Romain Carron

HEARING PRESERVATION AFTER GAMMA KNIFE RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS PRESENTING WITH HIGH-LEVEL HEARING

OBJECTIVEThe aim of this study was to evaluate long-term hearing preservation after gamma knife radiosurgery (GKS) for vestibular schwannomas in patients with initially normal or subnormal hearing (Gardner-Robertson Class 1) and to determine the predictive factors for functional hearing preservation. METHODSSince July 1992, more than 2053 vestibular schwannomas have been treated by GKS and followed at the Timone University Hospital, Marseille. A minimum of 3 years of follow-up (range, 3–11 years; median, 48 months) is available for 74 patients (without neurofibromatosis Type 2 or previous surgery) with Gardner-Robertson Class 1 hearing. RESULTSThe average age of the patients was 47.5 years (range, 17–76 years). The number of tumors in Koos Stage I was 8, the average number in Stage II was 21, the average number in Stage III was 43, and the average number in Stage IV was 2. The median number of isocenters was 8 (range, 2–45), and the median marginal dose was 12 Gy (range, 9–13 Gy). At the time of the last follow-up evaluation, 78.4% of the patients had preserved functional hearing. Tumor control was achieved in 93% of the cases. The probability of preserving functional hearing was higher in patients who had an initial symptom other than hearing decrease (91.1%), in patients younger than 50 years (83.7%), and in those treated with a dose to the cochlea of less than 4 Gy (90.9%). CONCLUSIONThis study shows that the probability of preserving functional hearing in the long term after GKS for patients presenting with unilateral vestibular schwannomas is very high. The positive predictive factors appear to be young age, an initial symptom other than hearing decrease, and a low dose to the cochlea.

Closing the loop of deep brain stimulation.

High-frequency deep brain stimulation is used to treat a wide range of brain disorders, like Parkinsons disease. The stimulated networks usually share common electrophysiological signatures, including hyperactivity and/or dysrhythmia. From a clinical perspective, HFS is expected to alleviate clinical signs without generating adverse effects. Here, we consider whether the classical open-loop HFS fulfills these criteria and outline current experimental or theoretical research on the different types of closed-loop DBS that could provide better clinical outcomes. In the first part of the review, the two routes followed by HFS-evoked axonal spikes are explored. In one direction, orthodromic spikes functionally de-afferent the stimulated nucleus from its downstream target networks. In the opposite direction, antidromic spikes prevent this nucleus from being influenced by its afferent networks. As a result, the pathological synchronized activity no longer propagates from the cortical networks to the stimulated nucleus. The overall result can be described as a reversible functional de-afferentation of the stimulated nucleus from its upstream and downstream nuclei. In the second part of the review, the latest advances in closed-loop DBS are considered. Some of the proposed approaches are based on mathematical models, which emphasize different aspects of the parkinsonian basal ganglia: excessive synchronization, abnormal firing-rate rhythms, and a deficient thalamo-cortical relay. The stimulation strategies are classified depending on the control-theory techniques on which they are based: adaptive and on-demand stimulation schemes, delayed and multi-site approaches, stimulations based on proportional and/or derivative control actions, optimal control strategies. Some of these strategies have been validated experimentally, but there is still a large reservoir of theoretical work that may point to ways of improving practical treatment.

Long-term safety and efficacy of Gamma Knife surgery in classical trigeminal neuralgia: a 497-patient historical cohort study

