The Role of Secondary in Human Epilepsy one third of patients epilepsy exhibit bilateral, mainly homotopic, apparently independent, epileptiform electroencephalographic (EEG) abnormalities in scalp-recorded tracings under normal physiologic recording conditions.1-4 Although this finding is well established, its significance with respect to pathophysiology is unclear. For example, does it mean that both hemispheres contain an epileptogenic lesion that is at least potentially clinically significant? Do these bilateral discharges imply that there are multiple primary foci and, if so, why are they so often symmetrical? Or, is it possible that one epileptogenic lesion may give rise to another? Equally obscure is the meaning of such bilateral epileptiform discharge with respect to the outcome of surgical treatment. Does the presence of an active spike focus
Approximately with focal
Epileptogenesis
age, eg, febrile seizures or encephalitis. Patients with strictly unitemporal foci were expected to have etiologic factors that were themselves completely later¬ alized, such as tumors. The second possible explanation to be considered, ifthe first failed, was that of secondary epileptogenesis, ie, that pro¬ cess by which a primary epileptogenic lesion of whatever cause may itself in¬ duce epileptiform behavior in initially normal cell populations with which the primary site is densely connected. Of course, these two hypotheses are not mutually exclusive; it is possible, in fact likely, that both mechanisms operate.
that bilateral foci are usually produced by central nervous system insults likely to cause widespread or bilateral dam-
From the Cleveland (Ohio) Clinic se¬ ries of temporal lobectomy candidates with medically intractable complex par¬ tial seizures, Lim et afselected 30 con¬ secutive patients with unitemporal in¬ terictal epileptiform discharges (IEDs) and 30 consecutive patients with bitemporal IEDs. The patients were chosen on the basis of noninvasive, scalp-re¬ corded EEGs derived from at least 4 days, continuous video/EEG monitor¬ ing. Patients were included in the bitemporal group only if IEDs in the less active temporal lobe accounted for at least 20% of the total discharges. The authors eliminated cases with extratemporal foci or where there was an extratemporal predominance of a tem¬ poral lobe IED. Thus, the groups were as cleanly separated as was feasible from the point of view of electrical pa¬ rameters under investigation, yet were comparable with respect to factors of sex, age, and intelligence quotient. Hospital charts, office files, and moni¬ toring results were then reviewed, so that etiologic information, frequency of seizures, duration of illness, and age at seizure onset could be compared across the two groups. Without doubt, the most striking finding of this study, and the most unex¬ pected, was the observation that those etiologic factors likely to cause multifo¬ cal damage, ie, febrile seizures and en¬
Accepted for publication August 19,1991. From the Department of Neurological Sciences, Rush Medical College, Chicago, Ill. Reprint requests to Department of Neurological Sciences, Rush Medical College, 1653 W. Congress Pkwy, Chicago, IL 60612 (Dr Morrell).
epileptiform abnormality. Indeed, sev¬ en of the 10 patients with a mass lesion showed bitemporal IEDs (70%). Al¬ though called "mass lesions," the tu-
contralateral to an intended excision afford a warning that the operative intervention is unlikely to result in cure? Is it rather a warning that operative intervention is needed more quickly? Or, as others have suggested,'' is such evi¬ dence of bilateral discharge of no signifi¬ cance whatsoever to the clinical out¬ come? I will return to these issues a bit later. But, it seems appropriate to con¬ sider first the etiologic and pathophysi¬ ologic implications of bilateral, indepen¬ dent epileptiform abnormalities in such a large number of patients with focal seizures. The article by Lim and col¬ leagues6 in this issue of the Archives directly addresses this latter problem in a simple and elegant example ofthe pro¬ ductive use of retrospective clinical data. The authors entertain two main ex¬ planations for the exceptionally high in¬ cidence of bilateral, independent epilep¬ tic discharge in their temporal lobect¬ omy series. The first, and the one that
they specifically
set out to
verify,
was
were, in fact, more common among the unifocal group, while tumors tended to be associated with bitemporal
cephalitis,
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mors were unassociated with ventricu¬ lar displacement or increased intra¬ cranial pressure that might account for contralateral disturbance of function. The authors were thus forced to the conclusion that the epileptiform abnor¬ malities contralateral to the presumed site of ictal onset (primary focus) were more likely a consequence of secondary epileptogenesis than ascribable to mul¬ tiple or diffuse primary injuries. Lim et al" are careful to recognize and point out that the correlative nature of their data does not allow causal inferences; never¬ theless, their findings are strongly sug¬ gestive and perhaps the more so be¬ cause
they were so unexpected.
THE EXPERIMENTAL PHENOMENON
These
findings were unexpected be¬ despite the fact that secondary epileptogenesis is a well-established phenomenon in animal models of focal epilepsy,7"14 strong evidence for its exis¬ cause,
tence in man has been difficult to obtain.
In the animal models, however, a clean, very discrete, and single epileptogenic lesion can be placed in an otherwise nor¬ mal brain, so that the issue of multiple injury does not intrude itself. This pri¬ mary epileptogenic lesion may be in¬ duced by any of a wide variety of agents,13 and its activity is easily moni¬ tored by the recording of localized IEDs, local seizure discharge, and clini¬ cal seizures ifthe lesion has been placed in "eloquent" cortex. After some weeks or months, epileptiform events begin to occur in the contralateral cortex at a
point precisely homotopic (or juxtahomotopic, depending on the exact axonal connections) with the region of the pri¬ mary focus
(mirror focus). At first, such
only in conjunction with similar events in the primary lesion and are simply evoked or conducted poten¬ tials. Removal or disconnection of the primary source results in immediate cessation of these secondary-evoked spikes. Thus, the first stage in second¬ ary epileptogenesis is called dependent and it is the initial manifestation of dis¬ tant epileptic activation. Eventually, the IEDs in the secondary or target spikes
occur
region begin to occur spontaneously, ie, not in conjunction with primary spikes, and occasional seizures may originate in the mirror region. When such temporal-
appear, the pro¬ has entered an intermediate stage. The intermediate stage differs from the dependent not only by virtue ofthe tem¬ poral independence of spiking and the occurrence of secondary site seizures, but primarily by the fact that excision of the original lesion does not lead to im¬ mediate cessation of secondary dis¬ charge. Indeed, spiking may continue in the satellite region for months and only gradually fade away. But these dis¬ charges ultimately do fade away and the EEG normalizes, ie, the process is still reversible. However, further exposure of the target cells to the activity of the prima¬ ry focus leads to an irreversible and per¬ manent epileptogenic transformation. The frequency of temporally indepen¬ dent spiking in both areas increases sub¬ stantially, clinical seizures arise from either site and—the defining character¬ istic—excision of the primary lesion does not result in resolution of epileptic activity in the secondary. The third stage is called independent to reflect the insouciance of the secondary focus to¬ ward whatever happens to the primary. A secondary epileptogenic focus in the third stage has acquired all the proper¬ ties of a primary lesion, including the appropriate microphysiologic abnor¬ malities.81617 It is fully autonomous and capable of establishing its own second¬ ary epileptogenic lesion. The autono¬ mous secondary focus represents the acquisition by an initially normal net¬ work of true and permanent epilepto¬ genic properties as a consequence of
ly independent spikes cess
prolonged exposure to an artificially in¬ duced epileptogenic lesion. The trans¬ formation takes place over well-estab¬ lished synaptic linkages using normal
of intercellular communication. Although the sequence described is
means
extraordinarily stereotyped across spe¬ cies and individuals, in the earlier ex¬ periments the timing of stages and par¬ ticularly the occurrence of spontaneous seizures was extremely variable and es¬ sentially uncontrolled. As is the case with human epilepsy, each experimen¬
