Epileptic Disorders
MENUFrom hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation? Volume 5, issue 4, December 2003
Figures
Auteur(s) : Philippe Kahane1, Philippe Ryvlin2, Dominique Hoffmann3, Lorella Minotti1, and Alim Louis Benabid3
1. Neurophysiopathologie de l’Epilepsie, CHU de Grenoble
(France)
2. Neurologie fonctionnelle et Epileptologie & CERMEP,
CHU de Lyon (France)
3. Neurochirurgie & INSERM U318, CHU de Grenoble
(France)
Presented at the International Symposium on Hypothalamic Hamartoma and Epilepsy, Montreal Neurological Institute, Montreal, Canada, November 29th 2001.
In patients suffering from the epileptic syndrome associated
with hypothalamic hamartoma (HH) [1], there is now strong evidence
that resection or disconnection of HH, as well as radiofrequency
thermocoagulation or gamma knife radiosurgery, may lead to complete
seizure control, and to improvement of behavioural disturbances
[2-14]. Thanks to neurosurgical advances, these therapeutic options
are now associated with limited morbidity which, together with
recent electrophysiological and functional neuroimaging findings,
make surgical treatment a reasonable choice when compared with the
relatively severe evolution of medically-treated HH associated
epilepsy [1, 15].
A few years ago, however, the pathophysiology of this puzzling
syndrome was poorly understood. Though some authors had discussed
the possible role of the hamartoma in generating
gelastic – or more rarely dacrystic – seizures
[16], evidence was lacking. In fact, the electro-clinical
presentation of the syndrome corresponded to that of a symptomatic
generalised epileptic encephalopathy in many patients, with
multiple seizure types, diffuse interictal scalp-EEG epileptiform
abnormalities, progressive intellectual decline, frequent
behavioural problems, and poor response to antiepileptic drugs [1,
15]. The relation between these diffuse abnormalities and the
hypothalamic lesion remained elusive, in as much as isolated
laughing (or crying) attacks, the hallmark feature of the syndrome,
were not associated with any convincing concurrent scalp-EEG
changes. In other patients, surface and intracranial EEG data
suggested a temporal or a frontal lobe ictal onset, but resections
of these regions consistently failed at reducing seizure frequency,
while corpus callosum section only seemed to reduce the number of
drop attacks in some patients [17].
At the beginning of the 90’, stereotactic intracerebral EEG (SEEG)
recordings showed for the first time that gelastic seizures [18] as
well as dacrystic attacks [19] correlated with ictal discharges
confined to the hamartoma. SEEG recordings and stimulations in a
few additional patients have confirmed this intrinsic HH
epileptogenicity [5, 20], which was subsequently corroborated by
ictal SPECT findings [5, 11, 21, 22] and magnetic resonance
spectroscopy data [23]. However, Munari and coworkers emphasized
that the other associated seizure types (i.e. without laughing or
crying component) did not arise from the hypothalamic mass but
originated in various cortical areas, thus suggesting that these
seizures might result from secondary epileptogenesis [18-20].
To date, five patients suffering from drug-resistant seizures
associated with a hypothalamic hamartoma have underwent a SEEG
study at our institution. Some of these observations have been
published elsewhere [18, 20, 24, 25], and we report here the main
electro-clinical features of all five cases, focusing our attention
on the relationships between the different seizure types, the
hamartoma, and the cortex.
Patients and methods
Population studied
All pertinent clinical data are presented in Tables 1 and 2.
The five patients, one of whom had a Pallister-Hall syndrome, were
suffering from a childhood onset long-lasting medically intractable
epilepsy. All patients experienced gelastic and/or dacrystic
attacks, whereas four of them also presented other seizure
types.
MRI showed an intra-hypothalamic mass in all cases (see figures 3 and 10), the
characteristics of which corresponded to those described as type
IIb’ by Valdueza et al. [4]. The hamartoma was predominantly
lateralized to the right side in three patients, to the left side
in one, and non-lateralized in the remaining patient.
Interictal scalp-EEG recordings showed diffuse abnormalities in
most patients (figure 1).
