In order to discuss the merits of radiosurgical thalamotomy, it is beneficial to consider the role of conventional radiofrequency thalamotomy in the treatment of patients with tremor. Tasker retrospectively studied patients who had radiofrequency thalamotomy and thalamic stimulation [1]. He noted tremor recurrence in 15 % of thalamotomy patients, as opposed to 5 % of DBS patients. Importantly, 23 % of the thalamotomy patients required repeat procedures for tremor control. In addition, thalamotomy resulted in a decline in writing performance in 23 % of patients, as opposed to no patients in the DBS group. All of the DBS patients achieved better than 50 % improvement in dexterity, writing, and drinking ability, where only half of the thalamotomy cohort obtained that level of benefit. With respect to complications, Tasker demonstrated that chronic stimulation had a lower incidence of ataxia and dysarthria, which are common complications associated with bilateral thalamotomy [1]. Moreover, when these complications occurred in the DBS group, simply adjusting the stimulation parameters served to abolish these problems. In another study that was a prospective, blinded study, Schuurman et al. randomized 68 patients (45 with PD, 13 with ET, and 10 with multiple sclerosis) to radiofrequency thalamotomy versus VIM DBS [35]. Both groups of patients had excellent suppression of tremor, but the VIM DBS group had greater improvements in activities of daily living (ADL), and more importantly, the VIM DBS group had fewer complications. Patients who underwent thalamotomy were more likely to develop somnolence, cognitive deterioration, and dysarthria, as well as gait or balance disturbance. Thus, Tasker and Schuurman et al. have both confirmed the higher complication rates associated with thalamotomy compared with VIM DBS, and it is in this context that the use of radiosurgical thalamotomy must be considered.

As opposed to both radiofrequency thalamotomy and DBS, GKT offers a noninvasive lesioning method that does not require a skin incision, burr hole, or passage of electrodes. In addition, it does not harbor any foreign hardware placement, and the risk of infection/erosion is eliminated. Hence, the surgical risk of complications is potentially lower than that of radiofrequency thalamotomy or DBS. This technique may be ideal for patients who are not suitable to undergo a surgical procedure due to medical comorbidities or to those who want to avoid open surgical procedures with hardware implantations. GKT is effective and reported to treat parkinsonian tremor, essential tremor, multiple sclerosis-related tremor, and posttraumatic-related tremor with different results [36]. A major disadvantage of GKT is the inability to confirm the target physiologically by using MER and macrostimulation (electrophysiological monitoring). One has to rely purely on imaging-defined anatomic targeting, which lacks the accuracy of brain mapping. In addition, the method of lesion generation is delayed, and as has been suggested in some recent publications, the lesion can be variable in size [37]. Hence, GKT has both advantages and disadvantages that may give it a role in the treatment of tremor.

