Background

Secondary post-anoxic generalized dystonia is a common cause of disability especially in socioeconomic settings that lead  to improper perinatal care, bilateral Pallidal  deep brain stimulation (DBS) and bilateral pallidotomy has been shown  extremely effective  in treating primary dystonia , however , in secondary dystonias , the clinical effects of bilateral  Pallidal DBS and also of bilateral Pallidotomy has been only  infrequently described , our aim is to compare the clinical effect and the safety of  bilateral Pallidal DBS and simultaneous bilateral posteroventaral Pallidotomy  in patients with secondary  post-anoxic generalized  dystonia

Methods

11  patients  diagnosed with secondary postanoxic generalized dystonia were treated 5 with bilateral Pallidal DBS and 6 with bilateral Pallidotomy, the change in the severity of dystonia after one year   was compared in both groups  by Burke–Fahn–Marsden dystonia rating scale, both movement score and disability score (MS, DS respectively), complications especially speech, dysphagia, visual field defects were also compared

Results

The BFM scores  improved  significantly in both  patient groups after 1 year ,  the MS by 42±4.6 in the DBS group and by  40±2.3%  in the Pallidotomy group  and the the DS improved by  32±4.9 in the DBS group and by 26±6.2 % in the pallidotmy , however no statistical significance was found in the improvement in both groups, two patients in the Pallidotomy groups and one patient in the stimulation group had visual field affection, one patient in the stimulation group had infection that necessitated removal of the entire system,  speech complications occurred in a single patient  from the  Pallidotomy group

Conclusion

Both   bilateral Pallidal deep brain stimulation and bilateral Pallidotomy  are equally effective in the  treatment of secondary post-anoxic generalized dystonia with the Pallidal DBS having potentially less adverse effects

Introduction

Dopaminergic medications and deep brain stimulation (DBS) are well-established treatments for controlling motor symptoms and improving quality of life in Parkinson’s disease (PD).(Cury et al., 2014; Odekerken et al., 2013) While these therapies ameliorate cardinal motor symptoms, their effects on postural instability and gait disturbance (PIGD) are not sustained at long-term.(Ferraye et al., 2008) At present, the treatment of PD patients who continue to experience PIGD even after optimized medical therapy and DBS is considered quite challenging. This is of importance as falls associated with postural instability(Bloem, Grimbergen, et al., 2001) and gait disturbance are major sources of morbidity and mortality in advanced PD.(Matinolli et al., 2011)

In rodent(Fuentes et al., 2009) and non-human primate PD models,(Santana et al., 2014) electrical stimulation of the spinal cord has been shown to improve locomotor activity and disrupt pathological neuronal oscillations in multiple basal ganglia structures. In humans, initial results of open label studies investigating the effectiveness of SCS in PD have been mixed. While one initial study did not demonstrate efficacy,(Thevathasan et al., 2010) recent reports have shown an improvement in both motor symptoms and gait.(Agari and Date, 2012; Fénelon et al., 2012; Hassan et al., 2013; Landi et al., 2013) Possible reasons for such discrepancies include patient selection, the spinal level of electrode implantation (e.g. thoracic vs. cervical) and a placebo effect.

We conduct a phase 1 clinical trial to study the safety and efficacy of SCS on PIGD in four patients with advanced PD previously treated with subthalamic nucleus (STN) DBS. To mimic preclinical studies, high frequency SCS (300Hz) was delivered through electrodes implanted in the upper thoracic spine. We found that this treatment improved gait measures, PD motor symptoms and quality of life in all four individuals. To further confirm these findings, patients receiving SCS at either 300Hz or 60Hz underwent blinded experiments to measure gait function. Despite perceiving similar paresthesias, objective improvements in gait were only observed at 300Hz.

Methods:

Patients

The study was conducted from June 2014 to March 2015 in the Division of Functional Neurosurgery of the Hospital das Clínicas, University of São Paulo. It was approved by the local Ethics Committee (CAPPESQ-HCFMUSP #12690213.0.0000.0068) and registered at ClinicalTrials.gov (NCT02388204). All patients provided signed informed consent.

Subjects were recruited from our multidisciplinary DBS center. Before inclusion in the trial, patients underwent a routine therapeutic program to optimize physiotherapy, medication intake and DBS programming. Despite adequate motor control, they still exhibited severe postural instability and gait disturbance, which were considered as problematic and major contributors to a poor quality of life.

Inclusion criteria were twofold: 1) Presence of advanced idiopathic PD; 2) Significant PIGD despite optimized treatment with medications and bilateral STN DBS. During the study, the levodopa dose was not significantly altered (Table 1).

Exclusion criteria were the presence of 1) dementia, active psychiatric symptoms, apathy, and/or behavioural disturbances and 2) medical conditions that precluded patients from undergoing spinal cord stimulation.

Surgery and stimulation parameters

The SCS system selected for this study automatically adjusted current amplitude according to position (i.e. increasing stimulation intensity when the patients stood up and decreasing it when they were laying supine). Paddle stimulating electrodes with three columns of 5, 6 and 5 contacts (5-6-5 Model 39565; Medtronic Inc., Minneapolis, MN, USA) were implanted under general anesthesia. After a small exposure of the interlaminar space, the ligamentum flavum was removed and the electrode placed in the epidural space covering the upper levels of the thoracic cord (T2 to T4). In a second procedure, electrodes were connected to a rechargeable pulse generator (Model 37714, Medtronic Inc.) implanted in the subcutaneous tissue of the upper buttock. Initial programming sessions were carried out 3-4 weeks later. To mimic preclinical experiments,(Fuentes et al., 2009; Santana et al., 2014) stimulation frequency and pulse width were set at 300Hz and 90μsec, respectively. Current amplitude was programmed at 105% of the sensory thresholds in the upright and supine positions.

