Gamma Knife for Functional Diseases Radiosurgery as neuromodulation therapy!

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1 Neurotherapeutics.2014;Epub 2014/06/08 Gamma Knife for Functional Diseases Regis, J.,Aix-Marseille University, INSERM, UMR 1106 and Timone University Hospital, Functional and Stereotactic Neurosurgery Service and Gamma Knife Unit, 264 rue Saint Pierre, 13385, Marseille, CEDEX 05, France, Acta Neurochir Suppl.2013;116( Epub 2013/02/19 Radiosurgery as neuromodulation therapy! Regis, J.,Department of Stereotactic and Functional Neurosurgery, Aix Marseille University, Timone University Hospital, and INSERM U751, 264 rue Saint Pierre, Marseille, 13385, Cedex 05, France. Radiosurgery is commonly considered to be effective through a destructive physical mechanism acting on neural tissue. However, the results of modern neurophysiological, radiological, and histological studies are providing a basis on which to question this assumption. There are now multiple pieces of evidence pointing to a nonlesional mechanism of the radiosurgical action. It appears that tissue destruction is absent or minimal and in almost all cases insufficient to explain the clinical effects produced. There is a real possibility that radiosurgery induces changes in the functioning of neural tissue by differential effects on various neuronal populations and remodeling the glial environment, leading to modulation of function while preserving basic processing. Hence, the majority of radiosurgical procedures induce the desired biological effect without histological destruction of tissue. These findings may result in a major paradigm shift in the treatment of functional brain disorders. Journal of Neurosurgery.2013;118(4): Epub 2013/02/05 Gamma Knife thalamotomy for tremor in the magnetic resonance imaging era Kooshkabadi, A., Lunsford, L. D., Tonetti, D., Flickinger, J. C. and Kondziolka, D.,Departments of Neurological Surgery and. Object The surgical management of disabling tremor has gained renewed vigor with the availability of deep brain stimulation. However, in the face of an aging population of patients with increasing surgical comorbidities, noninvasive approaches for tremor management are needed. The authors' purpose was to study the technique and results of stereotactic radiosurgery performed in the era of MRI targeting. Methods The authors evaluated outcomes in 86 patients (mean age 71 years number of procedures 88) who underwent a unilateral Gamma Knife thalamotomy (GKT) for tremor during a 15-year period that spanned the era of MRI-based target selection ( ). Symptoms were related to essential tremor in 48 patients (19 age >/= 80 years and 3 age >/= 90 years), Parkinson disease in 27 patients (11 age >/= 80 years [1 patient underwent bilateral procedures]), and multiple sclerosis in 11 patients (1 patient underwent bilateral procedures). A single 4-mm isocenter was used to deliver a maximum dose of 140 Gy to the posterior-inferior region of the nucleus ventralis intermedius. The Fahn-Tolosa-Marin clinical tremor rating scale was used to grade tremor, handwriting, and ability to drink. The median follow-up was 23 months. Results The mean tremor score was / before and / after (p < ) GKT the mean handwriting score was / and /- 1.04, respectively (p < ) and the mean drinking score was / and /- 1.15, respectively (p < ). After GKT, 57 patients (66%) showed improvement in all 3 scores, 11 patients (13%) in 2 scores, and 2 patients (2%) in just 1 score. In 16 patients (19%) there was a failure to improve in any score. Two patients developed a 1

2 temporary contralateral hemiparesis, 1 patient noted dysphagia, and 1 sustained facial sensory loss. Conclusions Gamma Knife thalamotomy in the MRI era was a safe and effective noninvasive surgical strategy for medically refractory tremor in the elderly or those with contraindications to deep brain stimulation or stereotactic radiofrequency (thermal) thalamotomy. Neurologia i Neurochirurgia Polska.2012;46(1): Epub 2012/03/20 [Stereotaktyczna radiochirurgia w leczeniu chorob ruchu] Sobstyl, M. and Zabek, M.,dr Michal Sobstyl, Klinika Neurochirurgii, Centrum Medycznego Ksztalcenia Podyplomowego, ul. Marymoncka 99, Warszawa, mrsob@op.pl. Nowadays, functional neurosurgery is an established treatment for movement disorders such as Parkinson's disease, essential tremor, and dystonia. The effectiveness and safety of neuromodulation procedures (deep brain stimulation) replaced in the last years ablative irreversible stereotactic lesions for movement disorders. Stereotactic radiosurgery with gamma knife is a non-invasive form of treatment for movement disorders. The main limitation of stereotactic radiosurgery is the impossibility of electrophysiological confirmation of the target structure. Nevertheless, patients with advanced age and significant medical conditions that preclude classic open stereotactic procedures or patients who must receive anticoagulation therapy may gain great functional be-nefit using gamma knife stereotactic radiosurgery. Neurosurgery.2012;70(3): Epub 2011/09/10 Gamma Knife Thalamotomy for Parkinson Disease and Essential Tremor: A Prospective Multicenter Study Ohye, C., Higuchi, Y., Shibazaki, T., Hashimoto, T., Koyama, T., Hirai, T., Matsuda, S., Serizawa, T., Hori, T., Hayashi, M., Ochiai, T., Samura, H. and Yamashiro, K.,*Functional and Gamma Knife Surgery Center, Hidaka Hospital, Takasaki, Japan double daggerdepartment of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan section signcenter for Neurological Diseases, Aizawa Hospital, Matsumoto, Japan Gamma Knife Center, Heisei Memorial Hospital, Fujieda, Japan paragraph signgamma Knife House, Chiba Cardiovascular Center, Ichihara, Japan #Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan **Department of Neurosurgery, Okinawa Central Hospital, Naha, Japan. BACKGROUND:: No prospective study of gamma knife thalamotomy for intractable tremor has previously been reported. OBJECTIVE:: To clarify the safety and optimally effective conditions for performing unilateral gamma knife (GK) thalamotomy for tremors of Parkinson disease (PD) and essential tremor (ET), a systematic postirradiation 24-month