tal alumina or freeze lesion had a some¬ what different degree of virulence. It gave rise to clinical seizures and to sec¬ ondary focus development in its own good time, often over a period of many months. Because the time of occurrence of clinical seizures from the primary or secondary site could not be predicted, if one wanted to observe them, it was nec¬ essary to employ continuous monitoring just as is done in man. Uncontrollable seizure occurrence remained a limita¬ tion until Graham Goddard18 discovered that an artificial electrical current deliv¬ ered directly to a local brain region
(34%) had evidence of second¬
could be substituted for the primary epi¬ his method "kindling."20 At one stroke, the discov¬ ery of kindling brought the entire pro¬ cess of secondary epileptogenesis under much more convenient experimenter control and it ushered in a veritable ex¬ plosion of experimental work in the field. However, it is important to stress that the replacement of a chemical agent such as alumina gel with electrical cur¬ rent does not require the introduction of any new principle in the understanding of secondary epileptogenesis. The elec¬ trical stimulus simply replicates or re¬ produces the electrical discharges asso¬ ciated with the interictal spike in the freeze or alumina focus (or, for that mat¬ ter, the one emanating from the prima¬ ry focus caused by a tumor or cicatrix in human focal epilepsy). There is no doubt that kindling and secondary epileptogenesis in general are phenomena of widespread preva¬ lence throughout the animal kingdom. These phenomena have been repro¬ duced in laboratories all over the world and in virtually all animal species in which they have been tested—in rep¬
cases, 16
Yet within the field of neurol¬ ogy and even among epileptologists, there has been a surprising resistance to the concept as applied to the human epi¬ lepsies. Two major reasons for this re¬ sistance come to mind. One of them is that many of the etiologic factors in the human disease, infection, trauma, birth injury, anoxia, and vasculitis are capa¬ ble of producing more than one site of injury in the brain. If the physician has ascribed a primary epileptogenic lesion to one of these potentially disseminated processes, is it not most parsimonious to assume that other foci have the same "cause"? The findings of Lim et al6 raise some questions about this argument be¬ cause in their study neither encephalitis nor febrile seizures were more common in patients with bitemporal EEG abnor¬ malities. It was, precisely, in an at¬ tempt to cope with the issue of multiple primary lesions that we initiated the series of studies restricted to patients in whom the epilepsy was caused by tumor or malformation. Our findings in three separate studies21,22,23 (and see review in reference 24) indicate that bilateral foci occur in 21% to 38% of patients with tumorigenic epilepsy. In one of these studies comprising 123 patients with temporal lobe tumors, 44 (35.7%) had independent secondary foci and in 19 of these 44 patients clinical attacks were documented by simultaneous EEG re¬ cording to have arisen at the secondary site.22 In a separate series of 47 tumor
The significance of secondary epilep¬ togenesis to the understanding and
leptic lesion.19 He called
tiles, amphibians, rodents, lagomorphs, felines, canines, and in several primate
species.
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ary epileptogenesis.21 Following surgi¬ cal resection ofthe tumor and surround¬ ing primary epileptogenic lesion, there
slow, but complete, resolution of the contralateral secondary focus in two thirds of the patients, whereas in one third the secondary focus persisted and continued to give rise to clinical sei¬ zures. It was postulated, therefore, that secondary epileptogenesis in man exists in both reversible and irrevers¬ ible forms (see the "Practical Implica¬ tions of Secondary Epileptogenesis" was a
section).
reason that neurologists appreciate the influence of sec¬ ondary epileptogenesis in man is that few of them (fortunately) have the op¬ portunity to observe the natural history of untreated epilepsy. It is pertinent to emphasize that, in contrast, virtually all of the experimental observations de¬
Another
may not
scribed above were made in unmedicated animals. Pharmacotherapy, even if only partially successful in treating the epileptic symptoms, obscures, if it does not eliminate,
progressive epileptogenesis.
PRACTICAL IMPLICATIONS OF SECONDARY EPILEPTOGENESIS
treatment of human disorders is sub¬ stantial. Yet, these implications have only begun to be explored. One of the simplest and most straightforward of these is that worsening of the EEG is not to be ignored. The appearance of a
focus of epileptiform abnormality in a patient whose past EEG records have consistently revealed only a single area of paroxysmal discharge should raise the question of the need for more vigorous therapy. A similar conclusion is implied by the appearance of a new seizure pattern in someone whose prior seizures have been single and stereo¬ typed. Ifthe new electrographic or clini¬ cal signs do not respond to medicinal adjustment, then surgical therapy might be considered at an earlier stage than would otherwise be the case. The selection of anticonvulsant drugs should take into account not only the need to prevent seizures, but the need to pro¬ vide antiepileptogenic prophylactic measures as well. Pharmacologie stud¬ ies using animal models of secondary epileptogenesis indicate, for instance, that while phenytoin, carbamazepine, phénobarbital, and valproic acid all ef¬ fectively prevent or dimmish seizures, ie, are all anticonvulsants, only phéno¬ barbital and valproic acid have any pro¬ tective effect against epileptogene¬ sis.25,26 And, of course, it is not only the physician but the pharmaceutical comnew
panies that might benefit from recogni¬ tion that acceptable clinical prophylac¬ tic agents are required. The search for such agents must be explicit, not acci¬ dental, and will demand the introduc¬
tion of new assay measures, different from those presently employed—per¬ haps actually using the kindling mod¬ el. 26,27 Renewed consideration should be given to prophylactic treatment of nonepileptic individuals at very high risk for developing seizures using agents de¬ signed for the purpose, rather than anti¬ convulsants such as phenytoin that are devoid of antiepileptogenic potency.25,28"3° With respect to surgical treatment, the implications of secondary epilepto¬ genesis are even more prominent. The occurrence of bitemporal epileptiform abnormality in the EEG of medically intractable patients, so often viewed as a contraindication to a surgical ap¬ proach, may, on the contrary, represent an indication to move more quickly to ablative therapy. However, the pathophysiology of sec¬ ondary epileptogenesis is complex. As indicated above, the process has both reversible and irreversible stages. These stages cannot be told apart on the basis of examination ofthe raw EEG or by the fact that clinical seizures may arise from each focus. Confronted with bilateral independent IEDs, the clini¬ cian must distinguish between the pos¬ sibilities of (1) multiple primary lesions, (2) secondary epileptogenesis in an irre¬ versible form, and (3) an intermediate or reversible stage of secondary epilep¬ togenesis. Ifthe latter circumstance ob¬ tains and if the primary lesion can be identified, it is reasonable to anticipate a surgical cure. Furthermore, in princi¬ ple, the finding that a secondary focus is still reversible lends some urgency to the timing of surgical intervention. On the other hand, either of the first two possibilities make a surgical cure much less likely. Separating the third from the other two hypotheses can be achieved by a careful analysis of the evolution and timing of the EEG changes, the time of appearance of a new seizure pattern, if any, and the re¬ sults of special pharmacologie chal¬ lenges (relative resistance of the focus in question to synaptic blockade—the methohexital suppression test21,24,31,32). Distinguishing multifocal epilepsy from an irreversible secondary epilep¬ togenic lesion is somewhat more diffi¬ cult, perhaps not as important from a practical surgical standpoint, but of con¬ siderable pathophysiologic interest. If the several EEG foci have arisen as a result of secondary epileptogenesis, then there should be a clear and unam¬ biguous relationship between the pre-
sumed primary and secondary sites—a relationship that is likely to occur only by chance in multifocal epilepsy. Sec¬ ondary epileptogenesis is a synaptically
