then declined, and he subsequently required special schooling. Neurologic examination was nonfocal but notable for a poor fund of knowledge and impaired cognition. An MRI scan showed a nonenhancing nodule in a cystic right frontal lesion with no evidence of contralateral frontal abnormality (Fig. 1A). Four days of continuous scalp EEG monitoring demonstrated independent asynchronous right and left frontal spikes in the interictal state (Fig. 2A). Three seizures were recorded preoperatively, but the ictal onset was obscured by muscle artifact. Neuropsychological testing showed borderline mild mental retardation with a full-scale I.Q. of 71. The right frontal lesion and a generous margin of surrounding cortex were excised. There was no evidence of extension or invasion of the contralateral hemisphere. Histopathologic examination demonstrated a ganglioglioma. He had no seizures for the first 3 months after operation, but tonic-clonic seizures then recurred at the preoperative frequency. Seizures have since persisted for more than 3 years. No other seizure types developed postoperatively. Four outpatient EEGs and 8 days of postoperative continuous video-EEG monitoring with scalp electrodes 14 months postoperatively showed left frontal interictal spikes and three seizures that originated in the left frontal lobe (Fig. 2B and C). There was no evidence of tumor recurrence or left-sided abnormality on postoperative MRI scans (Fig. lb). Three years 9 months after the right frontal resection, the patient was experiencing weekly clusters of 210 tonic-clonic seizures in several hours, which led him to consider having further surgery. Scalp EEG showed very frequent left frontal spikes in wakefulness and sleep as before, with extremely rare right frontal and frontotemporal spikes also noted in sleep. All tonic-clonic seizures originated at electrode F3, as before. With intracranial EEG, tonic-clonic seizures were confirmed to have left frontal lobe origin; however, two brief CPS were recorded arising from the resection margin in the right frontal lobe. Because of concerns that a resection would result in bifrontal syndrome, a left frontal subpial transection was performed. Several tonic-clonic seizures occurred on postoperative day J EPILEPSY, VOL. 10, NO. 2, 1997
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1 in the setting of low AED levels. In the month since discharge, no tonic-clonic seizures have occurred although two brief CPS were noted. No tissue was resected from the left frontal lobe, but inspection at operation disclosed no gross abnormalities or malformations. Therefore, this patient had evidence of independent secondary epileptogenesis, with interictal discharges and clinical attacks arising from the left frontal lobe in the setting of a right frontal primary tumor.
Discussion In a series restricted to patients with unilateral pathology, we found evidence of secondary epileptogenesis in a significant minority of patients. Interictal mirror foci were noted in approximately one quarter of the group, a percentage similar to that reported in earlier series (1,6-8,12-14). More striking was the finding of an independent secondary epileptogenic focus capable of generating seizures in 1 patient, confirmed by intracranial EEG. This was present 3 years 9 months after extirpation of the primary epileptogenic lesion and its surrounding cortex. The seizures arose from the same area as the interictal spike focus, and a sufficiently wide excision had been performed in the hemisphere containing the primary lesion; therefore, nearly all ipsilateral epileptiform EEG abnormalities had disappeared (for the first several years after operation); this finding was in marked contradistinction to those of the preoperative EEGs, which showed frequent bilateral independent interictal spikes. The presence of a persistent independent seizure focus in the contralateral hemisphere is consistent with secondary epileptogenesis, and our report is the only report other than that of Morrell (1) in which this finding has been noted in humans. Morrell has suggested that this stage requires long-term bombardment of densely connected contralateral cortex by the primary discharging focus. The patient in our study who developed the independent seizure focus indeed had long-standing epilepsy with frequent seizures, and appears to have had the requirements suggested by animal models (1,Z). The relatively frequent appearance of interictal mirror foci contrasts sharply with the paucity of ictal mirror foci. No patient in our series had contralateral seizures recorded preoperatively, and only 1 had seizures from the mirror focus postoperatively. Other investigators (8) reported secondary seizures arising from homotopic cortex in 1 of 82 1 EPILEPSY, VOL. 10, No, 2, 1997
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B mmHQ C+P4c*QM
Figure 2. A: Preoperative scalp EEG showing asynchronous rightfrontal (small arrows) and leftfrontal (large arrow) spikes and polyspikes in the patient described in the Case Report. B: Postoperative scalp EEG after right frontal lobectomy in the same patient showing persistent left frontal spikes and polyspikes carrow) and absence of right frontal spikes. C: Postoperative scalp EEG showing focal seizure onset in the left frontal lobe (arrow). This localization was confirmed by intracranial EEG.
