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Video-EEG evidence of lateralized clinical features in primary generalized

epilepsy with tonic-clonic seizures

Article in Epileptic Disorders · September 2003

DOI: 10.1684/j.1950-6945.2003.tb00005.x · Source: PubMed

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 Original article
Epileptic Disord 2003; 5: 149-56

Video-EEG evidence
of lateralized clinical features
in primary generalized epilepsy
with tonic-clonic seizures
Leanne Casaubon, Bernd Pohlmann-Eden, Houman Khosravani,
Peter L. Carlen, Richard Wennberg
Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada
Received May 26, 2003; Accepted July 3, 2003

ABSTRACT − Background : Whether cortical or subcortical structures, specifi-

cally the thalamus, play the dominant role in generating primary generalized
seizures has been the subject of long debate. Most experimental data implicate
a hyperexcitable cortical generator of spike-and-wave activity, with the thalamus
quickly recruited to sustain the generalized oscillations through a reverberating
thalamocortical network. However, there is little clinical evidence to support the
cortical generator hypothesis. We present video-EEG recordings of generalized
tonic-clonic seizures in three patients with proven primary generalized epilepsy
(PGE), all of whom showed a consistent pattern of lateralized seizure onset
compatible with a focal frontal lobe generator. Methods : Among 300 patients
referred for video-EEG monitoring for intractable epilepsy, three were found to
have PGE with tonic-clonic convulsions. All had a positive family history for
epilepsy and no other epilepsy risk factors. Epilepsy onset was during adoles-
cence (2/3) or childhood (1/3). Patients were taking 1-4 antiepileptic drugs
(AEDs) at admission, none of which was valproic acid. Results : Interictal EEG
showed very active, bilaterally synchronous generalized spike-and-wave or
polyspike-and-wave discharges between 2.5-4.5 Hz, maximal over the midfron-
tal structures symetrically in all patients. Ictal EEG showed generalized rhythmic
activity without lateralization at seizure onset. Surprisingly, in all 6 recorded
tonic-clonic seizures there was a sustained (10-15 seconds), stereotyped, clini-
cal lateralization at onset, which took the form of a tonic “fencing posture” in one
patient (two seizures) and forced head/eye/torso version in two patients (four
seizures). Two patients became seizure-free shortly after switching to valproate
monotherapy. One patient refused valproate but has improved more than 90 %
with a change in AEDs to lamotrigine and phenobarbital (follow-up in all
patients > 18 months). Conclusions : Tonic-clonic seizures are presumed to be
generalized from onset in patients with PGE. However, video-EEG monitoring in
these patients is rarely performed and the actual clinical features of the seizures
Presented in part at the American may be underappreciated. The demonstration of sustained lateralization at onset
Epilepsy Society meeting, in our patients, with features clinically indistinguishable from focal onset frontal
December 2002, Seattle, WA, USA
lobe seizures, is compatible with the hypothesis of a focal region of cortical
hyperexcitability situated in the frontal lobes of some patients with PGE.
Correspondence: Whether this cortical generator is autonomous or “triggered” by ascending,
R. Wennberg, MD, FRCPC possibly normal, thalamocortical volleys is unresolved. [Published with video
Division of Neurology, Toronto Western
sequences].
Hospital
399 Bathurst Street, 5W444
Toronto, ON, Canada M5T 2S8
KEY WORDS: clinical semiology, juvenile myoclonic epilepsy, lateralization,
Tel : (416) 603-5402 primary generalized epilepsy
Fax : (416) 603-5768
E-mail : [email protected]

Epileptic Disorders Vol. 5, No. 3, September 2003 149

Casaubon, et al.

