Epileptic Disorders
MENUThe treatment of patients with hypothalamic hamartomas, epilepsy and behavioural abnormalities: facts and hypotheses Volume 5, numéro 4, December 2003
Illustrations
Auteur(s) : André Palmini, Eliseu Paglioli-Neto, Jose Montes*, Jean-Paul Farmer*
From the Porto Alegre Epilepsy Surgery Program, Hospital São Lucas da PUCRS, Porto Alegre, Brazil; * Department of Neurology and Neurosurgery, Montreal Children’s Hospital, McGill University, Montreal, Canada
Presented at the International Symposium on Hypothalamic Hamartoma and Epilepsy, Montreal Neurological Institute, Montreal, Canada, November 29th 2001.
Patients with HH have been recognized for a long time, and are now identified by magnetic resonance imaging (MRI) [1-3]. The most common scenario is that of a child or adolescent with gelastic and other types of partial and generalized seizures and variable degrees of cognitive and behaviour abnormalities, whose evaluation shows the characteristic diencephalic lesion. Gelastic attacks are not specific to patients with HH, and can also occur in partial epilepsies originating from temporal or frontal lobe regions [4, 5]. However, sudden attacks of mechanical laughter’ in children or adolescents with cognitive and behavioural impairment should prompt a search for a HH [2, 3, 5-8].
The clinical spectrum of manifestations associated with HH has
been enlarged considerably since the initial reports on the
syndrome [3]. A group of patients with HH and precocious puberty
but who do not have epilepsy, or who have only rare seizures [9-11]
has been recognized. Recent reports also describe patients with
mild epilepsy characterized by a pressure to laugh’ and other
partial seizures, easily controlled by antiepileptic drugs (AEDs)
[12]. Another category includes patients with a somewhat more
severe epileptic disorder characterized by gelastic, partial and
generalized seizures, who do not have a catastrophic course and
whose seizures may be, at least partially, responsive to AEDs
[13-15]. The need to devise therapeutic options for children and
adolescents who have gelastic and other, much more malignant
partial and generalized seizure types, and in addition present with
progressive cognitive and behavioural abnormalities [16-18] remains
essential. We have recently suggested that the high seizure
frequency and the severity of the associated behavioural and
cognitive decline should prompt the inclusion of this form of
presentation of the HH syndrome in the group of the surgically
remediable, catastrophic epilepsies of childhood [16], in which
extremely frequent seizures, related to destructive, malformative
or inflammatory disorders, are responsible for a progressive
encephalopathy with delays or arrests of development, cognition,
motor function and behaviour [17-19]. Mechanisms of plasticity
cannot drive functional compensation unless the lesion is resected.
Such catastrophic syndromes are now regarded as surgically
remediable [20], and several lines of evidence suggest that the
earlier the surgical intervention to control the seizures and to
remove the continuous epileptic activity, the better the final
developmental outcome [21]. We believe that the most severe forms
of the syndrome of HH and refractory seizures should be regarded as
a form of ‘non-hemispheric’, surgically remediable, catastrophic
epilepsy [16]. Since recognition of a catastrophic epilepsy of
childhood is a call to neurological and neurosurgical action,
patients with HH and intractable seizures should be managed without
undue delay, by specialized epilepsy care units.
We will further discuss the medical and surgical management of
patients with HH and epilepsy, emphasising the rationale for
selection of specific surgical strategies to remove the lesion in
patients with catastrophic epilepsy. The discussion will evolve
from the milder to the more severe forms, addressing AEDs and
psychopharmacological management, yet concentrating upon surgical
strategies.
Hypothalamic hamartoma, epilepsy, and behavioural abnormalities: medical management
Patients with HH and epilepsy whose seizures are reasonably well
controlled with AEDs or that do not have a catastrophic evolution
have been reported [12-15, 22]. These are usually adult patients
with gelastic and complex partial seizures beginning in childhood,
without progression to symptomatic generalized epilepsy. Sturm
et al. [12] reported on three patients who had ‘pressure to
laugh’ and other partial seizure types. Complex partial and simple
motor seizures remained reasonably well controlled with
carbamazepine and/or lamotrigine; generalized seizures were not an
issue, and only the episodes of ‘pressure to laugh’ (‘embryonic’
forms of gelastic seizures) were refractory to medication,
recurring many times a day. The common denominators in these
patients were (i) the presence of very small (about 0.5 mm)
hypothalamic hamartomas; (ii) normal interictal and ictal EEGs; and
(iii) normal development and behaviour. Other authors also report
on patients who have medically refractory gelastic and complex
partial seizures, however in these patients, AEDs significantly
reduce seizure frequency to a point that many can lead reasonably
normal lives [13, 14]; [Palmini et al. unpublished
observations].