OBJECTIVEnGamma Knife surgery (GKS) is one of the surgical alternatives for the treatment of drug-resistant trigeminal neuralgia (TN). This study aims to evaluate the safety and efficacy of GKS in a large population of patients with TN with very long-term clinical follow-up.nnnMETHODSnBetween July 1992 and November 2010, 737 patients presenting with TN were treated using GKS. Data were collected prospectively and were further retrospectively evaluated at Timone University Hospital. The frequency and severity of pain, as well as trigeminal nerve function, were evaluated before GKS and regularly thereafter. Radiosurgery using the Gamma Knife (model B, C, 4C, or Perfexion) was performed with the help of both MR and CT targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range 4-14 mm) anterior to the emergence of the nerve (retrogasserian target). A median maximum dose of 85 Gy (range 70-90 Gy) was prescribed.nnnRESULTSnThe safety and efficacy are reported for 497 patients with medically refractory classical TN who were never previously treated by GKS and had a follow-up of at least 1 year. The median age in this series was 68.3 years (range 28.1-93.2 years). The median follow-up period was 43.8 months (range 12-174.4 months). Overall, 456 patients (91.75%) were initially pain free in a median time of 10 days (range 1-180 days). Their actuarial probabilities of remaining pain free without medication at 3, 5, 7, and 10 years were 71.8%, 64.9%, 59.7%, and 45.3%, respectively. One hundred fifty-seven patients (34.4%) who were initially pain free experienced at least 1 recurrence, with a median delay of onset of 24 months (range 0.6-150.1 months). However, the actuarial rate of maintaining pain relief without further surgery was 67.8% at 10 years. The hypesthesia actuarial rate at 5 years was 20.4% and at 7 years reached 21.1%, but remained stable until 14 years with a median delay of onset of 12 months (range 1-65 months). Very bothersome facial hypesthesia was reported in only 3 patients (0.6%).nnnCONCLUSIONSnRetrogasserian GKS proved to be safe and effective in the long term and in a very large number of patients. Even if the probability of long-lasting effects may be modest compared with microvascular decompression, the rarity of complications prompts discussion of using GKS as the pragmatic surgical first- or second-intention alternative for classical TN. However, a randomized trial, or at least a case-matched control study, would be required to compare with microvascular decompression.

A prospective single-blind study of Gamma Knife thalamotomy for tremor

Objective: To evaluate the safety and efficacy of unilateral Gamma Knife thalamotomy (GKT) for treatment of severe tremor with a prospective blinded assessment. Methods: Fifty patients (mean age: 74.5 years; 32 men) with severe refractory tremor (36 essential, 14 parkinsonian) were treated with unilateral GKT. Targeting of the ventral intermediate nucleus (Vim) was achieved with Leksell Gamma Knife with a single shot through a 4-mm collimator helmet. The prescription dose was 130 Gy. Neurologic and neuropsychological assessments including a single-blinded video assessment of the tremor severity performed by a movement disorders neurologist from another center were performed before and 12 months after treatment. MRI follow-up occurred at 3, 6, and 12 months. Results: The upper limb tremor score improved by 54.2% on the blinded assessment (p < 0.0001). All tremor components (rest, postural, and intention) were improved. Activities of daily living were improved by 72.2%. Cognitive functions remained unchanged. Following GKT, the median delay of improvement was 5.3 months (range 1–12 months). The only side effect was a transient hemiparesis associated with excessive edema around the thalamotomy in one patient. Conclusion: This blinded prospective assessment demonstrates that unilateral GKT is a safe and efficient procedure for severe medically refractory tremor. Side effects were rare and transient in this study. Classification of evidence: This study provides Class IV evidence that for patients with severe refractory tremor, GKT is well tolerated and effective in reducing tremor impairment.

Wait-and-see strategy compared with proactive Gamma Knife surgery in patients with intracanalicular vestibular schwannomas

