248
Eleetroencephalography and clinical Neurophysioh~gy, 82 (19921 248-254 ;~ 1992 Elsevier Scientific Publishers Ireland, Ltd. 11013-4649/92/$05.00
EEG 91113
Epileptiform activity in chronically isolated cerebral cortex in h u m a n s * Serge J.C. Pierre-Louis and Frank Morrell Department Of Neurology, Rush Medical ('enter. Chi(ago, IL (U.S.,4.)
(Accepted for publication: 18 December 1991)
Summary The ability of neuronally isolated human cerebral cortex to sustain epileptiform rhythms over long time intervals is unknown. We report here two patients after functional bemispherectomy for infantile hemiplegia and infantile meningoenccphalitis. Both patients had intractable seizures. EEG performed early and up to 3 years after surgery showed persistent epileptilonn activity in the isolated frontal cortex in both cases. This indicates that human isolated cortex retains its epileptogenic potential for years, independently of subcortical influences. Previous related animal and human studies are briefly reviewed. Key words: Isolated cortex; Functional hemispherectomy; Electroencephalograpby: Epilepsy surgery
T h e capacity for cerebral cortex to sustain epileptiform activity long after neuronal isolation is not well established. N u m e r o u s animal studies (Kristiansen and Courtois 1949; Frost and Gol 1966; Frost et al. 1966; Kellaway et al. 1966) have shown that s p o n t a n e o u s electrical activity can be recorded in the cortex up to 9 m o n t h s after partial or complete undercutting of axon fibers. These studies, however, in general did not look specifically at the evolution of epileptiform rhythms before and after cortical isolation. A n a d e q u a t e h u m a n model of complete neuronal cortical isolation did not exist until the advent of functional (Rasmussen) hemispherectomy for intractable epilepsy some 15 years ago. The p r o c e d u r e encompasses en bloc removal of the temporal and parietal lobes. The frontal and occipital poles are left in situ, after their callosal and subcortical connections have been severed. This creates a functionally complete though anatomically subtotal hemispherectomy. Curiously there has been virtually no report, to our knowledge, on the behavior of epileptiform abnormalities after such surgery. To assess the ability of isolated cortical n e u r o n s to maintain epileptiform discharges for long periods of
time, we reviewed electrographic findings in 2 patients before and after functional hemispherectomy.
Methods
E E G s were p e r f o r m e d while awake and during sleep, using the 10-20 international system of electrode placement and the N i h o n - K o h d e n machine. These included both bipolar recording (with anteroposterior, coronal and circumferential montages) and referential recording (with anteroposterior montages). Photic stimulation was p e r f o r m e d in both patients. Hyperventilation was performed only in the first patient. E E G s were obtained within 1 m o n t h preoperatively and 1 year postoperatively in both patients. Patient no. I had a subsequent E E G nearly 3 years after surgery. Hemis p h e r e c t o m y was performed u n d e r general methohexital anesthesia using the technique described by Rasmussen (1983).
Case reports Patient no. 1 Clinical history. A 12-year-old right-handed boy experienced Hemophilus influenzae meningitis at 11
Correspondence to: Dr. Serge J.C. Pierre-Louis, Rush-Presbyterian-St. Luke's Medical Center, Department of Neurological Sciences, 1653 West Congress Parkway, Chicago, IL 60612 (U.S.A.). Tel.: (312) 942-5939.
* Presented in part (abstract) at the AEEGS Annual Meeting in New Orleans, September 23-24 1989.
m o n t h s of age. This was complicated by convulsive seizures, a right subdural e m p y e m a and left hemiplegia. He was treated with phenytoin and phenobarbital for 2 years with no further seizures, which led to discontinuation of anticonvulsants. Subsequent course was marked by delayed developmental milestones, at-
EP1LEPTIFORM ACTIVITY IN I S O L A T E D C E R E B R A L C O R T E X
A
Pre - Op
249
131
2/2/88
Post -Operative 3/28/89
B2
Post - O p e r a t i v e 3/28/89 Fig, 1. MRI shuws a T2-weighted image of the brain in case no. 1 prior to surgery (A). Postoperative Tt-weighted images are seen in B 1 year later and illustrate the isolation of the right frontal pole.
250
S.J.C. PIERRE-LOUIS, F. MORREI,L
tention-deficit disorder with frequent mood swings as well as aggressive destructive behavior. At the age of 7, he developed complex partial seizures with secondary generalization preceded by an aura of "funny smell." His seizures had become medically intractable by the age of 12. Physical findings. Examination in February 1988 was remarkable for a short attention span, fairly normal speech output with poor writing and reading skills, a dense left homonymous hemianopia, slight left facial paresis, left hemiatrophy with absent finger movements, impaired left superficial and deep sensation, hyperreflexia and Babinski sign on the left. He ambulated independently with left lower extremity circumduction. Investigations. MRI without contrast material revealed extensive encephalomalacia of most of the right cerebral hemisphere, with no focal signal changes in the temporal lobe (Fig. 1). SPECT scan with iodoamphetamine disclosed hypoperfusion of the entire right hemisphere. Median nerve somatosensory evoked potentials were absent with left arm stimulation. Neuropsychological testing revealed full scale IQ of about 53, with non-verbal intelligence significantly superior to verbal intelligence. Injection of sodium amytal in the
right internal carotid artery did not worsen the left limb weakness: concomitant angiogram demonstrated lack of filling of the right middle cerebral artery. Preop EEG findings. Interictal scalp EEG, while receiving phenytoin and phenobarbital, showed a posterior alpha rhythm of 9 Hz, and marked attenuation of background activity as well as delta slowing over the right hemisphere. Beta activity was of higher amplitude on the left, and "mu" rhythms were present in the left central region. During drowsiness and light sleep, spikes and polyspike-waves as well as sharp and slow wave complexes were noted maximally in the right frontal (Fs) and mid-temporal (T4) leads. These abnormalities extended occasionally to the right posterior temporal area (T6) or synchronously to the opposite hemisphere. Runs of spike-wave discharges occurred on the right without clinical manifestations, during intensive EEGvideo monitoring. ECoG findings. On 25 February 1988 a right functional hemispherectomy was performed. The pre-excision electrocorticogram (ECoG) confirmed the wide distribution of epileptiform activity over the damaged cortex. The post-excision ECoG revealed persistent spikes and elcctrographic seizures in the neuronally isolated frontal pole (Fig. 2).