mediated event; it travels via callosal or commissural pathways or through ma¬ jor intrahemispheric linkages, such as the uncinate and superior longitudinal fasciculi. '" Secondary sites should be ho¬ motopic with that of contralateral pri¬ mary lesions or juxtahomotopic, if the commissural pathway is juxtahomoto¬ pic. In either case, the site of secondary discharge is guided specifically and ab¬ solutely by the axonal extentions of cells of the primary focus. Where callosal connections are absent or sparse, as in the primate precentrai representation of distal extremities, one does not ob¬ serve a contralateral secondary focus.21 This obligatory synaptic mediation car¬ ries an important implication with re¬ spect to the clinical seizures generated from the two foci, namely, the behavior¬ al manifestations reflect the activity of closely related neural networks. For ex¬ ample, one patient with a primary lesion of the right mesiotemporal region com¬ plained of an epigastric rising sensation that was followed by swallowing and lipsmacking automatisms as the main ictal event. Approximately 8 months after the first appearance of an independent left temporal spike in her EEG, she not¬ ed the onset of a different seizure con¬ sisting of an olfactory aura, ambulatory automatism and a rather prolonged post¬ ictal aphasia. The new pattern was just as clearly limbic in origin as was the original one, but with a different aura and with localizing features (the apha¬ sia) pointing to a dominant hemisphere source. (It was, in fact, documented to emanate from the left temporal lobe.) There is little doubt from a clinical standpoint that these two ictal manifes¬ tations were generated in interconnect¬ ed networks. In contrast, when more than one seizure type exists as a conse¬ quence of disseminated pathology, the ictal patterns are likely to be entirely unrelated, eg, a partial complex seizure as one pattern and a Jacksonian motor seizure as the other. Although extremely useful when pres¬ ent, these clinical distinctions are, of
course, not, by themselves, invariably accurate guides. Clearly disparate sei¬ zure patterns may not be present (or may not be described by the patient or family) in either the multifocal or sec¬ case. Further¬ of the causes of multifocal epilepsy (as Lim et al point out) may injure symmetrical brain regions (closed deceleration head trauma may bruise both frontal or temporal poles, for example, and some cases of compii-
ondary epileptogenesis
more,
some
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cated febrile convulsions may result in bilateral mesiotemporal sclerosis). However, when careful clinical analysis of ictal signs and symptoms and their sequence is correlated with detailed mapping ofthe IEDs (or sites of seizure origin, if seizures are being monitored) a reasonably accurate anatomical formu¬ lation is usually possible. OTHER IMPLICATIONS FOR PATHOPHYSIOLOGY
On
analogy with
the animal
experi¬
ments, it has been thought that if bilat¬
eral epileptogenic foci were commonly the result of secondary epileptogenesis, the incidence of bilateral foci should in¬ crease if duration of illness increases. Lim and colleagues6 point out that the literature contains discordant results on that score and that their own study did not confirm a relationship between bitemporal foci and long duration of ill¬ ness. Nor could they establish any cor¬ relation between frequency of seizures and the likelihood of bitemporal EEG abnormality. However, as the authors themselves emphasize, the failure to es¬ tablish such a statistical correlation is of limited significance particularly when populations with mixed etiologic factors are considered. Many of the causes of multifocal epilepsy are relatively acute, eg, trauma, encephalitis, anoxia, vascu¬ litis, and might be associated with more severe illness. The frequency of EEG tests might be expected to be greater in such a group. In a cohort derived from an EEG laboratory, such patients might bias the population with multiple spike foci toward a shorter duration of illness at the time in which the test was per¬ formed. In any event, the correlation has greater meaning with respect to the issue of secondary epileptogenesis where the possibility of several sites of cerebral injury can be minimized. Such was the case in our cohort of temporal lobe tumors where a positive relation¬ ship between duration of illness and bi¬ lateral independent EEG foci was found.22 It is also obvious that frequency of seizures and duration of illness may exert opposite influences in given cases. High seizure frequency leads to second¬ ary focus development in a shorter peri¬ od than might otherwise be the case. Even in an etiologically pure popula¬ tion with strictly unilateral disease, however, there are a number of factors that would tend to modify any simple association between duration of illness, frequency of seizures, and the incidence of secondary foci. The first of these is the age at which the epileptogenic insult occurs. It is the young brain that is par¬ ticularly prone to establishment of sat¬ ellite foci in the presence of an active
primary lesion.33,34 This special suscepti¬ bility of the young organism to the pro¬ cess of secondary epileptogenesis may
have clinical significance with respect to the optimal timing of surgical interven¬ tion. Furthermore, the age-dependent vulnerability found in the tumor cases is the counterpart to the decreased sus¬ ceptibility to kindling reported in aged animals34,3'1 and it stresses the biological continuity of pathophysiologic mecha¬ nisms in epilepsy, rather than any par¬ ticular uniqueness ofthe human host. A second major modifying variable is that of the anatomic site of the primary lesion. The density of excitatory synap¬ tic connections of primary focus cells and the excitability of the target cells exert a major influence on secondary epileptogenesis. In experimental ani¬ mals, secondary epileptogenic lesions arise more rapidly and reliably if the primary lesion is placed in territories with dense callosal and long intrahemis¬
pheric connections; conversely, place¬ ment of the primary lesion in regions with sparse commisurai outflow, eg, motor cortex, rarely results in second¬
ary foci. Clinical evidence corroborates this finding; in patients with Koshevnikoff's epilepsy having the highest sei¬ zure frequency we know of, a mirror focus is rare.21 The effect of certain anticonvulsant drugs has been mentioned earlier as a modifying factor, and the role of consti¬ tutional, hormonal, and other variables has yet to be ascertained. In this brief review and commentary, I have outlined the phenomenology and tried to stress some of the clinical impli¬ cations of the concept of secondary epi¬ leptogenesis. The notion clearly implies that at least some forms of epilepsy are progressive in nature because ofthe epi¬ lepsy itself, rather than some other un¬ derlying disease. Other forms of epilep¬ sy—for instance, most forms of primary generalized epilepsy—do not appear to be progressive. An understanding of the reason for this difference may pro¬ vide important insights into the funda¬ mental biology of this disorder. But even in the forms that are progressive, forms that exhibit secondary epilepto¬ genesis, generalized deterioration is relatively uncommon. Rather, the na¬ ture ofthe progression depends entirely on what particular cerebral circuits are involved in each individual case. For example, the mirror focus in a patient with occipital lobe epilepsy may ulti¬ mately give rise to occasional seizures in which visual experiences are limited to the visual field contralateral to the one originally involved. But it (an occipital mirror focus) is not usually associated with personality disturbance, memory
or cognitive impairment. Enand have emphasized the Shewmon36 gel development of behavioral disturbances as a consequence of secondary epilepto¬ genesis. It is important to note, howev¬ er, that they were discussing temporal lobe epilepsy in particular. It should be clear then that it is dan¬ gerous to draw oversimplified conclu¬ sions about the clinical consequences of
disorder,
secondary epileptogenesis. Generaliza¬
tions about diffuse brain
damage or global deterioration are premature and do not apply in most cases. Neverthe¬ less, there are implications with respect to progression in every case. It is the specifics of that case that need to be determined and clearly communicated to the particular patient. At a more basic level, it is the details of the pathophysiology that count. The need is to actively explore the variables, the propensities, and the constraints, rather than continuing to argue that the human host is immune to a process that affects almost all other complex brains. Frank Morrell, MD Chicago, Ill References 1. Niediek T, Franke HG, Degen R, Ettlinger G.
