Jeremy L. Freeman
pituitary, thyroid, adrenal and gonadal control, thirst, appetite and weight control, memory and emotional behaviour including aggression and laughter, and biological (circadian) rhythms. The functional anatomy of the hypothalamus and its major afferent and efferent neurological connections are described, with particular reference to hypothalamic hamartomas (HH), gelastic seizures, MRI of the hypothalamus, and potential effects of surgery for HH. Normal development of the hypothalamus is reviewed in relation to models of forebrain development, descriptive hypothalamic embryology and the importance of known transcription factors. Potential environmental antecedents to HH development are discussed, and the significance for sporadic, isolated HH of several syndromes associated with HH is explored.
Alexis A. Arzimanoglou, Edouard Hirsch, Jean Aicardi
other types of seizures, precocious puberty, and behavioral or cognitive deterioration. Combination of all these features is not constant and, when present, their evolution may be variable. When epilepsy proves intractable, surgery may be a solution but is not without risks. Therefore, it can only be justified on the basis of a considerable degree of certainty on the progressive character of the disorder, both in terms of epilepsy and global development. Even though epilepsy is a major and usually the most important problem, it is not always possible to predict its course and to be able to evaluate its potential effects on development. Available data suggests that deterioration is partly related to the epileptogenic activity. We reviewed data from 16 personal cases and discussed the possible evolutions of the epilepsy syndrome on the basis of 6 illustrative cases and a review of the literature. We point out that seizures may start early in life and evolve either towards a catastrophic encephalopathy or may be transiently severe and will progressively settle down. Intermediate situations also exist as well as cases presenting with a mild epilepsy. In almost all cases cognitive difficulties are present and may be associated with behavioral disturbances. They are of variable severity, usually in relation to the severity of the epilepsy and the evolution of the EEG abnormalities. Some of our cases also illustrate that, in young children whose seizures are limited to "a sensation of a pleasant feeling", "a pressure to laugh" or "smiling", early detection of the hamartoma may still be difficult and the epilepsy pattern may be misdiagnosed as an epilepsy temporal or frontal origin. Detailed analysis of the electro‐clinical evolution of representative cases highlights the variable expression of the epilepsy syndrome and renders difficult any dogmatic position on early surgery. However, recent data suggests that a surgical solution must be sought early. Prospective studies are needed to evaluate, not only outcome in terms of control the seizures without unacceptable side effects but also on the evolution of the cognitive and behavioral profile of children with HH and epilepsy are needed.
<i>[published with videosequences]</i>
and epilepsy, of whom three developed epilepsy only in adult life, are presented. The later onset of epilepsy appears to be associated with a milder epilepsy syndrome, less severe learning difficulties and behaviour problems, and better occupational and social status. Gelastic seizures are less prominent in this age group. Of particular interest, one patient had prominent sleep disturbances characterized by a reduction in total slow wave and REM sleep without daytime sleepiness. The milder epilepsy and preserved cognitive and social functioning have implications for management. A number of patients were controlled by anticonvulsant medication, and were functioning satisfactorily. For such patients minimally invasive surgical procedures, or medical therapy should be considered.
Philippe Kahane, Philippe Ryvlin, Dominique Hoffmann, Lorella Minotti, and Alim Louis Benabid
epileptic encephalopathy. There is now increasing evidence that the HH itself plays a crucial role in this syndrome, but the relationships between the lesion and the different types of seizures remain a questionable issue. Stereotactic intracerebral EEG recordings were performed in 5 patients suffering from a medically intractable epilepsy associated with a HH. The hamartoma was investigated in all cases, and various cortical areas were also evaluated in 4 of the 5 patients. The epileptic discharges arose and remained confined within the hamartoma in 3 of the 4 patients in whom laughing and crying episodes were recorded. In addition, interictal spikes were recorded from the hamartoma in 4 of the 5 patients, whereas the stimulation of the HH could reproduce gelastic or dacrystic episodes in 3. 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. Ictal onset appeared either bifrontal, right fronto‐central and lateral temporal, or bifrontal with a right side predominance. The cingulate gyrus was involved in all these 3 cases, and the lateralization of the ictal discharges was always ipsilateral to the predominating side of the hamartoma. Interestingly, these seizure types were sometimes immediately preceded by the laughing or crying attacks, as if ictal discharges within the hamartoma triggered those which seemed to originate in the cortex. Therefore, if these findings confirm the intrinsic epileptogenicity of HH, they also demonstrate that epileptic seizures associated with HH can exhibit different types of electroclinical patterns. 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 cortical interictal epileptiform abnormalities and then to seizures of cortical origin. Whether this proposal of secondary epileptogenesis is valid or not remains a major issue, since it could provide arguments on the moment to discuss surgery.
