GAMMA KNIFE RADIOSURGERY OF THE VIM: FROM THE LESIONAL EFFECT TOWARDS NEUROMODULATION

Gamma Knife radiosurgery (GKR) is a neurosurgical stereotactic procedure, combining image guidance, with high-precision convergence of multiple gamma rays, currently emitted by 192 sources of Cobalt-60 (Leksell Gamma Knife ICON®, Elekta Instruments, AB, Sweden). The intimate mechanisms of action are not all very well understood and vary according to the treated pathological condition. In functional disorders, GKR is used either to target a specific anatomical point [e.g. thalamus- ventro-intermediate nucleus (Vim) for tremor] or to target a larger zone, such as an epileptic focus. The present thesis focuses on Vim GKR for drug-resistant essential tremor (ET). Essential tremor is the most common movement disorder, with the predominant clinical finding being kinetic tremor of the arms. Radiosurgery (RS) has several limitations in this indication: (1) indirect targeting (Vim is not visible on current MR acquisitions), with (2) no intraoperative confirmation of the target, (3) delayed clinical effect, (4) inability to predict the radiological response and a (5) lack of understanding of its radiobiological effect. Moreover, despite a standard radiosurgical procedure, there is a variability of clinical effect, with a lower efficacy rate as compared to standard deep-brain stimulation, the reference technique. Gamma Knife radiosurgery has no access to tissue analysis, and targeting and follow-up evaluation are based only on neuroimaging. We addressed the limitation of the indirect targeting by using high-field 7 Tesla (T) MRI, and combining multimodal imaging for Vim definition, at both 3 and 7 T. The central core of this thesis was the understanding of radiobiology of RS for tremor, using both structural [e.g. T1 weighted (T1-w), voxel-based morphometry (VBM)] and functional resting- state functional MRI (rs-fMRI). We aimed for a direct Vim visualization using ultra-high field 7 T. The former allows an increased signal to noise ratio, an improved spatial resolution, as well as a superior sensitivity to magnetic susceptibility engendered contrast. Susceptibility-weighted images (SWI) might be an important step to allow a direct visualization of thalamic subparts (including the Vim). We explored 7T SWI advantages, which were done in a qualitative manner. We combined several different methodologies for Vim definition (in healthy subjects of different ages): manual delineation on 7T, quadrilatere of Guiot used in common clinical practice and automated segmentation based on diffusion weighted imaging and atlases (last two performed by and in collaboration with Dr Najdenovska). We concluded that although 7T SWI, alone or in combination with other neuroimaging modalities, is useful, several limitations need to be overcome yet, precluding a standardization of a direct Vim visualization, with the current state-of- the art. The T1-w and rs-fMRI based studies analyzed the radiobiology effects of Vim GKR for intractable tremor and led to several important contributions. The most relevant and novel was the presence of a visually-sensitive structural and functional network, involved in tremor generation and further arrest after Vim GKR. The patients with this network more integrated pretherapeutically benefited more from RS. The candidate had shaped the term “cerebello- thalamo-cortical” into the “cerebello-thalamo-visuo-motor” network, as a step forward in the understanding of essential tremor’s pathophysiology. Two structures were proposed as main calibrators of this network, in the light of the present thesis: the cerebellum (as the most probable) versus the thalamus itself. Moreover, a more classical basal ganglia network, interconnected with a salience one, as well as a cerebellar, interconnected with the motor and visual one, were reported. Other longitudinal changes involved dorsal attention, insular or supplementary motor area circuitries. Particular phenotypes of ET, including patients with head tremor, were analyzed and discussed. As a perspective and future work, in progress, the dynamics of the extrastriate cortex was further analyzed, using co-activation patterns. -- La radio-neurochirurgie par Gamma Knife (GK) est une