Compared with the large multicenter studies of deep brain stimulation for tremor, there are only a few published case series of patients treated by Gamma Knife radiosurgical thalamotomy for the treatment of parkinsonian tremor and essential tremor [6] (Table 56.1). Ohye was one of the first to advocate radiosurgical lesioning of the thalamus in patients who had a contralateral radiofrequency lesion or in patients who had a previously mapped lesion [38]. At present, Ohye has reported radiosurgical thalamotomy in 70 patients with PD and has reported tremor suppression of at least two thirds in more than 80 % of patients with no loss of effect even after 10 years in some patients [37, 39]. Duma et al. has reported their series of 42 radiosurgical thalamotomies in 38 patients over a 7-year period. In their series of patients, 24 % had complete relief of tremor, 55 % had “successful” results in improvement of their tremor, and 21 % of patients had only “mild” or no relief of tremor. Median follow-up in this series was 28 months [40, 41]. Niranjan et al. reported favorable results in 12 patients who were not candidates for open surgical procedures (nine patients with essential tremor and three patients with MS-related tremor) [42]. Eight of their 12 patients with essential tremor had complete tremor arrest, while the remaining four patients had improvement in tremor. The largest series of patients undergoing GKT has been published by Young et al. who retrospectively reviewed 158 patients who underwent radiosurgical thalamotomy [43]. Of the 74 patients with parkinsonian tremor followed at least 4 years, 79.7 % were still tremor-free, while 70.6 % of the 16 patients with essential tremor were tremor-free. In this series, only one patient sustained a transient complication, and two patients sustained permanent complications including hemiparesis and mild facial paresthesias. No cognitive changes were reported. Kondziolka et al. [44] reported a series of 31 essential tremor patients treated with SRS followed for a mean of 36 months. Of their patient cohort, 18 (66.6 %) reported improvement in action tremor and writing, 6 (22.2 %) showed improvement in action tremor alone, and 3 (11.1 %) showed no improvement. In this study, there were two complications (7.4 %) that were both permanent, including hemiparesis, dysphagia, and speech impairment. Recently, Lim et al. reported their experience with GKT for treating disabling tremor [36]. Although this study is derived from a single center, it is the only prospective blinded independent observer study that was done for GKT. In this series, assessment of tremor, ADL, complications, and long-term outcomes were analyzed in 14 patients with mean follow-up period of 7.3 months. They concluded that an improvement is achieved only in tremor and ADL, but this improvement seems to be modest, non-sustained, and less impressive than achieved with DBS. In this study, three patients developed delayed complications including hemiparesis and speech deficit.

In contrast to the major studies that were done to evaluate DBS, GKT reports lack the stringent standards to prove efficacy and safety (multicenter, double-blinded, randomization, long-term follow-up). This makes it difficult to compare these different modalities; however, the results of these studies suggest that radiosurgical thalamotomy is less superior to DBS or even radiofrequency thalamotomy.

In opposition to the immediate response and relief of tremor following DBS or thalamic radiofrequency ablation, Gamma Knife radiosurgical thalamotomy effect is delayed, and different studies reported different time frames from anywhere between immediate affects to 12 months [37, 40, 42]. Niranjan et al. [44] reported immediate relief in tremor following GKT. Moro et al. [36] reported in their study of 18 patients an improvement in tremor with a delay of 6–12 months following GKT. Ohye et al. [36] reported in their study improvement in tremor starting 1 year following GKT. This gap between treatment and functional progress must be taken under consideration when making a treatment decision, since most patients with movement disorders suffer daily and some cannot tolerate the time between treatment and clinical effect. This delay is related to neurobiological sequences that take place in the brain parenchyma following GKT and the time it takes the ionizing radiation to functionally damage or to destroy the tissue targeted. The time to lesion effect can be modified and accelerated with increased doses [45]; however, the optimal technique for Gamma Knife radiosurgical lesioning has not been established. Due to the different response of tissue to ionizing radiation, lesion size can be smaller than expected, while in other cases can be larger and expand to eloquent adjacent structures resulting in serious adverse effects [46]. Peak central doses can range from 120 to 200 Gy. Duma et al. reported a difference in clinical outcome with different doses, suggesting an improvement with higher doses [41]. Despite this correlation, most surgeons at this time now perform radiosurgical lesioning for functional disorders at lower doses (e.g., 140 Gy) [42]. This decision is partially based on the series of eight patients all treated at the same institution who developed complications published by Okun et al. [46]. In that series, all except one of the thalamotomy procedures were performed at exceptionally high doses using 200 Gy (one patient was treated at 150 Gy). Unfortunately, a systematic study of dose–response complication rate has not been performed to date.