Philippe Ryvlin, C. Ravier, S. Bouvard, François Mauguière, D. Le Bars, Alexis Arzimanoglou, Jérôme Petit, Philippe Kahane
with HH, remains an open issue, in as much as morphologically similar HH can be associated with dramatically different seizure types and cognitive outcomes. The aim of this study was to investigate brain glucose metabolism in patients with epileptogenic HH, in an attempt to identify signs of focal cortical and subcortical dysfunction which might correlate with other clinical data. We have studied five patients with epileptogenic HH using [
<sup>18</sup>F]‐fluoro‐desoxyglucose and positron emission tomography (FDG‐PET). All our patients also underwent an optimal MRI and a video‐EEG monitoring, as well as an intra‐cranial EEG recording in one of them. The anatomical distribution of FDG‐PET abnormalities was compared to that of interictal and ictal electro‐clinical findings. All five patients demonstrated focal hypometabolism, ipsilateral to the predominant EEG abnormalities and side of HH. Hypometabolic areas greatly varied between patients, but were grossly concordant with the cortical regions suspected to participate in the ictal discharges in each individual. Epileptogenic hypothalamic hamartomas are usually associated with focal cortical hypometabolism in regions which might participate in the overall HH‐driven epileptic network. Whether these cortical abnormalities only reflect the propagation of ictal discharges, or a potentially independent seizure onset zone remains unknown.
Ghislaine Savard, Nadeem H Bhanji, François Dubeau, Frederick Andermann, Abbas Sadikot
It is now realized that behavior and aggression improve after a complete resection of the hypothalamic hamartoma correlating with a good seizure control post‐surgically. We report on the longitudinal psychiatric history of a patient with hypothalamic hamartoma and rage whose severe and refractory epilepsy was ultimately treated by thalamic and intrahamartoma chronic stimulation. Our patient did not exhibit sham rage typical of hypothalamic lesions, but rather multifactorial aggressive bouts typical of challenging behaviors seen with mental retardation. The anxious and social features of the aggression suggest that psychiatric interventions, which have been neglected as the emphasis has been on seizure control, are worthwhile in the overall management of this difficult case.
Leslie G. Biesecker
hamartomas, they can be a powerful biological tool to help us understand the pathophysiology of these heritable disorders. Several disorders that include hypothalamic hamartomas are reviewed here and the current understanding of the biology of the lesions is summarized.
Jeremy L. Freeman, Margaret Zacharin, Jeffrey V. Rosenfeld, A. Simon Harvey
complications and the paucity of published endocrine data may dissuade clinicians from recommending HH surgery. We report the preoperative endocrine status and postoperative endocrine findings of patients undergoing HH surgery at our centre. Twenty‐nine patients aged 4‐23 years (mean 10 years) underwent detailed clinical assessment and biochemical testing of the hypothalamic‐pituitary axis before and after transcallosal resection of their HH. The perioperative evaluation included comprehensive evaluation of pubertal status, growth, weight, thyroid and adrenal function, and osmoregulation. Forty‐five percent of patients had CPP at presentation and this was not altered by HH surgery. Asymptomatic deficiencies in thyroid hormone, growth hormone and cortisol response were identified in several patients prior to surgery, and biochemical CPP was present in four, clinically prepubertal children. Free thyroxine fell after surgery in the majority, and to clinically significant levels prompting treatment in 5 patients. Low growth hormone was present in 5\8 patients who had had previous HH surgery and in 6\29 following transcallosal surgery at our centre; short stature did not result during the period of follow‐up. Hypernatraemia developed in most patients postoperatively with sodium > 150 mmol\L seen in 16 (55%) patients; however, this was asymptomatic, not often associated with polyuria, and transient; no patient required ongoing antidiuretic hormone replacement. Appetite stimulation and early postoperative weight gain occurred in 45% patients, but resolved in half. Disturbance of endocrine function may be clinically silent and should be routinely evaluated prior to HH surgery for intractable epilepsy. Following surgery, hypernatraemia, low thyroxine, low growth hormone, and weight gain are the main endocrine problems encountered. Prior, unsuccessful surgery may be a risk factor for endocrinopathy. Except for weight gain in some patients, these postoperative endocrine disturbances appear to be transient, mild or asymptomatic, and easily treated where necessary. Long term follow‐up of growth and sexual development in a large series of patients is required.
André Palmini, Eliseu Paglioli‐Neto, Jose Montes*, Jean‐Paul Farmer
the clinical presentations, pathophysiology and management of this entity. Patients with these lesions may occupy different points within a spectrum of severity of the epileptic and behavioural disorder, and may dynamically progress toward more malignant epilepsies with time. The role of the subcortical lesion in the generation of the gelastic seizures has been established, and encouraging results have been obtained with surgical resection, destruction or disconnection of the hamartoma. The present work highlights several aspects that should be taken into account for the selection of medical and surgical treatment for individual patients. We conclude with a reflection on what we still do not understand as regards in the genesis and surgical management of the neuropsychiatric disabilities related to this disorder.