Still other patients may have a transient, favourable response to
AEDs, but eventually become refractory and may progress to a more
severe form of epilepsy. We have recently re-examined a
4 year-old girl referred to us with a 1.2 cm HH and
delayed language development. She started with giggling attacks
during infancy, and evolved with complex partial and head dropping
attacks, which were reasonably well controlled with carbamazepine
until age 3. However, seizures recurred and she now has gelastic,
complex partial and head dropping seizures daily, despite high
dosages of carmabamazepine and clobazam. The interictal EEG during
the period in which she had mild, weekly attacks on carbamazepine
monotherapy is shown in figure 1. It is
possible that the delayed language development and the markedly
abnormal EEG predicted worsening of the epileptic picture with
time. We suggested that valproic acid be added to the AED regimen
and discussed the surgical alternative at length.
There are no studies specifically addressing the issue of AED
management in patients with HH. The choice of medication should be
tailored to the type of seizures, EEG abnormalities, and severity
of the condition in individual patients along the clinical spectrum
mentioned above. However, patients may move along the spectrum of
severity of the disorder, and the need for a dynamic view to
management should be kept in mind. Thus, in patients with only
gelastic and focal motor or complex partial seizures, associated
with predominantly focal EEG abnormalities, AEDs with proven
efficacy in partial and secondarily generalized seizures like
carbamazepine and lamotrigine may be appropriate choices, as well
as other drugs with similar pharmacodynamics (eg., phenytoin,
oxcarbazepine). Clobazam or clonazepam may be added in patients
with only partial response. In contrast, in patients presenting
with a symptomatic generalized epilepsy [3, 17, 18, 23], medical
management should aim to control tonic, tonic-clonic and atonic
seizures, including drop attacks [13]. EEG abnormalities are
usually more severe, with generalized, irregular slow spike and
wave complexes [17, 18, 23, 24]. Valproic acid, clonazepam,
nitrazepam, and topiramate are the AEDs that should be considered,
in variable associations with other drugs. However, the need for a
combination of drugs should not progressively lead to an irrational
polytherapy.
The management of the behavioural abnormalities in patients with
HH has also not been specifically addressed. The use of typical or
atypical neuroleptics complemented, as needed, by trazodone or
lithium has been our basic approach. Several of the AEDs used by
these patients could have a favourable impact on behaviour, but the
usually poor medical control of the aggressiveness attests to the
general medical intractability of the catastrophic side of the
syndrome.
Hypothalamic hamartoma and epilepsy: surgery not directed at the hamartoma
Seizure semiology, as well as scalp EEG, depth EEG from cortical regions, and metabolic (fluoro-deoxy-glucose [FDG]-PET) studies have suggested that seizures in patients with HH may result from associated cortical abnormalities. Focal cortical hypometabolism in PET and focal cortical seizure onsets recorded by intracranial EEG [25] have suggested that the main generators were indeed in the cortex. However, cortical resections targeted at these sites have uniformly failed [25-27].
Munari [26], Kahane [27] and colleagues have shown that different types of seizures in patients with HH originated from different regions of the brain. Using stereo-EEG, they inserted depth electrodes in both cortical and hypothalamic targets, and showed that gelastic attacks indeed originated from the hamartoma, while generalized tonic seizures, potentially leading to drop attacks, had a multifocal neocortical onset. Nonetheless, in these and other patients [16, 24, 27-29], a sizable resection, destruction or disconnection of the HH led to complete or very significant alleviationof these major attacks, demonstrated to originate from neocortical sites. Thus, seizures in patients with HH and epilepsy either originate in the HH [26, 27, 29] or originate in cortical structures but have a close pathogenetic relationship to the diencephalic lesion [26, 27]. These latter seizures, when refractory, have been proven to be controlled only through resection, destruction or disconnection of the hamartoma. Why should resection of the subcortical lesion alleviate generalized attacks, demonstrated to originate in the cortex, is not clear. In all likelihood, mechanisms of secondary epileptogenesis are involved. It has been hypothesized that the cortical regions generating seizures in patients with HH are in a “dependent phase of secondary epileptogenesis”, as suggested by Morrell for bitemporal foci [17, 18, 30]. This hypothesis could also explain why some patients do not improve even after removal of the hamartoma, in that dependency versus independency of the cortical focus from the primary hypothalamic lesion may hold the key to surgical success following resection of the lesion.