A
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,
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Fig. 2. lntraoperative electrocorticograms in case no. 1 (A and B) are continuous and show an electrographic seizure at electrodes 3-4 a0er isolation of the frontal cortex. Electrodes t - 5 are all located over the isolated right frontal pole.
251
E P I L E P T I F O R M A C T I V I T Y IN I S O L A T E D C E R E B R A L C O R T E X
W. Hu.
Postop EEG findings.
When seen at follow-up in March 1989, the patient had been seizure free since surgery while receiving phenytoin and phenobarbital. The neurological exam was comparable to pre-surgical baseline and the behavioral abnormalities had persisted. MRI disclosed absence of the right parietal and temporal lobes. E E G showed further attenuation of background activity over the right hemisphere. Frequent interictal spike activity was noted during sleep, restricted mainly to the right frontal and fronto-polar leads (Fs and FP2). Drug-induced beta rhythms were again of higher amplitude on the left and uncorrelated with similar rhythms on the right. Sleep spindles and K-complexes were absent on the right. Photic stimulation and hyperventilation produced no changes. The tracing was similar to one obtained 1 month after surgery in March 1988 (Fig. 3). Another tracing in January 1991, at a time when the patient was receiving carbamazepine, showed comparable findings (Fig. 4). Pathology. Extensive cortical and subcortical astrocytosis was noted microscopically in frontoparietal sections, with calcifications in parenchyma and blood vessel walls. In addition, mesial temporal sclerosis was present.
Patient no. 2 Cfinical history.
A 10-year-old left-handed girl with infantile hemiplegia started having seizures at the age of 3 months, after uncomplicated delivery with forceps.
Fp I - F 7 ,`.`~``.`.~``````~'~`v~`~`~`~`~3~,``~``~``~~..~`..`~,.~``````~.~``~-`~.~``~
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Fig. 3. E E G in case no. 1 in 3 / 8 8 , 1 month after hemispherectomy. Beta activity is prominent on the left; spike activity is restricted to the right frontal leads. Preoperative EEG (not shown) had revealed epileptiform activity extending more posteriorly in the right hemisphere and contralaterally.
Motor and speech delay as well as right hemiatrophy were noted later. Her seizures over the years were characterized by jerking movements of the right upper extremity, brief episodes of bilateral eye blinking, or generalized convulsions. Physical findings. When evaluated in June 1989, she had failed anticonvulsant drug treatment. She was receiving special education in school, where she had been found a year earlier to be functioning at a 3-4B FPl-F 7 ~
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252
S.J.C. PIERRE-LOUIS, F. M O R R E L L
year-old level. She could not read or add. She was easily distractable, obeyed commands sporadically and spoke occasionally in short sentences. There was a dense right homonymous hemianopia, without facial asymmetry. Hemiatrophy was maximal in the right arm, which was held spastically against her body with no finger movements. Marked hyperreflexia and Babinski sign were noted on the right. She reacted bilaterally to pain stimulation and ambulated independently with a spastic right leg. lnt,estigations. MRI revealed a cystic lesion in territory of left middle cerebral artery. SPECT scan disclosed absent perfusion of most of the left cerebral hemisphere and a smaller area of hypoperfusion in the right frontal lobe. Preop EEG findings'. Interictal E E G while receiving phenytoin, valproic acid and carbamazepine showed sparse posterior alpha rhythm at 11-12 Hz with moderate background slowing. Beta activity and sleep spindles were not clearly identifiable on the left. Vertex waves of sleep were present bilaterally. Constant left frontally predominant slow (2 Hz) spike-wave activity was seen, with intermittent bisynchrony. Occasional independent right frontal discharges were also noted at F4 (Fig. 5A). Ictal EEGs during prolonged EEG-video recording consisted usually of bursts of bilateral spikes and polyspike-waves. At other times generalized desynchronization of background rhythms, less prominent in the left f~rontal leads, was seen. Clinical seizures not always correlated with the electrographic findings, included myoclonic or tonic movements of the right arm, eye blinking, head drops and jerking of the entire body. Intravenous injection of methohexital during E E G recording disclosed independent epileptogenic foci in either frontal lobes, the left frontal and temporal leads (F~, F v, 'F0 being the most active. ECoG findings. On 14 September 1989 a left functional hemispherectomy was performed. A large cyst occupied most of the perisylvian area and the temporal lobe appeared quite fibrotic. The pre-excision corticogram showed frequent bursts of spike-waves,
frontally predominant, which persisted in the post-excision tracing. Postop EEG findings. Subsequent course was complicated by osteomyelitis, requiring removal of the bone flap in December 1989 and placement of a prosthesis a few months later. At follow-up in October 1990, the patient had been seizure free with carbamazepine and phenobarbital. Speech output was still poor, although understanding of spoken language had improved. Neurological exam had not otherwise significantly changed. E E G showed marked attenuation of background activity on the operated side, absent sleep spindles on the left, and asynchronous beta activity of higher amplitude on the left. Frequent spikes were noted in the left frontopolar region (Fig. 5B). Both pre- and postoperative tracings showed no response to photic stimulation. Hyperventilation could not be performed. Pathology. Pathologic findings were consistent with porencephalic cyst.