follow-up study was conducted at 6 institutions. We present the results of this multicenter collaborative trial. METHODS:: In total, 72 patients (PD characterized by tremor, n = 59 ET, n = 13) were registered at 6 Japanese institutions. Following our selective thalamotomy procedure, the lateral part of the ventralis intermedius nucleus, 45% of the thalamic length from the anterior tip, was selected as the GK isocenter. A single 130-Gy shot was applied using a 4-mm collimator. Evaluation included neurological examination, magnetic resonance imaging and/or computerized tomography, the unified Parkinson's disease rating scale (UPDRS), electromyography, medication change, and video observations. RESULTS:: Final clinical effects were favorable. Of 53 patients who completed 24 months of follow-up, 43 were evaluated as having excellent or good results (81.1%). UPDRS scores showed tremor improvement (parts II and III). Thalamic lesion size fluctuated but converged to either an almost spherical shape (65.6%), a sphere with streaking (23.4%), or an extended high-signal zone (10.9%). No permanent clinical complications were observed. 2

3 CONCLUSION:: GK thalamotomy is an alternative treatment for intractable tremors of PD as well as for ET. Less invasive intervention may be beneficial to patients. Journal of Neurosurgery.2010;112(6): Epub 2009/11/10 Gamma Knife thalamotomy for treatment of essential tremor: long-term results Young, R. F., Li, F., Vermeulen, S. and Meier, R.,Northwest Hospital Gamma Knife Center, Seattle, Washington 98133, USA. OBJECT: The goal of this report was to describe the safety and effectiveness of nucleus ventralis intermedius (VIM) thalamotomy performed with the Leksell Gamma Knife (GK) for the treatment of essential tremor (ET). METHODS: One hundred seventy-two patients underwent a total of 214 VIM thalamotomy procedures with the Leksell GK between February 1994 and March 2007 for treatment of disabling ET. Eleven patients were lost to follow-up less than 1 year after the procedures, so that in this report the authors describe the results in 161 patients who underwent a total of 203 thalamotomies (119 unilateral and 42 bilateral). RESULTS: There were statistically significant decreases (p < ) in tremor scores for both writing and drawing. The mean postoperative follow-up duration for all patients was 44 +/- 33 months. Fifty-four patients have been followed for more than 60 months posttreatment. There were 14 patients who suffered neurological side effects that were temporary (6) or permanent (8), which accounted for 6.9% of the 203 treatments. All complications were related to lesions that grew larger than expected. CONCLUSIONS: A VIM thalamotomy with the Leksell GK offers a safe and effective alternative for surgical treatment of ET. It is particularly applicable to patients who are not ideal candidates for deep brain stimulation but can be offered to all patients who are considering surgical intervention for ET. Rev Neurol Dis.2010;7(4):150-1 discussion Epub 2011/01/06 A late complication of gamma knife radiosurgery Rothstein, T. L.,Department of Neurology, George Washington University, Washington, DC, USA. An 85-year-old man was hospitalized after developing sudden weakness on his right side and mild expressive aphasia. He had undergone gamma knife stereotactic radiosurgery to the left thalamus 7.5 years earlier for a disabling essential tremor the surgery had led to remarkable improvement in his ability to write and use utensils. He was being treated with warfarin for chronic atrial fibrillation. A computed tomography scan of the brain revealed a 2-cm left thalamic hemorrhage in the precise region of the prior thalamotomy. Archives of Neurology.2010;67(5): Epub 2010/05/12 Gamma knife thalamotomy for disabling tremor: a blinded evaluation Lim, S. Y., Hodaie, M., Fallis, M., Poon, Y. Y., Mazzella, F. and Moro, E.,Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. BACKGROUND: Gamma knife thalamotomy (GKT) has been used as a therapeutic option for patients with disabling tremor refractory to medications. Impressive improvement of tremor has been reported in the neurosurgical literature, but the reliability of such data has been questioned. OBJECTIVE: To prospectively evaluate clinical outcomes after GKT for disabling tremor with blinded assessments. DESIGN: Prospective study with blinded independent neurologic evaluations. SETTING: University hospital. PATIENTS: Consecutive patients who underwent unilateral GKT for essential tremor and Parkinson disease tremor at our center. These patients were unwilling or deemed unsuitable candidates for deep brain stimulation or other surgical procedures. INTERVENTIONS: Unilateral GKT and regular 3

4 follow-up evaluations for up to 30 months, with blinded video evaluations by a movement disorders neurologist. MAIN OUTCOME MEASURES: Clinical outcomes, as measured by the Fahn-Tolosa-Marin Tremor Rating Scale and activities of daily living scores, and incidence of adverse events. RESULTS: From September 1, 2006, to November 30, 2008, 18 patients underwent unilateral GKT for essential tremor and Parkinson disease tremor at our center. Videos for 14 patients (11 with essential tremor, 3 with Parkinson disease tremor) with at least 6 months' postoperative follow-up were available for analysis (mean [SD] follow-up duration, 19.2 [7.3] months range, 7-30 months). The Fahn-Tolosa-Marin Tremor Rating Scale activities of daily living scores improved significantly after GKT (P =.03 median and mean change scores, 2.5 and 2.7 points, respectively [range of scale was 0-27]), but there was no significant improvement in other Fahn-Tolosa-Marin Tremor Rating Scale items (P =.53 for resting tremor, P =.24 for postural tremor, P =.62 for action tremor, P =.40 for drawing, P >.99 for pouring water, P =.89 for head tremor). Handwriting and Unified Parkinson's Disease Rating Scale activities of daily living scores tended to improve (P =.07 and.11, respectively). Three patients developed delayed neurologic adverse events. CONCLUSIONS: Overall, we found that GKT provided only modest antitremor efficacy. Of the 2 patients with essential tremor who experienced marked improvement in