C. Ajmone Marsan

Cortical cellular phenomena in experimental epilepsy: Interictal manifestations

Abstract After establishing an epileptogenic “focus” in the cats cerebral cortex, an intracellular analysis from the involved elements was carried out during the development and course of the organized rhythmical electrographic seizures simultaneously monitored with surface electrodes. Neurons were classified on the basis of their behavior as active or passive. In the former, changes in membrane polarization were observed which characterized the various phases of the ictal episode. The previously present paroxysmal hyperpolarization shifts disappear at the onset and a prominent afterdepolarization develops. During the tonic phase the membrane potential markedly decreases and rhythmical oscillations with (or rerely without) action potentials appear above a sustained excessively depolarized membrane potential level. The clonic phase corresponds to a slow repolarization process and the end of the episode seems to be due to inactivation rather than to true membrane hyperpolarization. Some neurons appear to be activated only in the later phases of the seizure.

Factors related to the occurrence of typical paroxysmal abnormalities in the EEG records of epileptic patients.

1 The incidence of typical paroxysmal (epileptiform) discharges has been determined in 1824 EEG records from 308 patients with a reasonably certain diagnosis of epilepsy (average 6 records/patient). 1055 records were considered positive (i.e., showing epileptiform discharges) and 769 negative (i.e., either normal or with non‐paroxysmal abnormalities). Patients were subsequently subdivided into three main groups: (a) 92 with all + records, (b) 54 with all – records, (c) 162 with mixed, + and – records and various subgroups. 2 The purpose of this study was to analyze a number of factors to determine their possible relationship with positivity and negativity of the records within the various patient groups. Such factors included: age at the time of EEG examination and of seizure onset, etiology, clinical‐EEG diagnosis and localization and clinical classification, background EEG patterns, presence of generalized convulsions, frequency of seizures, time since last seizure, presence of medication or length of time without medication. 3 Positive findings in the first examination were obtained in 55.5% of the patients. About 70% of the patients with mixed tracings had more than half of their records positive. Of 75 patients followed with repeated examinations for at least 1 year, all records remained persistently negative in only less than 8%. 4 The patients age, both at the time of the examination and at the onset of seizures, is suggestively related to presence or absence of epileptiform discharges. The percentage of positive records is very high in the first decade while negative tracings predominate after the age of 40. When seizures started past the age of 30, the number of patients with all their records negative was three times as great as that of patients with all positive records. 5 Etiological factors do not seem to play a role on the incidence of epileptiform discharges. 6 Seizure patterns, including the occurrence of generalized (grand mal) episodes, and different forms of clinical diagnostic groups were similarly unrelated to positivity or negativity of the records. Only the group of patients with temporal lobe epilepsy would show a significantly larger amount of positive tracings, only 2% of these patients having exclusively negative records. 7 Contingent factors such as (a) proximity of a seizure to the EEG examination, (b) frequency of seizures and (c) medication or lack thereof at the time of the examination, all appeared to be suggestively related to presence or absence of epileptiform discharges in the records. The relationship was in the expected direction for (a) and (b): i.e., the closer the examination to a seizure and/or the higher the seizure frequency, the greater the probability that a record would be positive. On the other hand, the results of the present analysis would not seem to support the common assumption that records obtained while the patient is on medication are less likely to be positive. Possible reasons for these somewhat paradoxical findings were discussed. Additional analyses were also performed in a selected group of patients with emphasis on the dynamic aspects of their records (i.e., “positivization” of a previously negative record and vice versa) as well as of some of these contingent factors.

Patterns of cortical discharges and their relation to routine scalp electroencephalography