Discussion
Since the original experiments of Bremer on the "enc~phale isol6" of cat in 1935, numerous investigators have confirmed that neuronally isolated cerebral cortex of animals can sustain spontaneous electrical activity provided that pial circulation remains intact (Bremer 1949; Kristiansen and Courtois 1949; Frost and Gol 1966; Frost et al. 1966; Kellaway et al. 1966). In spite of rare dissent (Burns 1950), it has generally been established that such activity appears immediately after partial or complete undercutting of cerebral cortex. It consists usually of high voltage aperiodic slow waves with superimposed fast rhythms, which may be intermittently interrupted by isoelectric episodes. Similar findings have been reported in cats after isolation of an entire cerebral hemisphere and have persisted even in chronic preparations 9 months later (Kellaway et al. 1966). Rhythmic activity has also been recorded
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Fig. 5. EEG in case no. 2. A: preoperative tracing with spike discharges occurring independently or synchronously in the frontal regions. B: postoperative tracing with epileptiform activity now restricted to the left frontopolar region.
EPILEPT1FORM ACTIVITY 1N ISOLATED CEREBRAL CORTEX in isolated cortex of cat after direct electrical stimulation, even when spontaneous activity was absent (Burns and Grafstein 1952; Burns 1954, 1955). None of these animal preparations included isolated epileptogenic cortex. Although less extensive, human studies have provided similar results. Henry and Scoville performed bilateral frontal lobotomy in patients with severe psychiatric disorders. Following surgical isolation of the frontal lobes by undercutting both the superior convexity and the orbital surface, burst-suppression activity was noted. That activity remained confined to the isolated cortex, was characteristically asynchronous between the two hemispheres and did not depend on the use of barbiturates or other anesthetics. In some cases it persisted over a year, though not apparent in scalp EEG, and was discovered when additional surgery was performed later. Henry postulated that such rhythmic activity was "related to the release of cortex from the influence of the reticular activating system" (Henry 1952). Echlin also studied psychiatric patients. In the course of carrying frontal lobotomies, he produced a suppression-burst pattern over an isolated slab of cerebral cortex, which was still present 5 weeks later. Intravenous injection of metrazol caused marked selective increase of the frequency and amplitude of the bursts. Noting similar burst-suppression rhythm in the cortex of a patient, adjacent to a brain tumor, Echlin suggested that such rhythms might be the result of partial isolation of masses of neurons. He also emphasized that partial isolation of neurons by various brain lesions might be an important factor in the genesis of paroxysmal hypersynchronous discharges and clinical seizures (Echlin et al. 1952). Interestingly, Echlin later showed in alert monkeys (Echlin 1975) that there was progressive development of supersensitivity to topical acetylcholine (ACh) over partially isolated frontal cortex. This took the form of decreased threshold of paroxysmal activity after intermittent brief application of ACh and after electrical stimulation of a contralateral peripheral nerve. In cases where the open end of the partial isolation extended into the precentral gyrus, prolonged peripheral nerve stimulation caused the abnormal focal cortical discharge to spread and give rise to a generalized convulsive seizure. This hypersensitivity phenomenon, which developed over the first 3 weeks after partial isolation and persisted more than 7 years in some cases, was thought by Echlin to represent a form of denervation sensitivity. Indeed, these physiological changes correlated with morphological (loss of dendritic spines) and biochemical (gradual drop in cholinesterase activity) changes that could all be prevented by daily electrical stimulation of the isolated cortex. The above observa-
253 tions, once again, did not specifically address the fate of epileptiform discharges in isolated cortex. A new era began with Krynauw's 1950 series of hemispherectomy for infantile hemiplegia and seizures. Numerous reports subsequently described electrographic findings after hemispherectomy. These included disappearance of slow waves in the contralateral hemisphere (Obrador and Larramendi 1950), decreased voltage of background activity on the intact side and rhythm in the alpha range on thc operated side (Marshall and Walker 1950), and characteristic behavior of potential fields on the scalp of the ablated side due to volume conduction (Cobb and Sears 1959). Ravenna and Benedetti (1965), quoted by Wilson (1970), reported that after hemisphercctomy electrical silence on the operated side is replaced within a few years by low amplitude, unstable, polymorphic posterior and central activity synchronous with that of the remaining hemisphere. At the samc time, early postoperative disorganized background activity on the intact side is soon reorganized with return of alpha activity. They also noted that sharp waves, theta activity and spikes, often focal, reappeared frequently over the intact hemisphere after several years without concomitant return of clinical seizures. All these reports, however, including a more recent one by Verity et al. (1982) dealt with EEG after total removal of a cerebral hemisphere. It soon became obvious that such a procedure was associated with an excessive amount of delayed complications, the most important being superficial cerebral hemosiderosis due to recurrent intracranial hemorrhages on the operated side. Modifications of the surgical technique, allowing subtotal removal of epileptogenic tissue, reduced the incidence of delayed complications at the cost of seizure control. Thereforc, by 1974 Rasmussen devised a furthcr modification of the technique, as described carlier. Recognizing the relatively short follow-up period of his series (2-6 years), Rasmussen in 1983 reported 8 patients who underwent functional hemisphcrectomy: the complication of delayed hemorrhage had been virtually eliminated. A degree of seizure control comparable to the one associated with total anatomical hemispherectomy had also been achieved. The technique of functional hemispherectomy constituted, in our view, an in viw) model par excellence of human isolated cortex with epileptogenic potential. Surprisingly, though, the last 15 years have witnessed a paucity of reports describing the behavior of epileptiform activity after such a procedure. Electrographic findings in our two cases indicate that human isolated cortex can sustain not only normal rhythms, but also epileptiform activity for 3 years or longer. It is of interest that in the first case electrographic seizures persisted acutely after cortical isolation, as docu-
