1. health and fitness
2. disease
3. epilepsy

Brain (1996), 119, 989-996
The running down phenomenon in temporal lobe
epilepsy
Vicenta Salanova,* Frederick Andermann, Theodore Rasmussen, Andre Olivier and Luis Quesney
Department of Neurology and Neurosurgery, McGill
University and the Montreal Neurological Institute and
Hospital, 3801 University Street, Montreal, PQ,
Canada H3A 2B4
Correspondence to: Dr Salanova, Department of
Neurology, Indiana University Medical Center, Riley
Hospital, Room 5999C, 702 Barnhill Drive, Indianapolis,
IN 46202-5200, USA
* Present address: Department of Neurology, Indiana
University Medical Center, Riley Hospital, Indianapolis,
USA
Summary
areas often involving the lateral temporal and posterior
temporal cortex. Other factors predictive of good outcome
were: a history of febrile seizures, predominantly unilateral
interictal spiking, anterior temporal localization, extent of
resection of the mesial temporal structures, surgery under
the age of 30 years, and the absence of habitual seizures in
the immediate postoperative period. Patients with history of
head trauma, encephalitis, posterior temporal localization
and bitemporal spiking had a worse outcome. The frequency
and types of aurae, and laterality of resection did not
correlate with outcome.
Keywords: epilepsy; surgery; outcome
Abbreviations: ECOG = electrocorticogram
Introduction
Those patients whose epileptogenic areas are surgically
removed, because of intractable epilepsy, are shown to follow
one of three well-defined clinical courses: (i) no further
seizures; (ii) continue to have seizures indefinitely; (iii)
seizures which ultimately remit after a period of months to
years following surgery. Rasmussen (1970) has called this
later phenomenon the 'running down phenomenon'.
Rasmussen (1970) postulated that in those patients
manifesting the running down phenomenon, the entire
epileptogenic area had not been removed, but that the
remaining epileptogenic area was 'not quite autonomous',
suggesting that a 'hard core, lowest threshold epileptogenic
area' had been removed at surgery, and the remaining
epileptogenic area was not sufficient to continue to generate
seizures indefinitely. This implies that epileptogenic areas
are of two types: one type must be so constituted that it
© Oxford University Press 1996
autonomously generates seizure activity, while another is not
fully autonomous, yet can generate seizure activity for some
time but not indefinitely.
The manner in which areas of differing epileptogenic
potential can be generated, as postulated by Rasmussen, was
defined by Morrell (1959/60, 1985); he showed that areas of
secondary epileptogenesis could be recruited into activity by
primary seizure foci, and that these areas of secondary
epileptogenesis often become unable to generate seizures
after periods ranging from months to years after removal of
the primary epileptogenic areas, thus accounting for the
running down phenomenon. Theoretically, the reason the
running down phenomenon occurs after the removal of the
pathologically damaged primary epileptogenic areas is that
in these cases secondary epileptogenesis was caused by
reversible pathophysiological phenomena such as transsynaptic facilitation.
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We compared 100 patients with temporal lobe epilepsy, who
exhibited the running down phenomenon following temporal
resections, with two groups of patients: 100 patients who
became seizure-free, and 100 patients who continued to have
frequent seizures following temporal resection. We found a
significant correlation between prognosis and the size of
the epileptogenic area as defined; patients with smaller
epileptogenic areas had the best prognosis (seizure-free
group). Patients exhibiting the running down phenomenon
had intermediate size epileptogenic areas, while those patients
who continued to have seizures had the largest epileptogenic
990
V. Salanova et al.
Material and methods
Initially, we had planned to analyse only those patients with
the running down phenomenon; however, Dr Pierre Gloor
suggested we compare those patients with two other groups
of patients with medically refractory temporal lobe epilepsy
treated surgically at the Montreal Neurological Institute.