Interestingly, these abnormalities predominated on the side
ipsilateral to the hamartoma in the four patients where the latter
clearly showed a side predominance. Ictal scalp-EEG proved
inconclusive during gelastic and/or dacrystic seizures which were
recorded in all but one patient (figure 2A).
Conversely, asymmetric bilateral EEG changes were observed at ictal
onset during the other seizure types also recorded in four of the
five patients (figure 2B). As for
interictal EEG abnormalities, the lateralization of ictal discharge
were ipsilateral to the predominating side of HH.
Table 1. General characteristics.
Pts (sex) | Age at SEEG | G/D szrs (onset) | Other szrs (onset) | Seizure frequency | PP (onset) | Clinical exam | Cognitive decline | AEDs at SEEG |
---|---|---|---|---|---|---|---|---|
1 (F) | 16 yrs | G (30 mths) | + (14 yrs) | > 5/day | – | small height | moderate | CBZ-GVG-CLB |
2 (F) | 19 yrs | D + / – G (10 yrs) | + (5 yrs) | > 1/day | + (5 yrs) | obesity | moderate | CBZ-PHT-CLB |
3 (M) | 27 yrs | G- > D (2 yrs) | + (5 mths) | 1-5/day | – | normal | mild | CBZ-PHT-GVG-PB-CLB |
4 (M) | 12 yrs | G (< 1 yr) | > 5/day | – | normal | mild | CBZ | |
5 (F) | 30 yrs | G (infancy) | + (13 yrs) | 30/mth | – | polydactyly | none | CBZ-CLB |
Table 2. Video-EEG monitoring.
Pts | Interictal findings | Gelastic/dacrystic seizures | Other types of seizures | ||
---|---|---|---|---|---|
EEG | semiology | EEG | Semiology | ||
1 | bursts of diffuse PSp and long-lasting sequences of bilat Sp & SpW | diffuse flattening | smiling and/or laughing | biF low-voltage fast activity | backward fall, contraction of the mouth corners, R eyes deviation, R arm hypertonia ± R or L head turning |
2 | bursts of diffuse PSp and R F-C PSp | delayed R F SW | crying ± preceded by an epigastric sensation | bilat (R > L) high-voltage fast activity | Staring, eyes blinking, flushing, swallowing ± preceded by a thoracic warm, auditory illusions, dizziness and pain in the L leg |
R F-C-T low-voltage fast activity | same as above, followed by bradycardia, R eyes deviation, L facial contraction, bilat (L > R) hypertonia, moaning, fall | ||||
3 | bursts of diffuse PSp | R anterior flattening | laughing leading to crying ± preceded by an epigastric sensation | bilat (R > L) high-voltage fast activity | sudden fall ± preceded by R oculocephalic deviation; possible secondary tonic-clonic generalisation |
4 | L hemispheric multifocal SW & Sp | L T-F-C-P theta activity | indefinable aura, flushing, laughing, gesticulating, R arm dystonia ± R body rotation; possible R hemibody hypertonia |
– |
– |
5 | R T-P SW & Sp | not recorded | cephalic sensation or pressure to laugh ± laughing, rarely déjà-vécu’ at onset | biT(-P) flattening (R > L) | eyes blinking, swallowing, gestural automatisms, L oculocephalic deviation |
SEEG procedure
Intracerebral EEG recordings were performed in the first four
patients with the aim to provide a three-dimensional assessment of
the epileptogenic network, and to precisely define the
relationships between the latter and the hamartoma. Thus, the
stereotactic placement of the intracerebral electrodes, as well as
their total number (n = 11 to 13), varied from one
patient to another one depending on the suspected origin and areas
of early seizure spread, but always targeted the HH (figure 3). Electrodes
were 0.8 mm in diameter and included 5, 10, or 15 leads
2 mm in length, 1.5 mm apart (Dixi, Besançon, France),
depending on the intra-cerebral target. Such multileads electrodes
allow to investigate all the structures crossed along their
trajectory, including the mesial and lateral aspects of the
different lobes, but also fissural cortices, as well as the
hamartoma.