254 m e r i t e d by E C o G . T h i s s u g g e s t s t h a t i n t r a c o r t i c a l c o n n e c t i o n s a l l o w s u f f i c i e n t n e u r o n a l s y n c h r o n y to p r o duce epileptic discharges, independently of subcortical i n f l u e n c e s , e v e n t h o u g h s u c h d i s c h a r g e s a r e b o u n d to r e m a i n clinically silent. O f e q u a l i n t e r e s t , m a i n l y i n o u r first case, is t h e a p p a r e n t a c t i v a t i o n o f t h e e p i l e p t i f o r m activity d u r i n g s l e e p . T h i s s u g g e s t s t h a t i s o l a t e d c o r t e x r e m a i n s s e n s i t i v e to c i r c a d i a n r h y t h m s ( p r e s u m a b l y via circulation) and that circulatory humoral factors during sleep, rather than direct influence from subcortical s t r u c t u r e s , m a y c o n t r i b u t e to t h e e s t a b l i s h m e n t o f functional states favoring paroxysmal discharges. It is n o t c l e a r w h e t h e r t h e p e r s i s t e n t e p i l e p t i f o r m activity is d u e solely to an i n h e r e n t p r o p e r t y o f c o r t i c a l n e u r o n s o r r e l a t e d to s o m e f o r m o f d e - a f f e r e n t a t i o n in an a l r e a d y h y p e r e x c i t a b l e c o r t e x . In any e v e n t , t h e l a c k o f s l e e p s p i n d l e s ( S t e r i a d e ct al. 1990), t h e r e s t r i c t e d field o f t h e s p i k e d i s c h a r g e a n d t h e a b s e n c e o f t h e preoperalive bilaterally synchronous spike-wave patt e r n c o n f i r m e d t h e i s o l a t i o n o f t h e f r o n t a l cortex. Therefore, the intermittent spike discharges over the i s o l a t e d c o r t e x a r e c o n s i d e r e d b e n i g n in n a t u r e a n d n o t e x p e c t e d to c a u s e clinical s e i z u r e s .
Addendum S i n c e this p a p e r was s u b m i t t e d f o r p u b l i c a t i o n , an a r t i c l e by S . J . M . S m i t h et al. a p p e a r e d in Neurology. In this article, t h e a u t h o r s r e p o r t e d E E G f i n d i n g s in 25 patients who underwent functional hemispherectomy. T h e y also o b s e r v e d p e r s i s t e n t s p i k i n g p o s t o p e r a t i v e l y , o v e r t h e i s o l a t e d c o r t e x e x c l u s i v e l y in 8 o f t h e i r patients, n o n e o f w h o m h a d clinical s e i z u r e s . We are indebted to Mrs. Connie M. Lambert for typing the manuscript.
References Bremer, F. Considerations sur l'origine et la nature des "ondes" c~rfibrales. Electroenceph. clin. Neurophysiol., 1949, 1: 177-193.
s.J.C. PIERRE-LOUIS, F. MORRELL Burns, B.D. Some properties of the cat's isolated cerebral cortex. J. Physiol. (Lond.), 1950, 111: 50-68. Burns, B.D. The production of after-bursts in isolated unanesthetized cerebral cortex. J. Physiol. (Lond.), t954, 125: 427-446. Burns, B.D. The mechanism of after-burst in cerebral cortex. J. Physiol. (Lond.) 1955, 127: 168-188. Burns, B.D. and Grafstein, B. The function and structure of some neurones in the cat's cerebral cortex. J. Physiol. (Lond.), 1952, 118: 412-433. Cobb, W. and Sears, T.A. A study of the transmission of potentials after hemispherectomy. Electroenceph. clin. Neurophysiol., 1959. 12: 371-383. Echlin, F. Time course of development of supersensitivity to topical acetylcholine in partially isolated cortex. Electroenceph. clin. Neurophysiol., 1975, 38: 225-233. gchlin, F.A., Arnen, V. and Zoll, J. Paroxysmal high-voltage discharges from isolated and partially isolated human and animal cerebral cortex, t952. Frost, Jr., J.D. and Gol, A. Computer determination of relationship between EEG activity and single unit discharges in isolated cerebral cortex. Exp. Neurol., 1966, 14:5[)6-519. Frost, Jr., J.D., Kellaway, P. and Gol. A. Single-unit discharges in isolated cerebral cortex. Exp. Neurol., 1966, 14:5(16 519. tienry, C.E. Suppression-burst activity from isolated cerebral cortex in man. Electroenceph. olin. Neurophysiol., 1952, 4: I 22. Kellaway, P., Gol, A. and Proler, M. Electrical activity of the isolated cerebral hemisphere and isolated thalamus. Exp. Neurol., [966, 14:281 304. Kristiansen, K. and Courtois. G. Rhythmic electrical activity from isolated cerebral cortex. Electroenceph. clin. Neurophysiol., 1949, 1: 265-212. Marshall, C. and Walker, E. The elcctrographic changes after hemispherectomy in man. Electroenceph. clin. Neurophysiol., 1950, 2: 147-156. Obrador, S. and Larramendi. M.H. Some observations on the brain rhythms after surgical removal of a cerebral hemisphere. Electroenceph, clin. Neurophysiol., 195[), 2:143 146. Rasmussen, T. Hemispherectomy for seizures revisited. Can. J. Neurol., 1983, 10:71 78. Smith, S.J.M. et al. Functional hemispherectomy: EEG findings, spiking from isolated brain postoperatively, and prediction of outcome. Neurology, 1991, 41: 179[)-1794. Steriade, M., Gloor, P., Llin~s, R.R., Lopes da Silva, F.H. and Mesulam, M.M. Basic mechanisms of cerebral rhythmic activities. Electroenceph. clin. Neurophysiol., 1990, 76:481 508. Verity, C.M. et al. Long-term follow-up after cerebral hcmispherectomy: neurophysiologic, radiologic and psychological findings. Neurology, 1982, 32: 629-639. Wilson, P.J.E. Cerebral hemisphercctomy for infantile hcmiplegia: a report of 51) cases. Brain. 197t), 93:147 18(/.
