Early Development

Before 1978, all uses of radiosurgery remained limited because of the lack of high-resolution, neuroimaging techniques to identify brain lesions or functional brain regions. Angiographic targeting of arteriovenous malformations proved successful, but still was limited by the two-dimensional estimates of complex target volumes, and difficulty with integrating the contributions of multiple isocenters. Functional radiosurgery was performed for a few patients with intractable pain related to malignancy, movement disorders, psychiatric dysfunction, and trigeminal neuralgia. In the early 1970s, percutaneous retrogasserian glycerol rhizotomy was developed during an observation made during the refinement of the Gamma Knife technique for trigeminal neuralgia. Hakänsson and Leksell attempted to localize the trigeminal nerve within its cistern using glycerol mixed with tantalum powder (as a radiopaque marker) placed before radiosurgery. However, after injection of the glycerol, trigeminal neuralgia pain was relieved.

For intractable pain related to malignancy, radiosurgery was used both for hypophysectomy as well as for medial thalamotomy. Although the procedure was noninvasive, the latency interval for lesion generation and pain relief was 1 major limitation. Steiner and colleagues presented results from an autopsy study after radiosurgery for cancer pain in 1980. Animal experiments using photons and protons proved helpful in determining the ablative dose to be used in patients. Initial patients who had radiosurgery for tissue ablation received maximum doses of 100 to 250 Gy. At small volumes, doses in excess of 150 Gy provided consistent tissue necrosis in animal models. Many of these first patients had advanced cancer and did not live long enough to provide information on safety. However, the clinical use of such doses proved to be the foundation for later use in tremor management.

Dose Selection

Early animal experiments showed consistent lesion creation at doses at or higher than 150 Gy. In patients, pain relief occurred usually within 3 weeks after radiosurgery. In rat experiments at 200 Gy using a single 4-mm isocenter, we found a consistent relationship for lesion generation that substantiated observations from that human study. Doses of 200 Gy were delivered to the rat frontal brain and then the brain was studied at 1, 7, 14, 21, 60, and 90 days after irradiation. At 1 and 7 days, we noted that the brain continued to appear normal. By 14 days, the parenchyma appeared slightly edematous within the target volume. However, by 21 days, a complete circumscribed volume of necrosis was identified within the radiation volume (4 mm diameter). Thus, the clinical observation of pain relief at 21 days noted by Steiner and colleagues was correlated with laboratory findings at the 200-Gy dose.

The ablative radiosurgery lesion appears as a discrete, circumscribed volume of complete parenchymal necrosis with cavitation. Within a 1-mm to 3-mm rim that characterizes the steep fall-off in radiation dose, normalization of the tissue appearance is found. In this zone, blood vessels appear thickened and hyalinized, and often protein extravasation can be identified. Inflammatory changes are noted in this region. Magnetic resonance imaging (MRI) shows all of these features after radiosurgical thalamotomy: a sharply defined, contrast-enhanced rim that defines the low signal lesion (on short repetition time [TR] images) surrounded by a zone of high-signal (on long TR images) brain tissue. Friehs and colleagues collected imaging data from 4 centers that created functional radiosurgery lesions (n = 56). These investigators found that maximum doses in excess of 160 Gy were more likely to produce lesions larger than expected and recommended single 4-mm isocenter lesions at doses lower than 160 Gy. The inflammatory changes can be treated with corticosteroid or other agents should they prove symptomatic in humans.

Studies at the University of Pittsburgh found that in both large-animal and small-animal models, doses at or higher than 100 Gy caused necrosis, but the delay to necrosis was longer. To identify the effect of increasing volume, we used an 8-mm collimator in a baboon model and found that half of the animals developed an 8-mm-diameter necrotic lesion at doses as low as 50 Gy. Additional thalamic studies in baboons using 100 Gy and a 4-mm collimator found 3-mm necrotic lesions at 6 months. Dose, volume, and time are the 3 key factors that determine the nature of the functional ablative lesion. Once created, this lesion remains stable over years.

Dose and volume effects are usually, but not always, reliable. The greatest reproducibility is with the smallest targets. When a larger brain target is desirable, the sharp fall-off in dose outside the target becomes less steep with increasing volume. The risk of an adverse radiation effect outside the target volume must be considered, and dose selection is crucial.