In the fifth patient (no 5), intracerebral EEG
recordings were conducted as part of a therapeutic procedure aiming
at chronically stimulate the HH. The rationale of this therapeutic
approach was based on our previous findings regarding the
intrinsic epileptogenicity of hypothalamic hamartoma, on the
potential benefit of chronic high frequency stimulation of the
epileptogenic zone as suggested by the Velasco’s group in temporal
lobe epilepsy patients, on the safety of deep brain stimulation in
patients with movement disorders, and on the possible reversibility
of the procedure. The hamartoma was investigated using three
4-leads deep-brain stimulation electrodes (Medtronic DBS lead 3389,
four contacts 1.27 mm in diameter, 1.5 mm long, space by
0.5 mm) in order to sample the entire hypothalamic lesion (see
figure 10).
In this patient, intra-cortical EEG recordings were not performed,
but scalp-EEG was recorded together with HH in order to provide
information on the cortical EEG activity.
Intracerebral recordings and stimulation
In all patients, concurrent video and intracerebral EEG were monitored for 7 to 23 days (Biomedical Monitoring System, Campbell, CA, USA; and since 1996, Micromed, Treviso, Italy). We used as a reference, one of the lead located in the white matter in four patients, and the Cz scalp-EEG electrode in patient no 5. Depth EEG activity was displayed using bipolar montage between contiguous contacts. Electrical stimulations were performed under continuous video-EEG control, during sessions that last one to three hours. According to our standard clinical practice [26], and validated safety parameters [27], stimulations were performed between contiguous leads at 1 Hz (pulse width = 3 ms) and 50 Hz (pulse width = 1 ms), using a constant current rectangular pulse generator (World Precision Instruments, New Haven, CT, USA; and since 1996, Micromed, Treviso, Italy). Chronic stimulation in patient n° 5 was applied according to the parameters used in movement disorders.
Results
The main depth EEG findings are summarized in Table 3.
Interictal SEEG findings
As expected from scalp-EEG recordings, spikes and spike-and-waves discharges were recorded in the cortex in the four patients in whom cortical recordings were available. These paroxysmal discharges, though widely extensive, were usually not recorded within the hamartoma (figure 4). Conversely, the latter usually exhibited independent well-localized spikes or spike-and-waves (see also figure 10), the frequency and amplitude of which varied from one patient to another. In one patient (no 4), however, the lesion HH was almost electrically silent, without any detectable paroxysmal discharge. Interestingly, in one patient (no 2), HH spikes were influenced by sleep, where they became continuous, but disappeared during short bursts of spindle-like’ activity of unclear significance, located in the hippocampus and the amygdala (figure 5).
Table 3. SEEG findings,
surgery and outcome.
Pts | interictal spikes | spontaneous seizures | electrically-induced seizures | surgery | outcome (follow-up) | |||
---|---|---|---|---|---|---|---|---|
HH | cortex | G/D | other types | G/D | other types | |||
1 | + | + | HH | biF | HH | – | stereotactic radiosurgery (2) | no change (4) (6 years) |
2 | + | + | HH | R F-C-T | HH | – | partial removal of the HH (3) | mild improvement (5 years) |
3 | + | + | HH | R F ? | – | – | – | no change (9 years) |
4 | - | + | ? (CG ?) | - | A (Hc) | - | L temporal lobectomy | no change (9 years) |
5 | + | not recorded | not recorded | not recorded | HH | – (1) | chronic HFS of the HH | No change (3 years) |
Gelastic and dacrystic seizures
Three of the four patients in whom gelastic or dacrystic
seizures were recorded demonstrated a concurrent low voltage fast
activity, followed by a spike-and-waves discharge which remained
confined to the hamartoma (figure 6A). One of
these patients (no 2) also presented many such HH
ictal discharges during sleep, which remained clinically silent
(figure 7A).
In all three patients, the HH discharges were associated with a
diffuse flattening of the cortical EEG activity and a disappearance
of interictal abnormalities. Subtle cortical changes (fast activity
and/or rythmic slow waves or spikes) were latter observed over the
two cingulate gyri in patient no 1, the right
fronto-centro-temporal region in patient no 2, or
the right orbito-cingulate cortex in patient
no 3.