procédure de neurochirurgie stéréotaxique, combinant l’utilisation d’une imagerie multimodale, avec la convergence de multiples rayons Gamma émis par 192 sources of Cobalt-60 (Leksell Gamma Knife ICON®, Elekta Instruments, AB, Suède). Ses mécanismes pathophysiologiques ne sont pas complètement élucidés et varient selon la condition traitée. Lors des procédures fonctionnelles, le GK est utilisé pour irradier avec une haute précision, soit un point précis (par exemple, le noyau ventro- intermediare, Vim, du thalamus pour le tremblement), soit une zone plus large, comme un foyer d’épilepsie. La présente thèse a comme sujet principal la radiochirugie du Vim (RC du Vim) pour le tremblement essentiel (TE). Le TE est un des mouvements anormaux le plus commun, manifesté principalement avec un tremblement d’action de la main. Toutefois, la RC du Vim a plusieurs limitations: (1) le ciblage est indirect (le Vim n’est pas visible sur les séquences IRM classiques), (2) elle ne permet pas la confirmation électrophysiologique de la cible, (3) l’effet clinique est délayé dans le temps, (4) la réponse radiologique est difficile à prédire et, (5) il manque une compréhension claire de son effet radiobiologique. De plus, malgré le fait que la procédure soit standardisée, il y a une variabilité de son effet clinique. La RC ne permet pas d’analyser le tissu et, le ciblage ainsi que le suivi, sont réalisés uniquement sur la base de la neuroimagerie. Nous avons analysé la limitation du ciblage indirect en utilisant l’IRM à haut champs [7 Tesla (T)] et en la combinant avec une imagerie multimodale, incluant des séquences 3T et 7T, pour la définition du Vim. La partie centrale de la thèse se focalise sur la compréhension de l’effet radiobiologique de la RC du Vim dans le TE. Cette partie se base tant de l’analyse de l’imagerie structurelle (séquence classique T1) que sur l’imagerie fonctionnelle (IRM de repos). Le but de la première partie de la thèse est la visualisation directe du Vim en utilisant l’IRM 7T, qui a plusieurs avantages par rapport à l’IRM 3T, y compris une meilleure résolution spatiale. Notamment, la séquence SWI a un intérêt particulier, mais elle n’avait encore jamais été explorée que de manière quantitative au niveau du thalamus (qui contient le Vim). Nous avons combinée plusieurs modalités pour définir le Vim (chez des sujets sains de différents âges): visualisation directe sur la 7T, quadrilatère de Guiot tel qu’utilisé en pratique clinique courante, ainsi que segmentation automatique en imagerie de diffusion ou par des atlas (ces dernières deux approches ont été réalisées par, et en collaboration avec, Dr Najdenovska). Nous avons conclu que la séquence 7T SWI, malgré certains avantages, et utilisée seule ou combinée avec d’autres modalités, présente certaines limitations qui ne permettent pas, à l’heure actuelle, de l’utiliser d’une manière standardisée, tant chez les sujets sains que chez les patients atteints de TE. Dans la deuxième partie, l’étude de la radiobiologie de la radiochirugie pour le TE a permis d’apporter plusieurs contributions. La plus importante est la mise en évidence d’un « réseau visuel » structurel et fonctionnel, impliqué dans la genèse du tremblement et dans son amélioration après une RC du Vim. Les patients dont ce réseau est mieux intégré avant la procédure ont de meilleures chances d’amélioration clinique du TE. Dans ce contexte, nous avons proposé d’adapter le terme classique d’ «axe cérébello-thalamo-moteur» en le modifiant en « axe cérébello-thalamo-visuo-moteur», ce qui pourrait aider à une meilleure compréhension de la pathophysiologie du TE. Nous proposons également que deux structures puissent jouer le rôle de neuromodulateur de ce réseau, le cervelet et le thalamus. Une autre contribution est la description de l’interconnexion entre le réseau classique impliquant les noyaux de la base et celui l’attention, ainsi que de l’interconnexion entre le réseau cérébelleux et celui des cortex moteur primaire et visuel associatif. Des phénotypes particuliers du tremblement ont été analysés, incluant par exemple des tremblements du chef. Des travaux en cours incluent l’étude de la dynamique du cortex extra-strié en utilisant de nouvelles approches, comme les patterns de co-activation