Imaging in Functional Surgery

Because physiologic information is excluded from the targeting component of a functional radiosurgery procedure, high-quality, accurate stereotactic neuroimaging must be performed. In addition, the imaging must be of sufficient resolution to identify the target structure but regional anatomy. MRI is the preferred imaging tool for functional radiosurgery. Computed tomography can be used with 1-mm to 1.25-mm slice thicknesses in patients with a contraindication to MRI.

The use of fast inversion recovery or other MR sequences with a long relaxation time helps to separate gray and white matter structures. However, the targeting of physiologically abnormal brain regions such as groups of kinesthetic thalamic tremor cells or epileptic foci using imaging alone remains indirect. We believe that with improvements in subcortical imaging using higher field strength magnets, Gamma Knife radiosurgery will play an expanded role in movement disorders. We have not considered that 3-T imaging provided any significant benefit over 1.5-T imaging. In 1 patient, we obtained nonstereotactic 7-T images to evaluate thalamic anatomy. Further studies are pending.

Radiosurgical Thalamotomy

Ventrolateral thalamic surgery for the management of tremor related to Parkinson disease (PD) remains a proven and time-honored concept within functional neurosurgery. Traditionally, this surgery has involved imaging definition of the thalamic target, placement of an electrode into the thalamus, physiologic recording and stimulation at the target site, and creation of a lesion or providing electrical stimulation. Radiosurgical thalamotomy by definition avoids placement of the electrode and evaluation of the physiologic response. In radiosurgery, imaging definition alone is used to determine lesion placement. Through the use of contrast ventriculography, computed tomographic imaging, and more recently stereotactic MRI, thalamotomy using the Gamma Knife has been performed at centers across the world. As discussed earlier, the issues of lesion volume and dose selection remain important. Although radiosurgery can abolish tremor, many surgeons believe that although adequate results might be obtained, better results may be possible with deep brain stimulation (DBS). The challenges inherent in choosing the best possible ablative target using imaging alone are significant. Radiosurgical thalamotomy, if performed, should be performed by surgeons experienced in radiofrequency thalamotomy or DBS.

Because of the absence of electrophysiologic information, the inability to stop the lesion during surgery, and the latency to the clinical response, most surgeons use radiosurgery primarily for patients with advanced age or medical disorders, in whom electrode placement would be associated with higher risk. Ohye began to perform radiosurgical thalamotomy contralateral to a previous radiofrequency lesion or to enlarge a previously mapped lesion. Duma and colleagues reported a 5-year experience with 38 thalamotomies using the Gamma Knife and 28-month mean follow-up. Complete tremor abolition was noted in 24%, excellent relief in 26%, good improvement in 29%, and little to no benefit in 21%. The median time to improvement was 2 months, consistent with data from previous animal experiments. They used a dose range of 110 to 165 Gy with better results at higher doses. Such higher doses may exert effects on a larger surrounding tissue volume of kinesthetic tremor cells (outside the sharply defined necrotic volume), which translates into tremor reduction and overcomes any limitations in target selection. Young and colleagues reported that 88% of 27 patients who had radiosurgical thalamotomy for tremor (120–160 Gy) became tremor free or nearly tremor free. Hirato and colleagues also found tremor suppression after GKT in a small patient series. Friehs and colleagues reported an experience of radiosurgical thalamotomy (n = 3) and caudatotomy (n = 10) with clinical improvement in most patients and no morbidity.

Our first report was published in 2008 and focused on essential tremor (ET). Gamma Knife radiosurgery proved to be effective in improving medically refractory ET in a predominantly elderly patient series. We recently evaluated our series of 86 patients with postradiosurgery evaluations who had either ET, PD, or multiple sclerosis. The median follow-up after gamma knife thalamotomy (GKT) was 11.5 months (range 1–152 months). The Fahn-Tolosa-Marin (FTM) clinical tremor rating scale was used to assess preoperative and postoperative tremor, handwriting, and ability to drink from a cup. Benefit was noted at an average of 2 months. Among the 48 treated patients who had ET, the mean preoperative FTM writing score was 2.7 ± 0.8 and mean postoperative writing score was 1.4 ± 1.1 ( P <.00001). The tremor score was 3.3 ± 0.8 preoperatively and 1.8 ± 1.2 ( P <.00001) postoperatively. The water score improved from 3.1 ± 0.8 before GKT to 1.7 ± 1.2 ( P <.00001) at the most recent follow-up. Of those diagnosed with ET, 20 patients (48%) showed either complete resolution or a barely perceivable tremor after GKT.