 Study design and outcomes

Locomotion and gait measurements were recorded serially at baseline, 1, 3, and 6 months after SCS using the following tests: 1) Timed up and go test (TUG):(Huang et al., 2011) Time in seconds required for patients to rise from a chair, walk 3 meters and return. The test was performed 3 times and the average value was considered for analysis. 2) Timed up and go test with dual task (TUG-DT):(Brauer et al., 2011) Patients had to do a verbal fluency test during the TUG. 3) 20 Meters Walking Test:(Combs et al., 2014) Time in seconds and number of steps required to walk a 20m path (10m to go and 10m to return). 4) 20 Meters Walking Test with obstacles:(Bloem, Valkenburg, et al., 2001) Same as above with obstacles placed along the path. The test was performed twice. First, the patient had to walk over the obstacle and then around it. 4) Stride length: Estimated by calculating the ratio between the average number of steps and distance during the 20 meters test. During the 6^th-month evaluation, testing was conducted “ON” and “OFF” medications (one week apart). In the latter, drugs were discontinued for at least 12h. As no major differences in gait were noticed with or without medication intake (Supplementary Fig. 1), in the main text we only report “OFF” drug outcome. To avoid severe “OFF” periods, gait analyses were always carried out while patients were receiving DBS.

Secondary outcomes were defined as changes in quality of life, motor scales and balance recorded at 6 months post-surgery as compared to preoperative baseline. These variables were evaluated using the: 1) the Parkinson Disease Questionnaire 39 (PDQ-39),(Souza et al., 2007) 2) the Unified Parkinson's Disease Rating Scale motor scores (UPDRS III), 3) the Berg Balance scale (BBS),(Scalzo et al., 2009) and 4) The Freezing of Gait Questionnaire (FOG-Q) at base line and after 6 months.(Giladi et al., 2009)

In addition to primary and secondary outcomes, patients were blindly assessed on the TUG and 20 meters walking test during a single session in the beginning of postoperative month 4. As subjects always noticed SCS-induced paresthesias, we have decided not to conduct regular “on/off stimulation” evaluations. Instead, we recorded their performance using two different stimulation frequencies (60Hz and 300Hz), which elicited paresthesias that were equally perceived by the patients. On the day of testing, patients were brought back to the clinic with their SCS system turned off for at least 6h and medications discontinued for at least 12h. As no major differences in gait were noticed with or without medications in open label evaluations carried out at 1 and 3 months (Supplementary Fig. 1), blinded assessments were only conducted in the “OFF” medication condition. Initial evaluations were recorded with the SCS OFF. After this baseline measurement, patients were randomly assigned to receive stimulation at 60 or 300Hz (i.e. 2 patients each). Following an initial round of testing, SCS was turned off for 2h. Thereafter, new assessments were carried out using the alternative frequency.

 Data analysis and statistics

Variables were measured at baseline, 1, 3 and 6 months following SCS onset. Comparisons were conducted using repeated measures ANOVA (Bonferroni post hoc) or the Paired Samples Test. Effect size was calculated using ω2. All results were presented as percentage of baseline. Significance was set at p≤ 0.05. Values for individual patients are reported in Supplementary Tables 1 and 2. 

 Results

Four patients with advanced PD were included in this study (Table 1). Average improvement after bilateral DBS without medication was 58% at 1 year. After 7.8 years, clinical improvement was reduced to 37% (Fig. 1). Despite an adequate control of motor symptoms, all patients experienced a significant decrease in quality of life due to prominent PIGD.

Surgical procedures for implanting SCS electrodes were uneventful. Stimulation was delivered around the T2 spinal cord segment with outer contacts selected as anodes and inner contacts as cathodes (Fig. 2). In the upright and supine positions, stimulation amplitude was set at 105% of the sensory threshold for paresthesias (4.6±1.9V while patients were standing and 2.0±0.5V while recumbent). At these voltages, SCS delivered at 300Hz, (90μsec pulse width) induced paresthesias that were relatively constant, did not produce any discomfort and did not change in intensity with the patient’s position.

 Primary outcomes:

All patients exhibited significant improvements in gait while receiving SCS in the “ON” DBS “OFF” Meds condition (Fig. 3, Table 2). At 6 months, TUG and TUG-DT scores improved by 63.2% (95% CI 32.8-93.6, p=0.006) and 54.0% (95% CI 13.7-94.2, p=0.021) when compared to baseline. In the 20 Meters Walking Test without obstacles, time and the number of steps to complete the task were reduced by 58.0% (95% CI 19.5-125.8, p=0.05) and 65.7% (95%CI 29.7-101.6, p=0.009), respectively. In addition, stride length was increased by 170% (p=0.01). Similar results were observed in the 20 Meters Walking Test with obstacles, with time and number of steps improving by 63.3% (95%CI 10.4-116.3, p=0.03) and 70.1% (95%CI 18.7-121.5, p=0.021). Findings described above in the “OFF” meds condition were similar to those observed while patients received medications.

Secondary outcomes:

PDQ39: Six months after SCS, total PDQ 39 improved by 44.7% compared to baseline (from 58.0±20.7 to 32.0 ±13.3; 95%CI: 29.9-59.5; p=0.002) (Table 3). Significant improvements were also observed in specific subscores such as Mobility (56.6%; 95%CI: 46.9-66.3; p<0.001), Activities of Daily Living subscales (28.3%; 95%CI: 8.8-47.8; p=0.019), Emotional Well-being (53.0%; 95%CI: 16.9-89.0; p=0.018) and Stigma (78.1%; 95%CI: 50.8-105.3; p=0.003). Differences between SCS and baseline were not found to be significant for the Cognition (p=0.39), Social Support (p=0.39), Communication (p=0.51) and Bodily Discomfort (p=1.0) subscores.

UPDRS Motor Scores: At baseline (after an average of 7.8 years from the initial DBS surgery), UPDRS III scores without medication were 33.0±13.7. In the “ON” DBS, “OFF” Meds condition improvement following SCS, at 1, 3, and 6 months was in the order of 36.8% (UPDRS III scores 22.0±14.3; p=0.18; 95%CI: 22.5-96.1), 48.7% (16.2±5.7; p=0.009; 95%CI 21.9-75.5) and 38.3% (19.7± 6.7; p=0.034; 95%CI: 5.3-64.6), respectively (Fig. 1). At 6 months, the UPDRS III score in the “ON” DBS, “ON” Meds, “ON” SCS state (15.0±4.24) was 50% lower than that recorded while patients were receiving DBS and medications prior to SCS (p=0.018; 95%CI 15.3-86.1; Supplementary Fig. 1).

Berg Balance Scale:  BBS was applied to access static balance and the risk of falls. All patients showed a significant improvement; preoperative scores went from 47.5±4.5 to a post SCS value of 51.5±5.0 (8% increase; p=0.005).

FOG-Q scores: All patients showed a significant improvement in freezing of gait at 6 months, as revealed by a 56.4% decrease in FOG-Q scores (from 17.8±0.9 at baseline to 7.8±0.9; p<0.001).