Eleetroencephalography and clinical Neurophysioh~gy, 82 (19921 248-254 ;~ 1992 Elsevier Scientific Publishers Ireland, Ltd. 11013-4649/92/$05.00
EEG 91113
Epileptiform activity in chronically isolated cerebral cortex in h u m a n s * Serge J.C. Pierre-Louis and Frank Morrell Department Of Neurology, Rush Medical ('enter. Chi(ago, IL (U.S.,4.)
(Accepted for publication: 18 December 1991)
Summary The ability of neuronally isolated human cerebral cortex to sustain epileptiform rhythms over long time intervals is unknown. We report here two patients after functional bemispherectomy for infantile hemiplegia and infantile meningoenccphalitis. Both patients had intractable seizures. EEG performed early and up to 3 years after surgery showed persistent epileptilonn activity in the isolated frontal cortex in both cases. This indicates that human isolated cortex retains its epileptogenic potential for years, independently of subcortical influences. Previous related animal and human studies are briefly reviewed. Key words: Isolated cortex; Functional hemispherectomy; Electroencephalograpby: Epilepsy surgery
T h e capacity for cerebral cortex to sustain epileptiform activity long after neuronal isolation is not well established. N u m e r o u s animal studies (Kristiansen and Courtois 1949; Frost and Gol 1966; Frost et al. 1966; Kellaway et al. 1966) have shown that s p o n t a n e o u s electrical activity can be recorded in the cortex up to 9 m o n t h s after partial or complete undercutting of axon fibers. These studies, however, in general did not look specifically at the evolution of epileptiform rhythms before and after cortical isolation. A n a d e q u a t e h u m a n model of complete neuronal cortical isolation did not exist until the advent of functional (Rasmussen) hemispherectomy for intractable epilepsy some 15 years ago. The p r o c e d u r e encompasses en bloc removal of the temporal and parietal lobes. The frontal and occipital poles are left in situ, after their callosal and subcortical connections have been severed. This creates a functionally complete though anatomically subtotal hemispherectomy. Curiously there has been virtually no report, to our knowledge, on the behavior of epileptiform abnormalities after such surgery. To assess the ability of isolated cortical n e u r o n s to maintain epileptiform discharges for long periods of
time, we reviewed electrographic findings in 2 patients before and after functional hemispherectomy.
Methods
E E G s were p e r f o r m e d while awake and during sleep, using the 10-20 international system of electrode placement and the N i h o n - K o h d e n machine. These included both bipolar recording (with anteroposterior, coronal and circumferential montages) and referential recording (with anteroposterior montages). Photic stimulation was p e r f o r m e d in both patients. Hyperventilation was performed only in the first patient. E E G s were obtained within 1 m o n t h preoperatively and 1 year postoperatively in both patients. Patient no. I had a subsequent E E G nearly 3 years after surgery. Hemis p h e r e c t o m y was performed u n d e r general methohexital anesthesia using the technique described by Rasmussen (1983).
Case reports Patient no. 1 Clinical history. A 12-year-old right-handed boy experienced Hemophilus influenzae meningitis at 11
Correspondence to: Dr. Serge J.C. Pierre-Louis, Rush-Presbyterian-St. Luke's Medical Center, Department of Neurological Sciences, 1653 West Congress Parkway, Chicago, IL 60612 (U.S.A.). Tel.: (312) 942-5939.
* Presented in part (abstract) at the AEEGS Annual Meeting in New Orleans, September 23-24 1989.
m o n t h s of age. This was complicated by convulsive seizures, a right subdural e m p y e m a and left hemiplegia. He was treated with phenytoin and phenobarbital for 2 years with no further seizures, which led to discontinuation of anticonvulsants. Subsequent course was marked by delayed developmental milestones, at-
EP1LEPTIFORM ACTIVITY IN I S O L A T E D C E R E B R A L C O R T E X
A
Pre - Op
249
131
2/2/88
Post -Operative 3/28/89
B2
Post - O p e r a t i v e 3/28/89 Fig, 1. MRI shuws a T2-weighted image of the brain in case no. 1 prior to surgery (A). Postoperative Tt-weighted images are seen in B 1 year later and illustrate the isolation of the right frontal pole.
250
S.J.C. PIERRE-LOUIS, F. MORREI,L
tention-deficit disorder with frequent mood swings as well as aggressive destructive behavior. At the age of 7, he developed complex partial seizures with secondary generalization preceded by an aura of "funny smell." His seizures had become medically intractable by the age of 12. Physical findings. Examination in February 1988 was remarkable for a short attention span, fairly normal speech output with poor writing and reading skills, a dense left homonymous hemianopia, slight left facial paresis, left hemiatrophy with absent finger movements, impaired left superficial and deep sensation, hyperreflexia and Babinski sign on the left. He ambulated independently with left lower extremity circumduction. Investigations. MRI without contrast material revealed extensive encephalomalacia of most of the right cerebral hemisphere, with no focal signal changes in the temporal lobe (Fig. 1). SPECT scan with iodoamphetamine disclosed hypoperfusion of the entire right hemisphere. Median nerve somatosensory evoked potentials were absent with left arm stimulation. Neuropsychological testing revealed full scale IQ of about 53, with non-verbal intelligence significantly superior to verbal intelligence. Injection of sodium amytal in the
right internal carotid artery did not worsen the left limb weakness: concomitant angiogram demonstrated lack of filling of the right middle cerebral artery. Preop EEG findings. Interictal scalp EEG, while receiving phenytoin and phenobarbital, showed a posterior alpha rhythm of 9 Hz, and marked attenuation of background activity as well as delta slowing over the right hemisphere. Beta activity was of higher amplitude on the left, and "mu" rhythms were present in the left central region. During drowsiness and light sleep, spikes and polyspike-waves as well as sharp and slow wave complexes were noted maximally in the right frontal (Fs) and mid-temporal (T4) leads. These abnormalities extended occasionally to the right posterior temporal area (T6) or synchronously to the opposite hemisphere. Runs of spike-wave discharges occurred on the right without clinical manifestations, during intensive EEGvideo monitoring. ECoG findings. On 25 February 1988 a right functional hemispherectomy was performed. The pre-excision electrocorticogram (ECoG) confirmed the wide distribution of epileptiform activity over the damaged cortex. The post-excision ECoG revealed persistent spikes and elcctrographic seizures in the neuronally isolated frontal pole (Fig. 2).