OBJECTnThe roles of the wait-and-see strategy and proactive Gamma Knife surgery (GKS) in the treatment paradigm for small intracanalicular vestibular schwannomas (VSs) is still a matter of debate, especially when patients present with functional hearing. The authors compare these 2 methods.nnnMETHODSnForty-seven patients (22 men and 25 women) harboring an intracanalicular VS were followed prospectively. The mean age of the patients at the time of inclusion was 54.4 years (range 20-71 years). The mean follow-up period was 43.8 ± 40 months (range 9-222 months). Failure was defined as significant tumor growth and/or hearing deterioration that required microsurgical or radiosurgical treatment. This population was compared with a control group of 34 patients harboring a unilateral intracanalicular VS who were consecutively treated by GKS and had functional hearing at the time of radiosurgery.nnnRESULTSnOf the 47 patients in the wait-and-see group, treatment failure (tumor growth requiring treatment) was observed in 35 patients (74%), although conservative treatment is still ongoing for 12 patients. Treatment failure in the control (GKS) group occurred in only 1 (3%) of 34 patients. In the wait-and-see group, there was no change in tumor size in 10 patients (21%), tumor growth in 36 patients (77%), and a mild decrease in tumor size in 1 patient (2%). Forty patients in the wait-and-see group were available for a hearing level study, which demonstrated no change in Gardner-Robertson hearing class for 24 patients (60%). Fifteen patients (38%) experienced more than 10 db of hearing loss and 2 of them became deaf. At 3, 4, and 5 years, the useful hearing preservation rates were 75%, 52%, and 41% in the wait-and-see group and 77%, 70%, and 64% in the control group, respectively. Thus, the chances of maintaining functional hearing and avoiding further intervention were much higher in cases treated by GKS (79% and 60% at 2 and 5 years, respectively) than in cases managed by the wait-and-see strategy (43% and 14% at 2 and 5 years, respectively).nnnCONCLUSIONSnThese data indicate that the wait-and-see policy exposes the patient to elevated risks of tumor growth and degradation of hearing. Both events may occur independently in the mid-term period. This information must be presented to the patient. A careful sequential follow-up may be adopted when the wait-and-see strategy is chosen, but proactive GKS is recommended when hearing is still useful at the time of diagnosis. This recommendation may be a main paradigm shift in the practice of treating intracanalicular VSs.

Is radiosurgery a neuromodulation therapy? : A 2009 Fabrikant award lecture.

Radiosurgery is commonly considered to be effective through a destructive physical mechanism on neural tissue. Since its invention by Leksell in the 1950s, clinical and experimental experience of radiosurgery has demonstrated that for classical indications, for example arteriovenous malformations and benign tumors, radiosurgery is effective because of its specific histological effects of thrombotic endothelial proliferation and apoptosis, not simple coagulative necrosis. In functional neurosurgery, the strategy is either to target a small volume of normal tissue (i.e., ventrointermediate nucleus, capsulotomy, trigeminal neuralgia, etc.) with a high dose (80–140xa0Gy at maximum) or to target a large volume of tissue (i.e., 5–9xa0cc in epilepsy radiosurgery) with a moderate dose (17–24xa0Gy at the marginal isodose). These procedures have been proposed, technically performed, and evaluated on the basis of the hypothesis that their mechanism of action is purely destructive. However, modern neurophysiological, radiological and histological studies are leading us to question this assumption. Tissue destruction is turning out to be either absent or minimal and in almost all cases insufficient to explain the clinical effects obtained. Therefore, one possibility is that radiosurgery is inducing changes in the functioning of the neural tissue, by inducing remodeling of the glial environment, and is leading to the modulation of function while preserving basic processing. Thus, most radiosurgery procedures may induce the desired biological effect without requiring the histological destructive effect for completion of the therapeutic objective. Therefore the concept of “lesional” radiosurgery may be incorrect and a completely hidden world of neuromodulatory effects may remain to be discovered.

Longitudinal analysis of hearing before and after radiosurgery for vestibular schwannoma