development of independent foci in epileptic patients. Arch Neurol. 1990;47:406-411. 2. Hughes JR. Long-term clinical and EEG changes in patients with epilepsy. Arch Neurol. The
1985;42:213-223.
3. Jasper H, Pertuisset B, Flanigin H. EEG and cortical electrogram in patients with temporal lobe seizures. Arch Neurol Psychiatry. 1951;65:272\x=req-\ 290. 4. Engel J Jr. Seizures and Epilepsy. Philadelphia, Pa: FA Davis Co; 1989. 5. Goldensohn ES. The relevance of secondary epileptogenesis to the treatment of epilepsy: kindling and the mirror focus. Epilepsia.
1984;25(suppl 2):S156-S173. 6. Lim SH, So NK, Luders H, Morris HH, Turnbull J. Etiologic factors for unitemporal vs bitemporal epileptiform discharges. Arch Neurol. In press.
7. Morrell F. Secondary epileptogenic Epilepsia. 1959/1960;1:538-560.
lesions.
8. Wilder BJ, Morrell F. Cellular behavior in Neurology. secondary epileptic lesions.
1967;17:1193-1204. 9. Holubar J, Strejckova A, Servit Z. Penicillin and mirror epileptogenic foci in the brain hemisphere of the frog. In: Servit Z, ed. Comparative and Cellular Pathophysiology of Epilepsy. Amsterdam, the Netherlands: Excerpta Medica; 1966:214-220. International Congress Series No. 124. 10. Morrell F. Callosal mechanisms in epileptogenesis: identification of two distinct kinds of spread of spread of epileptic activity. In: Reeves AG, ed. Epilepsy and the Corpus Callosum. New York, NY: Plenum Press; 1985:99-130. 11. Morrell F. Physiology and histochemistry of the mirror focus. In: Jasper HH, Ward AA, Pope A, eds. Basic Mechanisms of the Epilepsies. Boston, Mass: Little Brown & Co Inc; 1969:357-370. 12. Morrell F. Goddard's kindling phenomenon: a new model of the 'mirror focus.' In: Sabelli HC, ed. Chemical Modulation of Brain Function. New York, NY: Raven Press; 1973:207-233. 13. Morrell F. Animal models of human focal epilepsy. In: Klawans HL, ed. Models of Human
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Neurological Disease. Amsterdam, the Netherlands: Excerpta Medica; 1974:166-199. 14. Morrell F, Tsuru N. Kindling in the frog: development of spontaneous epileptiform activity. Electroencephalogr Clin Neurophysiol. 1976;40:1\x=req-\ 11.
15. Purpura DP, Penry JK, Tower DB, Woodburry DM, Walter RD, eds. Experimental Models of Epilepsy: A Manual for the Laboratory Worker.
New York, NY: Raven Press; 1972. 16. Morrell F. Cellular pathophysiology of focal
epilepsy. Epilepsia. 1969;10:495-505. 17. Twombly DA, Delgado-Escueta
AV. Cellular and membrane events in the mirror focus. In: Mayersdorf A, Schmidt RP, eds. Secondary Epileptogenesis. New York, NY: Raven Press; 1982:89-113. 18. Goddard GV. The development of epileptic seizures through brain stimulation at low intensity. Nature. 1967;214:1020-1021. 19. Goddard GV, Morrell F. Chronic progressive epileptogenesis induced by focal electrical stimulation of brain. Neurology. 1971;21:393. 20. Goddard GV, McIntyre D, Leech C. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol.
1969;25:295-330.
21. Morrell F. Secondary epileptogenesis in Arch Neurol. 1985;42:318-335. 22. Morrell F, Rasmussen T, Gloor P, deToledo\x=req-\ Morrell L. Secondary epileptogenic foci in patients with verified temporal lobe tumors. Electroencephalogr Clin Neurophysiol. 1983;54:26. 23. Morrell F, Rasmussen T, deToledo-Morrell L, Quesney LF, Gloor P. Frontal lobe epilepsy of neoplastic etiology: incidence of secondary epilepman.
togenesis. Epilepsia. 1984;25:654-655. 24. Morrell F. Varieties of human secondary epileptogenesis. J Clin Neurophysiol. 1989;6:227-275. 25. Morrell F, Baker L. Effect of drugs on secondary epileptogenic lesions. Neurology. 1961;11:651-664.
26. Silver JM, Shin C, McNamara JO. Antiepileptogenic effects of conventional anticonvulsants in the kindling model of epilepsy. Ann Neurol.
1991;29:356-363.
27. Burnham M. Anticonvulsants and the kin-
dling model. In: Morrell F, ed. Kindling and Synaptic Plasticity: The Legacy of Graham Goddard. Boston, Mass: Birkhauser; 1991:272-288. 28. Racine RJ, Livingston K, Joaquin A. Effects of procaine HCI diazepam and diphenylhydantoin on
cortical and subcortical structures in rats. Elec-
troencephalogr Clin Neurophysiol. 1975;38:355\x=req-\ 365.
29. Turner IM, Newman SM, Louis S, Kutt H. Pharmacological prophylaxis against the development of kindled amygdaloid seizures. Ann Neurol.
1977;2:221-224. 30. Wada JA, Sato M, Wake A, Green JR, Troupin AS. Prophylactic effects of phenytoin, phenobarbital and
carbamazepine
examined in
cat preparation. Arch Neurol.
kindling
1976;33:426-434.