22 patients with lesional epilepsy, and these were detected preoperatively. Morrell (1,2) reported preoperative seizures contralateral to the tumor in almost one quarter of patients evaluated for surgery. Although we noted no evidence of contralateral seizures in our patients before surgery, additional monitoring might have disclosed such evidence had we monitored all patients longer preoperatively. It is of interest that incidence of bilateral interictal epileptiform foci is similar in patients with (1,8,1214) and without (6,7) structural brain lesions. Gupta et al. (6) and Hughes et al. (7), respectively, found
evidence of bilateral interictal epileptiform discharges in 29 and 34% of patients without known intracranial structural lesions. Gilmore et al. (8) and Morrell (l), respectively, reported mirror foci in 32 and 34% of patients with unilateral brain tumors. Indeed, the similar rates of detection of mirror foci whether patients have other possible central nervous system injuries or not suggests that secondary epileptogenesis may be a more important factor in the development of bilateral interictal epileptiform discharges than is commonly recognized. In the kindling model (2), interictal mirror foci are more likely to evolve in younger animals (9), J EPILEPSY, VOL. 10, NO. 2, 1997
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occur more frequently with kindling of the amygdala than of other sites (3), and appear more often with an increasing number of kindling trials (2). Studies that have examined the phenomenon of mirror foci in humans have been less clear. Some studies (8,15), including the present one, suggest that the mirror focus phenomenon does not correlate with age of seizure onset, location of epileptic focus, or duration of epilepsy. In contrast, others have related age of seizure onset and duration of epilepsy in humans to increased incidence of mirror foci, particularly in the temporal lobes (12,15). However, there are several important differences between human epilepsy and animal kindling models (16). Other than the obvious anatomic differences, particularly in the types of interhemispheric connections, humans do not experience a stereotyped progression of symptoms over time as do kindled animals. The amygdala, which is the easiest site to kindle, is less frequently the site of epileptogenesis in humans, possibly in part because of its relative paucity of interhemispheric connections as compared with non-primate animal models. In addition, the development of a chronic seizure disorder from localized or generalized periodic electrical stimulation has rarely been reported in humans (17,18). Therefore, it is not surprising that the characteristics of mirror foci in human epilepsy differ from those of animal models. We found no relation between postoperative seizure relief and the presence of unilateral or bilateral IEDs in patients with mass lesions. Neither did Gilmore et al. (8) note any difference in postoperative seizure control between patients with preoperative mirror foci and those who had unilateral IEDs. This is consistent with a very limited tendency of the human brain to develop the independent stage of ictal secondary epileptogenesis. Other investigators examined seizure frequency in nonoperated patients with mirror foci, but their reports have not resolved the issue. Niediek et al. (15) noted that patients with bilateral IEDs had more frequent seizures than those with unilateral IEDs, but Hughes et al. (7) reported the opposite. Counting seizure frequency differs fundamentally from counting the number of sites from which seizure might originate, and this approach is unlikely to illuminate the issue of secondary epileptogenesis in humans. Several factors can potentially confound and influence studies of the mirror focus and secondary epileptogenesis. First, contralateral microscopic lesions invisible on MRI might be present. Morrell(1) was able to provide pathologic evidence for the lack of a multicentric tumor in 1 of his patients who had 84
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a postmortem examination, and the likelihood that the second tumor site would always be located in homotopic cortex renders that possibility an unlikely general explanation. Second, some patients might have additional risk factors for epilepsy such as complicated febrile convulsion or head trauma, which might produce brain injury and a second source of seizures that arise independently of the more obvious epileptic mass lesion. Careful methodology can usually eliminate this possibility. Almost 40% of our total sample of patients with tumors had some potential risk and had to be excluded from the present analysis. Last, repeated GTCs after epilepsy onset might independently cause anoxic brain injury with subsequent development of another epileptogenic lesion in Ammon’s horn (19). In some animal models, repeated seizures produce cell loss, reorganization, and epileptogenic changes in the hippocampus (20). However, other studies suggest that sometimes the degree of damage and long-term increase in seizure susceptibility are relatively modest and limited (21,22). Nonetheless, many patients with secondary epileptogenesis, both in the present series and Morrell’s series (l), had no history of GTCS. Our patient who developed postoperative independent seizures had a history of frequent tonic-clonic seizures for many years but developed a homotopic frontal focus, not a focus in vulnerable mesial temporal lobe structures as might be expected from the animal models. The data suggest that secondary epileptogenesis is not uncommon in humans, mainly manifest with interictal spikes rather than seizures. That this phenomenon differs from animal models is not surprising, given the differences in anatomy and etiology of epilepsy between these models and humans. Serial studies in additional patients will be needed to clarify further the characteristics of human secondary epileptogenesis. Acknowledgment: We thank Dr. Lucy Rorke of the University of Pennsylvania for reviewing the pathology slides and Dr. Frank Morrell for helpful comments regarding the manuscript. Dr. Sperling is partly supported by Grant No. POlNS14867 of the National Institutes of Health.