Hypothalamic hamartoma and epilepsy: surgical results when targeting the lesion
Several lines of evidence have converged to modify the concepts
involved in the surgical management of patients with catastrophic
epilepsies and HH. The momentum for the change was kindled by the
disappointing results obtained with cortical resections [25] and
also by reports appearing in the early 90s demonstrating that
favourable results could be obtained with resection of the
subcortical lesion [9, 31,32]. However, greater interest for the
lesional approach followed the demonstration by depth EEG and ictal
SPECT that gelastic attacks originated in the HH [ 16, 26, 27, 29,
33 ]. Thus, the surgical strategy for patients with HH became
the resection, destruction or disconnection of the lesion, and
several reports on series of patients treated this way are
available [16, 24, 34-36].
We and others have recently reported on 13 patients followed
for many years, in whom the HH was resected through the pterional
or subfrontal route [16]. They all had severe epilepsy, cognitive
impairment and behavioural abnormalities. On the basis of pre- and
post-operative MRI, lesion removal was rated as total in two
patients, subtotal in seven, and partial in four. Eight of the nine
patients (88%) in whom complete or subtotal resection of the
hamartoma was feasible had a complete or greater than 90% control
of the major generalized tonic-clonic seizures or drop attacks,
while none of the four who had only a partial resection had a good
result. Five patients were re-operated upon, two of whom had
additional resection of the lesion, and the other three had
alternative procedures, including a stereotactic lesion of the
mammillo-thalamic tract, gamma-knife surgery or implantation of a
vagus nerve stimulator. Those patients having additional resection
of the lesion and the one with interruption of the
mammillo-thalamic tract had significant, additional improvement.
Taking into account both the first and second surgical procedures,
11 of the 13 patients (84%) were either seizure-free or
had a greater than 90% reduction in the frequency of major
debilitating attacks. Minor attacks, including gelastic and complex
partial seizures persisted in most patients although with reduced
frequency. Even though only two patients were free of all seizure
types, the gains related to the control of the severe attacks
(generalized and drop) had a major impact on the quality of life.
In addition, all 13 patients had a most significant
improvement in behaviour and cognition as rated by parents and
teachers. Occasionally, aggressive or hyperactive behaviour
persisted to a minor degree, but this was still compatible with
productive relationships with family and peers. Post-operatively,
three patients had an anterior thalamic and one a capsular infarct,
which left only minimal long-term deficits. Despite a favourable
outcome, this rate of surgical complications attest to the delicate
balance involved in the decision to operate on these patients.
Lesion location, in relation to the interpeduncular fossa and to
the walls of the third ventricle, correlated with the extent of
excision, seizure control and complication rate. Resection was more
extensive with a lower rate of complications when the lesion
extended into the interpeduncular fossa, in comparison to patients
in whom the hamartoma was fully contained within the
hypothalamus.
Since the completion of that study [16], we have operated upon
several additional patients, taking into account the lessons
learned from the original retrospective series and also the
technical proposition by Rosenfeld et al. [24],
demonstrating that the HH could be effectively approached by a
transcallosal, interforniceal route (that is, from above’, instead
of from below’; see also Harvey et al. in this issue). The
rationale for the choice of the resective strategy is discussed
thereafter. The merits and difficulties involved with gamma-knife
surgery [35], complete surgical disconnection of the lesion [28,
36], as well as with stereotactic thermocoagulation or
radiofrequency ablations [24, 29, 37], are reviewed elsewhere in
this issue.
Choosing the direct operative approach: ‘from above or from below’?