31. Morrell F. Aspects of experimental epilepsy. In: Wada JA, ed. Modern Perspectives in Epilepsy. Montreal, Quebec: Eden Press; 1978:24-75. 32. Smith MC, Whisler WW, Morrell F. Neurosurgery of epilepsy. Semin Neurol. 1989;9:231-248. 33. Morrell F, deToledo-Morrell L. Kindling as a model of neuronal plasticity. In: Wada JA, ed. Kindling 3. New York, NY: Raven Press; 1986:17-35. 34. deToledo-Morrell L, Morrell F. Age-related alterations in long-term potentiation and susceptibility to kindling. In: Morrell F, ed. Kindling and Synaptic Plasticity: The Legacy of Graham Goddard. Boston, Mass: Birkhauser; 1991:160-176. 35. deToledo-Morrell L, Morrell F, Fleming S. Age-dependent deficits in spatial memory are related to impaired hippocampal kindling. Behav Neurosci. 1984;98:902-907. 36. Engel J Jr, Shewmon DA. Impact of the kindling phenomenon on clinical epileptology. In: Morrell F, ed. Kindling and Synaptic Plasticity: The Legacy of Graham Goddard. Boston, Mass: Birkhauser; 1991:195-210.
Approximately with focal
Epileptogenesis
age, eg, febrile seizures or encephalitis. Patients with strictly unitemporal foci were expected to have etiologic factors that were themselves completely later¬ alized, such as tumors. The second possible explanation to be considered, ifthe first failed, was that of secondary epileptogenesis, ie, that pro¬ cess by which a primary epileptogenic lesion of whatever cause may itself in¬ duce epileptiform behavior in initially normal cell populations with which the primary site is densely connected. Of course, these two hypotheses are not mutually exclusive; it is possible, in fact likely, that both mechanisms operate.
that bilateral foci are usually produced by central nervous system insults likely to cause widespread or bilateral dam-
From the Cleveland (Ohio) Clinic se¬ ries of temporal lobectomy candidates with medically intractable complex par¬ tial seizures, Lim et afselected 30 con¬ secutive patients with unitemporal in¬ terictal epileptiform discharges (IEDs) and 30 consecutive patients with bitemporal IEDs. The patients were chosen on the basis of noninvasive, scalp-re¬ corded EEGs derived from at least 4 days, continuous video/EEG monitor¬ ing. Patients were included in the bitemporal group only if IEDs in the less active temporal lobe accounted for at least 20% of the total discharges. The authors eliminated cases with extratemporal foci or where there was an extratemporal predominance of a tem¬ poral lobe IED. Thus, the groups were as cleanly separated as was feasible from the point of view of electrical pa¬ rameters under investigation, yet were comparable with respect to factors of sex, age, and intelligence quotient. Hospital charts, office files, and moni¬ toring results were then reviewed, so that etiologic information, frequency of seizures, duration of illness, and age at seizure onset could be compared across the two groups. Without doubt, the most striking finding of this study, and the most unex¬ pected, was the observation that those etiologic factors likely to cause multifo¬ cal damage, ie, febrile seizures and en¬
Accepted for publication August 19,1991. From the Department of Neurological Sciences, Rush Medical College, Chicago, Ill. Reprint requests to Department of Neurological Sciences, Rush Medical College, 1653 W. Congress Pkwy, Chicago, IL 60612 (Dr Morrell).
epileptiform abnormality. Indeed, sev¬ en of the 10 patients with a mass lesion showed bitemporal IEDs (70%). Al¬ though called "mass lesions," the tu-
contralateral to an intended excision afford a warning that the operative intervention is unlikely to result in cure? Is it rather a warning that operative intervention is needed more quickly? Or, as others have suggested,'' is such evi¬ dence of bilateral discharge of no signifi¬ cance whatsoever to the clinical out¬ come? I will return to these issues a bit later. But, it seems appropriate to con¬ sider first the etiologic and pathophysi¬ ologic implications of bilateral, indepen¬ dent epileptiform abnormalities in such a large number of patients with focal seizures. The article by Lim and col¬ leagues6 in this issue of the Archives directly addresses this latter problem in a simple and elegant example ofthe pro¬ ductive use of retrospective clinical data. The authors entertain two main ex¬ planations for the exceptionally high in¬ cidence of bilateral, independent epilep¬ tic discharge in their temporal lobect¬ omy series. The first, and the one that
they specifically
set out to
verify,
was
were, in fact, more common among the unifocal group, while tumors tended to be associated with bitemporal
cephalitis,
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mors were unassociated with ventricu¬ lar displacement or increased intra¬ cranial pressure that might account for contralateral disturbance of function. The authors were thus forced to the conclusion that the epileptiform abnor¬ malities contralateral to the presumed site of ictal onset (primary focus) were more likely a consequence of secondary epileptogenesis than ascribable to mul¬ tiple or diffuse primary injuries. Lim et al" are careful to recognize and point out that the correlative nature of their data does not allow causal inferences; never¬ theless, their findings are strongly sug¬ gestive and perhaps the more so be¬ cause
they were so unexpected.
THE EXPERIMENTAL PHENOMENON
These
findings were unexpected be¬ despite the fact that secondary epileptogenesis is a well-established phenomenon in animal models of focal epilepsy,7"14 strong evidence for its exis¬ cause,
tence in man has been difficult to obtain.