tremor, 1 subsequently experienced a serious adverse event. Further prospective studies with careful neurologic evaluation of outcomes are necessary before GKT can be recommended for disabling tremor on a routine clinical basis. World J Surg Oncol.2010;8(20. Epub 2010/03/24 Gamma knife radiosurgery for essential tremor: a case report and review of the literature Elaimy, A. L., Demakas, J. J., Arthurs, B. J., Cooke, B. S., Fairbanks, R. K., Lamoreaux, W. T., Mackay, A. R., Greeley, D. R. and Lee, C. M.,Gamma Knife of Spokane, 910 W 5th Ave, Suite 102, Spokane, WA 99204, USA. Approximately 5 million people in America are affected by essential tremors (ET), which are classified as a type of benign movement disorder. This disease manifests as tremors that usually occur in the hands, but they may also be present in the head, face, tongue, and lower limbs. Radiofrequency thalamotomy (RF) and deep brain stimulation (DBS) are common invasive procedures with proven track records that are used to treat ET. Although these procedures have high success rates, they still put patients at risk of potential side effects and are invasive by nature. Thalamotomy using the gamma knife (GK) also produces favorable outcomes in treating tremors, without the complications associated with invasive neurosurgery procedures. This report describes the presenting symptoms and extended treatment outcome for a patient with an advanced case of ET, who received GK thalamotomy treatment six years ago. Because of this non-invasive treatment, she regained the ability to paint and live with an improved quality of life. We also discuss and review the relevant literature regarding the risks and benefits of this treatment modality. GK thalamotomy is one effective option for the treatment of ET, and due to its noninvasive nature, it has a different risk profile than neurosurgery. We suggest that GK thalamotomy should be presented as one viable treatment option to all ET patients, and should be recommended to those who would be best served by less invasive treatment techniques. World J Surg Oncol.2010;8(61. Epub 2010/07/29 Gamma knife radiosurgery for movement disorders: a concise review of the literature Elaimy, A. L., Arthurs, B. J., Lamoreaux, W. T., Demakas, J. J., Mackay, A. R., Fairbanks, R. K., Greeley, D. R., Cooke, B. S. and Lee, C. M.,Gamma Knife of Spokane, 910 W 5th Ave, Suite 102, Spokane, WA 99204, USA. 4

5 Medication is the predominant method for the management of patients with movement disorders. However, there is a fraction of patients who experience limited relief from pharmaceuticals or experience bothersome side-effects of the drugs. Deep brain stimulation (DBS) and surgical lesioning of the thalamus and basal ganglia are respected neurosurgical procedures, with valued success rates and a very low incidence of complications. Despite these positive outcomes, DBS and surgical lesioning procedures are contraindicated for some patients. Stereotactic radiosurgery with the Gamma Knife (GK) has been used as a lesioning technique for patients seeking a non-invasive treatment alternative and for medication-intolerable patients, who are unable to undergo DBS or lesioning due to comorbid medical conditions. Tremors of various etiologies are treated using GK thalamotomy, which targets the ventralis intermedius nucleus. GK thalamotomy produces favorable outcomes when treating tremors, with success rates ranging from %. In contrast, GK pallidotomy targets the internal globus pallidus, and is used in treating bradykinesia, rigidity, and dyskinesia. Although radiosurgery has proven beneficial for tremors, radiosurgical pallidotomy for bradykinesia, rigidity, and dyskinesia remains questionable, with mixed success rates in the literature that ranges from 0-87%. We suggest that GK thalamotomy be offered along with other neurosurgical approaches as a feasible treatment option to patients who prefer the non-invasive nature of radiosurgery and to those who are unqualified candidates for the neurosurgical alternatives. Also, we advise that patients with bradykinesia, rigidity, and dyskinesia be educated about the variability in the literature pertaining to GK pallidotomy before proceeding with treatment. Prog Neurol Surg.2009;22( Epub 2008/10/25 Treatment of functional disorders with gamma knife thalamotomy Ohye, C. and Shibazaki, T.,Hidaka Hospital, Functional and Gamma Knife Surgery Center, Takasaki, Gunma, Japan. stereohye@dan.wind.ne.jp Gamma knife (GK) thalamotomy for functional disorders, primarily Parkinson disease and central pain, are described herein. The goal was to extend our present indications for selective thalamotomy. Our target for tremor surgery is about 45% of the thalamic length. Thus, this principle was applied to deciding the GK thalamotomy target. In most of our cases, the protocol was 130 Gy, delivered in one shot with a 4-mm collimator. The time courses of thalamic lesion changes and clinical improvement after irradiation were assessed. Thus, despite thalamic reaction changes being variable, we achieved a clinical success rate of approximately 80% with negligible complications. Acta Neurochirurgica.2008;150(8):823-7 discussion 827. Epub 2008/07/11 Microelectrode findings and topographic reorganisation of kinaesthetic cells after gamma knife thalamotomy Terao, T., Yokochi, F., Taniguchi, M., Kawasaki, T., Okiyama, R., Hamada, I., Nishikawa, N., Izawa, N., Shin, M., Kumada, S. and Takahashi, H.,Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan. tohru@jg7.so-net.ne.jp A 64-year-old woman with Parkinson is disease had a severe resting tremor that was not completely relieved by right-sided gamma knife thalamotomy (GKT). We performed bilateral staged thalamic deep brain stimulation (DBS) and compared the right and left ventral intermediate nucleus (Vim) of the thalamus including the frequency of single units recorded with microelectrodes, and also the somatotopical distribution of kinaesthetic cells (Ki). The average frequency of units for the presumed left Vim exceeded that of the right (22.6 +/ Hz vs /- 8.8 Hz). Regarding the somatotopic distribution of Ki, the receptive field for the leg, which is usually situated in the dorsolateral Vim, was more widely scattered in the right Vim than the non-lesioned left side. Our findings raise the possibility 5