References 1. Morrell F. Secondary epileptogenesis in man. Arch Neurol 1985;42:318-35. 2. Goldensohn E. The relevance of secondary epileptogenesis
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to the treatment of epilepsy: kindling and the mirror focus. Epilepsia 1984;25(suppl 2):S156-68. Goddard GV, M&tire DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 1969;25:295-330. Hiyoshi T, Masakazu S, Kakegawa N, et al. Evidence of secondary epileptogenesis in amygdaloid overkindled cats: electroclinical documentation of spontaneous seizures, Epilepsia 1993;34:408-15. Wada JA, Mizoguchi T, Komai S. Kindling epileptogenesis in orbital and mesial frontal cortical areas of subhuman primates. Epilepsia 1985;26:472-9. Gupta PC, et al. Secondary epileptogenic EEG focus in temporal lobe epilepsy. Epilepsia 1973;14:423-6. Hughes JR. Long-term clinical and EEG changes in patients with epilepsy. Arch Neurol 1985;42:213-23. Gilmore R, Morris H, Van Ness PC, Gilmore-Pollak W, Estes M. Mirror focus: function of seizure frequency and influence on outcome after surgery. Epilepsia 1994;35:258-63. Toledo-Morrell L, Morrell F, Flemming S. Age dependent deficits in spatial memory are related to impaired hippocampal kindling. Behav Neurosci 1984;98:902-7. Sperling MR, Engel J Jr. Sphenoidal electrodes. J Clin Neurophysiol 1986;3:67-73. Sperling MR, O’Connor MJ, Saykin AJ, et al. A noninvasive protocol for anterior temporal lobectomy. Neurology 1992; 42:41&22. Morrell F. Varieties of human secondary epileptogenesis. J Clin Neurophysiol 1989;6:227-75. Yeh H, Tew JM, Gartner M. Seizure control after surgery on
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cerebral arteriovenous malformations. J Neurosurg 1993;78: 12-8. Yeh H, Privitera MD. Secondary epileptogenesis in cerebral arteriovenous malformations. Arch Nemo1 1991;48:11224. Niediek T, Franke HG, Degen R, Ettlinger G. The development of independent foci in epileptic patients. Arch Neurol 1990;47:406-11. Engel J, Cahan L. Potential relevance of kindling to human partial epilepsy. In: Wada J, ed. Kindling 3. New York: Raven Press, 1986:37-51. Devinsky 0, Duchowny MS. Seizures after convulsive therapy: a retrospective case survey. Neurology 1983;33: 921-5. Sramka M, Sedlak I?, Nadvumik P. Observations of the kindling phenomenon in treatment of pain by stimulation of the thalamus. In: Sweet WH, Obrador S, Martin-Rodriquez, eds. Neurosurgical treatment in psychiatry, pain and epilepsy. Baltimore: University Park Press, 19776514. Corsellis JAN. The neuropathology of temporal lobe epilepsy, vol. 5. In: Williams D, ed. Modem trends in neurology. New York: Appleton-Century-Crofts, 1970:254-70. Sutula T, Xiao-Xian H, Cavazos J, Scott G. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 1988;239:1147-50. Holmes GL, Thompson JL. Effects of kainic acid on seizure susceptibility in the developing brain. Dev Brain Res 1988; 39:51-9. Stafstrom CE, Thompson JL, Holmes GL. Kainic acid seizures in the developing brain: status epilepticus and spontaneous recurrent seizures. Dev Brain Res 1992;65:227-36.