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251
E P I L E P T I F O R M A C T I V I T Y IN I S O L A T E D C E R E B R A L C O R T E X
W. Hu.
Postop EEG findings.
When seen at follow-up in March 1989, the patient had been seizure free since surgery while receiving phenytoin and phenobarbital. The neurological exam was comparable to pre-surgical baseline and the behavioral abnormalities had persisted. MRI disclosed absence of the right parietal and temporal lobes. E E G showed further attenuation of background activity over the right hemisphere. Frequent interictal spike activity was noted during sleep, restricted mainly to the right frontal and fronto-polar leads (Fs and FP2). Drug-induced beta rhythms were again of higher amplitude on the left and uncorrelated with similar rhythms on the right. Sleep spindles and K-complexes were absent on the right. Photic stimulation and hyperventilation produced no changes. The tracing was similar to one obtained 1 month after surgery in March 1988 (Fig. 3). Another tracing in January 1991, at a time when the patient was receiving carbamazepine, showed comparable findings (Fig. 4). Pathology. Extensive cortical and subcortical astrocytosis was noted microscopically in frontoparietal sections, with calcifications in parenchyma and blood vessel walls. In addition, mesial temporal sclerosis was present.
Patient no. 2 Cfinical history.
A 10-year-old left-handed girl with infantile hemiplegia started having seizures at the age of 3 months, after uncomplicated delivery with forceps.
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Motor and speech delay as well as right hemiatrophy were noted later. Her seizures over the years were characterized by jerking movements of the right upper extremity, brief episodes of bilateral eye blinking, or generalized convulsions. Physical findings. When evaluated in June 1989, she had failed anticonvulsant drug treatment. She was receiving special education in school, where she had been found a year earlier to be functioning at a 3-4B FPl-F 7 ~
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252
S.J.C. PIERRE-LOUIS, F. M O R R E L L
year-old level. She could not read or add. She was easily distractable, obeyed commands sporadically and spoke occasionally in short sentences. There was a dense right homonymous hemianopia, without facial asymmetry. Hemiatrophy was maximal in the right arm, which was held spastically against her body with no finger movements. Marked hyperreflexia and Babinski sign were noted on the right. She reacted bilaterally to pain stimulation and ambulated independently with a spastic right leg. lnt,estigations. MRI revealed a cystic lesion in territory of left middle cerebral artery. SPECT scan disclosed absent perfusion of most of the left cerebral hemisphere and a smaller area of hypoperfusion in the right frontal lobe. Preop EEG findings'. Interictal E E G while receiving phenytoin, valproic acid and carbamazepine showed sparse posterior alpha rhythm at 11-12 Hz with moderate background slowing. Beta activity and sleep spindles were not clearly identifiable on the left. Vertex waves of sleep were present bilaterally. Constant left frontally predominant slow (2 Hz) spike-wave activity was seen, with intermittent bisynchrony. Occasional independent right frontal discharges were also noted at F4 (Fig. 5A). Ictal EEGs during prolonged EEG-video recording consisted usually of bursts of bilateral spikes and polyspike-waves. At other times generalized desynchronization of background rhythms, less prominent in the left f~rontal leads, was seen. Clinical seizures not always correlated with the electrographic findings, included myoclonic or tonic movements of the right arm, eye blinking, head drops and jerking of the entire body. Intravenous injection of methohexital during E E G recording disclosed independent epileptogenic foci in either frontal lobes, the left frontal and temporal leads (F~, F v, 'F0 being the most active. ECoG findings. On 14 September 1989 a left functional hemispherectomy was performed. A large cyst occupied most of the perisylvian area and the temporal lobe appeared quite fibrotic. The pre-excision corticogram showed frequent bursts of spike-waves,
frontally predominant, which persisted in the post-excision tracing. Postop EEG findings. Subsequent course was complicated by osteomyelitis, requiring removal of the bone flap in December 1989 and placement of a prosthesis a few months later. At follow-up in October 1990, the patient had been seizure free with carbamazepine and phenobarbital. Speech output was still poor, although understanding of spoken language had improved. Neurological exam had not otherwise significantly changed. E E G showed marked attenuation of background activity on the operated side, absent sleep spindles on the left, and asynchronous beta activity of higher amplitude on the left. Frequent spikes were noted in the left frontopolar region (Fig. 5B). Both pre- and postoperative tracings showed no response to photic stimulation. Hyperventilation could not be performed. Pathology. Pathologic findings were consistent with porencephalic cyst.