Primary generalized epilepsy (PGE; also idiopathic) is epilepsy. Previous investigations included normal mag-
characterized by seizures showing bilaterally synchro- netic resonance imaging (MRI) of the brain and routine
nous, generalized spike-and-wave activity recorded by EEG reported to show brief episodes of spike-and-wave
electro-encephalography (EEG) with clinical manifesta- activity with a possible left frontal predominance. Formal
tions including some, or all of, absences, myoclonic ab- neuropsychological testing revealed a superior intellect
sences and/or myoclonic jerks, and generalized tonic- and no lateralizing abnormalities. He had been treated
clonic seizures. Whether the cerebral cortex or subcortical with carbamazepine monotherapy for five years with
structures, specifically the thalamus, plays the dominant modest seizure control. On admission to the EMU, J.L. was
role in generating these seizures has been the subject of having 4-6 generalized tonic-clonic seizures per year,
long debate. Thalamic onset of generalized seizures was with increased frequency during periods of stress, and
originally hypothesized, supported by experimental ani- daily morning myoclonic jerks and myoclonic absences.
mal models of epilepsy and some human studies, and Patient 2. S.W. is a 47 year-old woman, whose seizure
provided the initial evidence that primary generalized disorder commenced during early childhood, consisting
seizures were the product of bilateral reciprocal connec- of generalized tonic-clonic seizures and occasional star-
tions between specific thalamic nuclei and a hyperexcit- ing spells. Her mother had rubella during pregnancy, and
able cortex. There is now mounting evidence to support a S.W. was born with significant hearing deficits requiring
focal cortical generator as the initiator of cortical hyperex- hearing aids. There is a questionable family history of
citability and generalized seizures [1, 2]. Reverberating epilepsy in a sister. S.W. was treated with phenytoin and
cortico-thalamo-cortical circuits, through thalamic struc- phenobarbital over many years and had a brief trial of
tures that have a propensity for rhythmic oscillations, valproic acid, which reportedly caused significant moodi-
allow for maintenance of spike-and-wave activity and ness and resulted in its discontinuation. Eventually, she
propagation of the seizure in a generalized fashion. How- was switched to carbamazepine prior to being monitored
ever, evidence for the exact nature and localization of a in the EMU. She was having 10-20 generalized tonic-
focal cortical generator is lacking. clonic seizures per year and up to 2-3 staring spells per
Very few patients with PGE undergo video-EEG monitor- day. During her hospital admission, a brain MRI revealed
ing, likely given the usual clarity of clinical diagnosis and some non-specific white matter changes suggestive of
generally excellent response to monotherapy with valp- microangiopathic disease but was otherwise normal. Neu-
roic acid, and the clinical features of generalized tonic- ropsychological testing revealed no lateralizing abnor-
clonic seizures in PGE are typically based on historical malities.
information alone. Whether these seizures truly have a Patient 3. M.M. is a 34 year-old woman with a 19-year
generalized onset or a focal onset that rapidly secondarily history of generalized tonic-clonic seizures. She also had
generalizes is therefore not clear. Some reports in the other ‘spells’ consisting of subjective dizziness and a
literature have provided evidence to support a focal clini- sensation of choking, peri-orbital swelling, and limb shak-
cal onset in some patients with PGE [3-5]. We report three ing lasting for 30-40 minutes. Over many years she had
patients who underwent video-EEG monitoring whose been tried on multiple AEDs, and was taking carbam-
ultimate diagnosis was PGE based on clinical and EEG azepine, phenobarbital, topiramate, and clobazam on
criteria; interestingly all six recorded generalized tonic- admission to the EMU. She was having up to one to two
clonic seizures commenced with definite lateralizing fea- generalized seizures and several other “spells” weekly. In
tures. hospital, brain MRI was normal and neuropsychological
testing showed above average intellect and no lateralizing
Methods and patients deficits.

From 300 patients referred to the Epilepsy Monitoring Unit

(EMU) at the Toronto Western Hospital, University of
Results
Toronto, for continuous video-EEG investigation of refrac- Interictal EEG showed very active bilaterally synchronous
tory epilepsy, three patients were found to have PGE with generalized spike-and-wave or polyspike-and-slow wave
tonic-clonic convulsions. Interictal and ictal EEG record- discharges between 2.5-4.5 Hz, maximal over the mid-
ings and the corresponding video sequences were re- frontal structures symmetrically in all patients with no
viewed. evidence of lateralized focality (figures 1, 2, and 3). Coher-
Patient 1. J.L. presented at 19 years of age with a five-year ence analyses [6] of the spike-and-wave activity showed
history of seizures, including generalized tonic-clonic sei- no hemispheric time leads (data not shown). Recorded
zures and brief episodes of staring with occasional bilat- clinical seizures in these three patients all demonstrated
eral, symmetric myoclonic jerks. He is the product of a definite, sustained (10-15 seconds), lateralized clinical
normal pregnancy and delivery, and early development features at onset.
was normal. From the history there is no account of febrile Patient 1. Video-EEG revealed one generalized tonic-
or childhood seizures; there is a strong family history of clonic seizure, the culmination of increasingly frequent,

150 Epileptic Disorders Vol. 5, No. 3, September 2003

 Clinical lateralization in generalized epilepsy

Figure 1. Interictal EEG of patient J.L. Sequential pages of the EEG showing generalized polyspike-and-wave activity associated with myoclonic
jerks (note Patient Event marker) just prior to the ictal event in Figure 2; referential longitudinal montage, t9-t10 averaged reference (all figures);
70 Hz high frequency filter (HFF), time constant (TC) = 0.3 sec.

symmetric, early morning myoclonic jerks and myoclonic The EEG demonstrated increasing bursts of generalized
absences. The generalized tonic-clonic seizure com- spike-and-wave and polyspike-and-wave activity leading
menced with a sustained forced head and eye version to up to the ictal event, which consisted of generalized,
the left with extension of the left arm, followed by a initially 3 Hz bilaterally synchronous and symmetric slow
symmetric tonic phase and then bilateral clonic activity wave activity, which increased in amplitude and fre-
(videosequence 1). quency to 3-5 Hz, and then was obscured by muscle

Epileptic Disorders Vol. 5, No. 3, September 2003 151

Casaubon, et al.