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The Mirror Focus Phenomenon and Secondary Epileptogenesis in Human Epilepsy ’ Richard J. McCarthy,
2f3 Michael J. O’Connor,
and 2f4 Michael R. Sperling
Although the mirror focus and secondary epileptogenesis are described in animal models of focal epilepsy, the relevance of these phenomena to human epilepsy is controversial. We reviewed 30 patients with unilateral epileptogenie low-grade structural lesions and sought evidence of secondary epileptogenesis. Patients with evidence of mirror foci were compared with patients with unilateral discharges. The incidence of interictal mirror foci was 27%.
Location of the primary epileptogenic lesion, duration of epilepsy, age of onset of epilepsy, and postoperative seizure outcome were not affected by the presence of a mirror focus. One patient had evidence of independent secondary epileptogenesis and had had seizures arising independently from that focus of homotopic cortex contralateral to a tumor 3.75 years after excision of the primary lesion. We conclude that secondary epileptogenesis is not uncommon in
humans and that independent foci capable of generating seizures may be focus-Secondary epileptoformed. Key Words: Epilepsy-Tumor-Mirror 0 1997 by Elsevier Science Inc. All rights reserved. genesis-Outcome.
Secondary epileptogenesis encompasses a range of abnormalities that develop after the creation of a primary epileptogenic lesion in the brain in animal models of epilepsy (l-5). Interictal spikes first appear in the area of the primary lesion; in time, spikes develop in contralateral homotopic cortex. Although these spikes are initially dependent and linked temporally to spikes in the primary lesion, Received May 17,1996; accepted September 23,1996. From the ‘Department of Neurology, University of California San Francisco, San Francisco, CA; 2Comprehensive Epilepsy Center, The Graduate Hospital; 3Division of Neurosurgery, University of Pennsylvania School of Medicine; and 4Department of Neurology, Temple University School of Medicine, Philadelphia, PA, U.S.A. Address correspondence and reprint requests to Dr. Michael R. Sperling at Comprehensive Epilepsy Center, Graduate Hospital, 1 Graduate Plaza, Philadelphia, PA 19146, U.S.A. J. Epilepsy 1997;10:78-85 0 1997 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
with further passage of time spikes may develop in contralateral homotopic cortex that are not temporally linked to the discharging primary focus. These contralateral spikes, which have been termed a mirror focus, then occur asynchronously and reflect a fundamental change in the underlying excitability of that homotopic cortex. If ablation of the primary cortex is performed at this stage, the contralateral spike will ultimately disappear. However, if the primary lesion remains undisturbed, later excision of the primary lesion may not abolish the interictal spikes in homotopic cortex. The contralateral spikes may then be considered as independent, and this stage probably represents a fundamental change in the character of the secondary lesion (1). As the process progresses further, recurrent seizures may arise from that contralateral homotopic focus, which has become a fully independent cause of epilepsy in the animal. The duration of the process and
0896-6974/97/$17.00 PI1 SO896-6974(96)00077-l
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density of connections have been suggested to be the critical factors in determining whether secondary epileptogenesis will occur (1). Secondary epileptogenesis has been suggested to be relevant to human epilepsy, although this possibility has been debated (2). Nonetheless, many of the features observed in animal models of secondary epileptogenesis are also observed in humans (1). One quarter to one third of people with unilateral brain lesions and epilepsy may have bilateral interictal spike foci (1,6-Q However, this contralatera1 focus has several possible explanations. It could be due either to another primary brain abnormality related or unrelated to the obvious lesion, to brain injury directly caused by seizures (e.g., anoxia or head trauma), or secondary epileptogenesis. Given the wealth of animal data supporting secondary epileptogenesis, the amount of data bolstering the presence of such a process in humans is limited. However, the limitations in studying human epilepsy make secondary epileptogenesis difficult to document because of these potential confounding factors. Although there has been some evidence of seizures arising in the hemisphere opposite a tumor before surgery (1,8), to date only one investigator (1) has provided evidence of contralatera1 seizures that persisted long after excision of a primary epileptogenic lesion in humans. We reviewed the Graduate Hospital experience in patients with unilateral tumors and vascular malformations to seek further evidence of secondary epileptogenesis. We determined the incidence of contralateral interictal and ictal EEG foci and related their presence to risk factors suggested by previous animal work (2,3,9). Because of the enormous discrepancy regarding the incidence of secondary seizures in the literature (1,8), we also examined the frequency of seizures from the mirror focus before and after surgery and the relation between the mirror focus phenomenon and postoperative seizure relief.
