The seizure types were classified as follows: infantile spasms (2/18), gelastic seizures (17/18), dacrystic seizures (2/18), partial seizures (14/18), tonic seizures (8/18), atonic seizures (2/18) generalized tonic clonic (3/18) seizures. Eight of the 18 patients experienced three seizure types, eight patients had two seizure types and two had four seizure types. The seizure frequency ranged from six seizures per hour to four seizures weekly, with an average of 21 seizures daily.
Neurological examination showed no motor deficit in any patient. One patient had congenital deafness, and he was classified as Pallister-Hall syndrome (case No 4). Neuropsychological examination performed at the time of the operation showed a borderline intellectual quotient in four patients, a mild mental deficiency (IQ between 40 and 80) in seven and severe mental deficiency (IQ below 40) in five. One infant had a developmental quotient of 64 and the other, 60.
Six children among the most mentally impaired (cases 1, 3, 4, 8, 10, 18) had behavioral problems that encompassed hyperactivity, aggressiveness and psychotic features. One patient had a frontal syndrome (case 16), and another had an anxiety disorder (case 7). The other patients did not have major behavioral disorders.
Endocrinological disorders were observed in nine patients: four had polyphagia associated with obesity, five had precocious puberty, one had a gigantism associated with acromegaly and hypothyroidism. None of our patients had any visual impairment.
MRI was performed at least twice in each patient. The results showed the hamartoma as a non-enhancing, stable lesion with an iso-intense signal on T1-weighted images and an iso- or hyper-intense signal on T2-weighted images. In all cases, the implantation of the hamartoma was sessile with variable attachment to the hypothalamus and there was a great variety of size of the lesion.
Ictal SPECT was performed in four patients: in two cases it showed a hyperperfusion within the lesion and in the remaining two, it appeared to be non-contributive.

Surgical procedure

Twenty-six operations were performed in 18 patients: eight patients have been operated on twice.
The first patient underwent complete resection of the lesion, performed through a pterional route. Postoperatively, he became seizure-free (Engel class 1) but developed a right hemiplegia that partially improved, and a left 3^rd nerve palsy. Such a complication was unforeseen, and a post-operative MRI scan suggested a vascular complication. In order to avoid similar complications, we decided to proceed, in the following patients, with a disconnection associated with variable resection.
Over time, surgical procedures evolved with the purpose of making surgery suitable for the anatomical conditions of the hamartoma. In order to decide the best surgical route, we developed a classification with four types, based on the plane of insertion of the hamartoma upon the hypothalamus (see figure 1).
In type I, the implantation plane is horizontal and may be lateralized on one side; the microsurgical route will be pterional leading to a complete disconnection. (cases 3, 4, 6, 9, 15).
In type II, the insertion plane is vertical and intraventricular and the surgical procedure consists of a disconnection of the intraventricular component of the hamartoma using an endoscopic route with a frameless stereotactic robot (cases 14, 16); the endoscopic resection can be repeated in the case of an insufficient result.
In type III hamartomas, we suggest proceeding in 2 steps: the first step consists of the disconnection of the intraventricular part of the hamartoma using an endoscopic route, and the second step consists of a disconnection through a pterional route (cases 1, 2, 5, 7, 8, 10, 12, 13, 17, 18).
Type IV defines giant hamartomas and for these there are no specific surgical rules Case 11).
According to this classification, 14 patients have had a disconnection through a pterional route and ten patients (seven reinterventions and three primary interventions) underwent endoscopic surgery with the aid of the frameless stereotactic robot.
Post-operative complications consisted of meningitis (case 3), hemiplegia due to ischemia of the middle cerebral artery territory (case 5), ischemic lesion of the internal part of the frontal lobe (case 13), and transient diabetes insipidus (cases 9, 13).

None of the patients who underwent endoscopic disconnection have had any post-operative complications, and all of them were discharged from hospital three days after surgery.

Results

Seizure results

The first patient became seizure-free (follow-up: six years) and demonstrated a dramatic improvement in behavior and language performance. Antiepileptic drugs were withdrawn two years after the operation.

The fourteen patients who underwent open surgery had the following results: three patients became seizure-free (Engel class 1), 11 had a dramatic reduction in seizure frequency > 80% (Engel class 3) of all types of seizures, with total disappearance of tonic and generalized tonic-clonic seizures in five patients. Seven of these 11 patients underwent an additional endoscopic disconnection with a follow-up of 15 months to five years (mean: 27 months). Three patients became seizure-free (cases 10, 12, 13), one had only gelastic seizures remaining (case 2) and three showed reduced seizure frequency (case 7, 8, 17).

Among the three patients who underwent endoscopic disconnection only, two are seizure-free (case 14 and 18), and the other one is Engel class 3 (case 16) after the first operation and has been recently re-operated upon with no marked improvement (follow-up: 18 months).

In summary, considering all of the surgical approaches, nine (50%) patients are seizure-free, 1 patient (5%) has only brief gelastic seizures (Engel class 2), and eight (44%) are dramatically improved (Engel class 3).

Other results

Behaviour, as evaluated by the families of the patients and the physicians, as well as school performances are improved in Class 1 to Class 3 patients. No patient experienced any cognitive deterioration. One patient obtained his driving license, two patients are learning manual work and one patient (Class 2) has an IQ improved by 16 points, 15 months following surgery.

Two patients have definitive post-operative neurological deficits.