In summary, outcome data suggest that patients treated with SCS had significant improvement in locomotion, PD motor symptoms, freezing of gait, risk of falls and quality of life as compared to baseline.

Blinded evaluations 

ANOVA revealed that during the 20 meters walking test, both time (F(2.6)=24.4; p<0.001) and the number of steps (F(2.6)=22.8; p=0.002) were different across groups. This was also the case for TUG, with significant differences in time being recorded across groups (F(2.6)=35.5; p<0.001).

As shown in Fig. 3, the results described above were largely due to improvements in gait observed during 300Hz SCS. As compared to the non-stimulation condition, this treatment reduced both time (94.0±70.8 to 30.5±17.3; p=0.028) and the number of steps (74.0± 27.6 to 26.7 ±17.6; p=0.03) needed to complete the 20m waling test, as well as the TUG time (from 36.0±30.1 to 11.8±5.9; p=0.003). In contrast, SCS 60Hz was largely ineffective with no significant differences being recorded between this treatment and SCS “OFF”.

 Discussion

In this phase 1 clinical trial we have studied the safety and efficacy of SCS on PIGD in four patients with advanced PD previously treated with STN DBS. To mimic preclinical studies, high frequency stimulation (i.e. 300Hz) was delivered through paddle electrodes implanted in the upper thoracic spine.  Overall, we have objectively recorded a significant and sustained positive clinical response in several gait measurements, including walking and stride length, freezing. Improvement on PIGD occurred within minutes after stimulation onset and was seen in all patients. It lasted for the duration of the study (i.e.6 months) with no apparent loss of benefit over time.  In addition, SCS decreased the number of falls and seemed to synergistically improve UPDRS III scores when administered along with STN-DBS. Following an improvement in locomotion, patients reported a better quality of life, as measured by the PDQ-39.

Because our study had an open label design and patients reported stimulation-induced paresthesias, a concern that needed to be addressed was the possibility of a placebo effect. To specifically address this issue, we performed a blinded experiment in which SCS was randomly delivered at either 60 or 300Hz. While a similar degree of paresthesias was reported with either setting, gait improvement was only documented when SCS was delivered at 300Hz.

In 2009, Fuentes et al. showed that thoracic SCS was able to restore locomotion deficits in a rodent model of PD.(Fuentes et al., 2009) The authors hypothesized that the effects of high-frequency SCS were primarily due to a disruption in pathological cortico-striatal neuronal oscillatory activity. Similar findings were reproduced by the same group in non-human primates.(Fuentes et al., 2009; Santana et al., 2014) In recent work, Santana et al showed that the highly synchronized neuronal activity of cortico-basal ganglia-thalamic structures in a non-human primate model of PD was also blocked by SCS.(Santana et al., 2014) Whether this neurophysiological mechanism can also account for the clinical effects in humans remains to be demonstrated.

In preclinical experiments, SCS restored close to normal locomotion patterns right after stimulation was switched on. In the first clinical implementation of this technique, Thevathasan and colleagues failed to show a positive effect of SCS in PD.(Thevathasan et al., 2010) Those negative findings raised an interesting discussion about potential mechanism responsible for the sudden relief of akinesia/gait deficits in rodent models.(Nicolelis et al., 2010) In addition to the modulation of corticolimbic rhythms, a proposed mechanism was the so-called paradoxical kinesis. This would occur as a consequence of the intense arousal evoked by high frequency stimulation of sensory ascending fibers. Similar to the startle reflex, however, paradoxical kinesis habituates over time and cannot justify a chronic clinical response. In our study, startle-like responses during SCS were avoided by using an SCS system capable of delivering adjustable stimulation, which was finely tuned to induce mild paresthesias. Although some adjustments in stimulation intensity were required over time, we did not observe short-term habituation related to the gait effect produced by SCS. Therefore, it is unlikely that the observed locomotion improvement detected in our study resulted simply from paradoxical kinesis.

After the initial negative findings of Thevathasan et al., a few clinical studies have shown that SCS was able to improve gait and motor symptoms in a total of 24 PD patients. Agari et al. reported a 19% improvement in UPDRS motor scores 3 months after SCS onset in 15 PD patients who also had intractable back and leg pain.(Agari and Date, 2012) This was largely due to improvements in gait function and postural instability and associated with changes in bradykinesia or rigidity. As all patients in that trial had moderate to severe pain, however, it was not possible to rule out that the achieved results were a consequence of pain reduction. Hassan et al. described the effects of bilateral high cervical stimulation in a PD patient with post-traumatic neuropathic pain.(Hassan et al., 2013) Remarkably, SCS combined with medications improved UPDRS motor scores by 21% and 42% at 12 and 24 months. In addition, the timed 10m walk test was also improved by 35% after 24 months. Fénelon et al. reported another patient who underwent routine thoracic quadripolar stimulation for failed back syndrome and subsequently developed PD.(Fénelon et al., 2012) After SCS, a 47.6% improvement in UPDRS motor scores was recorded (15.3% add-on effect over medications alone). In contrast to other studies, specific analyses revealed a 40% improvement in bradykinesia, 65% in rigidity, 61.7% in tremor, and 21.5% in walking time after SCS. More recently, Nishioka & Nakajima reported three patients with chronic pain and PD who had significant improvements in both conditions after SCS.(Nishioka and Nakajima, 2015)

Overall, our study differs from the ones described above in several ways. First, electrodes were implanted in high thoracic regions and patients received SCS at 300Hz. In other words, it was the first time the implanted location and SCS protocol matched those employed in animal studies.(Fuentes et al., 2009, 2010; Santana et al., 2014) Second, only advanced PD patients who experienced significant PIGD following STN DBS were included. Third, SCS was delivered with a positional system, using a quantitative criterion for defining the stimulation amplitude (105% sensory threshold and presence of paresthesias). This protocol not only led to the positional control of current delivery, but also produced both a much lower level of discomfort following positional changes.(Abejon et al., 2014) Finally and most importantly, to clearly ascertain the role of stimulation on gait, we have conducted a blinded experiment comparing the effects of 60 and 300Hz. Our results show that only the latter frequency was capable of eliciting substantial improvements.