6 that the specific properties of the neurons changed due to partial coagulation by GKT within both the coagulated and the surrounding thalamic lesions. Journal of Neurosurgery.2008;108(1): Epub 2008/01/05 Gamma Knife thalamotomy for essential tremor Kondziolka, D., Ong, J. G., Lee, J. Y., Moore, R. Y., Flickinger, J. C. and Lunsford, L. D.,Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. OBJECTIVES: The purpose of this study was to evaluate the results following Gamma Knife thalamotomy (GKT) for medically refractory essential tremor in a series of patients in whom open surgical techniques were not desirable. METHODS: Thirty-one patients underwent GKT for disabling essential tremor after medical therapy had failed. Their mean age was 77 years. Most patients were elderly or had concomitant medical illnesses. A single 4-mm isocenter was used to target a maximum dose of 130 or 140 Gy to the nucleus ventralis intermedius. Items from the Fahn-Tolosa-Marin clinical tremor rating scale were used to grade tremor and handwriting before and after radiosurgery. RESULTS: The median follow-up was 36 months. In the group of 26 evaluable patients, the mean tremor score (+/- standard deviation) was 3.7 +/- 0.1 preoperatively and 1.7 +/- 0.3 after radiosurgery (p < ). The mean handwriting score was 2.8 +/- 0.2 before GKT and 1.7 +/- 0.2 afterward (p < ). After radiosurgery, 18 patients (69%) showed improvement in both action tremor and writing scores, 6 (23%) only in action tremor scores, and 3 (12%) in neither tremor nor writing. Permanent mild right hemiparesis and speech impairment developed in 1 patient 6 months after radiosurgery. Another patient had transient mild right hemiparesis and dysphagia. CONCLUSIONS: Gamma Knife thalamotomy is a safe and effective therapy for medically refractory essential tremor. Its use is especially valuable for patients ineligible for radiofrequency thalamotomy or deep brain stimulation. Patients must be counseled on potential complications, including the low probability of a delayed neurological deficit. Surgical Neurology.2007;68(4): Epub 2007/10/02 Gamma knife thalamotomy for multiple sclerosis tremor Mathieu, D., Kondziolka, D., Niranjan, A., Flickinger, J. and Lunsford, L. D.,Department of Neurological Surgery, University of Pittsburgh, Center for Image-Guided Neurosurgery, Pittsburgh, PA 15213, USA. BACKGROUND: Some patients with MS suffer from disabling tremor. Improvement with medical treatment is modest, at best. Stereotactic surgery targeting the vim nucleus of the thalamus has been successful in alleviating MS tremor. Gamma knife radiosurgery represents a minimally invasive alternative to radiofrequency lesioning and DBS that can provide improvement in patients suffering from essential and parkinsonian tremor. We reviewed our experience with GK thalamotomy in the management of six consecutive patients suffering from disabling MS tremor. METHODS: The median age at the time of radiosurgery was 46 years (range, 31 to 57 years). Intention tremor had been present for a median of three years (range 8 months to 12 years). One 4-mm isocenter was used to deliver a median maximum dose of 140 Gy (range, Gy) to the vim nucleus of the thalamus opposite the side of the most disabling tremor. Clinical outcome was assessed using the Fahn-Tolosa-Marin scale. RESULTS: The median follow-up was 27.5 months (range, 5-46 months). All patients experienced improvement in tremor after a median latency period of 2.5 months. More improvement was noted in tremor amplitude than in writing and drawing ability. In four patients, the tremor reduction led to functional improvement. One patient suffered from transient contralateral hemiparesis, which resolved after brief corticosteroid administration. No other complication was seen. CONCLUSION: Gamma knife radiosurgical thalamotomy is effective as a minimally invasive alternative to stereotactic surgery for the palliative treatment of disabling MS tremor. 6

7 Neurosurg Focus.2007;23(6):E3. Epub 2007/12/18 Stereotactic radiosurgery for functional disorders Friehs, G. M. Park, M. C. Goldman, M. A. Zerris, V. A. Noren, G. Sampath, P.,Department of Clinical Neurosciences Program in Neurosurgery and New England Gamma Knife Center, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA. Stereotactic radiosurgery (SRS) with the Gamma Knife and linear accelerator has revolutionized neurosurgery over the past 20 years. The most common indications for radiosurgery today are tumors and arteriovenous malformations of the brain. Functional indications such as treatment of movement disorders or intractable pain only contribute a small percentage of treated patients. Although SRS is the only noninvasive form of treatment for functional disorders, it also has some limitations: neurophysiological confirmation of the target structure is not possible, and one therefore must rely exclusively on anatomical targeting. Furthermore, lesion sizes may vary, and shielding adjacent radiosensitive neural structures may be difficult or impossible. The most common indication for functional SRS is the treatment of trigeminal neuralgia. Radiosurgical treatment for epilepsy and certain psychiatric illnesses is performed in several centers as part of strict research protocols, and radiosurgical pallidotomy or medial thalamotomy is no longer recommended due to the high risk of complications. Radiosurgical ventrolateral thalamotomy for the treatment of tremor in patients with Parkinson disease or multiple sclerosis, as well as in the treatment of essential tremor, may be indicated for a select group of patients with advanced age, significant medical conditions that preclude treatment with open surgery, or patients who must receive anticoagulation therapy. A promising new application of SRS is high-dose radiosurgery delivered to the pituitary stalk. This treatment has already been successfully performed in several centers around the world to treat severe pain in patients with end-stage cancer. Prog Neurol Surg.2007;20( Epub 2007/02/24 Movement disorder radiosurgery--planning, physics