Intraoperative MRI for the microsurgical resection of meningiomas close to eloquent areas or dural sinuses: patient series

BACKGROUND: Meningiomas are the most commonly encountered nonglial primary intracranial tumors. The authors report on the usefulness of intraoperative magnetic resonance imaging (iMRI) during microsurgical resection of meningiomas located close to eloquent areas or dural sinuses and on the feasibility of further radiation therapy. OBSERVATIONS: Six patients benefited from this approach. The mean follow-up period after surgery was 3.3 (median 3.2, range 2.1–4.6) years. Five patients had no postoperative neurological deficit, of whom two with preoperative motor deficit completely recovered. One patient with preoperative left inferior limb deficit partially recovered. The mean interval between surgery and radiation therapy was 15.8 (median 16.9, range 1.4–40.5) months. Additional radiation therapy was required in five cases after surgery. The mean preoperative tumor volume was 38.7 (median 27.5, range 8.6–75.6) mL. The mean postoperative tumor volume was 1.2 (median 0.8, range 0–4.3) mL. At the last follow-up, all tumors were controlled. LESSONS: The use of iMRI was particularly helpful to (1) decide on additional tumor resection according to iMRI findings during the surgical procedure; (2) evaluate the residual tumor volume at the end of the surgery; and (3) judge the need for further radiation and, in particular, the feasibility of single-fraction radiosurgery

Resection of the contrast-enhancing tumor in diffuse gliomas bordering eloquent areas using electrophysiology and 5-ALA fluorescence: evaluation of resection rates and neurological outcome—a systematic review and meta-analysis

Independently, both 5-aminolevulinic acid (5-ALA) and intraoperative neuromonitoring (IONM) have been shown to improve outcomes with high-grade gliomas (HGG). The interplay and overlap of both techniques are scarcely reported in the literature. We performed a systematic review and meta-analysis focusing on the concomitant use of 5-ALA and intraoperative mapping for HGG located within eloquent cortex. Using PRISMA guidelines, we reviewed articles published between May 2006 and December 2022 for patients with HGG in eloquent cortex who underwent microsurgical resection using intraoperative mapping and 5-ALA fluorescence guidance. Extent of resection was the primary outcome. The secondary outcome was new neurological deficit at day 1 after surgery and persistent at day 90 after surgery. Overall rate of complete resection of the enhancing tumor (CRET) was 73.3% (range: 61.9-84.8%, p < .001). Complete 5-ALA resection was performed in 62.4% (range: 28.1-96.7%, p < .001). Surgery was stopped due to mapping findings in 20.5% (range: 15.6-25.4%, p < .001). Neurological decline at day 1 after surgery was 29.2% (range: 9.8-48.5%, p = 0.003). Persistent neurological decline at day 90 after surgery was 4.6% (range: 0.4-8.7%, p = 0.03). Maximal safe resection guided by IONM and 5-ALA for high-grade gliomas in eloquent areas is achievable in a high percentage of cases (73.3% CRET and 62.4% complete 5-ALA resection). Persistent neurological decline at postoperative day 90 is as low as 4.6%. A balance between 5-ALA and IONM should be maintained for a better quality of life while maximizing oncological control

Long-Term Hearing Outcome After Radiosurgery for Vestibular Schwannoma: A Systematic Review and Meta-Analysis

BACKGROUND: Stereotactic radiosurgery (SRS) is one of the main treatment options in the management of small to medium size vestibular schwannomas (VSs), because of high tumor control rate and low cranial nerves morbidity. Series reporting long-term hearing outcome (>3 years) are scarce.OBJECTIVE: To perform a systematic review of the literature and meta-analysis, with the aim of focusing on long-term hearing preservation after SRS.METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we reviewed articles published between January 1990 and October 2020 and referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical study or case series of VSs treated with SRS (single dose), reporting hearing outcome after SRS with a median or mean audiometric follow-up of at least 5 years. Hearing preservation, cranial nerves outcomes, and tumor control were evaluated.RESULTS: Twenty-three studies were included. Hearing preservation was found in 59.4% of cases (median follow-up 6.7 years, 1409 patients). Main favorable prognostic factors were young age, good hearing status, early treatment after diagnosis, small tumor volume, low marginal irradiation dose, and maximal dose to the cochlea. Tumor control was achieved in 96.1%. Facial nerve deficit and trigeminal neuropathy were found in 1.3% and 3.2% of patients, respectively, both significantly higher in Linear Accelerator series than Gamma Knife series (P < .05).CONCLUSION: Long-term hearing preservation remains one of the main issues after SRS, with a major impact on health related quality of life. Our meta-analysis suggests that hearing preservation can be achieved in almost 60% of patients after a median follow-up of 6.7 years, irrespective of the technique.LM