EPILEPTOGENESIS
were excluded because of possible confounding epilepsy risk factors such as head trauma with loss of consciousness, childhood febrile convulsions, encephalitis, meningitis, perinatal complications, or central nervous system irradiation. These patients were excluded so that no other possible reasons would exist for epilepsy in this population. One additional patient was excluded because all his preoperative scalp EEGs were interpreted at an outside hospital and not reviewed at our institution. All patients had focal unilateral pathology on preoperative magnetic resonance imaging (MRI).
EEG Recording All patients had scalp EEG recorded with lo-20 system and sphenoidal electrodes (10). Eighteen subjects underwent prolonged ambulatory or inpatient video-EEG monitoring, and 12 had only outpatient interictal EEG recording. Inpatient monitoring was performed with a 16-21 channel Telefactor Corporation system (Conshohoken, PA) with automated spike and seizure detection or continuous paper write-out. Random interictal samples also were recorded. Ambulatory recording was obtained with a 16-channel system (Digitrace, Boston, MA) with automatic spike and seizure detection and random time samples. EEGs from all patients were examined in wakefulness and sleep. All EEGs were read by board-certified electroencephalographers. Outside EEG reports were not considered for the study. Results of intracranial monitoring were not considered in the study. All EEGs were examined for interictal spike and sharp waves. These were considered present only if they were observed more than once during EEG recording. Seizures were recorded before surgery in 11 patients. The remainder underwent surgery based on interictal EEG findings, MRI, and the neurologic history and examination.
Surgery, Surgical Pathology, and Outcome Methods Patients Fifty patients with intractable partial epilepsy underwent surgical resection of unilateral intracerebra1 tumors or vascular malformations between 1986 and 1993 at the Graduate Hospital in Philadelphia. Thirty patients were eligible for the present review, and 20 were excluded. Nineteen patients
The same neurosurgeon (M.J.0) performed all operations. Patients with temporal lobe lesions underwent anterior temporal lobectomies with the tumor or vascular malformation included in the margins. Patients with extratemporal tumors had their tumors excised along with a margin of adjacent tissue. All specimens were reviewed by a neuropathologist. The histopathology of tissue from patients with persistent postoperative seizures were also reviewed by a second neuropathologist (Dr. J EPILEPSY, VOL. 10, NO. 2, 1997
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Lucy Rorke) to verify diagnoses. Postoperative seizure outcome was determined in each patient at the time of most recent examination. Subjects were classified as either being seizure-free (class I); having fewer than three seizures a year or only nocturnal seizures (class II); having 80% reduction in seizures (class III); or having less than 80% reduction in seizures (class IV) (11).
Data Analysis Based on the preoperative interictal EEG, subjects were divided into three groups: (a) patients with spikes or sharp waves observed ipsilateral to the region of brain containing the tumor (unilateral interictal epileptiform discharge [IED] group); (b) patients with spikes or sharp waves recorded ipsilatera1 to the tumor and in contralateral cortex (bilateral IED group); and (c) patients without spikes or sharp waves. t-Tests were used to compare the length of follow-up and the average number of days of continuous monitoring were compared between the bilateral and unilateral IED groups, and Fisher’s exact test was used to compare differences in tumor location between the two groups. Differences between the two groups in age of seizure onset and duration of epilepsy before surgery were compared by f tests. In assessment of effect of IED on postoperative seizure outcome, patients were considered seizure-free or not seizure-free.
Results Of 30 patients, 17 were females and 13 were males. Age at operation was 13-63 years (mean 32 + 12 years). Age of epilepsy onset was 3-55 years (mean 20 ? 11 years). Duration of epilepsy before operation was 2-34 years (mean 12 + 8 years). Tumor types included ganglioglioma (n = 12), vascular malformation (n = 7), astrocytoma (n = 6), dermoid cyst (n = l), epidermoid cyst (n = 1), hamartoma (n = l), oligodendroglioma (n = l), and subependymoma (n = 1). At the time of most recent postoperative follow-up, 26 patients had class I, 2 had class II, 1 had class III, and 1 had class IV seizure outcome. Sixteen patients had unilateral IEDs on their preoperative scalp interictal EEGs, 8 patients had bilateral IEDs, and 6 patients had no IEDs on their preoperative interictal EEGs. Patients in the unilateral and bilateral IED groups had similar follow-up duration and intensity of EEG evaluation. All pa80 J EPILEPSY, VOL. 10, NO. 2, 1997
tients with unilateral IEDs had spikes in the region of the structural lesion. All contralateral spikes in the scalp EEG were homotopic. Table 1 summarizes findings for patients with unilateral and bilateral IEDs. There were no significant differences between tumor types or location between the two groups. Age of onset of epilepsy and duration of epilepsy before surgery were similar in the two groups as well. Moreover, there was no difference in postoperative seizure outcome between the two groups, as patients with either unilateral or bilateral IEDs had similar postoperative seizure-free rates.