OBJECTnThe aim of this study was to perform an accurate analysis of changes in hearing in patients with vestibular schwannoma (VS) who have undergone Gamma Knife surgery (GKS) and distinguish the impact of radiosurgery from the natural course of hearing deterioration due to the tumor itself.nnnMETHODSnThis study was a retrospective review of prospectively collected patient data. A group of 154 patients with unilateral nonsurgically treated VS was conservatively monitored for more than 6 months and then treated with GKS between July 1997 and September 2005. They were followed up with serial clinical examination, MRI, and audiometry. The annual hearing decrease rate (AHDR) was measured before and after radiosurgery, and the possible prognostic factors for hearing preservation were investigated.nnnRESULTSnThe mean dose prescribed to the tumor margins was 12.1 Gy. The mean radiological follow-up period after GKS was 60 months (range 7-123 months). The tumor control rate was 94.8%, and 8 patients underwent subsequent intervention due to tumor progression. The mean audiological follow-up times before and after GKS were 22 and 52 months, respectively. The mean AHDRs before and after GKS were 5.39 dB/year (95% CI 3.31-7.47 dB/year) and 3.77 dB/year (95% CI 3.13-4.40 dB/year), respectively (p > 0.05). The mean pre- and post-GKS AHDRs in patients who initially had Gardner-Robertson (GR) Class I hearing were -0.57 dB/year (95% CI -2.95 to 1.81 dB/year) and 3.59 dB/year (95% CI 2.52-4.65 dB/year), respectively (p = 0.007). The mean pre- and post-GKS AHDRs in patients who initially had GR Class II hearing were 5.09 dB/year (95% CI 1.36-8.82 dB/year) and 4.98 dB/year (95% CI 3.86-6.10 dB/year), respectively (p > 0.05). A subgroup of 80 patients had both early and late post-intervention AHDR assessment (with early referring to the period from GKS to the assessment closest to the 2-year follow-up point and late referring to the period from that assessment to the most recent one); in these patients, the mean early post-GKS AHDR was 5.86 dB/year (95% CI 4.25-7.50 dB/year) and the mean late post-GKS AHDR was 1.86 dB/year (95% CI 0.77-2.96 dB/year) (p < 0.001). A maximum cochlear dose of less than 4 Gy was found to be the sole prognostic factor for hearing preservation.nnnCONCLUSIONSnThe present study demonstrated the absence of an increase in AHDR after radiosurgery as compared with the preoperative AHDR. There was even a trend indicating a reduction in the annual hearing loss after radiosurgery over the long term. To fully elucidate a possible protective effect of radiosurgery, longer-term follow-up with a larger group of patients will be required.

A quantitative comparison of radiosurgical treatment parameters in vestibular schwannomas: The Leksell Gamma Knife Perfexion versus Model 4C

PurposeThe world’s first Gamma Knife Perfexion (PFX) was installed in Marseille in July 2006. The aim of this study was to investigate the impact of the PFX technology on the quality of dose planning for vestibular schwannomas (VS).MethodsWhen the PFX was first introduced, a comparative randomized prospective study of 200 patients was conducted. Seventy-eight of the 200 patients in that study had VS, of whom 38 were randomized to treatment with the Gamma Knife Model 4C (group 4C) and 40 were randomized to treatment with PFX (group P1). The authors also incorporated a matched group of 40 patients with VS consecutively treated with PFX after the initial learning curve period (group P2). Dose planning was compared and evaluated by measuring the conformity index (CI), selectivity index (SI), gradient index (GI), energy index (EI), unit isocenters (UI) and cochlear dose. Patients were also stratified into subgroups according to target volume (≥0.5xa0ml).ResultsIn the whole population, CI, EI and cochlear dose were significantly better in group P2 (CIu2009=u20090.917, EIu2009=u20091.35, cochlear doseu2009=u20093.55) than in group 4C (CIu2009=u20090.864, EIu2009=u20091.27, cochlear doseu2009=u20095.10). In the subgroup of lesions ≥0.5xa0ml, CI, GI, EI, UI and cochlear dose in group P2 (CIu2009=u20090.929, GIu2009=u20092.67, EIu2009=u20091.37, UIu2009=u200910.6, cochlear doseu2009=u20093.55) were significantly better than in group 4C (CIu2009=u20090.874, GIu2009=u20092.85, EIu2009=u20091.30, UIu2009=u200914.5, cochlear doseu2009=u20095.10).ConclusionsThe investigation of the dose planning capabilities of the PFX on a cohort of VS demonstrates a better conformity and energy distribution, with better cochlear sparing and without any particular drawback. In addition, there is an improvement in peripheral dose gradient in larger lesions. Further clinical studies will be required before drawing any conclusions about the clinical benefit achieved by these dose planning improvements.