Because of the delay in effect after GKT, an accurate documentation of complications requires vigilant follow-up. The complications that can occur mainly include radiation necrosis, brain edema, and bleeding. There isn’t an established time frame for the occurrence of complication, and they can happen even years following GKT treatment. Rothstein et al. [47] reported an intrathalamic hemorrhage in the precise site of prior GKT 7.5 years after treatment. In Young’s series, 3 of 74 patients developed a complication [43]. Other reports are single-center reports of complications without a denominator to define the total number of procedures or patients who underwent GKT. Siderowf et al. reported one case of a complex, involuntary movement after Gamma Knife radiosurgical thalamotomy [2]. Unfortunately, specific dose parameters were not specified in that case report. Okun et al. reported a series of eight patients who developed multiple complications, including hemiplegia, homonymous visual field deficits, hand weakness, dysarthria, hypophonia, aphasia, arm and face numbness, pseudobulbar laughter, and death [46]. Mathieu et al. reported progressive contralateral hemiplegia following GKT with T2 changes around targeted lesion [48]. These complications all developed after treatment at different Gamma Knife centers, and it does not appear that the same rate of complications have developed at all radiosurgical centers. Nevertheless, the true incidence of complications after radiosurgical thalamotomy is not well known.

One particular explanation of the complications associated with radiosurgical thalamotomy may be related to the variability in lesion size. Animal studies in rodents and nonhuman primates have demonstrated the ability to create necrotic lesions in animal brain parenchyma [45, 49, 50]. Young et al. reported a clear correlation between lesion volume and complication. In their study, the mean lesion volume in which no complications were noticed was 188 m, while the mean volume for complications was 871 mm [51]. Dose, volume, and time are the three key factors that determine the nature of the functional ablation [45]. Higher doses can create necrosis faster as can the use of a larger-volume collimator, although almost all movement disorder GK lesions employ a 4-mm-diameter collimator. This dose–volume–time response curve can roughly be correlated in humans; however, despite this apparent consistency in dose delivery and tissue response, Friehs et al. report variable size on follow-up imaging after GK radiosurgical ablation for functional procedures. Friehs et al. examined follow-up imaging after 140 Gamma Knife radiosurgical lesions produced in the treatment of patients with PD, pain, and ET [52]. In all cases, the 4-mm collimator was used for the Gamma Knife, but the postoperative scans demonstrated lesion sizes that ranged from undetectable to 4,000 mm³. Friehs correlated the higher doses with greater lesion volume and suggested that doses of 160 Gy and above were associated with inordinately large volumes. Franzini et al. reported in their study that older patients have a higher chance of having an unexpected response, and lesion size cannot be predicted [53]. Thus, although lesion size appears to be correlated with radiation dose, there appears to be a patient to patient variability in response to Gamma Knife radiosurgical lesioning. In addition, Ohye reports two different types of lesions after radiosurgical lesions using the single 4-mm collimator isocenter with central doses of 130 Gy: “circumscribed round high signal area of approximately 7- to 8-mm diameter surrounding a smaller low signal area. The other is characterized by an irregular-shaped high signal zone extending into the medial thalamic area and/or internal capsule and often accompanied by streaking along the thalamo-capsular border” [37, 41]. Ohye speculates that the delivery time may influence lesion size. Since the cobalt sources of the Gamma Knife need to be replaced over time, delivery of the same 143-Gy dose may require double the length of time with old sources compared with new sources [37]. “After reloading, the restricted lesion was more frequent and the lesion volume was smaller.”

In conclusion, both DBS of the VIM or GKT have been employed in the treatment of tremor. Several well-conducted trials have demonstrated the efficacy and complication rate of DBS of the VIM thalamic nucleus in the treatment of both parkinsonian tremor and essential tremor. In contrast, large, well-conducted trials of Gamma Knife radiosurgical thalamotomy have not been performed. Thus, it is difficult to compare directly the efficacy and risks of GKT of the VIM nucleus for the treatment of tremor. Nevertheless, lesioning of the thalamus is an alternative treatment for tremor, and Gamma Knife ablation may be effective when properly performed. Hence, the first-line surgical therapy in the treatment of patients with medically refractory tremor is VIM DBS, and GKT remains an option for patients who cannot undergo an open surgical procedure secondary to medical comorbidities. Gamma Knife radiosurgery of the VIM thalamus, however, should only be performed by neurosurgeons who have experience in both deep brain stimulation and radiofrequency thalamic procedures to optimize results.