Preoperative EEG Findings Scalp EEG demonstrated preoperative seizures in 62% (5/8) of the bilateral IED group and 38% (6/16) of the unilateral IED group. All the preoperative seizures arose from the area of the brain involved by tumor, with two exceptions. One patient in the bilateral IED group had seizure onset obscured by muscle artifact, so that no localization could be as-
Table 1.
Parameter Mean duration of follow-up, range (mo) Mean no. of days of continuous EEG monitoring bw) Tumor type Ganglioglioma Arteriovenous malformation Astrocytoma Epidermoid cyst Hamartoma Oligodendroglioma Subependymoma Tumor location Temporal Frontal Parietal Mean age at onset of epilepsy (range) (in years) Mean duration of epilepsy, yr (range) No. of seizure-free patients after surgery (%) Postoperative seizure class I II III IV
Unilateral IED group (n = 16)
Bilateral IED group (n = 8)
40 + 19 (10-73) 2+3 (O-8)
50 f 33 (7-94) 3*3 (O-7)
13 1 2 20+11 (3-38) 12+7 (2-30) 15 (94%)
5 3 0 21 f 15 (7-55) 12 + 7 (2-24) 6 (75%)
15 1 0 0
6 0 1 1
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certained. Another patient in the bilateral IED group had seizures that appeared to localize in cortex contralateral to the tumor on scalp EEG. Intracranial recording later showed that the scalp EEG was misleading, and all seizures had onset in the area of brain involved by tumor. This patient has been seizure-free postoperatively.
Postoperative EEG Findings Patients with Unilateral
IEDs Before Surgery
Postoperative routine outpatient EEG recordings were available in 10 of the 16 patients in the preoperative unilateral IED group. Nine of these patients had no postoperative IEDs, including the 1 patient with class II outcome. One patient had IEDs ipsilateral to the site of surgical resection; this patient is seizure-free 42 months postoperatively. Patients with Bilateral
IEDs Before Surgery
Postoperative EEGs were available in 6 of the 8 patients in the bilateral IED group. None of the 4 seizure-free patients with EEGs had postoperative IEDs. One patient with class III seizure outcome had 1 outpatient day and 18 inpatient days of monitoring after surgery that showed spikes in the area of surgical excision as well as one seizure that was not clearly localized. One patient with class IV outcome had four outpatient EEGs and inpatient monitoring on two occasions. These showed spikes and seizures arising from homologous cortex contralatera1 to the site of surgical resection as well as rare spikes from the site of surgical resection and were recorded 14 months and 3.67 years after resection of the primary tumor. Further detail is provided in the following case history.
Case His tory A 33-year-old right-handed man was evaluated for intractable epilepsy. Despite normal birth and development, no history of head trauma, and a negative family history of epilepsy, complex partial seizures (OS) had onset at age 7 years and were refractory to 11 anti-epileptic drugs (AEDs) over the years. A cystic mass lesion in the right frontal lobe was biopsied when he was 10 years old and was interpreted as showing gliosis and inflammation. At the time of surgical evaluation, he had three seizure types: (a) generalized tonic-clonic seizures (GTCs) which began with left arm fencing posture,
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lasted 15-20 s, and were followed by 1 h of postictal fatigue; (b) CPS with 2 min of staring and unresponsiveness, and (c) rare drop attacks during which he would drop to the floor for a second and then immediately arise. He had one to two tonicclonic seizures a day and one to two CPS a week. He did well in school until onset of his epilepsy. According to his parents, his intellectual abilities then declined, and he subsequently required special schooling. Neurologic examination was nonfocal but notable for a poor fund of knowledge and impaired cognition. An MRI scan showed a nonenhancing nodule in a cystic right frontal lesion with no evidence of contralateral frontal abnormality (Fig. 1A). Four days of continuous scalp EEG monitoring demonstrated independent asynchronous right and left frontal spikes in the interictal state (Fig. 2A). Three seizures were recorded preoperatively, but the ictal onset was obscured by muscle artifact. Neuropsychological testing showed borderline mild mental retardation with a full-scale I.Q. of 71. The right frontal lesion and a generous margin of surrounding cortex were excised. There was no evidence of extension or invasion of the contralateral hemisphere. Histopathologic