The object of the present study was that of determining the relationship between an electrical event recorded at the cortical level and its scalp correlate. Taking into consideration the limitations implicit in this study, as well as the numerous possible sources of error, the following observations were made: 1. 1. A considerable number of epileptiform discharges present at a cortical level will not be recorded with the routine (overlying) scalp electrodes. 2. 2. A certain number of paroxysmal discharges will, instead, also be recorded with routine scalp electrodes, and their amplitude appears to be directly proportional to that of the cortical discharge. 3. 3. Another group of discharges will also be recorded with the routine scalp electrodes, but their amplitude is definitely not related to that of the original discharge. 4. 4. The ratio of the amplitudes cortical-scalp, is highly variable and values may oscillate from as high as 58 to 1 to as low as 2 to 1. 5. 5. The method employed for scalp recording (bipolar or monopolar) and the position of the “indifferent” electrode, are important factors in determining the value of the ratios. 6. 6. The size of the cortical area involved in the discharge also appears important in determining presence and amplitude of the scalp discharge. 7. 7. Amplitude of the “original” discharge and extent of the area involved by the discharge itself are not the only factors responsible for presence or absence of spread to the scalp; however, the morphology of the discharge shows no characteristic of constant features to suggest its role in the spread. 8. 8. Cortical spikes do not seem to spread more easily or more constantly than cortical paroxysmal waves, and the duration of the spike itself is immaterial in the process of spread. 9. 9. Regardless of the amplitude of the “original” cortical discharge the voltage variations of the event at the scalp level are very comparable to those of the event simultaneously “projected” to deeply located structures. 10. 10. Preferential spread to the different scalp electrodes has been described and analyzed. Some facts of practical significance result from this study. It is an accepted notion in the field of clinical EEG that a rather considerable number of proven epileptics may present repeatedly a negative, if not completely normal, record. It would seem logical to explain this on a functional basis, or, in other words, by taking for granted that the epileptic tissue may be “quiet” for more or less long periods of time, and becoming activated for some known or unknown reasons only sporadically, in analogy to the clinical behavior, which is in fact characteristic of the epileptic syndrome. It is dangerous to generalize, however, from our observations one would take a slightly different view on this problem. In their interseizure periods, all of our patients would show a very high number of paroxysmal discharges (from 1 up to 20 or more every 10 sec.) and yet only a small percentage, and in some cases, an exceedingly small percentage of these discharges would spread and become recordable with the routine scalp electrodes. In view of this fact, one would be justified in considering a negative routine EEG in a proven epileptic, not as the expression of temporary “quietness” of the epileptogenic process, but only as an attenuation in absolute amplitude and in cortical distribution of its discharges, these factors being, for the moment at least, the only two which seem to play a role in determining the appearance of the discharges on the scalp. In analogy, the interpretation of the so-called “electrically silent” seizures becomes clearer. Following our observations, one not only has to consider the lack of electrical correlates during a clinical attack as only apparent, but should not conclude that because of this negativity of the routine scalp EEG the seizure itself must “originate” and remain localized in the depth, as suggested by many authors. The activation could well be mainly or exclusively cortical, and yet have no correlate on the scalp. On the other hand, the presence of a “positive” scalp EEG provides only some information of what is going on in the cortex. Thus, to a given discharge recorded from one scalp electrode could correspond a similar discharge at the cortical level with an amplitude, however, which could be larger from two up to about sixty times. The absolute voltage of the scalp transient would, in addition, reflect the extent of the cortical area involved in a given discharge and, according to which method is used in scalp EEG, voltage variations could indicate either an increase or a decrease in the extent of this area. In the specific case of temporal lobe epilepsy, our observations have provided some useful indications on the methodology and on the interpretation of EEG records, pointing to the limitations of some bipolar linkages, and confirming the inadequacy of monopolar recording with reference on the ipsilateral ear in comparison to similar recordings with a relatively “more truly” indifferent electrode. From a more theoretical standpoint, and in particular, in regard to the mechanism of spread from cortex to scalp, further study is obviously needed. Our analysis has proved rather negative. Although at times the amplitude as well as the extent of the cortical distribution of the “original” discharge seems to play a role, the morphology itself did not correlate consistently. This fact makes it rather difficult to explain the extreme variability of ratio between cortical and scalp discharge. In fact, if one assumes that the size of the field depends on factors such as amplitude, distribution and form of a discharge, one would expect that when these three parameters are constant, the resulting scalp event would also be constant. As this is definitely not the case, one has to consider other factors which presently escape our analysis such as variability in the impedance of the volume conductor, variability in the orientation of the dipole or even occasional presence of a second, “destructive” field. On the other hand, the cortical distribution of the discharge could not be checked extensively in view of the limited number of electrodes employed, and it might as well be that its extent at the cortical level varies continously in a fashion similar to that described for the spikes component of the 3/sec. spike-and-wave complexes of petit mal epilepsy (Fischgold et al. 1955). If such were the case, the discrepancy between cortical and scalp recording would only be apparent and could probably be understood. In conclusion, we have the impression that such type of study is justified and that it should be carried on in more detail. The new field of depth electrography has definitely enlarged the possibilities of research in the field of EEG and in particular in the field of the epilepsies; however, we strongly feel that answers to too many questions are necessary before this method can be accepted, its reliability established, and the wealth of information it provides, profitably used.