Today, the treatment of PIGD is one of the most challenging problems in Parkinson’s disease. This is of importance because PIGD significantly increases the risk of falls(Bloem, Grimbergen, et al., 2001) and collaborates to enhance the morbidity and mortality in advanced PD.(Matinolli et al., 2011) Currently investigated neuromodulation treatments for PIGD, particularly in patients who do not improve after STN or GPi DBS, include stimulation of the pedunculopontine nucleus (PPN) or substantia nigra reticulata (SNr). Evidence is now mounting that PPN DBS, particularly when conducted bilaterally, can improve gait and FOG. Such improvement, however, is inconsistent across studies and mostly reported to be mild to moderate.(Moro et al., 2010; Thevathasan et al., 2012) While initial studies found that high frequency stimulation of the SNr induced similar improvements in gait and postural instability when compared to STN DBS,(Chastan et al., 2009) recent work suggests that the combination STN/SNr stimulation may yield short-term positive results.(Weiss et al., 2011, 2013) In addition to the techniques described above, some degree of improvement may also be reached with rehabilitation therapies(Alves da Rocha et al., 2015) and wearable devices,(Lopez et al., 2014) though this is somewhat limited in patients with advanced PD. With a much less invasive nature SCS may become an attractive alternative to treat PIGD if proven efficacious and capable of producing long-lasting clinical effects.

In summary, our pilot study provides open label evidence that 300Hz SCS is safe and effective in improving PIGD in advanced PD patients previously treated with STN DBS. Although our findings still need to be corroborated in a larger cohort followed for a longer interval, they do suggest that 300Hz SCS may elicit significant gait improvements in advanced PD patients.  

Funding

This study was funded by the Division of Functional Neurosurgery of Institute of Psychiatry of the Hospital das Clinicas of the University of São Paulo Medical School (HCFMUSP). 

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Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment in patients with Parkinson’s disease (PD). The surgical approach can be with or without intraoperative microelectrode recording (MER). Centers using MER to delineate the neurophysiological boundaries of the STN, acknowledge its value. MER can be accompanied by spontaneous improvement of the Parkinsonian motor symptoms, which is known as a micro-lesion effect. While the phenomenon is well-known, its quantitative impact on motor symptoms is largely unknown. In this prospective study, we have studied the micro-lesion effect of MER in 30 patients with PD undergoing DBS of the STN. The change in the scores of tremor, rigidity, bradykinesia was collected using the Unified Parkinson’s Disease Rating Scale. The preoperative medication off scores was compared to the intraoperative scores after MER. We found a significant change (p<0.05) in the motor score due to a lesion effect only in the upper extremities  The micro-lesion effect was more pronounced in tremor and bradykinesia when compared to rigidity. Although the micro-lesion effect was quantitatively higher in patients with a higher levodopa response rate, there was no significant correlation between these two parameters. Similarly, there was no significant relationship between the micro-lesion effect and age, disease duration, and the number of MER electrodes used. Micro-lesion effect due to MER in patients with PD has specific effects on the motor symptoms and is independent of the number of MER electrodes used. 

Huntington’s disease (HD) is an autosomal dominant and a progressive neurodegenerative disorder. It is caused by an increase in the number of CAG repeats in the Huntingtin gene. Patients suffer from cognitive, emotional and motor disorders. For patients with predominant motor symptoms, deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been suggested. Patients with chorea-dominant HD were referred to our University hospital and underwent bilateral DBS of the posteroventrolateral part of the GPi with the distal electrodes in the external part of the globus pallidus. The patients had no severe cognitive or emotional dysfunctions or other major comorbidities. Here, we report on the clinical outcomes as measured with the Unified Huntington’s Disease Rating Scale (UHDRS) at one-year postoperatively. Chorea improved in all patients substantially and patients, families and caregivers were satisfied by this improvement. One patient experienced a transient dysarthria. The stimulation frequency was set at 130 Hz and the contacts located in the GPi were activated. In our experience, patients with chorea-dominant HD, which form the vast minority of the HD population, with no major cognitive and emotional disturbances, are suitable candidates for chorea DBS-surgery.

OBJECTIVES. Parkinson’s disease (PD) is one of the most widespread progressive neurodegenerative diseases, which in most cases has bilateral clinical signs. DBS for PD is a proven technology that significantly improves motor function, reduces disability of patients suffering from the adverse effects of L-dopa therapy. Meanwhile the application of ablative surgical procedures remains important in the treatment of extrapyramidal movement disorders in view of economical, geographical and some other reasons. The purpose of the study is to evaluate the effectiveness of stereotactic lesion procedures for PD.

METHODS. 465 patients with PD underwent stereotactic ablative surgery from 2011 to 2015. Among them unilateral thalamotomy performed in 422 (90.8%) cases, unilateral pallidotomy – in 22 (4.7%) cases, thalamotomy and contralateral pallidotomy at 20 (4.2%) cases, thalamotomy and contralateral subthalamotomy at 10 (2.1%) cases and bilateral pallidotomy at 1 (0.2%) case. Neurological and psychological status assessed by: UPDRS II, Hoehn and Yahr scale, Schwab and England scale, MMSE, Beck's Depression Inventory, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale and PDQ-39. Surgery performed on CRW Stereotactic system using StereoPlan, StereoAtlas (Radionics) and FrameLink (Medtronic) softwares. Intraoperative macrostimulation was used to delineate the optimal target location. Postoperative follow-up was from 6 months to 8 years (mean 4.8 ± 0.5 years). 

RESULTS. Patient’s age ranged from 30 to 84 years (mean – 58.8 years). Mean disease duration before surgery was 9.9 years. L-dopa therapy used 394 (85%) patients with mean dose 780.4 mg/day. Mean duration of L-dopa therapy was 5.5 years, 172 (43.7%) of them had motor fluctuations and / or levodopa-induced dyskinesia. Overall regression of tremor observed in 85% patients, rigidity - in 88%, bradykinesia - in 59% patients. In 1 year after the intervention UPDRS score improved by 52% in ON period and by 41% in OFF period. The dose of levodopa decreased in average on 33% - from 780.4 mg/day to 522.7 mg/day. After treatment Schwab and England score increased from to 56.7% to 80.6%. Surgical complications, which include hemorrhage, local ischemia, infection and pulmonary embolism were observed in 15 (3.1%) patients. Neurological complications have happened in 26 patients (5.5%), in most cases they were combined and include speech disturbances – 10 (2.1%), pseudobulbar palsy – 1 (0.2%), gait disturbances – 6 (1.3%), hemiballism - 2 (0.4%), memory disturbances and cognitive impairment - 12 (2.6%), syndrome of vegetative irritation - 4 (0.8%), contralateral dyspraxia - 2 (0.4%). Postoperative mortality rate was 0.4% (one patient dead after pulmonary embolism and second – after intracerebral hemorrhage).