None of these patients had foreign tissue lesions. We used
Rasmussen's classification of seizure outcome (1974). The
first group (Grade O, follow-up 2-39 years), comprised 100
patients operated on during the period 1950-85 who remained
seizure-free since surgery. The second group (Grade I, followup 2 ^ 0 years) comprised 100 patients operated on during
the period 1950-80; these patients had seizures in the early
postoperative months or years, but subsequently became and
remained seizure-free (running down group). The third group
consisted of 100 patients operated on during the period 1950—
85 who continued to have seizures (Grade IV, follow-up 239 years).
These three groups of patients were selected from a
large number of patients undergoing surgery for medically
refractory temporal lobe epilepsy at the Montreal
Neurological Institute during the period 1950-85. We did
not include those patients in the intermediate groups who
were assessed at Rasmussen's Grades II and III, with rare
seizures or significant reduction in seizure frequency, because
we reasoned that the comparison between diametrically
opposed groups was most likely to show significant
differences, and help to clarify the nature of the running
down phenomenon.
Rasmussen collected these data for years with a view to
elucidating the nature of the running down phenomenon. He
had kept a detailed follow-up on these patients through clinic
visits and personal correspondence. The epilepsy surgery
files were reviewed, and patients with the most complete
data who also fulfilled the above criteria were chosen for
the study.
Most of these patients were studied prior to the era
of video EEG recordings, and head CT and MRI. The
epileptogenic area is defined as 'that portion of the brain
which initiates the clinical seizure, whose removal or
disconnection is necessary for the abolition of seizures'
(Liiders et al., 1993). At the Montreal Neurological Institute
all data available, including clinical semiology, neurological
findings, imaging studies, neuropsychological testing,
epileptiform and non-epileptiform EEG and electrocorticogram (ECOG) abnormalities are used to determine the
localization of the epileptogenic area (Gloor, 1975; Quesney
and Gloor, 1985). Most patients had serial surface interictal
EEGs using sphenoidal electrodes; some also had ictal
recordings. The neurophysiologist conducting the presurgical
evaluation determined whether unilateral or bitemporal
interictal spiking was present. This was a qualitative decision
based on reviewing multiple recordings for several days.
Most records were interpreted by Drs H. Jasper, P. Gloor
and L. P. Quesney. Most patients had pneumoencephalograms,
and many also had cerebral angiograms. As previously
reported (Gloor, 1975; Rasmussen, 1975; Stefan et al., 1991),
intraoperative electrocorticography, and cortical stimulation
was used to confirm, and to determine the extent of the
epileptogenic area. The ECOG tracing was obtained from a
wide exposure of the fronto-centro-temporo-parietal region.
In most patients, recordings were also obtained from the
mesial temporal structures using two depth electrodes inserted
through the second temporal gyrus. The first one was inserted
2.5-3 cm behind the temporal tip and the second one 2 cm
behind the first.
The degree of resection of the mesial temporal structures
was assessed by the neurosurgeon at the time of surgery.
Post-resection residual ECOG spiking was classified by the
neurophysiologist and given a prognostic rating from I (poor
prognosis, significant spiking) to 4 (good prognosis, no
spiking). Identification of the mesial temporal structures in
the pathological specimen could not be used to assess the
degree of resection as many patients had removal of these
structures by suction. Post-operative MRIs to confirm the
extent of resection were not available. In most patients
the pathological diagnosis consisted of different degrees of
neuronal loss and gliosis; however, no further detail was
possible. Most patients were treated with phenytoin,
phenobarbital and primidone; however, details about
anticonvulsant levels and dosages are not available.
We analysed the following factors: (i) the age of seizure
onset and age at time of surgery; (ii) duration of epilepsy;
(iii) the types of aurae and other clinical manifestations; (iv)
neurological examination; (v) EEG findings; (vi) pre-resection
and post-resection ECOG; (vii) laterality of resection; (viii)
extent of resection of the mesial temporal structures; (ix)
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Rasmussen (1983) observed that the running down
phenomenon occurred irrespective of the cortical zone
generating the seizures.
In an earlier study Rasmussen (1982), compared 101
patients with temporal lobe epilepsy who became seizurefree following temporal resection with 46 patients who
manifested the running down phenomenon, and suggested
that 'the epileptic mechanisms essential for the production
of the clinical seizures were somewhat more extensive in the
46 patient series.'