Multiple Sclerosis-Related Trigeminal Neuralgia: A Prospective Series of 43 Patients Treated with Gamma Knife Surgery with More than One Year of Follow-Up

Background: Trigeminal neuralgia (TN) related to multiple sclerosis (MS) is more difficult to manage pharmacologically and surgically. Objective: This article aims to evaluate the safety and efficacy of Gamma Knife surgery (GKS) in this special group of patients. Methods: Between July 1992 and November 2010, 43 cases with more than 1 year of follow-up were operated with GKS for TN related to MS and prospectively evaluated in the Timone University Hospital, Marseille, France. Radiosurgery using the Gamma Knife (model B or C or Perfexion) was performed. A single 4-mm isocenter was positioned at a median distance of 8 mm (range 5.7-14.7) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 75-90) was delivered. Results: The median follow-up period was 53.8 months (12-157.1). Thirty-nine patients (90.7%) were initially pain free. Their actuarial probability of remaining pain free without medication at 6 months, 1, 3, 5 and 10 years was 87.2, 71.8, 43.1, 38.3 and 20.5%, respectively, and remained stable till 12 years. The hypoesthesia actuarial rate at 6 months, 1 and 2 years was 11.5, 11.5 and 16%, and remained stable till 12 years. Conclusions: GKS proved safe and effective in this special group of patients.

Patterns of pain-free response in 497 cases of classic trigeminal neuralgia treated with Gamma Knife surgery and followed up for least 1 year

OBJECTnThe goal of this study was to establish whether clear patterns of initial pain freedom could be identified when treating patients with classic trigeminal neuralgia (TN) by using Gamma Knife surgery (GKS). The authors compared hypesthesia and pain recurrence rates to see if statistically significant differences could be found.nnnMETHODSnBetween July 1992 and November 2010, 737 patients presenting with TN underwent GKS and prospective evaluation at Timone University Hospital in Marseille, France. In this study the authors analyzed the cases of 497 of these patients, who participated in follow-up longer than 1 year, did not have megadolichobasilar artery- or multiple sclerosis-related TN, and underwent GKS only once; in other words, the focus was on cases of classic TN with a single radiosurgical treatment. Radiosurgery was performed with a Leksell Gamma Knife (model B, C, or Perfexion) using both MR and CT imaging targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.8 mm (range 4.5-14 mm) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 70-90 Gy) was delivered. Using empirical methods and assisted by a chart with clear cut-off periods of pain free distribution, the authors were able to divide patients who experienced freedom from pain into 3 separate groups: patients who became pain free within the first 48 hours post-GKS; those who became pain free between 48 hours and 30 days post-GKS; and those who became pain free more than 30 days after GKS.nnnRESULTSnThe median age in the 497 patients was 68.3 years (range 28.1-93.2 years). The median follow-up period was 43.75 months (range 12-174.41 months). Four hundred fifty-four patients (91.34%) were initially pain free within a median time of 10 days (range 1-459 days) after GKS. One hundred sixty-nine patients (37.2%) became pain free within the first 48 hours (Group PF(≤ 48 hours)), 194 patients (42.8%) between posttreatment Day 3 and Day 30 (Group PF((>48 hours, ≤ 30 days))), and 91 patients (20%) after 30 days post-GKS (Group PF(>30 days)). Differences in postoperative hypesthesia were found: in Group PF(≤ 48 hours) 18 patients (13.7%) developed postoperative hypesthesia, compared with 30 patients (19%) in Group PF((>48 hours, ≤ 30 days)) and 22 patients (30.6%) in Group PF(>30 days) (p = 0.014). One hundred fifty-seven patients (34.4%) who initially became free from pain experienced a recurrence of pain with a median delay of 24 months (range 0.62-150.06 months). There were no statistically significant differences between the patient groups with respect to pain recurrence: 66 patients (39%) in Group PF(≤ 48 hours) experienced pain recurrence, compared with 71 patients (36.6%) in Group PF((>48 hours, ≤ 30 days)) and 27 patients (29.7%) in Group PF(>30 days) (p = 0.515).nnnCONCLUSIONSnA substantial number of patients (169 cases, 37.2%) became pain free within the first 48 hours. The rate of hypesthesia was higher in patients who became pain free more than 30 days after GKS, with a statistically significant difference between patient groups (p = 0.014).