and complication avoidance Duma, C. M.,Department of Neurosurgery, Hoag Memorial Hospital Presbyterian, Newport Beach, CA 92663, USA. cduma@hoaghospital.org Gamma Knife radiosurgical thalamotomy is an effective and useful alternative to invasive radiofrequency techniques for patients at high surgical risk. The mechanical accuracy of the gamma unit combined with the anatomical accuracy of high-resolution MRI make radiosurgical lesioning safe and precise. Higher radiosurgical doses are more effective than lower ones at eliminating or reducing tremor, and are generally without complications. The results from radiosurgical pallidotomy, as opposed to those of gamma thalamotomy, have been disappointing. A 50% complication rate in the former (homonymous field cuts, hemipareses and dysphagias) combined with a poor success rate has led us to reevaluate the indications for this procedure in the face of the excellent results from radiofrequency pallidotomy with physiological monitoring and deep brain stimulation. Perhaps experience with lowered radiosurgical prescription doses will improve the complication rate. There appears to be a differential sensitivity of the pallidum to radiation, anatomically, than the thalamus. Age-related or anatomy-related susceptible blood supply to the area may lead to hypoxia after singlefraction radiosurgery, in a nuclear complex known to be especially susceptible to hypoxia. In addition, varying levels of iron deposition within the pallidum may catalyze free radical formation in the elderly only to be further exacerbated by tissue hypoxia. Although reported, the success of radiosurgical caudatotomy, subthalamotomy and lesioning of the VL nucleus remains to be further elucidated. Stereotactic and Functional Neurosurgery.2006;84(4): Epub 2006/08/15 7

8 From selective thalamotomy with microrecording to gamma thalamotomy for movement disorders Ohye, C.,Functional and Gamma Knife Surgery Center, Hidaka Hospital, Takasaki, Gunma, Japan. A theoretical and practical process from microrecording-guided thalamotomy to gamma knife thalamotomy was briefly reviewed. Based on our own experiences of selective thalamotomy with microrecording, we are trying to apply gamma knife to the treatment of movement disorders. An important technical problem is how to determine the exact thalamic target. At first we refer to the posterior commissure and coordinate of the standard atlas for approximately determining the lateral part of the ventral intermediate nucleus. Then the point is further corrected by anatomical landmark (45% of the thalamic length) to compensate the individual difference. A final lesion is made by gamma knife using a 4-mm collimator, 130 Gy in 1 shot. The average delay of clinical improvement is about 6 months after irradiation. Thus far the results are satisfactory, being 80-85% successful without any noticeable complications. Only 3 days of hospitalization with minimal invasion could be a big advantage for the patient. Further technical progress may improve the clinical results in the future. Stereotactic and Functional Neurosurgery.2005;83(2-3): discussion Epub 2005/08/10 Neurophysiological evaluation of the optimum target in gamma thalamotomy: indirect evidence Sato, S., Ohye, C., Shibazaki, T., Zama, A. and Cai, X.,Functional and Gamma Knife Surgery Center, Hidaka Hospital, Takasaki, Gunma, Japan. sumito@ba.mbn.or.jp Gamma thalamotomy has been useful for the treatment of Parkinson's disease and other movement disorders, but it has disadvantages, such as a delayed clinical effect after irradiation and the inaccuracy of targeting because depth recording is not available. Therefore, we sought to determine the optimum target in gamma thalamotomy based on the results of conventional selective thalamotomy with reference to the AC-PC line. To obtain indirect support for the appropriateness of the optimum target, we performed depth recording around the region of the estimated optimum target based on the results of conventional thalamotomy. Four patients with tremor caused by Parkinson's disease or essential tremor were used as subjects after they gave their fully informed consent. The targets were determined as points 6-8 mm anterior to the posterior commissure, 4-6 mm dorsal to the level of the intercommissural line, and mm lateral from the midline. Rhythmic discharge time-locked to tremor and/or kinesthetic neurons were found within the expected target area in all patients. Finally, in all cases, the tremor was abolished without complications after coagulative lesions were made with dual coagulation needles to cover the supposed Vim zone according to the depth recording. We considered that the target point determined in the same way as in gamma thalamotomy is suitable from an anatomophysiological perspective. Journal of Neurosurgery.2005;102 Suppl( Epub 2005/01/25 Gamma knife thalamotomy for movement disorders: evaluation of the thalamic lesion and clinical results Ohye, C., Shibazaki, T. and Sato, S.,Functional and Gamma Knife Surgery Center, Hidaka Hospital, Gunma, Japan. stereohye@dan.wind.ne.jp OBJECT: The authors studied the effects of gamma knife thalamotomy (GKT) on Parkinson diseaserelated tremor and essential tremor before and after reloading of radioactive cobalt. METHODS: Based on experience in stereotactic thalamotomy aided by depth microrecording, the target was located at the lateral border of the thalamic ventralis intermedius nucleus (VIM). For more precise targeting, the percentage representation of the thalamic VIM in relation to the entire thalamic length is useful. The location of the target was determined on magnetic resonance (MR) imaging and computerized 8