The exact pathophysiology of the running down
phenomenon remains unknown. Gloor (1987), suggested that
'gradations in the seizure producing potential' of epileptogenic areas exist, which may explain why removal of the
area of seizure onset did not lead to complete cessation
of attacks.
• In order to study this phenomenon further, we compared
100 patients with temporal resections, who manifested the
running down phenomenon, with an equal number of patients,
who immediately became seizure-free, and with another 100
patients, who continued to have frequent habitual seizures.
Unfortunately, the very nature of this phenomenon precludes
any but a retrospective analysis.
Surgery^ of temporal lobe epilepsy
presence of seizures in the immediate postoperative period.
We also analysed the duration of seizures in the early
postoperative months or years for the group of patients
who subsequently became seizure-free (running down
phenomenon).
Results
Grade 0 (seizure-free group, n = 100 patients)
Aetiological factors
Thirty-eight patients had a history of febrile seizures under
the age of 5 years; in 10 patients focal features with postictal
hemiparesis were reported. Fifteen patients had a history of
head trauma, 10 of difficult birth, eight had a history of
meningitis, two had a history of encephalitis, one had a
hypoxic event, one an arachnoid cyst, and another patient
had onset of seizures during pregnancy. Twenty-four patients
had no aetiological factors.
Surface EEG
The surface EEG showed unilateral anterior temporal
interictal epileptiform discharges in 69 patients; in one
maximum spiking was in the posterior temporal region.
Thirty patients had bitemporal independent epileptiform
discharges, but with predominance on the side of eventual
resection; one of these patients also had spiking in the
posterior temporal region. One patient had no epileptiform
discharges.
Pre-resection ECOG
Sixty-five patients had spiking involving the mesial and
lateral temporal structures; 27 of these patients also had
spiking in the suprasylvian region. Of the remaining patients,
in 24 the most active spiking was recorded from the mesial
temporal structures, and in six from the lateral temporal
region. Two patients had no spiking and in three the data
were not available.
Types of resection
Fifty-seven patients had left- and 43 right-sided resections.
Forty-nine patients had resection of the temporal neocortex,
amygdala, and most of the hippocampus. The hippocampal
resection ranged from 1 to 3 cm; most patients had resection
of the anterior 1.5 cm of the hippocampus. Twelve patients
had resection of the temporal neocortex, pes hippocampus,
and adjacent part of the body of the hippocampus. Twentyseven had resection of the temporal neocortex, amygdala and
pes hippocampus, six of the lateral temporal lobe and
amygdala, and the remaining six patients had only resection
of the lateral temporal region. Three patients also had small
extra-temporal corticectomies, including the orbital surface
of the frontal lobe (n = 2), and a small parietal corticectomy
(n = 1).
Post-resection ECOG
Post-resection ECOG was available in 95 patients; 70 out of
95 (73.6%) showed no residual or minimal spiking (prognostic
rating 3, 4) and 25 out of 95 (26.3%) showed residual spiking
(prognostic rating 1, 2).
Postoperative seizures
Seven patients had habitual seizures in the immediate
postoperative period, 15 had neighbourhood and/or
generalized seizures, and in four patients the seizures were
not clearly defined. The seizures occurred in the first few
days following the surgery. The 'neighborhood seizures' were
not the typical patients' typical seizures, and were felt to be
precipitated by surgical trauma, oedema or metabolic factors.
Grade I (running down phenomenon, n = 100
patients)
The mean age of onset of seizures was 14.9 years (9 months
to 48 years), the mean age at surgery 27.68 years (12-53
years), and the mean duration of epilepsy 12.8 years ( 1 48 years).
Age at onset of seizures
In 11 patients the age at onset of seizures ranged from
9 months to 4 years; in 19 from 5 to 9 years; in 26 from
10 to 14 years; in 18 from 15 to 19 years; in 18 from 20 to
29 years and in eight from 30 years to 48 years.