Discussion
Since the original experiments of Bremer on the "enc~phale isol6" of cat in 1935, numerous investigators have confirmed that neuronally isolated cerebral cortex of animals can sustain spontaneous electrical activity provided that pial circulation remains intact (Bremer 1949; Kristiansen and Courtois 1949; Frost and Gol 1966; Frost et al. 1966; Kellaway et al. 1966). In spite of rare dissent (Burns 1950), it has generally been established that such activity appears immediately after partial or complete undercutting of cerebral cortex. It consists usually of high voltage aperiodic slow waves with superimposed fast rhythms, which may be intermittently interrupted by isoelectric episodes. Similar findings have been reported in cats after isolation of an entire cerebral hemisphere and have persisted even in chronic preparations 9 months later (Kellaway et al. 1966). Rhythmic activity has also been recorded
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Fig. 5. EEG in case no. 2. A: preoperative tracing with spike discharges occurring independently or synchronously in the frontal regions. B: postoperative tracing with epileptiform activity now restricted to the left frontopolar region.
EPILEPT1FORM ACTIVITY 1N ISOLATED CEREBRAL CORTEX in isolated cortex of cat after direct electrical stimulation, even when spontaneous activity was absent (Burns and Grafstein 1952; Burns 1954, 1955). None of these animal preparations included isolated epileptogenic cortex. Although less extensive, human studies have provided similar results. Henry and Scoville performed bilateral frontal lobotomy in patients with severe psychiatric disorders. Following surgical isolation of the frontal lobes by undercutting both the superior convexity and the orbital surface, burst-suppression activity was noted. That activity remained confined to the isolated cortex, was characteristically asynchronous between the two hemispheres and did not depend on the use of barbiturates or other anesthetics. In some cases it persisted over a year, though not apparent in scalp EEG, and was discovered when additional surgery was performed later. Henry postulated that such rhythmic activity was "related to the release of cortex from the influence of the reticular activating system" (Henry 1952). Echlin also studied psychiatric patients. In the course of carrying frontal lobotomies, he produced a suppression-burst pattern over an isolated slab of cerebral cortex, which was still present 5 weeks later. Intravenous injection of metrazol caused marked selective increase of the frequency and amplitude of the bursts. Noting similar burst-suppression rhythm in the cortex of a patient, adjacent to a brain tumor, Echlin suggested that such rhythms might be the result of partial isolation of masses of neurons. He also emphasized that partial isolation of neurons by various brain lesions might be an important factor in the genesis of paroxysmal hypersynchronous discharges and clinical seizures (Echlin et al. 1952). Interestingly, Echlin later showed in alert monkeys (Echlin 1975) that there was progressive development of supersensitivity to topical acetylcholine (ACh) over partially isolated frontal cortex. This took the form of decreased threshold of paroxysmal activity after intermittent brief application of ACh and after electrical stimulation of a contralateral peripheral nerve. In cases where the open end of the partial isolation extended into the precentral gyrus, prolonged peripheral nerve stimulation caused the abnormal focal cortical discharge to spread and give rise to a generalized convulsive seizure. This hypersensitivity phenomenon, which developed over the first 3 weeks after partial isolation and persisted more than 7 years in some cases, was thought by Echlin to represent a form of denervation sensitivity. Indeed, these physiological changes correlated with morphological (loss of dendritic spines) and biochemical (gradual drop in cholinesterase activity) changes that could all be prevented by daily electrical stimulation of the isolated cortex. The above observa-
253 tions, once again, did not specifically address the fate of epileptiform discharges in isolated cortex. A new era began with Krynauw's 1950 series of hemispherectomy for infantile hemiplegia and seizures. Numerous reports subsequently described electrographic findings after hemispherectomy. These included disappearance of slow waves in the contralateral hemisphere (Obrador and Larramendi 1950), decreased voltage of background activity on the intact side and rhythm in the alpha range on thc operated side (Marshall and Walker 1950), and characteristic behavior of potential fields on the scalp of the ablated side due to volume conduction (Cobb and Sears 1959). Ravenna and Benedetti (1965), quoted by Wilson (1970), reported that after hemisphercctomy electrical silence on the operated side is replaced within a few years by low amplitude, unstable, polymorphic posterior and central activity synchronous with that of the remaining hemisphere. At the samc time, early postoperative disorganized background activity on the intact side is soon reorganized with return of alpha activity. They also noted that sharp waves, theta activity and spikes, often focal, reappeared frequently over the intact hemisphere after several years without concomitant return of clinical seizures. All these reports, however, including a more recent one by Verity et al. (1982) dealt with EEG after total removal of a cerebral hemisphere. It soon became obvious that such a procedure was associated with an excessive amount of delayed complications, the most important being superficial cerebral hemosiderosis due to recurrent intracranial hemorrhages on the operated side. Modifications of the surgical technique, allowing subtotal removal of epileptogenic tissue, reduced the incidence of delayed complications at the cost of seizure control. Thereforc, by 1974 Rasmussen devised a furthcr modification of the technique, as described carlier. Recognizing the relatively short follow-up period of his series (2-6 years), Rasmussen in 1983 reported 8 patients who underwent functional hemisphcrectomy: the complication of delayed hemorrhage had been virtually eliminated. A degree of seizure control comparable to the one associated with total anatomical hemispherectomy had also been achieved. The technique of functional hemispherectomy constituted, in our view, an in viw) model par excellence of human isolated cortex with epileptogenic potential. Surprisingly, though, the last 15 years have witnessed a paucity of reports describing the behavior of epileptiform activity after such a procedure. Electrographic findings in our two cases indicate that human isolated cortex can sustain not only normal rhythms, but also epileptiform activity for 3 years or longer. It is of interest that in the first case electrographic seizures persisted acutely after cortical isolation, as docu-