9 tomography scanning. A maximum dose of 130 Gy was delivered to the target by using a single isocenter with the 4-mm collimator. In more recent cases, a systematic follow-up examination was performed at 3, 6, 12, 18, and 24 months after GKT. Since 1993, the authors have treated 70 patients with PD. Throughout the series the same dosimetric technique has been used. The course after GKT was compared between the 25 cases with PD treated before reloading and the 35 cases treated after reloading. In the majority (80-85%) treated after reloading, tremor and rigidity were reduced around 6 months after GKT. In the cases treated before reloading this effect took approximately 1 year. The thalamic reaction on MR imaging showed the same two lesion types in both series: a restricted and a diffuse. After reloading the restricted lesion was more frequent and the lesion volume was smaller. CONCLUSIONS: The shorter delay in clinical improvement and smaller lesion size may be related to an increased radiation dose. Journal of the Louisiana State Medical Society.2004;156(3): Epub 2004/07/06 A case report of complete disappearance of essential tremor after Gamma Knife radiosurgery Jawahar, A., Cardenas, R. J., Zwieg, R. M., Willis, B. K. and Nanda, A.,Department of Neurosurgery, Louisiana State University Health Sciences Center, Shreveport, USA. Pharmacological therapy for essential tremor (ET), the most common movement disorder, remains largely unsatisfactory. Surgical options such as radiofrequency or thermocoagulation are only suitable for a select group of patients, the young and those free of pre-existing medical conditions. Radiosurgery using the Leksell Gamma Knife has recently gained acceptance as a viable treatment option for tremor control in ET patients. We describe our experience with the first reported ET patient treated with radiosurgery in Louisiana. Journal of Neurosurgery.2002;97(5 Suppl): Epub 2003/01/01 Thalamic lesions produced by gamma thalamotomy for movement disorders Ohye, C., Shibazaki, T., Zhang, J. and Andou, Y.,Hidaka Hospital, Functional and Gamma Knife Surgery Center, Takasaki, Gunma, Japan. stereohye@dan.wind.ne.jp OBJECT: The treatment of Parkinson disease and other kinds of involuntary movement by gamma knife radiosurgery (GKS) is presented. This is an extension of previous work. The clinical course and thalamic lesions were the main factors examined. METHODS: Seventeen new cases were added to the previously reported 36 cases. The course and results for the whole series of 53 patients were examined. Treatment was undertaken using a single 4-mm collimator shot to deliver 130 Gy to the target. The target was determined in the previously treated patients by using classic methods involved in conventional stereotactic thalamotomy with microrecording. More recently, target localization has been performed by relating the target point to the total length of the thalamus. Points may then be defined as percentages of that length measured from the anterior pole. Targets can then be determined in relationship to the appropriate percentage. Thirty-five patients have been followed for more than 2 years and the longest follow up was 8 years. Two kinds of thalamic lesion were seen after GKS. Volumetric analysis on MR imaging revealed that the larger lesion was 400 to 500 mm3 at the beginning and gradually decreased in size. The smaller lesion occupied approximately 200 mm3 and also shrank over several months. Eighty percent of the treated cases showed good results and no significant complications, with the tremor subsiding at 1 year (Type 1). Several cases deviated from this standard course in four different ways (Types 2-5). If tremor persisted, conventional stereotactic thalamotomy with microrecording was performed. During such operations, normal neuronal activity was recorded from the region adjacent to the GKS thalamotomy target. This was the region showing a high signal on MR imaging. The activity patterns included the rhythmical grouped discharge of tremor rhythm. 9

10 CONCLUSIONS: Gamma thalamotomy for functional disorders is still under development, but because the results with careful target planning are satisfactory, there are grounds for increasing optimism. Archives of Neurology.2002;59(10):1660 author reply Epub 2002/10/11 Gamma knife thalamotomy for disabling tremor Kondziolka, D., Movement Disorders.2001;16(5): Epub 2001/12/18 Emergence of complex, involuntary movements after gamma knife radiosurgery for essential tremor Siderowf, A., Gollump, S. M., Stern, M. B., Baltuch, G. H. and Riina, H. A.,Department of Neurology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA. Gamma knife radiosurgery is generally considered a safer alternative to traditional pallidotomy or thalamotomy. We report the case of a 59-year-old patient with essential tremor who developed a complex, disabling movement disorder following gamma knife thalamotomy. This case illustrates the need for long-term follow-up to fully evaluate the potential for complications following radiosurgery. Journal of Neurosurgery.2000;93 Suppl 3( Epub 2001/01/06 Gamma knife thalamotomy for treatment of tremor: long-term results Young, R. F., Jacques, S., Mark, R., Kopyov, O., Copcutt, B., Posewitz, A. and Li, F.,Neuroscience Institute and Gamma Knife Centers, Good Samaritan Hospital, Los Angeles, California, USA. OBJECT: The purpose of this study was to investigate the long-term effects of gamma knife thalamotomy for treatment of disabling tremor. METHODS: One hundred fifty-eight patients underwent magnetic resonance imaging-guided radiosurgical nucleus ventralis intermedius (VIM) thalamotomy for the treatment of parkinsonian tremor (102 patients), essential tremor (52 patients), or tremor due to stroke, encephalitis, or cerebral trauma (four patients). Preoperative and postoperative blinded assessments were performed by a team of independent examiners skilled in the evolution of movement disorders. A single isocenter exposure with the 4-mm collimator helmet of the Leksell gamma knife unit was used to make the lesions. In patients with Parkinson's disease 88.3% became fully or nearly tremor free, with a mean follow up of 52.5 months. Statistically significant improvements were seen in Unified Parkinson's Disease Rating Scale tremor scores and rigidity scores, and these improvements were maintained in 74 patients followed 4 years or longer. In patients with essential tremor, 92.1% were fully or nearly tremor free postoperatively, but only 88.2% remained tremor free by 4 years or more post-gks. Statistically significant improvements were seen in the Clinical Rating Scale for tremor in essential tremor patients and these improvements were well maintained