Age at operation
In 20 patients the age at surgery ranged from 10 to 19 years;
in 26 from 20 to 24 years; in 18 from 25 to 29 years; in 25
from 30 to 39 years, and in 11 from 40 to 53 years.
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The mean age at onset of seizures was 10.8 years (range 3
months to 42 years). The mean age at surgery was 26.3 years
(range 13-51 years), and the mean duration of epilepsy was
15 years (range 3—41 years). The neurological examination
was abnormal in only two patients; one had a mild left
hemiparesis and another smaller right extremities. The clinical
characteristics were typical of temporal lobe epilepsy; 72%
experienced aurae. The most common aurae were epigastric,
present in 40 patients, followed by experiential aurae
exhibited by 22 patients (deja vu, fear, complex visual or
auditory hallucinations). Five patients had dizziness, four
olfactory aurae, two gustatory, one conscious confusion, five
aphasic aurae, one forced thinking and three were unable to
describe the aura. In 28 patients no aura was mentioned.
Some patients had more than one aura.
991
992
V. Salanova et al.
Duration of epilepsy prior to surgery
In nine patients the duration of epilepsy prior to surgery
ranged from 1 to 4 years; in 31 from 5 to 9 years; in 30
from 10 to 14 years; in eight from 15 years to 19 years; in
18 from 20 to 29 years and in four 30 to 48 years.
The neurological examination was abnormal in seven
patients; two had left homonymous hemianopsia, one a right
quadrantic visual field defect, one a mild hemiparesis, one
smaller left extremities, one left-sided hyper-reflexia, and the
remaining one hypotonia of the lower extremities.
Forty-five patients had epigastric, and 28 experiential aurae
(fear, deja vu, complex visual or auditory hallucinations).
Six had cephalic sensation or dizziness sensations, four had
aphasic aurae, three olfactory, four gustatory, two pilomotor,
one forced thinking, one conscious confusion, one numbness,
and two were unable to describe the aura. Seventeen patients
had no aura. Some patients had more than one aura.
Aetiological factors
No. of patients
Seizures in the early postoperative months/years
2-12 months
33
2 years
20
3 years
12
10
4 years
11
5-6 years
14
7-8 years
Seizure-free years after early seizures
2-5 years
16
6-10 years
27
11-15 years
18
16-20 years
17
21-30 years
15
31-40 years
7
Types of resection
Fifty-two patients had left- and 48 right-sided resections.
Forty-eight patients had extensive resections involving the
temporal cortex, amygdala, and part of the hippocampus; 14
of these patients also had small extratemporal corticectomies
of orbitofrontal cortex (n = 7); frontal operculum (n = 3);
post-central face area (n = 1); parietal operculum (n = 2)
and central operculum (n = 1). Twenty-two patients had
resection of the temporal cortex, pes hippocampus and
adjacent body of the hippocampus. Eighteen had resections
of the temporal cortex, amygdala and pes hippocampus; one
of these also had a small removal of the orbitofrontal cortex.
Nine had resections of temporal cortex and amygdala, and
three had only resections of the temporal neocortex. Thus,
70% had some resection of the hippocampus, and another
18 had resection of the pes hippocampus.
Scalp EEG
Scalp EEG showed unilateral anterior temporal interictal
epileptiform discharges in 71 patients, bitemporal independent
spiking in 28, and no spiking in one patient. In eight out of
99 patients spiking also involved the suprasylvian region,
and in five out of 99 the posterior temporal region.
Pre-resection ECOG spiking
Sixty-three patients had widespread spiking involving the
temporal neocortex, and the mesial temporal structures; 29
of these patients also had spiking in the suprasylvian region,
and in seven of these patients spiking involved also the
posterior temporal region. Of the remaining patients, 18 had
maximum spiking in the mesial temporal structures, and in
two of these patients involved the posterior temporal
structures. Fourteen had maximum spiking in the lateral
temporal region, and in three of these spiking involved the
posterior temporal region. Four patients had no spiking and
the information was not available in one patient. Thus, in
13% (12 out of 95) of patients, active spiking involved the
posterior temporal structures.