In the animal models, however, a clean, very discrete, and single epileptogenic lesion can be placed in an otherwise nor¬ mal brain, so that the issue of multiple injury does not intrude itself. This pri¬ mary epileptogenic lesion may be in¬ duced by any of a wide variety of agents,13 and its activity is easily moni¬ tored by the recording of localized IEDs, local seizure discharge, and clini¬ cal seizures ifthe lesion has been placed in "eloquent" cortex. After some weeks or months, epileptiform events begin to occur in the contralateral cortex at a
point precisely homotopic (or juxtahomotopic, depending on the exact axonal connections) with the region of the pri¬ mary focus
(mirror focus). At first, such
only in conjunction with similar events in the primary lesion and are simply evoked or conducted poten¬ tials. Removal or disconnection of the primary source results in immediate cessation of these secondary-evoked spikes. Thus, the first stage in second¬ ary epileptogenesis is called dependent and it is the initial manifestation of dis¬ tant epileptic activation. Eventually, the IEDs in the secondary or target spikes
occur
region begin to occur spontaneously, ie, not in conjunction with primary spikes, and occasional seizures may originate in the mirror region. When such temporal-
appear, the pro¬ has entered an intermediate stage. The intermediate stage differs from the dependent not only by virtue ofthe tem¬ poral independence of spiking and the occurrence of secondary site seizures, but primarily by the fact that excision of the original lesion does not lead to im¬ mediate cessation of secondary dis¬ charge. Indeed, spiking may continue in the satellite region for months and only gradually fade away. But these dis¬ charges ultimately do fade away and the EEG normalizes, ie, the process is still reversible. However, further exposure of the target cells to the activity of the prima¬ ry focus leads to an irreversible and per¬ manent epileptogenic transformation. The frequency of temporally indepen¬ dent spiking in both areas increases sub¬ stantially, clinical seizures arise from either site and—the defining character¬ istic—excision of the primary lesion does not result in resolution of epileptic activity in the secondary. The third stage is called independent to reflect the insouciance of the secondary focus to¬ ward whatever happens to the primary. A secondary epileptogenic focus in the third stage has acquired all the proper¬ ties of a primary lesion, including the appropriate microphysiologic abnor¬ malities.81617 It is fully autonomous and capable of establishing its own second¬ ary epileptogenic lesion. The autono¬ mous secondary focus represents the acquisition by an initially normal net¬ work of true and permanent epilepto¬ genic properties as a consequence of
ly independent spikes cess
prolonged exposure to an artificially in¬ duced epileptogenic lesion. The trans¬ formation takes place over well-estab¬ lished synaptic linkages using normal
of intercellular communication. Although the sequence described is
means
extraordinarily stereotyped across spe¬ cies and individuals, in the earlier ex¬ periments the timing of stages and par¬ ticularly the occurrence of spontaneous seizures was extremely variable and es¬ sentially uncontrolled. As is the case with human epilepsy, each experimen¬
tal alumina or freeze lesion had a some¬ what different degree of virulence. It gave rise to clinical seizures and to sec¬ ondary focus development in its own good time, often over a period of many months. Because the time of occurrence of clinical seizures from the primary or secondary site could not be predicted, if one wanted to observe them, it was nec¬ essary to employ continuous monitoring just as is done in man. Uncontrollable seizure occurrence remained a limita¬ tion until Graham Goddard18 discovered that an artificial electrical current deliv¬ ered directly to a local brain region
(34%) had evidence of second¬
could be substituted for the primary epi¬ his method "kindling."20 At one stroke, the discov¬ ery of kindling brought the entire pro¬ cess of secondary epileptogenesis under much more convenient experimenter control and it ushered in a veritable ex¬ plosion of experimental work in the field. However, it is important to stress that the replacement of a chemical agent such as alumina gel with electrical cur¬ rent does not require the introduction of any new principle in the understanding of secondary epileptogenesis. The elec¬ trical stimulus simply replicates or re¬ produces the electrical discharges asso¬ ciated with the interictal spike in the freeze or alumina focus (or, for that mat¬ ter, the one emanating from the prima¬ ry focus caused by a tumor or cicatrix in human focal epilepsy). There is no doubt that kindling and secondary epileptogenesis in general are phenomena of widespread preva¬ lence throughout the animal kingdom. These phenomena have been repro¬ duced in laboratories all over the world and in virtually all animal species in which they have been tested—in rep¬
cases, 16
Yet within the field of neurol¬ ogy and even among epileptologists, there has been a surprising resistance to the concept as applied to the human epi¬ lepsies. Two major reasons for this re¬ sistance come to mind. One of them is that many of the etiologic factors in the human disease, infection, trauma, birth injury, anoxia, and vasculitis are capa¬ ble of producing more than one site of injury in the brain. If the physician has ascribed a primary epileptogenic lesion to one of these potentially disseminated processes, is it not most parsimonious to assume that other foci have the same "cause"? The findings of Lim et al6 raise some questions about this argument be¬ cause in their study neither encephalitis nor febrile seizures were more common in patients with bitemporal EEG abnor¬ malities. It was, precisely, in an at¬ tempt to cope with the issue of multiple primary lesions that we initiated the series of studies restricted to patients in whom the epilepsy was caused by tumor or malformation. Our findings in three separate studies21,22,23 (and see review in reference 24) indicate that bilateral foci occur in 21% to 38% of patients with tumorigenic epilepsy. In one of these studies comprising 123 patients with temporal lobe tumors, 44 (35.7%) had independent secondary foci and in 19 of these 44 patients clinical attacks were documented by simultaneous EEG re¬ cording to have arisen at the secondary site.22 In a separate series of 47 tumor
The significance of secondary epilep¬ togenesis to the understanding and
leptic lesion.19 He called
tiles, amphibians, rodents, lagomorphs, felines, canines, and in several primate
species.
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ary epileptogenesis.21 Following surgi¬ cal resection ofthe tumor and surround¬ ing primary epileptogenic lesion, there
slow, but complete, resolution of the contralateral secondary focus in two thirds of the patients, whereas in one third the secondary focus persisted and continued to give rise to clinical sei¬ zures. It was postulated, therefore, that secondary epileptogenesis in man exists in both reversible and irrevers¬ ible forms (see the "Practical Implica¬ tions of Secondary Epileptogenesis" was a
section).
reason that neurologists appreciate the influence of sec¬ ondary epileptogenesis in man is that few of them (fortunately) have the op¬ portunity to observe the natural history of untreated epilepsy. It is pertinent to emphasize that, in contrast, virtually all of the experimental observations de¬
Another
may not
scribed above were made in unmedicated animals. Pharmacotherapy, even if only partially successful in treating the epileptic symptoms, obscures, if it does not eliminate,
progressive epileptogenesis.
PRACTICAL IMPLICATIONS OF SECONDARY EPILEPTOGENESIS
treatment of human disorders is sub¬ stantial. Yet, these implications have only begun to be explored. One of the simplest and most straightforward of these is that worsening of the EEG is not to be ignored. The appearance of a
focus of epileptiform abnormality in a patient whose past EEG records have consistently revealed only a single area of paroxysmal discharge should raise the question of the need for more vigorous therapy. A similar conclusion is implied by the appearance of a new seizure pattern in someone whose prior seizures have been single and stereo¬ typed. Ifthe new electrographic or clini¬ cal signs do not respond to medicinal adjustment, then surgical therapy might be considered at an earlier stage than would otherwise be the case. The selection of anticonvulsant drugs should take into account not only the need to prevent seizures, but the need to pro¬ vide antiepileptogenic prophylactic measures as well. Pharmacologie stud¬ ies using animal models of secondary epileptogenesis indicate, for instance, that while phenytoin, carbamazepine, phénobarbital, and valproic acid all ef¬ fectively prevent or dimmish seizures, ie, are all anticonvulsants, only phéno¬ barbital and valproic acid have any pro¬ tective effect against epileptogene¬ sis.25,26 And, of course, it is not only the physician but the pharmaceutical comnew
panies that might benefit from recogni¬ tion that acceptable clinical prophylac¬ tic agents are required. The search for such agents must be explicit, not acci¬ dental, and will demand the introduc¬