in the 17 patients, followed 4 years or longer. Only 50% of patients with tremor of other origins improved significantly. One patient sustained a transient complication and two patients sustained mild permanent side effects from the treatments. CONCLUSIONS: Gamma knife VIM thalamotomy provides relief from tremor equivalent to that provided by radiofrequency thalamotomy or deep brain stimulation, but it is safer than either of these alternatives. Long-term follow up indicates that relief of tremor is well maintained. No long-term radiation-induced complications have been observed. Journal of Neurosurgery.2000;93 Suppl 3( Epub 2001/01/06 Evaluation of gamma thalamotomy for parkinsonian and other tremors: survival of neurons adjacent to the thalamic lesion after gamma thalamotomy Ohye, C., Shibazaki, T., Ishihara, J. and Zhang, J.,Functional and Gamma Knife Surgery Center, Hidaka Hospital, Takaski, Gunma, Japan. stereohe@showa.gunma-u.ac.jp 10

11 OBJECT: The effects of gamma thalamotomy for parkinsonian and other kinds of tremor were evaluated. METHODS: Thirty-six thalamotomies were performed in 31 patients by using a 4-mm collimator. The maximum dose was 150 Gy in the initial six cases, which was reduced to 130 Gy thereafter. The longest follow-up period was 6 years. The target was determined on T2-weighted and proton magnetic resonance (MR) images. The point chosen was in the lateral-most part of the thalamic ventralis intermedius nucleus. This is in keeping with open thalamotomy as practiced at the authors' institution. In 15 cases, gamma thalamotomy was the first surgical procedure. In other cases, previous therapeutic or vascular lesions were visible to facilitate targeting. Two types of tissue reaction were onserved on MR imaging: a simple oval shape and a complex irregular shape. Neither of these changes affected the clinical course. In the majority of cases, the tremor subsided after a latent interval of approximately 1 year after irradiation. The earliest response was demonstrated at 3 months. In five cases the tremor remained. In four of these cases, a second radiation session was administered. One of these four patients as well as another patient with an unsatisfactory result underwent open thalamotomy with microrecording. In both cases, depth recording adjacent to the necrotic area revealed normal neuronal activity, including the rhythmic discharge of tremor. Minor coagulation was performed and resulted in immediate and complete arrest of the remaining tremor. CONCLUSIONS: Gamma thalamotomy for Parkinson's disease seems to be an alternative useful method in selected cases. Neurology.2000;55(3): Epub 2000/08/10 Functional outcomes after gamma knife thalamotomy for essential tremor and MS-related tremor Niranjan, A., Kondziolka, D., Baser, S., Heyman, R. and Lunsford, L. D.,Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Twelve patients with a median age of 75 years underwent gamma knife thalamotomy for essential tremor (ET) (n = 9) or MS-related tremor (n = 3). All 11 evaluable patients noted improvement in action tremor. Six of eight ET patients had complete tremor arrest, and the violent action tremor in all three patients with MS was improved. One patient developed transient arm weakness. Stereotactic radiosurgery for ET and MS-related tremor is safe and effective for patients who may be poor candidates for other procedures. Stereotactic and Functional Neurosurgery.1999;72(2-4): Epub 2000/06/15 A comparison of surgical approaches for the management of tremor: radiofrequency thalamotomy, gamma knife thalamotomy and thalamic stimulation Niranjan, A., Jawahar, A., Kondziolka, D. and Lunsford, L. D.,Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. OBJECTIVE: Between April 1994 and January 1999, 39 stereotactic procedures for patients with intractable tremor were performed at the University of Pittsburgh Medical Center. A retrospective analysis of results of radiosurgical thalamotomy (n = 15), MR-guided stereotactic radiofrequency thalamotomy (n = 13), and deep brain thalamic stimulation (DBS n = 11) was performed to study relative advantages and risks of these procedures. METHODS: All options were discussed with the patients, but radiosurgery usually was performed in elderly patients with concurrent medical problems. Stereotactic thalamotomy and DBS was performed with MR guidance and macrostimulation. For radiosurgery, a median dose of 140 Gy (range Gy) was delivered using a single 4-mm collimator. RESULTS: Of the 13 patients who underwent radiofrequency thalamotomy, 5 had immediate complete arrest of tremor, 6 had a significant reduction and 2 had partial reduction. All 11 patients who underwent DBS had excellent control of tremor immediately after the procedure, and in longer-term follow-up 10/11 maintained excellent tremor control. Of the 12 evaluable radiosurgery patients, 10 11

12 noted excellent relief and 2 had partial relief. CONCLUSION: Stereotactic procedures for tremor control are safe and effective. Each procedure has specific advantages and disadvantages that are important for patient selection. Neurosurgery.1999;44(1):12-20 discussion Epub 1999/01/23 Functional radiosurgery Kondziolka, D.,Department of Neurological Surgery, Center for Image-Guided Neurosurgery, University of Pittsburgh, Pennsylvania, USA. Although the application of stereotactic radiosurgery for the management of functional brain disorders began in 1951, almost 50 years elapsed before it received appropriate attention. Radiosurgical techniques are used to create image-guided, physiological inactivity or focally destructive brain lesions without neurophysiological guidance. The lack of neurophysiological guidance remains the greatest argument against the use of radiosurgery for selected disorders. Current anatomic targets include the trigeminal nerve (for trigeminal neuralgia), the thalamus (for tremor or pain), the cingulate gyrus or anterior internal capsule (for pain or psychiatric illness), the globus pallidus (for symptoms of Parkinson's disease), and the hippocampus (for epilepsy). The use of radiosurgery as a "lesion generator" is based on extensive animal studies that defined the dose, volume, and