Figure 2. Patient J.L. Ictal EEG onset of the seizure in Videosequence 1; clinical seizure onset at*; 15 Hz HFF to highlight ictal pattern (obscured
by muscle artifact with 70 Hz HFF), TC = 0.3 sec.

artifact. Subsequently, the recording showed a clonic de- subsequent generalized tonic-clonic motor activity (vide-
recruiting response associated with clinical clonic seizure osequence 2).
activity, followed by ictal offset (figure 4). The EEG recordings during the clinically lateralized tonic-
A diagnosis of juvenile myoclonic epilepsy (JME) was clonic seizures showed ictal activity consisting of initially
made, and J.L. was changed from carbamazepine to valp- 3 Hz spike-and-wave activity that merged into lower am-
roic acid with complete cessation of his seizures and plitude faster activity and which ended with a clonic
morning myoclonus, now with over 18 months follow-up. de-recruiting response (figure 5).
Patient 2. Four separate clinical seizures were recorded. A diagnosis of PGE was made, and S.W. was changed to
The first was a typical absence seizure lasting several lamotrigine and phenobarbital with over 90 % seizure
seconds. The other seizures began with a definite reduction. S.W. has not agreed to retry valproic acid
head/eye/torso version to the right followed by a cry and therapy.

Figure 3. Interictal EEG of patient S.W. showing a typical generalized polyspike-and-wave discharge; 70 Hz HFF, TC = 0.3 sec.

152 Epileptic Disorders Vol. 5, No. 3, September 2003

 Clinical lateralization in generalized epilepsy

Figure 4. Patient S.W. Ictal EEG onset of the seizure in Videose- Figure 5. Interictal EEG of patient M.M. showing a typical general-
quence 2; clinical motor seizure onset at*; 15 Hz HFF, TC = 0.3 sec. ized spike-, and polyspike-and-wave discharge; 70 Hz HFF,
TC = 0.3 sec.

Patient 3. M.M. had one prolonged non-epileptic episode M.M. was taken off all of her admission medications
and two clinical epileptic seizures. The non-epileptic except phenobarbital and was started on valproic acid.
event lasted twenty minutes and entailed hyperventila- She has remained seizure-free (including her non-
tion, followed by trembling of the face and body and epileptic “spells”) for over one and a half years.
finally an arrhythmic shaking of all extremities. The fea-
tures fluctuated over time, and she was able to respond
appropriately to questions from her nurse during the event. Discussion
The clinical seizures both commenced with a forced head
version to the left followed by a leftward fencing posture. Generalized tonic-clonic seizures in primary generalized
The seizures evolved into generalized tonic-clonic motor epilepsy (PGE) are presumed to commence clinically and
activity, which at offset were briefly asymmetric involving electrographically in a bilaterally synchronous and sym-
unilateral clonic movements of the right face and arm metric fashion. The pathophysiologic substrate for these
(videosequence 3). seizures includes reciprocal connections between tha-
No EEG changes were recorded in association with the lamic and cortical neurons; connections that are normally
non-epileptic event. The ictal EEG for the epileptic sei- responsible for oscillating rhythms including sleep
zures showed a generalized, bilaterally synchronous and spindles [1]. At the cellular level, alterations in receptor
symmetric 4.5 Hz spike-and-wave activity with a bifrontal function in the thalamic nuclei have been postulated to be
maximum. The EEG evolved into 4 Hz sharp theta wave involved in the generation of abnormal synchronized
activity before becoming obscured by muscle artifact, rhythmic discharges [7] that correlate clinically with gen-
though at times an 8 Hz rhythmic epileptic discharge was eralized seizures in animal models of PGE. To elucidate
visible (figure 6). whether the initial rhythmic discharges of a generalized
A final diagnosis of PGE was made (as well as non- ictal electrographic event arise from the thalamus, several
epileptic events to account for her prolonged “spells”) and studies using depth electrode recordings within various

Epileptic Disorders Vol. 5, No. 3, September 2003 153

Casaubon, et al.