tion of new assay measures, different from those presently employed—per¬ haps actually using the kindling mod¬ el. 26,27 Renewed consideration should be given to prophylactic treatment of nonepileptic individuals at very high risk for developing seizures using agents de¬ signed for the purpose, rather than anti¬ convulsants such as phenytoin that are devoid of antiepileptogenic potency.25,28"3° With respect to surgical treatment, the implications of secondary epilepto¬ genesis are even more prominent. The occurrence of bitemporal epileptiform abnormality in the EEG of medically intractable patients, so often viewed as a contraindication to a surgical ap¬ proach, may, on the contrary, represent an indication to move more quickly to ablative therapy. However, the pathophysiology of sec¬ ondary epileptogenesis is complex. As indicated above, the process has both reversible and irreversible stages. These stages cannot be told apart on the basis of examination ofthe raw EEG or by the fact that clinical seizures may arise from each focus. Confronted with bilateral independent IEDs, the clini¬ cian must distinguish between the pos¬ sibilities of (1) multiple primary lesions, (2) secondary epileptogenesis in an irre¬ versible form, and (3) an intermediate or reversible stage of secondary epilep¬ togenesis. Ifthe latter circumstance ob¬ tains and if the primary lesion can be identified, it is reasonable to anticipate a surgical cure. Furthermore, in princi¬ ple, the finding that a secondary focus is still reversible lends some urgency to the timing of surgical intervention. On the other hand, either of the first two possibilities make a surgical cure much less likely. Separating the third from the other two hypotheses can be achieved by a careful analysis of the evolution and timing of the EEG changes, the time of appearance of a new seizure pattern, if any, and the re¬ sults of special pharmacologie chal¬ lenges (relative resistance of the focus in question to synaptic blockade—the methohexital suppression test21,24,31,32). Distinguishing multifocal epilepsy from an irreversible secondary epilep¬ togenic lesion is somewhat more diffi¬ cult, perhaps not as important from a practical surgical standpoint, but of con¬ siderable pathophysiologic interest. If the several EEG foci have arisen as a result of secondary epileptogenesis, then there should be a clear and unam¬ biguous relationship between the pre-
sumed primary and secondary sites—a relationship that is likely to occur only by chance in multifocal epilepsy. Sec¬ ondary epileptogenesis is a synaptically
mediated event; it travels via callosal or commissural pathways or through ma¬ jor intrahemispheric linkages, such as the uncinate and superior longitudinal fasciculi. '" Secondary sites should be ho¬ motopic with that of contralateral pri¬ mary lesions or juxtahomotopic, if the commissural pathway is juxtahomoto¬ pic. In either case, the site of secondary discharge is guided specifically and ab¬ solutely by the axonal extentions of cells of the primary focus. Where callosal connections are absent or sparse, as in the primate precentrai representation of distal extremities, one does not ob¬ serve a contralateral secondary focus.21 This obligatory synaptic mediation car¬ ries an important implication with re¬ spect to the clinical seizures generated from the two foci, namely, the behavior¬ al manifestations reflect the activity of closely related neural networks. For ex¬ ample, one patient with a primary lesion of the right mesiotemporal region com¬ plained of an epigastric rising sensation that was followed by swallowing and lipsmacking automatisms as the main ictal event. Approximately 8 months after the first appearance of an independent left temporal spike in her EEG, she not¬ ed the onset of a different seizure con¬ sisting of an olfactory aura, ambulatory automatism and a rather prolonged post¬ ictal aphasia. The new pattern was just as clearly limbic in origin as was the original one, but with a different aura and with localizing features (the apha¬ sia) pointing to a dominant hemisphere source. (It was, in fact, documented to emanate from the left temporal lobe.) There is little doubt from a clinical standpoint that these two ictal manifes¬ tations were generated in interconnect¬ ed networks. In contrast, when more than one seizure type exists as a conse¬ quence of disseminated pathology, the ictal patterns are likely to be entirely unrelated, eg, a partial complex seizure as one pattern and a Jacksonian motor seizure as the other. Although extremely useful when pres¬ ent, these clinical distinctions are, of
course, not, by themselves, invariably accurate guides. Clearly disparate sei¬ zure patterns may not be present (or may not be described by the patient or family) in either the multifocal or sec¬ case. Further¬ of the causes of multifocal epilepsy (as Lim et al point out) may injure symmetrical brain regions (closed deceleration head trauma may bruise both frontal or temporal poles, for example, and some cases of compii-
ondary epileptogenesis
more,
some
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cated febrile convulsions may result in bilateral mesiotemporal sclerosis). However, when careful clinical analysis of ictal signs and symptoms and their sequence is correlated with detailed mapping ofthe IEDs (or sites of seizure origin, if seizures are being monitored) a reasonably accurate anatomical formu¬ lation is usually possible. OTHER IMPLICATIONS FOR PATHOPHYSIOLOGY
On
analogy with
the animal
experi¬
ments, it has been thought that if bilat¬
eral epileptogenic foci were commonly the result of secondary epileptogenesis, the incidence of bilateral foci should in¬ crease if duration of illness increases. Lim and colleagues6 point out that the literature contains discordant results on that score and that their own study did not confirm a relationship between bitemporal foci and long duration of ill¬ ness. Nor could they establish any cor¬ relation between frequency of seizures and the likelihood of bitemporal EEG abnormality. However, as the authors themselves emphasize, the failure to es¬ tablish such a statistical correlation is of limited significance particularly when populations with mixed etiologic factors are considered. Many of the causes of multifocal epilepsy are relatively acute, eg, trauma, encephalitis, anoxia, vascu¬ litis, and might be associated with more severe illness. The frequency of EEG tests might be expected to be greater in such a group. In a cohort derived from an EEG laboratory, such patients might bias the population with multiple spike foci toward a shorter duration of illness at the time in which the test was per¬ formed. In any event, the correlation has greater meaning with respect to the issue of secondary epileptogenesis where the possibility of several sites of cerebral injury can be minimized. Such was the case in our cohort of temporal lobe tumors where a positive relation¬ ship between duration of illness and bi¬ lateral independent EEG foci was found.22 It is also obvious that frequency of seizures and duration of illness may exert opposite influences in given cases. High seizure frequency leads to second¬ ary focus development in a shorter peri¬ od than might otherwise be the case. Even in an etiologically pure popula¬ tion with strictly unilateral disease, however, there are a number of factors that would tend to modify any simple association between duration of illness, frequency of seizures, and the incidence of secondary foci. The first of these is the age at which the epileptogenic insult occurs. It is the young brain that is par¬ ticularly prone to establishment of sat¬ ellite foci in the presence of an active
primary lesion.33,34 This special suscepti¬ bility of the young organism to the pro¬ cess of secondary epileptogenesis may
have clinical significance with respect to the optimal timing of surgical interven¬ tion. Furthermore, the age-dependent vulnerability found in the tumor cases is the counterpart to the decreased sus¬ ceptibility to kindling reported in aged animals34,3'1 and it stresses the biological continuity of pathophysiologic mecha¬ nisms in epilepsy, rather than any par¬ ticular uniqueness ofthe human host. A second major modifying variable is that of the anatomic site of the primary lesion. The density of excitatory synap¬ tic connections of primary focus cells and the excitability of the target cells exert a major influence on secondary epileptogenesis. In experimental ani¬ mals, secondary epileptogenic lesions arise more rapidly and reliably if the primary lesion is placed in territories with dense callosal and long intrahemis¬
pheric connections; conversely, place¬ ment of the primary lesion in regions with sparse commisurai outflow, eg, motor cortex, rarely results in second¬
ary foci. Clinical evidence corroborates this finding; in patients with Koshevnikoff's epilepsy having the highest sei¬ zure frequency we know of, a mirror focus is rare.21 The effect of certain anticonvulsant drugs has been mentioned earlier as a modifying factor, and the role of consti¬ tutional, hormonal, and other variables has yet to be ascertained. In this brief review and commentary, I have outlined the phenomenology and tried to stress some of the clinical impli¬ cations of the concept of secondary epi¬ leptogenesis. The notion clearly implies that at least some forms of epilepsy are progressive in nature because ofthe epi¬ lepsy itself, rather than some other un¬ derlying disease. Other forms of epilep¬ sy—for instance, most forms of primary generalized epilepsy—do not appear to be progressive. An understanding of the reason for this difference may pro¬ vide important insights into the funda¬ mental biology of this disorder. But even in the forms that are progressive, forms that exhibit secondary epilepto¬ genesis, generalized deterioration is relatively uncommon. Rather, the na¬ ture ofthe progression depends entirely on what particular cerebral circuits are involved in each individual case. For example, the mirror focus in a patient with occipital lobe epilepsy may ulti¬ mately give rise to occasional seizures in which visual experiences are limited to the visual field contralateral to the one originally involved. But it (an occipital mirror focus) is not usually associated with personality disturbance, memory
or cognitive impairment. Enand have emphasized the Shewmon36 gel development of behavioral disturbances as a consequence of secondary epilepto¬ genesis. It is important to note, howev¬ er, that they were discussing temporal lobe epilepsy in particular. It should be clear then that it is dan¬ gerous to draw oversimplified conclu¬ sions about the clinical consequences of
disorder,
secondary epileptogenesis. Generaliza¬
tions about diffuse brain
damage or global deterioration are premature and do not apply in most cases. Neverthe¬ less, there are implications with respect to progression in every case. It is the specifics of that case that need to be determined and clearly communicated to the particular patient. At a more basic level, it is the details of the pathophysiology that count. The need is to actively explore the variables, the propensities, and the constraints, rather than continuing to argue that the human host is immune to a process that affects almost all other complex brains. Frank Morrell, MD Chicago, Ill References 1. Niediek T, Franke HG, Degen R, Ettlinger G.