CONCLUSION. Our results demonstrate that ablative surgery is effective and safe method of treatment for PD. Such treatment improves overall motor function, increased patient’s mobility, daily living activities and improves quality of life. Stereotactic lesion interventions allow patients to reduce levodopa dose, providing them with increased freedom from a complex medication regimen. The best candidates for ablative surgery include patients with tremor, rigidity, L-dopa induced dyskinesia and minimal bradykinesia. Poor prognostic factors for lesion intervention in patients with PD include arterial hypertension, hydrocephalus, atherosclerotic microangiopathy and diabetes. Careful identification and selection of patients for ablative surgery allows to achieve optimal results in the treatment of PD.

Objectives

To evaluate the clinical effect of re-operation to another target after failure of initial deep brain stimulation (DBS) for Parkinson’s disease (PD).

Methods

We descriptively analyzed the baseline characteristics, the effect of initial surgery and re-operation of NSTAPS (Netherlands SubThalamic and Pallidal Stimulation) patients and previously published cases that underwent re-operation to a different target.  The evaluation included motor symptoms at baseline (off-drug and on-drug), after initial DBS surgery (on-stimulation, off-drug), before re-operation (on-stimulation, off-drug), and after re-operation (on-stimulation, off-drug). We evaluated motor symptoms using the Unified Parkinson’s Disease Rating Scale motor examination (UPDRS-III). For the NSTAPS, blinded assessments were available at 12 and 36 months after the initial surgery. We dichotomized motor outcome: an off-drug UPDRS-III score improvement of 30% or more one year after DBS compared to baseline is considered a treatment success and less than 30% is considered unsuccessful.

Results

A total of 14 patients were identified in the NSTAPS (n=8) study and literature review (n=6).  

NSTAPS trial: The mean off-drug UPDRS-III before the first surgery (baseline) was 45 (range 24-88), and the mean percentage of improvement with levodopa was 71% (range 49-82%). Re-operation occurred between 12 and 67 months after start of DBS therapy. The mean pre-re-operation off-drug UPDRS-III score was 39 (range 22-56) and the mean score after re-operation was 31 (range 18-40), with two postoperative scores missing. In quantitative terms, two of the eight re-operations were considered a success, that is, a UPDRS-III improvement greater than 30%.  Subjectively, five of the eight patients considered their re-operation a success.

Literature review: three articles were identified that describe a total of six cases, of which three patients initially received bilateral GPi DBS and three received STN DBS (supplement 1 and table 1). The off-drug UPDRS-III score at baseline was not available in most patients and the percentage of improvement on levodopa was available in three patients only (57%, 81%, 74%). Of the patients who were re-operated from STN to GPi none had improvement of their off-drug UPDRS-III scores (-3%, -11%, -22%), but two of them reported subjective improvement. All patients who were re-operated from GPi to STN had a post-operative improvement of the off-drug UPDRS-III (37%, 59%, 64%) and also subjectively experienced improvement.

Summary of all cases: Five out of 11 patients that were re-operated from GPi DBS to STN DBS showed more than 30% improvement of off-drug motor symptoms. Of the three patients re-operated from STN DBS to GPi DBS, none showed more than 30% off-drug motor improvement.

Conclusions

Half the patients re-operated to STN DBS showed objective clinical improvement of more than 30% on the off-drug UPDRS-III score. However, three out of five of these improved cases were from the systematic review, so this finding is prone to a publication bias. None of the three patients re-operated to GPi DBS showed objective improvement. In conclusion, if insufficient clinical improvement is obtained after GPi DBS and patient selection and electrode placement were correct, re-operation to the STN is worth considering. Currently, there are insufficient data that indicate if re-operating from STN to GPi has a comparable effect.

Objectives

Parkinsonian patients undergoing subthalamic nucleus (STN) DBS surgery have traditionally been required to stop their dopaminergic medications preoperatively. This was done to enable assessment of the effect of intraoperative stimulation on their parkinsonian state. We perform the procedure under GA and prefer to give the patients their medications to avoid a variety of dopamine-withdrawal effects such as pain and stiffness. The authors have previously demonstrated the technical feasibility of STN DBS under GA, with intraoperative microelectrode recording (MER) guidance, in a small cohort of patients who continued on their medications¹. This paper presents the results of a prospective cohort analysis to verify the outcome of the initial study, and report on wider aspects of clinical outcome and postoperative recovery.

Methods

All patients were allowed to continue their routine dopaminergic medications up until GA was administered. Patients’ demographics, duration of PD and L-dopa Equivalent Daily Dose (LEDD) on admission were recorded.  The number of intraoperative microelectrode (MER) tracks required to detect satisfactory STN activity, the length of the STN specific MER (LOR), the duration of surgery and the time required for extubation, as well as the recovery time from GA in the post-anaesthesia care unit in theatres (PACU) were recorded prospectively. Clinical outcome was assessed using Hoen-Yahr scale, the duration of ‘OFF’ periods during the wake hours, and the percentage of the ‘ON’ hours where patient had dyskinesia. These variables were prospectively assessed at 6 months postoperatively and compared to the baseline on admission. All perioperative complications were recorded.

Results

30 consecutive patients underwent the procedure between May 2014-Dec. 2015 while ‘on-medications’. This was compared to a similar cohort (26 patients) who underwent the same procedure ‘off-medications’. Baseline characteristics (gender, duration of PD, first presenting symptoms, and preoperative LEDD) were statistically comparable between the two groups. Patients in the ‘on-medications’ group were slightly younger, 60 (51 - 64) years versus 64 (56 - 69) years, p= 0.043. Results expressed as median (Inter-Quartile Range, IQR).

Both groups were comparable in the number of tracks required intraoperatively to detect satisfactory STN-MER.  60% in the ‘on-medications’ group and 58% in the ‘off-medications’ group required only one track on either side of the brain (p=1.000). Analysis of the total LOR  for STN- MER (the sum for both sides of the brain) found this to be significantly higher in the ‘on-medications’ group, with a median of 9 mm vs. 7mm  (p=0.037). A trend towards better recovery from anaesthesia in the ‘on-medications’ group was noted, with shorter time for discharge from PACU in the ‘on-medications’ group; 60 (50 - 84) minutes Vs.  89 (62 - 120) minutes, p =0.09.