Combined use of intraoperative MRI and awake tailored microsurgical resection to respect functional neural networks: preliminary experience

INTRODUCTION: The combined use of intraoperative MRI and awake surgery is a tailored microsurgical resection to respect functional neural networks (mainly the language and motor ones). Intraoperative MRI has been classically considered to increase the extent of resection for gliomas, thereby reducing neurological deficits. Herein, we evaluated the combined technique of awake microsurgical resection and intraoperative MRI for primary brain tumours (gliomas, metastasis) and epilepsy (cortical dysplasia, non-lesional, cavernomas). PATIENTS AND METHODS: Eighteen patients were treated with the commonly used "asleep awake asleep" (AAA) approach at Lille University Hospital, France, from November 2016 until May 2020. The exact anatomical location was insular with various extensions, frontal, temporal or fronto-temporal in 8 (44.4%), parietal in 3 (16.7%), fronto-opercular in 4 (22.2%), Rolandic in two (11.1%), and the supplementary motor area (SMA) in one (5.6%). RESULTS: The patients had a mean age of 38.4 years (median 37.1, range 20.8-66.9). The mean surgical duration was 4.1 hours (median 4.2, range 2.6-6.4) with a mean duration of intraoperative MRI of 28.8 minutes (median 25, range 13-55). Overall, 61% (11/18) of patients underwent further resection, while 39% had no additional resection after intraoperative MRI. The mean preoperative and postoperative tumour volumes of the primary brain tumours were 34.7 cc (median 10.7, range 0.534-130.25) and 3.5 cc (median 0.5, range 0-17.4), respectively. More-over, the proportion of the initially resected tumour volume at the time of intraoperative MRI (expressed as 100% from preoperative volume) and the final resected tumour vol-ume were statistically significant (p= 0.01, Mann-Whitney test). The tumour remnants were commonly found pos-terior (5/9) or anterior (2/9) insular and in proximity with the motor strip (1/9) or language areas (e.g. Broca, 1/9). Further resection was not required in seven patients because there were no remnants (3/7), cortical stimulation approaching eloquent areas (3/7) and non-lesional epilepsy (1/7). The mean overall follow-up period was 15.8 months (median 12, range 3-36). CONCLUSION: The intraoperative MRI and awake microsurgical resection approach is feasible with extensive planning and multidisciplinary collaboration, as these methods are complementary and synergic rather than competitive to improve patient oncological outcomes and quality of life

Re-irradiation of recurrent vertebral metastasis after two previous spinal cord irradiation: A case report

BackgroundManagement of a recurrent vertebral metastasis in a situation of previously irradiated spinal cord is a challenging clinical dilemma.Case presentationWe report a first case of second retreatment of a spinal metastasis initially irradiated with standard radiotherapy and stereotactic body radiation therapy (SBRT), who subsequently progressed with imaging-confirmed local tumor progression at the same level. After a third course of irradiation with SBRT, a complete response was achieved. After 8 months of follow-up, the patients remain free of local recurrence.ConclusionA third course of vertebral irradiation for a recurrent vertebral metastasis failing to two previous irradiations, in this particular case, have shown the feasibility and efficacy of the technique as a salvage treatment option. This approach could be used in a selected group of patient if an adequate dose is delivered to the target while observing critical tissue tolerance limits

Brainstem cavernous malformations: observation, microsurgical resection or stereotactic radiosurgery

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