Among 29 patients with PD who underwent GKT, the mean FTM writing score changed from 2.4 ± 0.6 preoperatively to 1.3 ± 0.9 ( P <.0001) afterward. The mean tremor score was 3.0 ± 0.8 before GKT and 1.5 ± 1.1 ( P <.0001) after GKT, and the mean water score was 2.9 ± 0.8 before treatment and 1.5 ± 1.0 ( P <.0001) after treatment. Results for the 11 patients with multiple sclerosis showed mean writing scores of 3.7 ± 0.5 before GKT and 2.4 ± 0.8 ( P <.003) after GKT. Mean tremor scores were 3.9 ± 0.3 preoperatively and 2.5 ± 0.9 ( P <.001) postoperatively. Mean pretreatment FTM drinking scores were 3.9 ± 0.3 and 2.5 ± 1.0 ( P <.003) at the most recent follow-up. Patients with MS had significantly higher preoperative scores but showed a similar FTM score improvement after GKT: an improvement of 1.3 in writing score, an improvement of 1.4 in tremor score, and an improvement of 1.4 in the drinking score. Two patients experienced temporary contralateral hemiparesis 6 months after GKT, 1 patient experienced dysphagia after 8 months, and 1 patient described a perioral burning sensation with left-sided facial numbness.

The thalamotomy lesion that developed in patients was visible on the first MRI scan (obtained as early as 3 months). MRI imaging was requested 4 months after radiosurgery and was not routinely repeated unless new symptoms developed, because in an early cohort of patients the observed lesions remained stable for 2 years and then decreased in size ( Fig. 1 ). The effect was a well-circumscribed contrast-enhanced lesion with central hypointensity. The mean contrast-enhanced short TR MRI lesion diameter was 5 mm. Few patients underwent MRI after 1 year but persistent contrast-enhanced lesions could be seen within years 1 to 2, with regression of enhancement after year 2. The patients who had any complication had onset of symptoms beginning at 6 months after thalamotomy. Imaging performed at that time showed evidence of larger contrast-enhancing lesions as a result of blood-brain barrier disruption with inflammation, and later regression. In a recent multicenter report from Japan, 72 patients with PD and ET were described. The dose was 130 Gy. Of 53 patients who completed 24 months of follow-up, 43 were found to have excellent or good results (81.1%) using formal rating scales.

( A ) MRI scan at Gamma Knife radiosurgery in an 83-year-old woman with ET. The dose plan is shown ( B ). Significant tremor reduction was noted without side effects. MRI 4 months later shows the contrast-enhanced radiosurgical lesion ( C ) and the peritarget signal change on flair imaging ( D ).

As noted earlier, the target volume is crucial. Early results with larger target volumes using an 8-mm collimator were reported by Lindquist and colleagues Delayed cerebral edema and regions of radiation necrosis at high doses testified to the volume effects of radiosurgery. Similar problems have been noted using combinations of 4-mm isocenters to construct a cylindrical rather than spherical target volume. Nevertheless, the ability to create a small-volume lesion using radiosurgery without invasive placement of an electrode remain attractive considerations.

Radiosurgical Pallidotomy and Subthalamotomy

There was a resurgence in the use of radiofrequency-based stereotactic pallidotomy for patients with advanced PD beginning in 1992. Some investigators then performed Gamma Knife pallidotomy using image guidance alone as an alternative to electrode techniques. Rand and colleagues reported their preliminary results after radiosurgical pallidotomy and noted relief of contralateral rigidity in 4 of 8 patients. No patient in their series sustained a complication. Friedman and colleagues reported on 4 patients after Gamma Knife pallidotomy (180 Gy), with improvement in only 1 patient. These investigators noted variability in lesion volumes on MRI, a finding also documented by others. These lesions were less consistent than thalamic lesions, perhaps related to effects on perforating arteries. At our center, only 1 radiosurgical pallidotomy has been performed. At present, this technique is performed rarely, and DBS remains a more valuable concept for most patients with an array of PD symptoms.