In the ‘on-medications’ group all clinical outcome measures (Hoen-Yahr, ‘OFF’ periods, and period of ‘ON hours’ spent in dyskinesia) have significantly improved postoperatively, p <0.001. Similarly the total LEDD for the ‘on medications’ group has significantly dropped postoperatively compared to the preoperative baseline, 553 (360 - 728) mg/day Vs  1221 (1000 - 1640) mg/day, P<0.001.

No cases of dopamine-withdrawal or problems with immediate postop dyskinesia were recorded in the ‘on medications group’. The observed rate of dopamine-withdrawal side effects in the ‘off-medications’ group was 15%.

Conclusions

The continuation of dopaminergic treatment for patients with PD does not affect the efficacy of the STN- DBS surgery. Neurophysiological markers of intraoperative STN localisation and postoperative clinical outcome measures for this group are comparable to those treated previously with medications withheld. The continuation of routine dopaminergic therapy will reduce the risk of dopamine-withdrawal adverse effects, and appears to be correlated with better recovery in the immediate postoperative period. Continuing medications perioperatively will enhance the patient’s experience and should improve clinical outcome.

Reference:

1-M J. Asha, J Kausar,  H Krovvidi, C Shirley, A White, R Chelvarajah,  J A. Hodson, H Pall, R D. Mitchell (2016) The effect of dopaminergic therapy on intraoperative microelectrode recordings for subthalamic deep brain stimulation under GA: can we operate on patients ‘on medications’?. Acta Neurochir (Wein) 158:387–393

According to some data, about 30% of patients with cerebral gliomas are considered to be inoperable due to the location of neoplasms in deep-seated and eloquent areas of the brain. However, it is well known that the effectiveness of treatments such patients strongly depends on possibility end extent of tumor resection, and patients treated only with the chemotherapy and irradiation demonstrate decreased survival rates as compared to operable cases. Radiosurgery is not always suitable in such situations. This problem can be dissolved due to the stereotactic method of neurosurgery operations which allows making operations in the deep areas of a brain thanks to a minimum invasive surgical approach and precision preoperative planning.

Last years, the method of stereotactic destruction of deep brain tumor by means of laser heating began to enter in neurosurgical practice. In this method, the ablation of tumor with a laser is performed under MRI control (Jethva P.R. et al., 2012; Sloan A.E., 2013). There are also reports about stereotactic radiofrequency termoablation of brain tumors (Chrastina J. et al., 2008; Takahashi H. et al., 2009). Because of this, patients with difficult-to-access brain tumors can be cured with a relatively low risk of complications.

But in our opinion based on the literature in the field of general and neurologic oncology and also on our own experience, a cryosurgery stereotactic ablation of brain tumors has some advantages. Among of them there are predictability of shapes and dimensions of tumor cryonecrosis foci formed by a cryoprobe; a rather mild response of adjacent tissues; possibility of an exploratory (reversible) impact on tissue within the temperature range of -20^OC-30^OC; and also ablastic, hemostatic and immunostimulating effects.

We have designed the special cryosurgical device for the purposes of stereotactic neurosurgery. It cools the brain tissue in a target zone up to -73^OC resulting to a formation of a zone of cryonecrosis within a tumor. This device uses a solid carbon dioxide (dry ice) as a cooling agent, and has some advantages over devices, using liquid nitrogen. They include easy control of temperature at an active tip of a cryoprobe, its good adhesion to a brain tissue, absence of “icy fractures” of a frozen tissue, simplicity and safety.

In patients with deep-seated gliomas, we perform a multi-positional destruction of neoplasms using the cryosurgery device and stereotactic apparatus. Stereotactic targeting is based on results of preoperative MRI fused with ¹¹C-methionine PET/CT of brain. The maximum accumulation of ¹¹C-methionine indicate the most malignant zones of tumors to be selectively biopsied and then stereotactically ablated. During operations, we insert a cryoprobe into intratumoral target points through a burr hole by means of stereotactic manipulator and perform consecutive cryoexpositions. Operations are made under local anesthesia for possibility of performing the neurological control on patient, considering the deep and eloquent location of tumors. Before the freezing, we perform the reversible (diagnostic) cooling of target points to the temperature of -20-30^OC to prevent the possible side effects. A monitoring of operation is also provided with a neuronavigate station and intraoperative ultrasound scanning.

From 2000 by now we have operated 158 patients with tumors located in thalamus, cerebral peduncle, insula, corpus callosum, basal ganglia, deep-seated areas of temporal, frontal and occipital lobes, central gyri. There were two groups of patients. In the first group, deep seated tumors were less than 3 cm in diameter. These tumors were destructed totally during stereotactic surgery. In the second group, with larger lesions, we selectively ablated only the areas of the maximum ¹¹C-methionine accumulation regarded as zones of maximum cells proliferation. Postoperative mortality was about 1%. The majority of cases had no worsening of life quality: permanent impairment of a neurologic state was watched only in 8.5% of patients. The survival rate in the operated cases was reliably higher than in patients treated with radio- or chemotherapy in every group of patients with grades II, III and IV tumors. Moreover, it was almost identical as in patients underwent total removal of tumors. Thus MRI/PET-guided stereotactic cryodestruction is effective and relatively safe method for treatment of patients with brain tumor localization prohibiting their conventional removal.

Introduction: External reviews of specialized radiation modalities such as SRS and SBRT has been recommended by various organizations including ASTRO to insure the highest quality of patient care.  Until recently, there existed no international program that met all the requirements of peer reviewed analysis and recommendations designed to accomplish this.  The Novalis Certified program was created to fill this need.  This study reports on the early experience and success of the Novalis certification program.

Process: The program was conceived and developed through an iterative process involving identified experts in medical physics, radiation oncology and neurosurgery.  The result was a comprehensive standards document, based on national and international standards with detailed requirements in program structure and clinical application, personnel, training, technology, and quality management. The voluntary credentialing process includes an institution-generated self-study and extensive off-site document review followed by a one-day, onsite audit. Reviewers generate a descriptive report, which is reviewed by the multidisciplinary expert panel.  Outcomes of the review may include mandatory requirements and optional recommendations.

