Georg Dorfmüller

Vertical Parasagittal Hemispherotomy: Surgical Procedures And Clinical Long-Term Outcomes In A Population Of 83 Children

OBJECTIVE Hemispherotomy techniques have been developed to reduce complication rates and achieve the best possible seizure control. We present the results of our pediatric patients who underwent vertical parasagittal hemispherotomy and evaluate the safety and global long-term outcome of this technique. METHODS Eighty-three patients underwent vertical parasagittal hemispherotomy by the same neurosurgeon (OD) between 1990 and 2000. We reviewed all patients between 2001 and 2003 for a standard global evaluation. The general principle is to achieve, through a posterior frontal cortical window, the same line of disconnection as performed with the classic hemispherectomy, while leaving the majority of the hemisphere intact along with its afferent and efferent vascular supply. METHODS Seventy-four percent of the patients were seizure-free; among them, 77% were seizure-free without further drug treatment. Twelve percent rarely had seizures (Engel Class II) and 14% continued to have seizures (Engel Class III or IV). The results varied according to the etiology, but this variation was not statistically significant. The early postoperative course was uneventful for 94% of the children, and shunt placement was necessary in 15%. We found a correlation between the preoperative delay and the Vineland Adaptive Behavior score: children with a longer duration of seizures had lower performances. CONCLUSION Vertical parasagittal hemispherotomy is an effective surgical technique for hemispheric disconnection. It allows complete disconnection of the hemisphere through a cortical window with good results in terms of seizure outcome and a comparably low complication rate.

Subependymal giant-cell astrocytomas in pediatric tuberous sclerosis disease: when should we operate?

OBJECTIVEA small percentage of tuberous sclerosis patients will develop a subependymal giant-cell astrocytoma. Given the morbidity and mortality when such a lesion is left undiagnosed, successive follow-up imaging in pediatric patients has been recommended. Surgical removal of the lesion has become the procedure of choice; however, the timing of this surgery is still a controversial subject. By analyzing our own series of data, as well as other published series, we have attempted to reach a consensus on the benefits of early versus late surgery. METHODSWe retrospectively reviewed 19 patients treated surgically for intraventricular tumors in Foch Hospital and at the Fondation Adolphe de Rothschild in Paris, France, and we analyzed published pediatric reports from 1980 to 2006. RESULTSThe results from our own population, as well as from other published pediatric series (15 series), indicate that subependymal giant-cell astrocytomas have a good prognosis when a macroscopically total resection has been performed. In our series, residual lesions tended to enlarge, but residual tumors remaining stable have been reported. Careful follow-up examination should be undertaken because late recurrences do occur. Larger or symptomatic lesions tend to have a higher morbidity. CONCLUSIONWe think that any lesion fulfilling the criteria for a subependymal giant-cell astrocytoma as previously described in the literature (lesion around the foramen of Monro, greater than 5 mm, with incomplete calcifications) should be removed as soon as clear evidence of growth has been confirmed.

Surgical Management of Hypothalamic Hamartomas with Epilepsy: the Stereoendoscopic Approach

OBJECTIVE: Hypothalamic hamartomas (HHs) require surgical treatment in patients presenting with refractory epilepsy. METHODS: The authors report on a single-center series of 33 patients (24 males, 9 females) who underwent surgery between January 1997 and April 2004. They experienced several types of seizure (gelastic, tonic, partial, atonic, generalized tonic-clonic, dacrystic, infantile spasm, mental retardation, and behavioral and endocrinological abnormalities). Forty-nine interventions were carried out. Every patient, with the exception of the first, underwent hamartoma disconnection (pterional approach, six patients; endoscopy, 15 patients; both, 11 patients). The endoscopic approach was carried out with a frameless stereotactic system to enhance feasibility and efficacy of the disconnecting procedure. RESULTS: Surgery-related neurological complications occurred in two patients, both after a pterional microsurgical approach. Furthermore, two patients experienced panhypopituitarism and one patient experienced transitory central insipid diabetes. All patients but one showed recovery or considerable improvement of their epilepsy (Engel Class 1, 48.5%; Engel Class 2, 3%; Engel Class 3, 45.5%; mean follow-up duration, 1 yr 7 mo). CONCLUSION: According to the proposed classification of sessile HH into four types, the best candidates for endoscopic disconnection are Type 2 and Type 3 HHs. In the present series, 90% of patients affected by Type 2 HH became seizure free and the remaining 10% improved; of those with Type 3 HH at presentation, 35.3% recovered and 60% improved. Neuropsychological and endocrinological test results showed improvement in many patients. Data from our series demonstrate that frameless stereotactic endoscopic disconnection should be considered as the treatment of choice in the presence of favorable anatomic conditions.

Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model

Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1+/− mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in Tsc1+/− mice in vivo and in vitro. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.

Stereo-electroencephalography (SEEG) in 65 children: an effective and safe diagnostic method for pre-surgical diagnosis, independent of age

AIM We report our experience of stereoelectroencephalography (SEEG) in 65 children with drug-resistant seizures, with a particular emphasis on young children. METHODS We retrospectively studied all SEEG performed between 2009 and 2011 in our centre. As SEEG can have several indications, the patients were classified into three categories, according to the probability of surgery. The contribution of SEEG to the final decision regarding surgery was evaluated for each category separately. We also compared the main demographic and surgical data of children younger than 5 years of age (Group 1; 21 children) with those older than five years of age at the time of investigation (Group 2; 44 patients). RESULTS MRI was not contributory in 20% of patients (9.5% in group 1; 25% in group 2). Electrical stimulations localised the motor area in all patients when performed (49% of patients), even in group 1 (62% of patients). SEEG led to surgery in 78% of patients (90.5% in group 1; 73% in group 2), after a second invasive investigation in 9.2 % of patients. The resection involved more than one lobe in 25% of patients (37% in group 1; 19% in group 2). Ultimately, 78% of patients with a low probability of having surgery before SEEG received surgery (88% in group 1). The surgical outcome of Engel class 1 was reported for 67% of patients (79% of patients in group 1 and 59% in group 2). No complications occurred. CONCLUSION SEEG in children is safe and useful, and the surgical outcome in younger children is as good as, or sometimes even better than, that in older children. As a result of lower rates of complication and morbidity, SEEG appears to be more appropriate, in comparison to subdural grids, in situations where it is unclear if patients will have surgery after an invasive investigation.

Invasive explorations in children younger than 3 years

PURPOSE In children with drug-resistant focal epilepsy who are candidates for surgery, invasive exploration is sometimes required. However, this is being controversially discussed for children younger than 3 years. The question of its necessity, feasibility and its risks is often raised, since it concerns primarily lesional epilepsy and a lesionectomy might be proposed right away. However, this attitude does not take into account the specificities of epilepsy at this age, including poor specificity of electroclinical semiology and the ongoing myelination challenging the interpretation of magnetic resonance imaging (MRI). METHODS We retrospectively studied the records of children with drug-resistant epilepsy who were younger than 3 years of age at the time of their invasive exploration at our institution from 2000 to 2009. We reviewed the clinical, imaging and electrophysiological data, and included post-operative outcome for those who underwent surgery. KEY FINDINGS 26 Children met the inclusion criteria. All had drug-resistant epilepsy that started at an average of 5.2 months (range 0-20 months) with multiple daily seizures in all and developmental delay in 16. The average age at the time of exploration was 21.8 months (range 5-35). In 20 children, subdural electrodes in combination with two or three depth electrodes were implanted, and in six children aged over 2 years a stereo-electro-encephalography (SEEG) was performed. SEEG was considered technically difficult to achieve before the age of 2 years. The tolerance of invasive exploration was good with a 3% morbidity consisting of one subdural hematoma during exploration by subdural electrodes, evacuated without any particular sequelae. In 25 patients, the exploration permitted to propose a focal resection. The surgical intervention was in the frontal lobe in 12 cases, the parietal lobe in six, the occipital lobe in two patients, and the temporal lobe in one child who underwent an additional resection. Four children had a resection of two or three lobes. Five underwent a second surgery, following a second invasive exploration. Histologically, the resected tissue revealed focal cortical dysplasia in 21 cases (including three patients with tuberous sclerosis), two post-ischemic lesions, one dysembryoplastic neuroepithelial tumor, and one gangliglioma associated with dysplasia. The mean postoperative follow-up period was 51 months (range 4-110). For the children operated on twice, follow-up was counted from the second surgery on. Seventeen children (68%) had an outcome of Engel class 1. In five (20%), seizure frequency was significantly improved (Engel class 3). In two of three patients without improvement in seizure frequency (Engel class 4), a new SEEG is planned and the third is presently a candidate for hemispherotomy. SIGNIFICANCE Invasive exploration is feasible, well tolerated and carries a low morbidity in children under 3 years of age. At this age, it is indicated for drug-resistant lesional epilepsy associated with developmental delay. It permits delineating the lesion, which is not possible with MRI. The choice of the technique is in part age-dependent. The discussion of its indication arises in the same way as in the older child.