examination demonstrated a ganglioglioma. He had no seizures for the first 3 months after operation, but tonic-clonic seizures then recurred at the preoperative frequency. Seizures have since persisted for more than 3 years. No other seizure types developed postoperatively. Four outpatient EEGs and 8 days of postoperative continuous video-EEG monitoring with scalp electrodes 14 months postoperatively showed left frontal interictal spikes and three seizures that originated in the left frontal lobe (Fig. 2B and C). There was no evidence of tumor recurrence or left-sided abnormality on postoperative MRI scans (Fig. lb). Three years 9 months after the right frontal resection, the patient was experiencing weekly clusters of 210 tonic-clonic seizures in several hours, which led him to consider having further surgery. Scalp EEG showed very frequent left frontal spikes in wakefulness and sleep as before, with extremely rare right frontal and frontotemporal spikes also noted in sleep. All tonic-clonic seizures originated at electrode F3, as before. With intracranial EEG, tonic-clonic seizures were confirmed to have left frontal lobe origin; however, two brief CPS were recorded arising from the resection margin in the right frontal lobe. Because of concerns that a resection would result in bifrontal syndrome, a left frontal subpial transection was performed. Several tonic-clonic seizures occurred on postoperative day J EPILEPSY, VOL. 10, NO. 2, 1997
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1 in the setting of low AED levels. In the month since discharge, no tonic-clonic seizures have occurred although two brief CPS were noted. No tissue was resected from the left frontal lobe, but inspection at operation disclosed no gross abnormalities or malformations. Therefore, this patient had evidence of independent secondary epileptogenesis, with interictal discharges and clinical attacks arising from the left frontal lobe in the setting of a right frontal primary tumor.
Discussion In a series restricted to patients with unilateral pathology, we found evidence of secondary epileptogenesis in a significant minority of patients. Interictal mirror foci were noted in approximately one quarter of the group, a percentage similar to that reported in earlier series (1,6-8,12-14). More striking was the finding of an independent secondary epileptogenic focus capable of generating seizures in 1 patient, confirmed by intracranial EEG. This was present 3 years 9 months after extirpation of the primary epileptogenic lesion and its surrounding cortex. The seizures arose from the same area as the interictal spike focus, and a sufficiently wide excision had been performed in the hemisphere containing the primary lesion; therefore, nearly all ipsilateral epileptiform EEG abnormalities had disappeared (for the first several years after operation); this finding was in marked contradistinction to those of the preoperative EEGs, which showed frequent bilateral independent interictal spikes. The presence of a persistent independent seizure focus in the contralateral hemisphere is consistent with secondary epileptogenesis, and our report is the only report other than that of Morrell (1) in which this finding has been noted in humans. Morrell has suggested that this stage requires long-term bombardment of densely connected contralateral cortex by the primary discharging focus. The patient in our study who developed the independent seizure focus indeed had long-standing epilepsy with frequent seizures, and appears to have had the requirements suggested by animal models (1,Z). The relatively frequent appearance of interictal mirror foci contrasts sharply with the paucity of ictal mirror foci. No patient in our series had contralateral seizures recorded preoperatively, and only 1 had seizures from the mirror focus postoperatively. Other investigators (8) reported secondary seizures arising from homotopic cortex in 1 of 82 1 EPILEPSY, VOL. 10, No, 2, 1997
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B mmHQ C+P4c*QM
Figure 2. A: Preoperative scalp EEG showing asynchronous rightfrontal (small arrows) and leftfrontal (large arrow) spikes and polyspikes in the patient described in the Case Report. B: Postoperative scalp EEG after right frontal lobectomy in the same patient showing persistent left frontal spikes and polyspikes carrow) and absence of right frontal spikes. C: Postoperative scalp EEG showing focal seizure onset in the left frontal lobe (arrow). This localization was confirmed by intracranial EEG.