Results: A total of 125 institutions have enrolled in the Novalis certification program.  To date, 17 have received Novalis Certification, including 3 in the US, 7 in Europe, and 6 in Asia/Pacific, 1 in Latin America. The initial reviews generated 9 required actions, which were all addressed within three months of the on-site review.  In addition, 84 specific recommendations ranging from programmatic to technical in nature were identified.   Survey of reviewed Institutions indicates the credentialing process addressed a critical need and was highly valuable to the institution.

Conclusions: Novalis Certification is a unique peer review program assessing safety and quality in SRS and SBRT, based on international standards, that recognizes high caliber practice. The approach is capable of highlighting outstanding requirements and providing recommendations to enhance both new and established programs.  Independent credentialing programs can potentially have a significant impact in ensuring quality and safety in specialized radiotherapy programs.

INTRODUCTION:

Stereotactic Body Radiotherapy (SBRT) has become a technique increasingly used for the treatment of spine metastases versus conventional radiotherapy. The objective of this technique is to improve local control, relieve symptoms quickly, restore neurological status, prevent spine instability and the reirradiation.

OBJECTIVE:

To evaluate our clinical outcomes in selected spine metastases patients (KPS> 70% and three vertebral locations but no more than two consecutive lesions) treated with LINAC SBRT plus Image Guided Radiotherapy (IGRT) (Elekta Synergy®).

PATIENTS AND METHODS:

In ONCOSUR-Granada-Cordoba, between August 2010 and April 2016, we have treated 15 patients (8 women and 7 men) with 24 locations (1-3 metastases) and a mean age of 64 years (42-82).

The protocol includes a 2-mm CT with oral contrast to the esophagus and MR study of 2 mm. The bone has been outlined in T2 (6 mm above and below the afected vertebral body). Volumes have been identified following the criteria of the International Spine Radiosurgery Consortium (ISRC).

We have evaluated the clinical and therapeutic data.

RESULTS:

Primary tumors were: breast (4), lung (2), kidney (2), colon (2), sarcoma (2), prostate (2), and unknown primary (1).

Radiation therapy techniques used were: 22 locations with Volumetric Modulated Arc Therapy (VMAT); 2 Intensity Modulated Radiation Therapy Step-and-Shoot (IMRT SS).

The hypofractionated schemes used were: 9 Gy x 3 fractions (15 locations), 8 Gy x 3 fractions (2); 6 Gy x 5 fractions (2), 5 Gy x 8 fractions (1) and 6 Gy x 4 fractions (2). All patients received sessions on alternate days.

No acute side effects (mielitis or spine fractures) were detected.

With a median follow-up of 11 months (4-28). Two patients are still under treatment. Nine patients are alive (60%), 4 with over 1 year survival and two of them free of disease.

CONCLUSIONS:

The spine SBRT is effective for local control and a safe and comfortable treatment of spine metastases. SBRT must be promoted for selected patients with oligometastatic disease, tumors resistant to the standard fractionations and higher probability of survival at one year (breast and prostate).

INTRODUCTION

Frameless radiosurgery has become a technique increasingly used for the treatment of brain metastases. A non-invasive system mask with Image Guided Radiation Therapy (IGRT) is a very attractive and comfortable alternative (Elekta ® system).

OBJECTIVE:

We evaluate our clinical results in brain metastases treated with frameless radiosurgery plus IGRT.

PATIENTS AND METHODS:

In ONCOSUR-Granada, between August 2010 and April 2016, we have treated 40 patients (50% male) with 131 brain metastases (1-11) and a mean age of 58.68 years (33-83). We have performed a total of 62 treatments. Our PTV margin was 2-3 mm.

We have evaluated the clinical and therapeutic data.

RESULTS:

Primary tumors were 17 lung, 10 breast, 5 melanomas, 2 kidneys, 1 cervix, 1 esophagus, 1 rectum, 1 ovary, 1 unknown primary, and 1 bladder.

Only 16 patients were also treated with whole brain radiotherapy (WBRT).

Radiation therapy techniques used were: 41 Volume Modulated Arc Therapy (VMAT); 21 Intensity Modulated Radiation Therapy Step-and-Shoot (IMRT SS).

The hypofractionation schemes used were: 6 x 6 Gy fractions (8 cases) and 10 Gy x 3 fractions (16 cases). All patients received 2-3 weekly fractions.

In the literature the positioning accuracy was between 1 to 4 mm for frameless stereotactic systems. In our series, the variation in repositioning with IGRT was: X = 0.24 mm (0.01-0.65); Y = 0.23 mm (0.06-0.66); and Z = 0.23 mm (0.01-0.45).

No severe side effects were detected.

With a mean follow-up of 11.1 months (1-102), 7 patients are alive, 32 died (19 of them without WBRT). Our local control was 60% (treated patients have an average of 3.3 lesions). The causes of death were: brain progression in 16 patients; lung progression in 8 patients; liver progression in 2 patients; unknown reason in 4 patients and general deterioration in 3 patients.

CONCLUSIONS:

Frameless radiosurgery is effective for local control and a comfortable treatment in the treatment of brain metastases.

The noninvasive mask system plus IGRT is associated with a highly accurate repositioning.

Objective: To investigate gamma knife radiosurgery (GKS) for benign tumor-associated secondary trigeminal neuralgia (TN).

Methods: From 2006 to 2015, 21 patients with secondary TN from meningioma were treated by GKS. The mean age of patients was 56.5 ± 12.2 years. The 50% isodose was 12.5 ± 1.1 Gy for the first GKS for meningioma. Retrogasserian targeting of the trigeminal nerve at 90 Gy with a 4-mm collimator was used for the second GKS.

Results: The delay from the onset of pain until GKS was 1.9 ± 1.9 years. The meningiomas were located in the cisternal space in 13 patients (56.5%) and involved the skull base in 8 patients (43.5%). The mean follow-up duration was 3.7 ± 2.7 years. The pain control outcomes were Barrow Neurological Institute pain scores (BNI) of I–III in 15 patients (71%). In six (29%) BNI IV patients, we performed a second GKS that targeted the trigeminal nerve resulting in a BNI of II–III. The tumor size did not increase in any patient and decreased >10% in 12 (80%) of the 15 patients who were followed for at least 1 year. Trigeminal nerve visibility may improve after tumor shrinkage. Retrogasserian targets could be used even with invisible trigeminal nerves using Meckel’s cave as an anatomical marker.