Post-resection ECOG
Twenty-eight patients had no or minimal post-resection
spiking. Forty-five had residual spiking, mainly in the
posterior resection margin; seven of these also had spiking
in the suprasylvian region, and another five in the insula.
Fifteen patients had spiking in the insula only; one of these
also had spiking in Broca's area, and another in the posterior
temporal region. Seven showed spiking only in the
suprasylvian region, and three had no pre-resection or postresection spiking. In two patients the data were not available.
Seizures in the immediate postoperative period
Sixty-five patients had no seizures in the immediate
postoperative period. Thirteen had habitual seizures, 18
neighbourhood seizures and in four patients the seizures were
unclassified.
Years of postoperative seizures
Table 1 shows the number of years of postoperative seizures.
The frequency of seizures ranged between one or two
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Twenty-four patients had a history of febrile seizures, 18 had
a history of head trauma, and 10 had a history of difficult
birth. Three patients had a history of meningitis; three had a
history of brain abscess; one of toxaemia of pregnancy; one
had a history of cerebral malaria; one of electroconvulsive
treatment; one of CNS infection; one had a small hamartoma;
one an occult vascular malformation and one had radon seeds
implanted into the temporalis muscle. Thirty-five patients
had no identifiable aetiological factors.
Table 1 The running down phenomenon—Grade I (n =100)
Surgery of temporal lobe epilepsy
per year to several per month. The median duration of
postoperative seizures was 2 years. A few patients had
seizures up to 7-8 years before becoming seizure-free.
Total number of seizure-free years after early
seizures
Table 1 shows the number of seizure-free years after early
seizures. Follow-up range was 2-40 years.
993
these patients also had spiking in the suprasylvian region,
and in 15 patients the maximum spiking was in the posterior
temporal region. Of the remaining patients, in 21 the
maximum spiking was in the lateral temporal region, and 11
out of 21 of these patients had maximum spiking in the
lateral posterior temporal region. Eight patients had maximum
spiking in the mesial temporal structures, and in two of these
patients it was maximum in the posterior mesial temporal
structures. Six had no or minimum spiking, and in two the
data were not available.
Grade IV (failure group, n = 100)
Aetiological factors
Thirty-four patients had a history of head trauma; 16 of
difficult birth; 13 of encephalitis; eight of febrile seizures;
one of meningitis; one of an infarct; one had an hypoxic
episode and one was proven to have micropolygyria. Twentyfive patients had no recognizable aetiological factors.
Scalp EEG
Fifty-three patients had bitemporal interictal epileptiform
discharges; 14 of these patients were studied with intracranial
electrodes. Forty-five patients had unitemporal interictal
epileptiform discharges, and one had no epileptiform
discharges. In one patient the data were not available. The
epileptogenic area extended to the posterior temporal region
in 20 out of 98 (20.4%) of the patients.
Pre-resection ECOG spiking
Sixty-three patients had widespread spiking involving the
lateral temporal and the mesial temporal structures; 40 of
Types of resection
Fifty-nine patients had left- and 51 right-sided resections.
Thirty-six patients had resection of the temporal neocortex,
amygdala, and part of the hippocampus; 19 had resection of
the temporal neocortex, amygdala, and pes hippocampus, 16
of the temporal cortex, pes hippocampus and part of the
adjacent body of the hippocampus, 18 of the temporal cortex
and amygdala, and 11 of the temporal cortex only. Ten
patients also had small extratemporal corticectomies most
often including the parietal or frontal operculum or the
orbitofrontal cortex.
Post-resection ECOG
The post-resection ECOG was available in 91 patients; 22
out of 91 (24.1%) had no residual or significant reduction of
spiking. The remaining 69 patients had residual spiking
mainly in the posterior resection margin and in the
suprasylvian region, and a few patients had spiking also in
the insula.
Seizures in the immediate postoperative period
Forty patients had seizures in the immediate postoperative
period: of these, 18 were described as habitual, 13 as
neighborhood and/or generalized, and in nine patients the
seizures were not described in detail.