A. Simon Harvey, Jeremy L. Freeman, Samuel F. Berkovic, Jeffrey V. Rosenfeld
centres. We describe the results of transcallosal resection of HH in 29 consecutive patients undergoing surgery at one centre. Twenty‐nine patients aged 4‐23 years (mean 10 years) underwent HH surgery with a minimum of 12 months follow‐up. A comprehensive, presurgical epilepsy evaluation, supplemented with endocrine and ophthalmological assessments was performed in all cases. HH were resected via a transcallosal, interforniceal approach to the third ventricle, with the assistance of frameless stereotaxy, limiting the resection to the margins of the third ventricular walls and floor and minimising traction and diathermy. Complete or near‐complete (> 95%) resection of the HH was achieved in 18\29 patients, 75‐95% resection was achieved in seven patients (four of whom had complete or near‐complete disconnection of residual HH) and less than 50% resection was achieved in four. Postoperatively (follow‐up 12‐70 months, mean 30 months), 15 became seizure‐free (nine off antiepileptic medication), seven had > 90% reduction in seizure frequency, three had 55‐80% reduction in seizure frequency, and four had less than 40% reduction in seizure frequency. Of 16 patients who had seizures in the early postoperative period, six became seizure. No patient or lesion characteristics were associated with postoperative seizure freedom, including features of symptomatic generalised epilepsy. Neurobehavioural improvement and resolution of EEG abnormalities were seen in the majority. Complications were transient hemiparesis in two, transient hypernatraemia in 17, short‐term memory impairment in 14 (persistent in four), weight gain in ten (persistent in five), need for supplemental thyroxine in five, and lowered growth hormone (uncertain clinical significance) in six. Transcallosal resection of HH is an effective treatment for intractable epilepsy, with 76% patients in our seizures being seizure‐free or having > 90% seizure reduction. The operative risks include stroke, short‐term memory disturbance, weight gain and minor endocrine disturbances. Based on published data, the transcallosal approach appears to be safer and more effective than other operative strategies.
Martine Fohlen, Arielle Lellouch, Olivier Delalande
patients aged from 9 months to 32 years underwent surgery between 1997 and 2002. The mean age at seizure onset was 15.5 months. Seventeen patients had gelastic seizures, 14 had partial seizures, two had infantile spasms, 10 had tonic or atonic seizures and three had generalized seizures. The mean seizure frequency was 21 per day. Four patients had borderline intellectual disability and the others were mentally retarded. Five patients had precocious puberty, one had acromegaly and four suffered from obesity. Brain MRI, performed at least twice in each patient showed the hamartoma as a stable, homogeneous interpeduncular mass implanted either on the mammilary tubercle or on the wall of the third ventricle, with variable extension to the bottom. Ictal SPECT, performed in four patients, showed hyperperfusion within the hamartoma in two. Surgical procedure: twenty‐six operations were performed in 18 patients. The first patient underwent a total removal of the hamartoma, whereas the following patients underwent a disconnection, either through open surgery (14 patients) or endoscopy (10 patients). Results: regarding the seizure outcome with a mean follow up of three years four months (one year to 4.5 years), nine patients are seizure‐free, one patient has only brief gelastic seizures and eight are dramatically improved. Surgery was uncomplicated in all but two patients: one had transitory hemiplegia and paresis of the third cranial nerve, the other presented with hemiplegia due to ischemia of the middle cerebral artery territory. The quality of life, behavior and school performance were greatly improved in most of the patients. Conclusion: our series illustrates the feasibility and relative safety of disconnecting surgery of hypothalamic hamartomas, with seizure relief in 50% and a dramatic improvement in the others. Endoscopic disconnection seems to be a very safe way to treat the intra‐ventricular part of hamartomas.
Ruben I. Kuzniecky, Barton L. Guthrie
We present data on patients who underwent stereotactic radiofrequency with or without endoscopy. Epilepsy improved in 60% of patients with minimal morbidity. This approach was less succesful in large lesions. These results indicate that this approach should be considered in patients with small\medium lesions.
Charles E Polkey
into a syndrome with multiple seizures, developmental delay and a moderate to severe behaviour disorder. The other presents later with a milder epileptic syndrome, again usually including gelastic seizures, but with normal intellect and behaviour. Magnetic resonance imaging identifies and gives a detailed anatomical picture of these lesions. Direct surgery, using microsurgical techniques and neuronavigation guidance has been used for these lesions. Three surgical approaches have been used, one lateral pterional, another midline frontal through the lamina terminalis and a third is a transcallosal interforniceal approach. In addition a disconnection procedure, usually pterional, aims to disconnect the lesion without the risks of major resection. The transcallosal interforniceal approach is the most successful with 69% of patients seizure‐free. There are complications in about 24% of patients, the same as other approaches, but the complications are milder and include fewer neurological deficits than the other routes. Alternate strategies include stereotactic radiosurgery and radiofrequency ablation under stereotactic control.