In contrast, patient no 4 showed an ictal
discharge which predominated at the cortical level, with a diffuse
flattening of EEG activity associated with a marked low voltage
fast activity over the left cingulate gyrus, and to a lesser
degree, the left hippocampus, whereas only subtle changes were
recorded in the hamartoma.
Other seizure types
The three patients in whom other types of seizure were recorded
showed that the latter were associated with cortical ictal
discharges not affecting the HH (see figure 6B). In patient
no 2, similar cortical ictal discharges were also
recorded during sleep (see figure 7B), but proved
clinically silent.
Ictal onset appeared either bifrontal (patient
no 1), right fronto-central and lateral temporal
(patient no 2), or bifrontal with a right side
predominance (patient no 3). The lateralization of
these ictal discharges was always ipsilateral to the predominating
side of the hamartoma.
Interestingly, ictal discharges involved the cingulate gyrus in all three patients, as well as the regions which showed subtle depth EEG changes during gelastic/dacrystic seizures. In fact, the latter could precede the other seizure types, suggesting a causal relationship between the two (figure 9).
Electrical stimulations
Acute stimulation of the hamartoma and the cortex
Acute stimulation of the hamartoma could reproduce gelastic or
dacrystic seizures in three of the five patients, when using high
frequency parameters (50 Hz), but in only one patient when
stimulating at 1 Hz. These stimulation-induced HH seizures
were always associated with an epigastric sensation, which was
recognized as being part of the dacrystic attacks in one patient
(no 2). Other symptoms could also be induced in
patient no 5, the type of which varied depending on
the part of HH which was stimulated (figure 10).
Conversely, cortical stimulations, performed in two of the three
patients with stimulation-induced HH seizures, failed to elicit any
ictal discharge or symptom.
In one of the two patients without electrically-induced HH
seizure, the stimulation of the hamartoma induced an unknown
sensation of warmth over the face (no 3). In the
other patient (no 4), stimulation of the amygdala
could reproduce his usual and complex gelastic seizures, whereas
hippocampal stimulation elicited comparable episodes but which
lacked their laughing component. However, the left temporal
lobectomy performed in this patient failed to control these
seizures.
Chronic stimulation of the hamartoma
In patient no 5, the implantation of three
intra-hamartoma electrodes was designed to chronically stimulate
the HH.
The patient first underwent subacute stimulation
(130 Hz-100 µs – 0.4 mA) during depth-EEG
monitoring in order to evaluate the tolerability as well as the
impact of the stimulation on the HH firing pattern. Interictal
spikes recorded from the hamartoma and from scalp-EEG, almost
totally disappeared during the stimulation, and reappeared when the
stimulation was interrupted (figure 11). No side
effect was reported.
These findings encouraged us to pursue with chronic stimulation
which was started in November 1999. We initially decided to
stimulate all the leads of the three electrodes, simultaneously,
using the following parameters: 130 Hz/90 µs/0.5V, and
then 185 Hz/60 µs/0.1V. The patient progressively
complained of increasingly frequent cephalic auras and pressure to
laugh (up to 30 per day), as well as from weight gain (from
63 kgs to 68 kgs during a 84 days period), leading
us to stop the stimulation. The latter was resumed five months
later, by only stimulating the electrode contact which had been
stimulated during the subacute stimulation protocol. Seizure
frequency, as well as seizure type, were not clearly modified over
a 12 months period during which stimulation was alternatively
turned off and on (figure 12), while the
patient reported frequent headaches and a weight gain from
66 kgs to 72 kgs. Stimulation was then definitively
stopped, allowing the weight to progressively return to 61 kgs
during the following months.
Discussion
In this study, we have clearly demonstrated that epileptic
seizures associated with hypothalamic hamartoma could exhibit
different types of electroclinical patterns. During the most
typical seizures, i.e., laughing and crying episodes, the epileptic
discharges usually arose and remained confined within the
hamartoma. In addition, interictal spikes were recorded from the
hamartoma in the majority of patients, whereas the stimulation of
the HH could reproduce gelastic or dacrystic seizures, as observed
by others [5]. These findings, corroborated by the results of ictal
SPECT which showed increased blood flow changes from the
hypothalamic region during gelastic seizures [5, 11, 21, 22],
strongly support the intrinsic epileptogenicity of hypothalamic
hamartomas, in as much as its removal, disconnection, irradiation,
or coagulation can control the seizures [2-14]. These findings are
reminiscent of the observation that patients suffering from
hemifacial spasms and cerebellar gangliogliomas demonstrate ictal
discharges originating in the vincinity of the tumor, which removal
results in seizure remission [28-30].