Endocrinological follow-up shows hyperphasia with weight gain in one patient, panhypopituitarism in another, and association of hypothyroidism, human growth hormon deficiency in the third with no change in the others.

Histopathology

Histologically, the sample removed consisted of neuronal tissue made of scattered neurons and glial cells. The cellularity was sometimes increased (cases 14, 15, 16) or normal (case 17). The glial cells were mainly microglia with a elongated cell aspect’ (cases 14, 16). The neuronal cells were sometimes ganglionic neurons, and in three cases the neurons had degenerative features, characterized by the loss of basophilia of the cytoplasm and the disappearance of the Nissl bodies (cases 15, 17, 18); in two patients (cases 15, 17), axons were present in great numbers with numerous axonal bowls, which were disclosed by the neurofilament coloration. The combination of the lack of cytoplasmic basophilia, preservation of neuronal architecture, axonal bowls and macrophagic activity is consistent with a degenerative process.

Discussion

Since the first paper of Kammer in 1980 [18], several types of surgical approach and other techniques (radiosurgery, radiofrequency) have been reported for HH treatment. Most of these papers involve single cases or series, some with precocious puberty only, others with epilepsy only, or both [19].

Discussion of surgical approaches and techniques

Different operative routes for the surgical treatment of HH have been reported in the English literature [13-16, 20] with variable success on epilepsy outcome. In all of these cases, the goal of the treatment was the removal of the entire lesion since it is commonly believed that the hamartoma is the trigger of the epilepsy [4-8, 20, 21] and that, to achieve good seizure remission, the resection of HH must be as complete as possible [22].
Nevertheless, as previously reported [17] we believe that the complete removal of the hamartoma can be replaced by a disconnection, using either open surgery or endoscopy, since the hamartoma is a stable lesion and entire anatomical removal is not necessary for treating the epilepsy. Such a surgical strategy was first applied to epilepsy in the form of hemispherotomy [23] instead of hemispherectomy, with similar results upon the outcome of seizures, whereas operative risks and postoperative complications were lower. More recently, a disconnection was performed on two children with hamartoma of the fourth ventricle associated with facial hemispasms, with an excellent outcome regarding the seizures [24]. Moreover, the endoscopic approach allows a disconnection of the intraventricular part of the hamartoma and is very well tolerated by the patients; in case of failure or insufficient results, it can be performed again. The difficulty is to accurately define the borders of the disconnection since there are no clear-cut limits between the hamartoma and the neighboring normal brain tissue (also see Freeman, this issue), so, the outcome of the epilepsy remains the only evidence of a sufficient disconnection.
Recently, Rosenfeld et al. described a series of five children who underwent transcallosal resection [16]. Three of them are seizure-free and two are improved. The only postoperative complications were endocrinological, such as hyperphagia and transient diabetes insipidus (see Harvey et al., this issue).
Our endoscopic route is very similar to this transcallosal approach but it seems to us that the transcallosal approach may be insufficient for cases in which the implantation of the hamartoma spreads horizontally below the hypothalamus (Delalande’s type 1), and in the latter we recommend open surgery with a pterional route.

Discussion of operative versus radiosurgery gamma knife surgery treatment

Radiosurgery appears to be an alternative treatment of HH with epilepsy. In 2000, Regis et al. reported a series of eight patients with sessile HH and drug-resistant epilepsy treated with gamma knife surgery (GKS) [12]. Four of these patients were seizure-free or have greatly improved, and the remaining four patients exhibited marked improvement after a median latency in seizure cessation of nine months. No side effects were reported within a median follow-up of 28 months. The main argument advocated for the radiosurgical treatment rather than microsurgery is the surgical risk of the resection of the hamartoma (see also Regis, in this issue). Our first patient who underwent total resection of a large pediculate hamartoma had post-operative complications of oculo-motor palsy and hemiplegia. Therefore, in the following patients, we decided to perform disconnection of the lesion rather than resection. With such an approach, the complications are infrequent, the results as regards the epilepsy are apparent shortly after, and endoscopic disconnection can be repeated in case of failure. In addition, patients are protected from long term complications reported in GKS mesial temporal lobe epilepsy [25]. Moreover, large, implanted as well as small, intraventicular lesions can be treated by disconnection, whereas, only small HH located inside the third ventricle or in the floor are good candidates for GKS.

Other treatment approaches

In 1999, Fukuda reported a single patient with HH treated by stereotactic radiofrequency thermocoagulation in the course of an exploration with a depth electrode implanted within the lesion, associated with subdural grids. Two gelastic seizures were recorded, originating from the hamartoma. In order to cure the patient, the electrode of stimulation was replaced by an electrode allowing coagulation. Gelastic seizures ceased thereafter, whereas tonic seizures disappeared four months later. This patient is now seizure-free with a follow-up of 14 months [8]. To the best of our knowledge, he is the only patient treated in this way and this technique seems to be suitable for type II hamartomas of Valdueza’s classification.

Conclusion

Our series illustrates the feasability and acceptable morbidity of disconnective surgery in hypothalamic hamartomas. This kind of surgery has become safer as technical procedures evolve. The safest method is stereotactic endoscopy which is appropriate for cases with endo- or periventricular hypothalamic insertion. Since the prognosis of epilepsy linked to HH is currently poor, surgical treatment has to be performed early, as soon as the epilepsy appears to be drug-resistant in order to prevent behavioral disorders and delayed development in children. n

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