development of independent foci in epileptic patients. Arch Neurol. 1990;47:406-411. 2. Hughes JR. Long-term clinical and EEG changes in patients with epilepsy. Arch Neurol. The
1985;42:213-223.
3. Jasper H, Pertuisset B, Flanigin H. EEG and cortical electrogram in patients with temporal lobe seizures. Arch Neurol Psychiatry. 1951;65:272\x=req-\ 290. 4. Engel J Jr. Seizures and Epilepsy. Philadelphia, Pa: FA Davis Co; 1989. 5. Goldensohn ES. The relevance of secondary epileptogenesis to the treatment of epilepsy: kindling and the mirror focus. Epilepsia.
1984;25(suppl 2):S156-S173. 6. Lim SH, So NK, Luders H, Morris HH, Turnbull J. Etiologic factors for unitemporal vs bitemporal epileptiform discharges. Arch Neurol. In press.
7. Morrell F. Secondary epileptogenic Epilepsia. 1959/1960;1:538-560.
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8. Wilder BJ, Morrell F. Cellular behavior in Neurology. secondary epileptic lesions.
1967;17:1193-1204. 9. Holubar J, Strejckova A, Servit Z. Penicillin and mirror epileptogenic foci in the brain hemisphere of the frog. In: Servit Z, ed. Comparative and Cellular Pathophysiology of Epilepsy. Amsterdam, the Netherlands: Excerpta Medica; 1966:214-220. International Congress Series No. 124. 10. Morrell F. Callosal mechanisms in epileptogenesis: identification of two distinct kinds of spread of spread of epileptic activity. In: Reeves AG, ed. Epilepsy and the Corpus Callosum. New York, NY: Plenum Press; 1985:99-130. 11. Morrell F. Physiology and histochemistry of the mirror focus. In: Jasper HH, Ward AA, Pope A, eds. Basic Mechanisms of the Epilepsies. Boston, Mass: Little Brown & Co Inc; 1969:357-370. 12. Morrell F. Goddard's kindling phenomenon: a new model of the 'mirror focus.' In: Sabelli HC, ed. Chemical Modulation of Brain Function. New York, NY: Raven Press; 1973:207-233. 13. Morrell F. Animal models of human focal epilepsy. In: Klawans HL, ed. Models of Human
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Neurological Disease. Amsterdam, the Netherlands: Excerpta Medica; 1974:166-199. 14. Morrell F, Tsuru N. Kindling in the frog: development of spontaneous epileptiform activity. Electroencephalogr Clin Neurophysiol. 1976;40:1\x=req-\ 11.
15. Purpura DP, Penry JK, Tower DB, Woodburry DM, Walter RD, eds. Experimental Models of Epilepsy: A Manual for the Laboratory Worker.
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epilepsy. Epilepsia. 1969;10:495-505. 17. Twombly DA, Delgado-Escueta
AV. Cellular and membrane events in the mirror focus. In: Mayersdorf A, Schmidt RP, eds. Secondary Epileptogenesis. New York, NY: Raven Press; 1982:89-113. 18. Goddard GV. The development of epileptic seizures through brain stimulation at low intensity. Nature. 1967;214:1020-1021. 19. Goddard GV, Morrell F. Chronic progressive epileptogenesis induced by focal electrical stimulation of brain. Neurology. 1971;21:393. 20. Goddard GV, McIntyre D, Leech C. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol.
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26. Silver JM, Shin C, McNamara JO. Antiepileptogenic effects of conventional anticonvulsants in the kindling model of epilepsy. Ann Neurol.
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27. Burnham M. Anticonvulsants and the kin-
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cortical and subcortical structures in rats. Elec-
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29. Turner IM, Newman SM, Louis S, Kutt H. Pharmacological prophylaxis against the development of kindled amygdaloid seizures. Ann Neurol.
1977;2:221-224. 30. Wada JA, Sato M, Wake A, Green JR, Troupin AS. Prophylactic effects of phenytoin, phenobarbital and
carbamazepine
examined in
cat preparation. Arch Neurol.
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31. Morrell F. Aspects of experimental epilepsy. In: Wada JA, ed. Modern Perspectives in Epilepsy. Montreal, Quebec: Eden Press; 1978:24-75. 32. Smith MC, Whisler WW, Morrell F. Neurosurgery of epilepsy. Semin Neurol. 1989;9:231-248. 33. Morrell F, deToledo-Morrell L. Kindling as a model of neuronal plasticity. In: Wada JA, ed. Kindling 3. New York, NY: Raven Press; 1986:17-35. 34. deToledo-Morrell L, Morrell F. Age-related alterations in long-term potentiation and susceptibility to kindling. In: Morrell F, ed. Kindling and Synaptic Plasticity: The Legacy of Graham Goddard. Boston, Mass: Birkhauser; 1991:160-176. 35. deToledo-Morrell L, Morrell F, Fleming S. Age-dependent deficits in spatial memory are related to impaired hippocampal kindling. Behav Neurosci. 1984;98:902-907. 36. Engel J Jr, Shewmon DA. Impact of the kindling phenomenon on clinical epileptology. In: Morrell F, ed. Kindling and Synaptic Plasticity: The Legacy of Graham Goddard. Boston, Mass: Birkhauser; 1991:195-210.