Size and location of the hamartomatous lesion may help decide the type of direct surgical approach. When the HH is small, surgical difficulties relate to the preservation of surrounding hypothalamic structures, which have not been displaced by the lesion. Internal decompression of the lesion does not provide a safe surgical corridor’. Many delicate arteries surround the hamartoma and should be dissected and preserved. When the lesion is too large, it may displace the hypothalamus, blurring the boundaries between the lesion and the normal structures. The location of the lesion in regard to the hypothalamus, the interpeduncular cistern, and the third ventricle is another important issue. When discussing surgical strategy, we refer to the anatomical plane at the level of the optic tracts as a dividing line: when the hamartoma is above this plane, we find it difficult to perform a sizable resection through the pterional route, and these lesions probably should be approached “from above”, preferably through Rosenfeld and Harvey’s transcallosal – interforniceal route [24] (figure 2). In contrast, we think that hamartomas predominantly located below the level of the optic tracts are better approached through the pterional route (that is, “from below”), which offers a more direct view of the lesion (figures 3 and 4).
Surgical treatment of HH and epilepsy: what more do we need to know?
Despite recently accumulated knowledge, several issues still
need clarification. One point is why subtotal or apparently
complete resection of the lesion may have a greater impact on the
major seizures than on the minor attacks. It is possible that minor
gelastic and complex partial seizures would still occur if any
amount of hamartomatous tissue is left in place, which is a common
occurrence in the face of the lack of a clear anatomical plane
between the hamartoma and the surrounding hypothalamic tissue.
Furthermore, we do not know why some patients reported in
different series fail to improve despite similar extents of
resection. Extent of resection or disconnection is a major
determinant of the surgical outcome, and limited resections could
explain less satisfactory results in some patients [2, 13,
21 ]. However, this is apparently not a universal explanation,
as illustrated by at least two cases. Pascual-Castroviejo et
al. recently reported a 24 year-old man [38] who had the
classical picture of catastrophic epilepsy related to HH:
refractory partial and generalized seizures, cognitive
deterioration and behavioural abnormalities. Their figure 3 depicts only a
modest resection of the anterior portion of the HH, in spite of
which the patient is completely seizure-free, much improved from
behavioural and cognitive standpoints, and close to complete AED
withdrawal. A 12 year-old girl whom we evaluated and operated
upon twice illustrates the opposite situation. When first seen, she
had a catastrophic picture, characterized by intense aggressiveness
and impulsive behaviour, prolonged trains of generalized slow spike
and wave complexes associated with mental clouding, as well as
frequent falls and generalized tonic-clonic seizures. Gelastic
attacks represented the least of her problems. The hamartoma and
the MRI pictures of the two operations are illustrated in figure 5. The
lesion was initially approached through a
transcallosal-interforniceal route, with attempts to spare the
mammillary body (figure 5b). She had an
excellent course for a few weeks, being seizure-free and much more
alert. Seizures gradually returned to the preoperative frequency,
and she was evaluated again a year later in view of another
operation. MRI showed that resection had been almost complete,
except for the ipsilateral mammillary body (figure 5b). We
hypothesized that the transitory improvement after the first
resection was due to post-operative swelling, functionally
interrupting the spread of epileptic activity through the
mammillo-thalamic tract. Once the swelling subsided, ictal activity
originating (probably) within the mammillary body could have led to
seizure recurrence. We then resected the mammillary body through a
pterional route (figure 5c) and
obtained a remarkable control of seizures and behavioural
improvement in the first month after operation. However, exactly as
after the first procedure, seizures and behaviour progressively
deteriorated again after the first post-operative month. Cognitive
problems and aggressive behaviour persisted, and improvement was
obtained some months later after the institution of a ketogenic
diet. Since the hamartoma was apparently entirely resected (figure 5c), we
can speculate that in some patients with HH, the neurobiology of
the epilepsy and the behaviour abnormalities transcends the
anatomic boundaries of the lesion. We do not know whether such
patients develop an independent stage of secondary cortical
epileptogenesis [17, 18] or if something else accounts for the
failure to obtain seizure control following virtually complete
resection of the hamartoma. The contrast between these two patients
challenges our understanding of this disorder and of the intricate
relationships between cortical and subcortical regions in the
production of epilepsy and abnormal behaviour. n