However, the HH of one of our patient failed to demonstrate spikes
or either spontaneous or electrically-induced seizures, raising the
issue of other ictal onset sites responsible for gelastic seizures.
However, the limited number of intra-hamartoma recording leads, as
compared to the size of the HH, could also explained our negative
findings in that patient. This possibility was well-illustrated in
another patient where three 4-leads electrodes were placed within
the hamartoma, showing differences in electrically-induced clinical
symptoms from one part of the HH to another (see figure 10).
Alternatively, both interictal and ictal EEG findings could be
consistent with the view that this patients’ gelastic seizures
arose from the cortex. Accordingly, the associated ictal semiology
was more rich and complex than that observed during laughing
attacks in the three previous patients.
If it is now well-established that gelastic and dacrystic
seizures usually originate from the hamartoma itself [31], the
pathogenesis of the epileptic syndrome associated with HH is far
from being fully understood. Particularly, the almost constant
occurrence of seizures other than gelastic/dacrystic episodes
remains puzzling, in as much as they seem to arise from various
cortical areas the removal of which has consistently failed to
control the epilepsy. We have no clear explanation for the
mechanisms underlying these seizures, but several arguments support
the hypothesis of secondary epileptogenesis. First, the epilepsy
associated with HH usually starts with gelastic seizures, while the
other seizure types will tend to occur later during the evolution
of the ilness. Second, scalp-EEG interictal epileptiform
abnormalities, which proved to be independent from those recorded
in the hamartoma, usually worsen with time, particularly when
non-gelastic seizures develop [21]. Third, we observed that the
laughing or crying attacks were sometimes immediately followed by
the other seizure types, as if ictal discharges within the
hamartoma triggered those which seemed to originate in the cortex.
Last but not least, data from various centres show that resection
of HH, when fully achieved, can control all seizure types.
Secondary epileptogenesis in HH have also been suggested by others
[32]. This phenomenon could occur as a consequence of repetitive
intra-hamartoma ictal discharges, affecting neighbouring structures
involved in the neuromodulation of cortical activity. In that
respect, we propose a speculative pathophysiology in which the
mamillo-thalamo-cingulate tract would serve as a relay of HH
discharges towards the cortex, the excitability of which would then
progressively increase, first leading to interictal epileptiform
abnormalities and then to seizures (figure 13). This view
is supported by the following observations: i) cortical discharges
do not seem to occur randomly in the cortex, as showed by the
lateralization of scalp EEG abnormalities and intracranially
recorded seizures, which proved always ipsilateral to the lesion in
those of our patients in whom the hamartoma demonstrated a side
predominance; a similar concordance in lateralization was also
found between interictal hypometabolism on 18FDG-PET and
HH (Ryvlin et al., this issue); ii) hypothalamic hamartomas
which give rise to epileptic seizures are located within the
hypothalamus with tight connections with the mamillary bodies [4,
33, 34]; iii) ictal SPECT findings during gelastic seizures have
showed that thalamic hyperperfusion could coexist with that
observed in the HH [5], whereas thalamic hypometabolism,
ipsilateral to HH, was demonstrated by interictal
18FDG-PET [Ryvlin et al., this issue]; iv) the
cingulate gyrus was consistently involved during non-gelastic
seizures in this series.
Whether this proposal is valid or not remains a very important
issue, since it could provide arguments on the moment to discuss
surgery (e.g., worsening of interictal EEG abnormalities,
appearance of seizures other than gelastic/dacrystic, behavioral
problems) in order to prevent the development of a definite
secondary epileptogenesis. It seems likely that this latter, once
established, makes more aleatory the effectiveness of the lesion
elimination on both kind of seizures. n