Presurgical language mapping in children with epilepsy: Clinical usefulness of functional magnetic resonance imaging for the planning of cortical stimulation

Purpose:  Presurgical language mapping in dominant hemisphere epilepsy to evaluate the risk of postoperative deficit is particularly difficult in children. Extraoperative invasive cortical stimulation can show some areas critical to language, but not all of them, due to scarce sampling, poor cooperation, cortical immaturity, or network reorganization, whereas functional magnetic resonance imaging (fMRI) displays entire networks involved in, but not necessarily critical to, language. In a homogeneous series of children with epilepsy, we compared the contributions of language fMRI and depth electrode stimulations to optimize language mapping.

Inhibitory actions of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome†

The mechanisms of epileptogenesis in Sturge‐Weber syndrome (SWS) are unknown. We explored the properties of neurons from human pediatric SWS cortex in vitro and tested in particular whether gamma‐aminobutyric acid (GABA) excites neurons in SWS cortex, as has been suggested for various types of epilepsies.

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy.

Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies. Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR. Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother–daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

Endoscopic disconnection of hypothalamic hamartomas: safety and feasibility of robot-assisted, thulium laser–based procedures

OBJECT Hypothalamic hamartomas (HH) may induce drug-resistant epilepsy (DRE), thereby requiring surgical treatment. Conventionally, treatment is aimed at removing the lesion, but a disconnection procedure has been shown to be safer and at least as effective. The thulium laser (Revolix) has been recently introduced in urological endoscopy because of its ability to deliver a smooth cut with good control of the extent of tissue damage. The authors sought to analyze the safety and efficacy of the thulium 2-μm laser applied through navigated, robot-assisted endoscopy in disconnection surgery for HHs. METHODS Twenty patients with HH who were drug resistant were treated during a 12-month period. Conventional disconnection by monopolar coagulation (endoscopic electrode) was performed in 13 patients, and thulium laser disconnection was performed in the remaining 7 patients. The endoscope was inserted into the ventricle contralateral to the attachment of the HH on the third ventricular wall. Results in terms of safety, efficacy, and ease of use of the instrument were analyzed. RESULTS All 20 patients achieved a satisfactory postoperative Engel score (Classes I-III). At 12 months, the Engel class was I or II in 8 of 13 patients (61.5%) who underwent monopolar coagulation and in 6 of 7 patients (85.7%) who underwent laser disconnection (p = 0.04). Seven of 13 patients (53.8%) who underwent monopolar coagulator disconnection and 2 of 7 patients (28.6%) who underwent laser disconnection had immediate postoperative complications. At the 3-month follow-up, only 2 patients (15.4%) treated by coagulation still experienced mild surgery-related recent memory deficits. No complications persisted at the 12-month follow-up. CONCLUSIONS The disconnection procedure is a safe and effective treatment strategy to treat drug-resistant epilepsy in patients with HHs. With the limitations of initial experience and a short-term follow-up, it appears that the thulium 2-μm laser has the technical features to replace the standard coagulation in this procedure.