22 patients with lesional epilepsy, and these were detected preoperatively. Morrell (1,2) reported preoperative seizures contralateral to the tumor in almost one quarter of patients evaluated for surgery. Although we noted no evidence of contralateral seizures in our patients before surgery, additional monitoring might have disclosed such evidence had we monitored all patients longer preoperatively. It is of interest that incidence of bilateral interictal epileptiform foci is similar in patients with (1,8,1214) and without (6,7) structural brain lesions. Gupta et al. (6) and Hughes et al. (7), respectively, found
evidence of bilateral interictal epileptiform discharges in 29 and 34% of patients without known intracranial structural lesions. Gilmore et al. (8) and Morrell (l), respectively, reported mirror foci in 32 and 34% of patients with unilateral brain tumors. Indeed, the similar rates of detection of mirror foci whether patients have other possible central nervous system injuries or not suggests that secondary epileptogenesis may be a more important factor in the development of bilateral interictal epileptiform discharges than is commonly recognized. In the kindling model (2), interictal mirror foci are more likely to evolve in younger animals (9), J EPILEPSY, VOL. 10, NO. 2, 1997
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occur more frequently with kindling of the amygdala than of other sites (3), and appear more often with an increasing number of kindling trials (2). Studies that have examined the phenomenon of mirror foci in humans have been less clear. Some studies (8,15), including the present one, suggest that the mirror focus phenomenon does not correlate with age of seizure onset, location of epileptic focus, or duration of epilepsy. In contrast, others have related age of seizure onset and duration of epilepsy in humans to increased incidence of mirror foci, particularly in the temporal lobes (12,15). However, there are several important differences between human epilepsy and animal kindling models (16). Other than the obvious anatomic differences, particularly in the types of interhemispheric connections, humans do not experience a stereotyped progression of symptoms over time as do kindled animals. The amygdala, which is the easiest site to kindle, is less frequently the site of epileptogenesis in humans, possibly in part because of its relative paucity of interhemispheric connections as compared with non-primate animal models. In addition, the development of a chronic seizure disorder from localized or generalized periodic electrical stimulation has rarely been reported in humans (17,18). Therefore, it is not surprising that the characteristics of mirror foci in human epilepsy differ from those of animal models. We found no relation between postoperative seizure relief and the presence of unilateral or bilateral IEDs in patients with mass lesions. Neither did Gilmore et al. (8) note any difference in postoperative seizure control between patients with preoperative mirror foci and those who had unilateral IEDs. This is consistent with a very limited tendency of the human brain to develop the independent stage of ictal secondary epileptogenesis. Other investigators examined seizure frequency in nonoperated patients with mirror foci, but their reports have not resolved the issue. Niediek et al. (15) noted that patients with bilateral IEDs had more frequent seizures than those with unilateral IEDs, but Hughes et al. (7) reported the opposite. Counting seizure frequency differs fundamentally from counting the number of sites from which seizure might originate, and this approach is unlikely to illuminate the issue of secondary epileptogenesis in humans. Several factors can potentially confound and influence studies of the mirror focus and secondary epileptogenesis. First, contralateral microscopic lesions invisible on MRI might be present. Morrell(1) was able to provide pathologic evidence for the lack of a multicentric tumor in 1 of his patients who had 84
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a postmortem examination, and the likelihood that the second tumor site would always be located in homotopic cortex renders that possibility an unlikely general explanation. Second, some patients might have additional risk factors for epilepsy such as complicated febrile convulsion or head trauma, which might produce brain injury and a second source of seizures that arise independently of the more obvious epileptic mass lesion. Careful methodology can usually eliminate this possibility. Almost 40% of our total sample of patients with tumors had some potential risk and had to be excluded from the present analysis. Last, repeated GTCs after epilepsy onset might independently cause anoxic brain injury with subsequent development of another epileptogenic lesion in Ammon’s horn (19). In some animal models, repeated seizures produce cell loss, reorganization, and epileptogenic changes in the hippocampus (20). However, other studies suggest that sometimes the degree of damage and long-term increase in seizure susceptibility are relatively modest and limited (21,22). Nonetheless, many patients with secondary epileptogenesis, both in the present series and Morrell’s series (l), had no history of GTCS. Our patient who developed postoperative independent seizures had a history of frequent tonic-clonic seizures for many years but developed a homotopic frontal focus, not a focus in vulnerable mesial temporal lobe structures as might be expected from the animal models. The data suggest that secondary epileptogenesis is not uncommon in humans, mainly manifest with interictal spikes rather than seizures. That this phenomenon differs from animal models is not surprising, given the differences in anatomy and etiology of epilepsy between these models and humans. Serial studies in additional patients will be needed to clarify further the characteristics of human secondary epileptogenesis. Acknowledgment: We thank Dr. Lucy Rorke of the University of Pennsylvania for reviewing the pathology slides and Dr. Frank Morrell for helpful comments regarding the manuscript. Dr. Sperling is partly supported by Grant No. POlNS14867 of the National Institutes of Health.
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