Gamma Knife radiosurgical subthalamotomy has been performed by neurosurgeons Marcus Keep, Bernardo Perez, and Jean Régis with their respective teams (personal communications, 2013). Outcomes in clinical series remain to be published. Presentations at meetings have shown that this procedure can be safe with 4-mm collimation and a dose of 120 Gy. It may be a reasonable option in patients not suitable for subthalamic DBS.

Radiosurgery for Pain

The use of radiosurgery as an ablative tool to treat pain has a long history. Too few patients have been managed to draw any strong conclusions. Since the case report by Leksell in 1968 and the larger series by Steiner and colleagues in 1980, there have been few reports. In Leksell’s 2 patients with carcinoma, the centrum medianum target received doses of 250 and 200 Gy. The second patient had bilateral radiosurgery spaced by 2 months and became pain free. In Steinern and colleagues’ series, doses as high as 250 Gy were believed unnecessary because of the sharp dose gradient. Young and colleagues performed medial thalamotomy for the treatment of chronic noncancer pain in patients who had failed comprehensive medical, surgical, and behavioral therapies. In 1996, they described that two-thirds of their 41-patient series had at least a 50% reduction in pain intensity estimates, with improvements in physical and social functioning. As might be expected, patients with deafferentation pain responded poorly, but more encouraging results were identified in patients with nociceptive syndromes. These investigators cautioned on the use of larger volumes higher than that obtained with a single 4-mm isocenter, and on the use of doses higher than 160 Gy.

Hayashi and colleagues performed pituitary gland-stalk ablation by Gamma Knife radiosurgery, targeting the border between the pituitary stalk and gland with a maximum dose of 160 Gy using the 8-mm collimator to control cancer pain. They enrolled 9 patients who had bone metastases and pain controlled well by morphine (Karnofsky Performance Status >40) and with no previous radiation therapy. All patients had failed the previous pain treatments except morphine. All patients became pain free within a few days after radiosurgery, which was maintained as long as they lived. No recurrence of pain occurred. In addition, there was no panhypopituitarism and diabetes insipidus in the patients. This strategy of pituitary gland-stalk ablation for pain control also showed a good initial response (87.5%) of 8 patients with thalamic pain syndrome, However, most patients (71.4%) experienced pain recurrence during the 6-month follow-up.

Radiosurgery for Behavioral Disorders

There is renewed interest in radiosurgical lesioning of the anterior internal capsule (anterior capsulotomy) in patients with medically refractory obsessive-compulsive disorder (OCD). Radiosurgery for obsessive-compulsive and anxiety neurosis has been performed for more than 45 years. The first radiosurgical capsulotomy was performed by Leksell in 1953 using 300-kV x-rays. Initially, pneumoencephalography was used for target definition in the placement of bilateral anterior internal capsule lesions. Five of the initial 7 patients had long-term benefit after 7 years of follow-up. Since 1988, an additional 10 patients have been treated at the Karolinska Institute using stereotactic MRI guidance. The initial use of an 8-mm collimator resulted in excessive edema, so these investigators recommended the use of only 4-mm isocenters. The results seem to be as efficacious as when conventional radiofrequency lesioning is performed. Kihlstrom and colleagues described the stable imaging appearance of radiosurgical lesions 15 to 18 years after capsulotomy. Oval radiosurgical lesions in the anterior internal capsule or cingulate gyrus may affect affective disorders or anxiety neuroses. Recently, Ruck and colleagues reported on long-term follow-up in 25 patients, 16 with an electrode and 9 with Gamma Knife surgery. Response rates did not differ between methods, and these investigators concluded that capsulotomy was effective in reducing OCD symptoms.

A series of patients from Brown University and the University of Pittsburgh have been presented at national meetings. Radiosurgical capsulotomy is performed only after comprehensive psychiatric evaluation and management, leading to a diagnosis of severe OCD, and after failure of nonsurgical approaches. In Pittsburgh, we have performed Gamma Knife surgery on 5 patients with severe, medically intractable OCD ( Fig. 2 ). According to our protocol, all patients were evaluated by at least 2 psychiatrists who recommended the capsulotomy procedure. The patient had to request the procedure, and have severe OCD according to the Yale Brown Obsessive Compulsive Scale (YBOCS). Patient ages were 37, 55, and 40 years, and preradiosurgery YBOCS scores were 32/40/39/40, and 39/40. Bilateral lesions were created with 2 4-mm isocenters to create an oval volume in the ventral capsule at the putaminal midpoint. A maximum dose of 140 to 150 Gy was used. There was no morbidity after the procedure and all returned immediately to baseline function. The first 3 patients in our recent report had functional improvements, and reduction in OCD behavior. We believe that this technique should be evaluated further in patients with severe and disabling behavioral disorders.