seizures, the latter likely a manifestation of seizure spread

to frontal lobe structures. Other well-defined lateralizing
features include ictal fencing posture [13], asymmetrical
tonic limb posture [14], contralateral ictal dystonia [15],
postictal nose rubbing [16, 17], and asymmetrical termi-
nating clonic jerks [18]. Focal features described in the
context of PGE are rare, though reports of circling or
versive seizures [19, 20], hemiconvulsive seizures [3] and
seizures with lateralized onset [5] have provided evidence
to support a focal seizure generator. Lateralized findings in
JME are more commonplace and both clinical, specifically
asymmetric myoclonus, and EEG asymmetries can be
noted in up to 30 % of patients in some series [4].
We show here six seizures with definite clinical lateraliza-
tion in three patients in whom a confident diagnosis of JME
(one patient) or PGE (two patients) was made. Our patients
have no focal structural, neuropsychological, or electro-
graphic abnormalities to account for the lateralized clini-
cal onset of tonic-clonic seizures and they meet all criteria
(including clinical and EEG features, family history, and
response to appropriate AED) for a diagnosis of PGE.
However, all of these seizures commenced with forced
head/eye/torso version or a tonic fencing posture clinically
indistinguishable from frontal lobe seizures. These fea-
tures support the existence of a focal cortical generator,
plus or minus a lateralized propagation preference, situ-
ated in the frontal lobes of such patients with PGE who
present with stereotyped lateralization at onset of clinical
Figure 6. Patient M.M. Ictal EEG onset of the seizure in Videose-
quence 3; clinical seizure onset at *; 15 Hz HFF, TC = 0.3 sec.
seizures, which may represent a region of functional hy-
perexcitability difficult to elucidate with current electro-
physiological or imaging techniques. A recent study using
focal magnetic transcranial stimulation demonstrated
thalamic nuclei compared with surface EEG recordings asymmetries in the motor thresholds in patients with PGE
have resulted in conflicting results. In 1941, Penfield and versive or circling seizures, although a consistent
proposed a “centrencephalic” hypothesis: using surface lateralization was not found [21]. It would be interesting to
EEG recordings with nasopharyngeal electrodes, Penfield know if ictal SPECT or interictal PET studies, unavailable
and Jasper concluded that the thalamus was the focus of in our patients, could demonstrate localized frontal lobe
“grand mal” (tonic-clonic) seizures based on phase rever- functional abnormalities in such patients. Newer tech-
sal of epileptiform discharges at the nasopharyngeal elec- niques including transcranial magnetic stimulation, func-
trodes [8]. Other studies have refuted this hypothesis, in tional MRI with simultaneous EEG recording, and sophis-
animal models of feline penicillin generalized epilepsy [9, ticated models of source imaging with
10] and in human depth electrode studies [11], showing magnetoencephalography combined with MRI may fur-
evidence for cortical initiation of generalized seizures. At ther clarify the unresolved questions regarding the origin
present, no definitive conclusion can be drawn as to the of primary generalized seizures.
anatomical and physiological origin of generalized sei- Future efforts to better understand the underlying neu-
zures in PGE though clearly an integral role exists for the roanatomical and pathophysiological nature of the gen-
reciprocal connections within the cortico-thalamo- erator(s) of primary generalized seizures may benefit from
cortical network in seizure propagation and maintenance a focus on patients with PGE who demonstrate clinical
[1]. features of lateralized seizure onset demonstrated with
Some clinical reports have provided evidence contrary to video-EEG monitoring. Based on previous evidence and
the postulated generalized onset of seizures in PGE, with our findings, the hypothesis of a hyperexcitable focal
either lateralized clinical features or with EEG asymme- cortical generator in some patients with PGE appears
tries [3-5]. Lateralized clinical features are very common feasible. Whether this cortical generator is truly autono-
in partial epilepsies. Forced head version prior to gener- mous or, alternatively, is “triggered” by ascending, possi-
alization lateralizes to the contralateral hemisphere [12] bly normal, thalamocortical volleys remains unre-
and is seen in both frontal lobe seizures and temporal lobe solved. M

154 Epileptic Disorders Vol. 5, No. 3, September 2003

 Clinical lateralization in generalized epilepsy

00:23 Leftward fencing posture (left arm tonic

Video-EEG caption extension and right arm flexed to right
above head), then clonic jerks of right
arm
Time 00:40 Tonic extension of all extremities fol-
sequence Clinical features lowed by bilateral clonic jerks
J.L. 01:11 End of clinical seizure with final clonic
00:00 Awake; lying supine on bed jerk in right arm
00:09 Start of bilateral limb myoclonus, ap- 01:25 End of video segment
pearing every 5-15 sec; then increasing
myoclonic jerks at 03:54
04:15 Raises right arm to adjust (lower) head of
bed; ongoing myoclonic jerks
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