Depth and direct cortical recording in seizure disorders of extratemporal origin.

This study is based on 28 patients with intractable seizures in whom exclusively extratemporal or a combination of temporal and extratemporal electrodes were chronically implanted for the localization of the epileptogenic process and possible surgical treatment. Clinical and electrographic data are briefly summarized, the indications for the use of implanted electrodes are outlined, and the number and position of the electrodes and the findings in each individual case are given. Four illustrative examples are described in greater detail. Mainly on the basis of data derived from this particular technique of investigation, surgical treatment was eventually carried out in 14 patients. It is concluded that the use of implanted electrodes in seizure disorders of probable extratemporal origin can be of real diagnostic benefit in certain specific situations. In most instances, however, this technique simply serves to demonstrate the complexity of an apparently simple case or, of greater clinical consequence, might tend to oversimplify cases that are actually very complex. Indeed, many data in this study raise some doubts about the validity of the classic concepts of “focal” epilepsy.

Unitary analysis of “projected” epileptiform discharges

Abstract 1. 1. Epileptogenic foci have been induced in the cortex of 33 cats (25 cerveau isole preparations, eight under barbiturate anesthesia), by means of local application of penicillin or strychnine. The activity of cortical units at the site of the focus was then compared with that of units located in the contralateral homologous region. 2. 2. Characteristic features were found which seem to differentiate, at the neuronal level, a local from a projected epileptic process. In the latter: (a) a substantially smaller number of units are activated, and (b) their firing pattern seldom consists of high frequency bursts of spikes. 3. 3. These findings are discussed in relation to interpretation and functional significance of similar events in the field of clinical EEG.

Co‐existence of Focal and Bilateral Diffuse Paroxysmal Discharges in Epileptics: Clinical‐electro graphic study

1 Thirty‐five epileptic patients with co‐existent focal and bilaterally synchronous, diffuse paroxysmal electrographic discharges are evaluated and their electrographic features are correlated with clinico‐pathological data. The findings are compared with information derived from a control group of 67 patients with clearly defined and uncomplicated focal epileptiform discharges. 2 Statistically significant differences were found between the control and study groups in regard to the following variables.

Fluorometric monitoring of NADH levels in cerebral cortex: preliminary observations in human epilepsy

In 14 patients operated upon for focal cerebral seizures under local anesthesia, cortical electrical activity was compared with the levels of nicotinamide adenine dinucleotide (NADH) observed fluorometrically. NADH levels fell 3 to 15% in response to 5-second intervals of cortical stimulation in 42 of 70 observations. Although a rough correlation was seen between the quantity of current delivered (milliamperes X seconds) and the NADH decrease, this varied from case to case. The presence of cortical afterdischarge often, but not invariably, corresponded to a greater percentage of change in the NADH levels. Averaging the NADH response to sporadic interictal epileptiform discharges failed to demonstrate concomitant NADH reductions. A similar lack of change was seen in four patients in whom low frequency spike foci were induced by topically applied penicillin in cortex destined for excision. Preliminary studies of the topography of spread of NADH change after cortical stimulation indicate that this is usually asymmetrical in human epileptogenic cortex. Under experimental conditions in cats, it seemed possible to differentiate primary from projected epileptiform activity, in that the projected activity had little or no concomitant fall in the NADH level after the electrographic spike. Pathological examination of the excised sites of NADH recording showed, with one exception, fibrous astrocytic transformation of the central cortex layers.

A newly Proposed Classification of Epileptic Seizures. Neurophysiological Basis

Some aspects of the mechanisms that might be involved in the pathophysiology of seizure disorders are briefly mentioned and discussed on the basis of pertinent experimental data. This analysis was performed following the systematization of seizure types suggested in the recently proposed classification, while looking for possible pathophysiological bases that might apply to, and be compatible with the different seizure groups which are identified in this classification.

Problems in the EEG Analysis of Epileptic Activity in Patients with Massive Cerebral Lesions

Epileptic attacks are a rather common complication in cerebral palsy (about 50% in the large series of Gibbs, Perlstein and Gibbs, 1953). When they occur, they present a very serious problem for both management and reeducation. In many cases. the existence of seizures is the main reason for which the patients are brought to our attention, and the control of the convulsive disorder is the ccrollary necessary to institute an advantageous training program.