Bilateral anterior capsulotomies are shown on coronal contrast-enhanced MRI, 1 year after Gamma Knife radiosurgery (140 Gy) in a patient with OCD ( A , axial; B , coronal). Two years after radiosurgery, the degree of contrast enhancement is less ( C ).

Radiosurgery for Epilepsy

There is interest in the use of radiosurgery for patients with focal epilepsy. The observation that brain irradiation (via radiation therapy or radiosurgery) could lead to cessation of seizures has spurred several groups to work in this field despite the lack of a consistent approach to defining the target volume. In 1985, Barcia-Salorio and colleagues reported on 6 patients with epilepsy who had low-dose radiosurgery. The epileptic focus was localized by means of conventional scalp electroencephalogram (EEG), subarachnoid electrodes, and depth electrodes. Radiosurgery (a 10-mm collimator to deliver an estimated dose of 10 Gy) was performed using a cobalt unit coupled to a stereotactic localizer. These investigators hypothesized that this low radiation dose provided a specific effect on epileptic neurons, without inducing tissue necrosis. In 1994, they provided a long-term analysis in a series of 11 patients using a dose range of 10 to 20 Gy. Five patients had complete cessation of seizures, and an additional 5 were improved. Seizures began to decrease gradually after 3 to 12 months after radiosurgery. After this work, Lindquist and colleagues at the Karolinska Institute began to perform epilepsy radiosurgery using advanced localization techniques, which included magnetoencephalography (MEG) to define interictal activity. In some patients, the epileptic dipole activity identified on MEG before radiosurgery later resolved along with seizure cessation. Radiosurgery was evaluated in animal models of epilepsy. We used the kainic acid model of hippocampal epilepsy in the rat, and were able to stop seizures and improve animal behavior. Rats were randomized to control or radiosurgery arms (20, 40, 60, or 100 Gy) and then evaluated with serial EEG, behavioral studies, functional MRI, and histology.

More recently, radiosurgery has been of value in patients with gelastic or generalized seizures related to hypothalamic hamartomas. A larger indication may rest with the use of epilepsy to create an amygdalohippocampal lesion for patients with mesial temporal sclerosis as proposed by Régis and colleagues. In 1993, Régis and associates in Marseille performed selective amygdalohippocampal radiosurgery for mesial temporal lobe epilepsy. Gamma Knife radiosurgery was used to create a conformal volume of radiation for the amygdala and hippocampus. This approximate 7-mL volume represented the largest functional target irradiated to that time. They delivered a margin dose of 25 Gy to the 50% isodose line, a dose that later caused target necrosis. The first patient became seizure free immediately and the second after a latency of almost 1 year. Serial MRI scans showed target contrast enhancement that corresponded to the 50% isodose line. Patients managed at their center have been part of a multidisciplinary prospective evaluation and treatment protocol. A recently published longer-term evaluation with 8-year mean follow-up (margin dose of 24 Gy), found that 9 of 16 patients were seizure free. The 2010 review by Régis and colleagues on their experience with functional radiosurgery is excellent.

The first prospective multicenter clinical trial in the United States was recently completed. This study with 3-year outcomes evaluated effects on epilepsy, cognition, and neurologic function. Seizure control was higher at 48 Gy compared with 40 Gy, and similar to what is reported after hippocampectomy. Neuropsychological testing reported that radiosurgery was safe. However, several important questions remain to be addressed regarding the role of radiosurgery for mesial temporal sclerosis-related epilepsy. The optimal target may include both amygdala and hippocampus, but the total target volume remains debated ( Fig. 3 ). Target volume helps to determine dose selection, including the dose received by regional structures such as the brainstem or optic tract. Investigators need to determine whether the balance between seizure response and morbidity is acceptable, particularly compared with surgical resection. For these reasons, a randomized trial comparing radiosurgery with resection was begun under the leadership of Dr Nicholas Barbaro (Indiana University) and Dr Mark Quigg (University of Virginia). Entitled the Radiosurgery or Surgery for Epilepsy (ROSE) trial, the study is under way at centers in several countries.

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