Conclusions: We have shown the reproducible feasibility of a two-session GKS procedure using higher radiation doses: the first to treat the tumor and the second to treat the trigeminal nerves using retrogasserian targeting.

OBJECTIVE:

To report the preliminar clinical experience in our center (CINAC-HM Puerta del Sur) in the treatment of essential (ET) with MRI guided High-Intensity Focused Ultrasound (MRgHIFU).

BACKGROUND:

Ablative neurosurgery for the treatment of movement disorders such as ET has been performed for decades. However, after the appearance of Deep brain stimulation in the late 80’s, lesional strategies were practically relegated. The recent development of the non-surgical low-invasive MRgHIFU has paved the way for the rebirth of ablative approaches for the treatment of Movement Disorders.

METHODS:

From July 2015 to February 2016 twelve ET patients underwent unilateral thermal thalamotomy with MRgHIFU. Tremor severity was assessed with the Clinical Rating Scale for Tremor (CRST) in all patients at baseline and 3 month after treatment. A visual analogue scale for the assessment of overall quality of life (ranging from 0 to 100% with higher scores indicating better perceived quality of life) was also given pretreatment and after procedure. Treatment-related adverse events were also registered. Topographic radiologic analysis of the lesions was performed.

RESULTS:

Total CRST score showed an improvement mean reduction of 56% (p<0,00001). Furthermore, scores for tremor corresponding to the treated hemibody were reduced from to 74% (p<0,00001). The part C of the CRST evaluating disability in activities of daily living improved from to 75% (p<0,00001). The VAS improved from 44 % at baseline to 77% (p<0,00001).

During the procedure, all patients complaint of nausea and/or headache with different degrees of severity, in one case it resulted in incomplete sonication. The most frequent postreatment adverse event was gait unstability and ipsilateral limb ataxia (5 patients) which progressively improved in the follow-up (only in one patient persisted 3 months after treatment).  Three patients reported mild bucal paresthesias that persisted 3 months after treatment.

Medium volume size lesion was 64,9mm3 (8,1 x 4 x 7,2 mm) and location was 14,8mm lateral from AC-PC and 8,2 anterior from PC. We found a positive correlation between tremor improvement and percentage of Vim lesioned.

CONCLUSION:

This pilot study supports previous evidence showing that MRgHIFU is safe and effective for the treatment of ET tremor and results in huge reduction of daily living disability. Larger, controlled and randomized trials are mandatory to confirm these findings.

Objective: This study aims at reporting the variability of the individual response to GK thalamotomy for the treatment of intractable tremor through the analysis of postoperative MR neuro-imaging features of the thalamic lesion and at establishing correlations with the clinical results.
Methods: Between April 2004 and March 2015, a Vim Gammaknife thalamotomy was performed in 319 patients for essential or Parkinsonian tremor in Marseille University hospital with a very stereotyped procedure. A neuro-imaging and clinical assessment was performed at one year FU for 253 patients. The volume of the lesion defined as the whole area of post-contrast enhancement was calculated for each patient in mm³ and the amount of edema evaluated according to a semi-quantitative scale. The coordinates of the centre of the lesion in relation to the coordinates of the planned target  and also regarding AC-PC landmarks were analyzed. A comprehensive clinical evaluation by expert neurologists was performed at the same time. Statistical analysis was performed using R software (R Studio Version 0.98.1091).
Results: Clinical and imaging data were analyzable and reviewed for a total of 169 patients. The median volume of the lesion at 12 months FU (+/- 3 months) was 89.5 mm³ (Mean = 175, Min:0, Max :1890 SD:284). Lesion volume was found to be 4 times above mean in 10 "hyper-responder" patients (764-1890 mm³; 6.1 % of patients) and 4 times below in 36 "hypo-responders" (0-44 mm³;22 %). The amount of edema around the lesion, according to our semi-quantitative scale was found to fit into a Gaussian distribution. The discrepancy between the coordinates of the planned target and the centre of the lesion visible upon FU was minimal (in terms of mean (median,min,max,SD) respectively : Δx=0,47 (0,4;0-2.6;0.43), Δy=0,45 (0.3;0-3.5;0.45) Δz=0,65(0,6;0-2,3;0.21), mainly ascribable to the fusion process of the FU images and did not account for clinical failure. In this cohort, the center of the lesion on imaging was located 14.7 mm laterally to the midline (14.81;10.3-18.4), 7.4 mm anterior to PC (7.32; 3.1-9.9) or 5.0 mm (median value)posterior to mid-commissural point. A correlation was established between the volume of the lesion and the percentage of tremor reduction at one year follow-up (Pearson's coefficient of correlation r =+ 0,22 p=0,018).Chronoradiobiological parameters such as time at the outset of treatment were not found to explain the hypo or hyperresponsive patterns. Beam-on time was not correlated to the type of response either.
Conclusions: As previously shown in a much smaller series of patients, the patients with respect to the volume of the lesion and amount of surrounding oedema fall into three response profile types (normo, hypo and hyper-responders) that correlate with the clinical outcome. These data confirm our previous results derived from 50 patients with blinded analysis of clinical outcome (Witjas and al. Neurology, 2015). Factors involved in the variability of the response to GK thalamotomy are of utmost importance and currently under investigation.

Obsessive compulsive disorder (OCD) is a challenging psychiatric condition. The authors evaluated their experience with Gamma Knife capsulotomy for treating patients with medical resistant and very severe OCD. A review of prospectively maintained data base was conducted for patients treated for untreatble OCD. Twelve patients were identified, Gamma Knife Radiosurgery with Elekta GK unit was used to target the anterior limb of the internal capsule bilaterally. Two 4 mm collimators shots was used in each side, maximun dose 120 Gy. All twelve patients were assessed preoperatively and postoperatively for clinical response by using both subjective and objective metrics; seven patients have postoperative neurorradiological follow up. the median clinical follow-up was 16 months (mean 32, 6-100 months). At the last follow-up nine patients showed good control of the obsessions and compulsions. One patient after a good response showed worsening and was considered a failure. Seven patients showed marked clinical improvement. the median YBOCS score was11 at the last follow-up. Neuroimaging with tractography confirmed the interruption of the internal capsule wich correlated with the clinical improvement. No adverse clinical effects were observed after radiosurgery.

Capsulotomy with GK is a promising and safe treatment for severe OCD cases. We discuss different items such aa anatomical localization of targets, dosimetry and follow-up of these patients.