Comparison between the groups (Tables 2
and 3)
When we compared the three groups we found that 38% of
seizure-free patients had a history of febrile seizures compared
with 8% of those who were not seizure-free; this difference
was highly significant statistically (P < 0.001). Twenty-four
percent of patients in the running down group had a history
of febrile seizures compared with 8% of those who did not
become seizure-free; this was also statistically significant
(P = 0.002). More patients in the group who were not
seizure-free had an abnormal neurological examination.
More patients in the group who were not seizure-free
(Grade IV) had a history of head trauma and encephalitis,
compared with the seizure-free patients (P = 0.002, and P =
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The mean age of onset of seizures was 12.8 years (1 day to
45 years), the mean age at surgery 28.01 years (range, 6-51
years), and the mean duration of epilepsy 15.4 years (2-43
years). The neurological examination was abnormal in 10
patients: three had a mild hemiparesis; two had smaller
extremities contralateral to the epileptogenic area; one mild
hemiparesis and mild dysphasia; one a left hemiparesis and
a left upper quadrantic defect; two homonymous hemianopsias and the remaining patient had impaired contralateral
two-point discrimination. Sixty-nine patients had aurae (69
out of 94, 73%), 25 had no aurae, and in six patients it was
not mentioned. Twenty-eight patients had epigastric, and 24
experiential aurae, consisting predominantly of fear and deja
vu, three patients exhibited complex visual and one complex
auditory hallucinations; one patient exhibited elementary
visual hallucinations described as 'coloured lights', and
another patient manifested 'visual hallucinations'; however,
no further description was available. Three had aphasic aurae,
one olfactory, one gustatory, one conscious confusion, one
forced thinking, two numbness in face and limbs, two chillin-the-back like an electric shock, and one could not describe
the aura.
994
V. Salanova et al.
Table 2 Clinical characteristics in temporal lobe epilepsy
History of febrile seizures
History of head trauma
History of encephalitis*
Age at surgery under 30 years
Scalp EEG localization
Anterior temporal
Interictal spiking
Unilateral temporal
Bilateral
Almost complete hippocampal resection
Post-resection ECOG spiking
Seizures in post-operative period
Seizure-free
patients
(n = 100)
Not seizure-free
patients
(n = 100)
Statistical
significance
(P)
38
15
2
75
8
34
13
57
<0.001
0.002
0.00545
0.007
97/99 (97.9%)
78/98 (79.5%)
<0.001
69/9 (69.6%)
30/99 (30.3%)
61
25/95 (26.3%)
26
45/98 (45.9%)
53/98 (54%)
52
69/91 (75.8%)
40
0.001
0.001
0.199
<0.001
0.035
The P values were obtained via 2X2 contingency tables. *Denotes Fisher's exact test was used.
Table 3 Clinical characteristics in temporal lobe epilepsy
Not seizure
free patients
(n = 100)
24
18
00
64
8
34
13
57
0.002
0.010
0.00016
0.311
94/99 (94.9%)
78/98 (79.5%)
0.001
71/99 (71.7%)
28/99 (28.2%)
70
67/98 (68.3%)
35
45/98 (45.9%)
53/98 (54%)
52
69/91 (75.8%)
40
<0.001
<0.001
0.009
0.254
0.465
Statistical
significance
(P)
The P values were obtained via 2X2 contingency tables. *Denotes Fisher's exact test was used.
0.00545, respectively), and the running down group (P =
0.010, and P = 0.00016). These differences were statistically
highly significant.
Surface EEG localization showed anterior temporal
epileptiform discharges in 98%, and 94% of patients in Grade
O and Grade I, respectively. However, 20.4% of patients in
Grade IV had maximum spiking in the posterior temporal
region on surface recordings. Bitemporal independent
interictal epileptiform discharges were also more frequent in
those patients with poor outcome (Grade IV). These differences also reached statistical significance (Tables 2 and 3).