254 m e r i t e d by E C o G . T h i s s u g g e s t s t h a t i n t r a c o r t i c a l c o n n e c t i o n s a l l o w s u f f i c i e n t n e u r o n a l s y n c h r o n y to p r o duce epileptic discharges, independently of subcortical i n f l u e n c e s , e v e n t h o u g h s u c h d i s c h a r g e s a r e b o u n d to r e m a i n clinically silent. O f e q u a l i n t e r e s t , m a i n l y i n o u r first case, is t h e a p p a r e n t a c t i v a t i o n o f t h e e p i l e p t i f o r m activity d u r i n g s l e e p . T h i s s u g g e s t s t h a t i s o l a t e d c o r t e x r e m a i n s s e n s i t i v e to c i r c a d i a n r h y t h m s ( p r e s u m a b l y via circulation) and that circulatory humoral factors during sleep, rather than direct influence from subcortical s t r u c t u r e s , m a y c o n t r i b u t e to t h e e s t a b l i s h m e n t o f functional states favoring paroxysmal discharges. It is n o t c l e a r w h e t h e r t h e p e r s i s t e n t e p i l e p t i f o r m activity is d u e solely to an i n h e r e n t p r o p e r t y o f c o r t i c a l n e u r o n s o r r e l a t e d to s o m e f o r m o f d e - a f f e r e n t a t i o n in an a l r e a d y h y p e r e x c i t a b l e c o r t e x . In any e v e n t , t h e l a c k o f s l e e p s p i n d l e s ( S t e r i a d e ct al. 1990), t h e r e s t r i c t e d field o f t h e s p i k e d i s c h a r g e a n d t h e a b s e n c e o f t h e preoperalive bilaterally synchronous spike-wave patt e r n c o n f i r m e d t h e i s o l a t i o n o f t h e f r o n t a l cortex. Therefore, the intermittent spike discharges over the i s o l a t e d c o r t e x a r e c o n s i d e r e d b e n i g n in n a t u r e a n d n o t e x p e c t e d to c a u s e clinical s e i z u r e s .
Addendum S i n c e this p a p e r was s u b m i t t e d f o r p u b l i c a t i o n , an a r t i c l e by S . J . M . S m i t h et al. a p p e a r e d in Neurology. In this article, t h e a u t h o r s r e p o r t e d E E G f i n d i n g s in 25 patients who underwent functional hemispherectomy. T h e y also o b s e r v e d p e r s i s t e n t s p i k i n g p o s t o p e r a t i v e l y , o v e r t h e i s o l a t e d c o r t e x e x c l u s i v e l y in 8 o f t h e i r patients, n o n e o f w h o m h a d clinical s e i z u r e s . We are indebted to Mrs. Connie M. Lambert for typing the manuscript.
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s.J.C. PIERRE-LOUIS, F. MORRELL Burns, B.D. Some properties of the cat's isolated cerebral cortex. J. Physiol. (Lond.), 1950, 111: 50-68. Burns, B.D. The production of after-bursts in isolated unanesthetized cerebral cortex. J. Physiol. (Lond.), t954, 125: 427-446. Burns, B.D. The mechanism of after-burst in cerebral cortex. J. Physiol. (Lond.) 1955, 127: 168-188. Burns, B.D. and Grafstein, B. The function and structure of some neurones in the cat's cerebral cortex. J. Physiol. (Lond.), 1952, 118: 412-433. Cobb, W. and Sears, T.A. A study of the transmission of potentials after hemispherectomy. Electroenceph. clin. Neurophysiol., 1959. 12: 371-383. Echlin, F. Time course of development of supersensitivity to topical acetylcholine in partially isolated cortex. Electroenceph. clin. Neurophysiol., 1975, 38: 225-233. gchlin, F.A., Arnen, V. and Zoll, J. Paroxysmal high-voltage discharges from isolated and partially isolated human and animal cerebral cortex, t952. Frost, Jr., J.D. and Gol, A. Computer determination of relationship between EEG activity and single unit discharges in isolated cerebral cortex. Exp. Neurol., 1966, 14:5[)6-519. Frost, Jr., J.D., Kellaway, P. and Gol. A. Single-unit discharges in isolated cerebral cortex. Exp. Neurol., 1966, 14:5(16 519. tienry, C.E. Suppression-burst activity from isolated cerebral cortex in man. Electroenceph. olin. Neurophysiol., 1952, 4: I 22. Kellaway, P., Gol, A. and Proler, M. Electrical activity of the isolated cerebral hemisphere and isolated thalamus. Exp. Neurol., [966, 14:281 304. Kristiansen, K. and Courtois. G. Rhythmic electrical activity from isolated cerebral cortex. Electroenceph. clin. Neurophysiol., 1949, 1: 265-212. Marshall, C. and Walker, E. The elcctrographic changes after hemispherectomy in man. Electroenceph. clin. Neurophysiol., 1950, 2: 147-156. Obrador, S. and Larramendi. M.H. Some observations on the brain rhythms after surgical removal of a cerebral hemisphere. Electroenceph, clin. Neurophysiol., 195[), 2:143 146. Rasmussen, T. Hemispherectomy for seizures revisited. Can. J. Neurol., 1983, 10:71 78. Smith, S.J.M. et al. Functional hemispherectomy: EEG findings, spiking from isolated brain postoperatively, and prediction of outcome. Neurology, 1991, 41: 179[)-1794. Steriade, M., Gloor, P., Llin~s, R.R., Lopes da Silva, F.H. and Mesulam, M.M. Basic mechanisms of cerebral rhythmic activities. Electroenceph. clin. Neurophysiol., 1990, 76:481 508. Verity, C.M. et al. Long-term follow-up after cerebral hcmispherectomy: neurophysiologic, radiologic and psychological findings. Neurology, 1982, 32: 629-639. Wilson, P.J.E. Cerebral hemisphercctomy for infantile hcmiplegia: a report of 51) cases. Brain. 197t), 93:147 18(/.