temporal response of the irradiated tissue. The usefulness of radiosurgery has been compared with that of microsurgical, percutaneous, and electrode-based techniques used for functional neurological disorders. At present, the long-term results after functional radiosurgery procedures remain to be documented. The current indications and expected outcomes after radiosurgery are discussed. Neurosurgery Clinics of North America.1999;10(2): Epub 1999/03/31 Imaging changes after radiosurgery for vascular malformations, functional targets, and tumors Kihlstrom, L. and Karlsson, B.,Department of Neurosurgery, Clinical Neurosciences Gamma Knife Center, Karolinska Hospital, Stockholm, Sweden. Normal brain tissue is probably the most important tissue compartment in the brain involved in adverse radiation effects (AREs). The capabilities of computerized tomography, magnetic resonance imaging, and positron emission tomography in repeat examinations of a treatment outcome provide a baseline by which to monitor the AREs in vivo and to follow their sequential changes. This article relates the AREs seen after radiosurgery to the dose/volume and specific tissue effects established from 30 years of collected experience with radiosurgery at the Karolinska Hospital. Radiology.1999;212(1): Epub 1999/07/16 Stereotactic radiosurgical pallidotomy and thalamotomy with the gamma knife: MR imaging findings with clinical correlation--preliminary experience Friedman, D. P., Goldman, H. W., Flanders, A. E., Gollomp, S. M. and Curran, W. J., Jr.,Department of Radiology, Wills Eye Hospital, Philadelphia, PA, USA. friedm11@jeflin.tju.edu PURPOSE: To evaluate the temporal evolution and appearance of a radiosurgical lesion at magnetic resonance (MR) imaging and the clinical response in patients undergoing stereotactic radiosurgical pallidotomy or thalamotomy with the gamma knife. MATERIALS AND METHODS: Seventeen patients with medically refractory movement disorders underwent stereotactic radiosurgical pallidotomy (n = 2) or thalamotomy (n = 15). A single dose of Gy was administered to a target in the globus pallidus interna or ventralis intermedius thalamic nucleus. Postprocedure gadolinium-enhanced MR imaging and clinical assessment were performed at 1 month and 3 months. RESULTS: At 3 months, the radiosurgical lesion most commonly (n = 11) appeared as a ring-enhancing focus 5 mm or less in diameter surrounded 12

13 by vasogenic edema that extended less than 7 mm in radius beyond the target. Five patients had ringenhancing lesions 7 mm or more in diameter four of these developed symptomatic perilesional edema at 3 (n = 2) or 8 (n = 2) months after the procedure. Onset of therapeutic effect began approximately 4 weeks after treatment. In the 15 patients with tremor, there was a mean decline of 2.1 on the Tremor Rating Scale. CONCLUSION: Findings in this pilot study suggest that radiosurgical thalamotomy is a promising treatment for medically refractory tremor. Three-month follow-up MR studies show a ringenhancing lesion surrounded by a variable amount of vasogenic edema. Visualization of the radiosurgical lesion and the clinical response are delayed compared to that with radio-frequency procedures. Neurosurgery Clinics of North America.1999;10(2): Epub 1999/03/31 The treatment of movement disorders using Gamma Knife stereotactic radiosurgery Duma, C. M., Jacques, D. and Kopyov, O. V.,Hoag/University of California Irvine Gamma Knife Program, Department of Neurosurgery, Hoag Memorial Hospital Presbyterian, Newport Beach, California 92663, USA. In this era of modern neurosurgery, we are able to provide adequate amelioration of disabling symptoms for the small subset of patients who have conditions that may make them unacceptable candidates for invasive stereotactic neurosurgical intervention. Gamma Knife radiosurgical thalamotomy is an effective and useful alternative to invasive radiofrequency techniques for patients at high surgical risk. The mechanical accuracy of the gamma unit combined with the anatomical accuracy of highresolution magnetic resonance imaging makes radiosurgical lesioning safe and precise. Neurosurgery.1999;45(5): discussion Epub 1999/11/05 Evaluation of the spatial accuracy of magnetic resonance imaging-based stereotactic target localization for gamma knife radiosurgery of functional disorders Bednarz, G., Downes, M. B., Corn, B. W., Curran, W. J. and Goldman, H. W.,Department of Radiation Oncology, Kimmel Cancer Center of the Jefferson Medical College, Thomas Jefferson University, and the Neurosensory Institute of Wills Eye Hospital, Philadelphia, Pennsylvania , USA. PURPOSE: This study was undertaken to determine the impact of geometric distortions on the spatial accuracy of magnetic resonance imaging (MRI)-guided stereotactic localization for gamma knife functional radiosurgery. METHOD: The spatial accuracy of MRI was evaluated by comparing stereotactic coordinates of intracranial targets, external fiducials, and anatomic structures defined by computed tomographic and MRI studies of the Radionics skull phantom (Radionics, Inc., Burlington, MA), the Rando head phantom, and 11 patients who underwent gamma knife functional radiosurgery. The distortion in MRI was assessed from computed tomographic and MRI fusion studies for these patients, as well as from MRI studies acquired by swapping the direction of the magnetic field gradients for five patients who underwent gamma knife radiosurgery and three patients who underwent MRI-guided frameless surgery. A follow-up program to compare the location of the created lesion with the intended target complemented the analysis. RESULTS: The average difference between computed tomographic and MRI stereotactic coordinates of external fiducials, intracranial targets, and anatomic landmarks was of the order of 1 pixel size (0.9 x 0.9 x 1 mm3) along the x, y, and z axes. The average linear scaling along these axes as determined by fusion studies was approximately 0.8% and consistent with a single pixel. The follow-up studies, available for seven patients, revealed good agreement between the location of the created lesion and the intended target. CONCLUSION: The spatial accuracy of an MRI-based 13