Preresection ECOG showed larger interictal ECOG
epileptogenic areas in the patients who did not become
seizure-free (Grade IV), and in 28 out of 92 (30.4%) this
extended into the posterior temporal region. Those patients
exhibiting the running down phenomenon (Grade I) also had
larger interictal ECOG epileptogenic areas, when compared
with the seizure-free patients, and in 13% of the patients
the interictal epileptogenic area extended into the posterior
temporal region. In addition more patients in the group who
did not become seizure-free had maximum spiking in the
lateral temporal region when compared with the seizurefree patients.
When we reviewed the extent of resection we found that
more of the seizure-free, and running down patients had
complete or almost complete hippocampal resection when
compared with patients in Grade IV. This difference was
statistically significant when comparing the running down
patients with the patients who were not seizure-free patients
(P = 0.009), but did not reach statistical significance when
comparing the seizure-free with the not seizure-free patients
(P = 0.199). In addition, fewer patients in Grade O and
Grade I had ECOG post-resection residual epileptiform
discharges compared with those in Grade IV. However, this
was statistically significant only when comparing the seizurefree with the not seizure-free patients (P < 0.001).
Other factors correlating with better outcome were surgery
under the age of 30 years, and no seizures in the immediate
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History of febrile seizures
History of head trauma
History of encephalitis*
Age at surgery under 30 years
Scalp EEG localization
Anterior temporal
Interictal spiking
Unilateral temporal
Bitemporal
Almost complete hippocampal resection
Post-resection ECOG spiking
Seizures in postoperative period
Running down
phenomenon
(n = 100)
Surgery' of temporal lobe epilepsy
postoperative period, but these were statistically significant
only when comparing the seizure-free with the not seizurefree patients.
We found that the age of onset, duration of epilepsy,
presence or absence of aurae, and laterality of resection were
not significantly different between the three groups.
Discussion
involve a wider and wider area of cortical surface' (Morrell,
1959/60).
Following removal of the primary epileptogenic area,
Morrell (1959/60) observed recovery in the area of secondary
epileptogenesis, which frequently stopped generating
paroxysmal activity; the animals with more chronic lesions
had a worse prognosis. He also studied patients with small
tumours for evidence of secondary epileptogenesis, and
observed that this occurred more frequently in those whose
seizure disorder was of longer duration. Some patients
developed independent foci, which did not resolve after
surgery; but there were others, like the ones we present,
who exhibited a running down period, in whom secondary
epileptogenesis (intermediate stage) resolved after a period
of months to years following removal of the primary lesion.
We found that the running down phenomenon continued
to occur even years after initial removal of the primary
lesion. We also found that those patients who would be
expected to have small areas of epileptogenesis, such as
those whose seizures began after febrile convulsions, did, in
fact, have the best prognosis, while those whose epilepsy
was caused by more extensive pathology, such as encephalitis
or head trauma, had the worst prognosis. This difference was
statistically highly significant.
The concept of secondary epileptogenesis as shown in
animals and in patients with temporal and frontal lobe
tumours has generally been equated with development of
mirror foci in contralateral homologous cortex, which become
capable of generating independent seizures (Morrell, 1985,
1989; Morrell et al., 1993; Gilmore et al., 1994). However,
as Morrell et al. (1987) suggested, secondary epileptogenesis
'can also refer to the progressive extension of the primary
epileptogenic zone'. Our study suggests that secondary
epileptogenesis leading to larger epileptogenic areas in the
same hemisphere by recruiting adjacent cortex, contributes
significantly to the epileptogenic process, explaining why
seizures tend to become more frequent and difficult to treat
(Reynolds et al., 1983), more elaborate with the passage of
time (French et al., 1993; Williamson et al., 1993), and may
be related to the latent period between injury and the onset
of clinical epilepsy.
In view of our findings, it appears likely that the more
widespread structural abnormalities produced by encephalitis
and head injury produce larger areas of primary
epileptogenesis, thus accounting for the poor prognosis these
patients have after surgery, for it is difficult to remove all of
the extensive autonomous, primary epileptogenic areas in
these patients. These findings suggest that the group who
were not seizure-free represents a different category of
patients with temporal lobe epilepsy.
Morrell (1985) found that patients with mirror foci had
longer duration of epilepsy, and more than one seizure type.
However, Gilmore et al. (1994) found that their patients with
mirror foci did not. This indicates that longer duration of
epilepsy is not always a prerequisite for the development of
secondary epileptogenesis, and other factors like the severity
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Our findings suggest that the clinical course followed by a
patient after surgery for epilepsy depends on the nature and
extent of the interictal epileptogenic area.
The patients who became immediately seizure-free were
those who had the smallest interictal epileptogenic area, or
who had a history of febrile seizures, which are likely to
produce damage largely limited to sharply circumscribed
vulnerable areas, such as the hippocampus.
These patients were more likely to have unilateral anterior
temporal spiking on scalp EEG, preresection ECOG spiking
recorded predominantly over the anterior temporal region
and from mesial temporal structures, and the least postresection ECOG spiking.
Those patients who manifested the running down
phenomenon had intermediate size interictal epileptogenic
areas at times extending into the lateral temporal and posterior
temporal region, while those who continued to have seizures
had the largest epileptogenic areas with widespread spiking on
scalp EEG and pre-resection ECOG, often involving the lateral
and posterior temporal regions. This last group more often
exhibited post-resection ECOG spiking, and a larger number
of these patients had neurologic deficits prior to surgery.
These results support Rasmussen's (1970) original
hypothesis: that a minimal area of residual epileptogenic cortex
is required to generate seizures, and that some of those who
continue to have seizures will became seizure-free, because
the residual epileptogenic area is 'not quite autonomous'.
In those patients who manifested the running down
phenomenon, Rasmussen (1970) postulated that the 'hard core,
lowest threshold epileptogenic area' was removed at surgery.
It is possible that this 'hard core area' represented structurally
and functionally abnormal cortex, and that in these patients,
the residual spiking on ECOG was caused by secondary
epileptogenesis. That such a phenomenon actually occurs was
shown by Morrell's clinical and experimental data (1959/60,
1985). He produced epileptogenic lesions in cats and rabbits
by the application of ethyl chloride spray, and studied the
development of secondary epileptogenesis, and the response
of the foci of secondary epileptogenesis to removal of the
primary epileptogenic lesion, and to neuronal isolation.
Morrell (1959) found that 'the exact topographic
relationships depended principally upon the size of the
original ethyl chloride lesion, and to some extent, on the
degree of paroxysmal abnormality developed at the primary
site'. 'Those with actively discharging lesions >2—4 mm had
a more widespread mirror focus, and 'In the course of time
the paroxysmal abnormality in both hemispheres tended to
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V. Salanova et al.
and extent of the initial injury may play a role. Similarly,
we did not find multiple-seizure types, or longer duration of
epilepsy in our patients with non-tumoural lesions who
exhibited the running down phenomenon.
In addition to a history of febrile seizures and smaller
interictal epileptogenic areas, other factors predictive of a good
outcome were: unilateral interictal spiking, anterior temporal
localization, and surgery under the age of 30 years. Many of
these observations have been reported previously (Falconer and
Serafetinides, 1963; Falconer, 1974; Davidson and Falconer,
1975; Nayel et al., 1991; Olivier, 1992; Abou-Khalil et al.,
1993; French et al., 1993; Williamson et al., 1993; Salanova
et al., 1994). Bengzon et al. (1968) also reported that surgery
under the age of 30 years, complete hippocampal removal,
no epileptiform abnormality in the post-resection ECOG and
absence of seizures in the immediate postoperative period
correlated with a better outcome.
Acknowledgements
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Received June 1, 1995. Revised December 18. 1995.
Accepted February 13, 1996
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We wish to thank Dr Pierre Gloor who contributed to the
ideas and suggested the methods by which the subject
should be approached and Mrs Martha Stanley for secretarial
assistance in preparation of the manuscript.
Jr, editor. Surgical treatment of the epilepsies. 2nd ed. New York:
Raven Press, 1993: 137-53.