Dedicated Linear Accelerator Radiosurgery for Classic Trigeminal Neuralgia: A Single-Center Experience with Long-Term Follow-Up.

BACKGROUND: During the past decades, stereotactic radiosurgery, and Gamma Knife in particular, has proved its safety and efficacy for drug-resistant classic trigeminal neuralgia. However, few large series exist using linear accelerator (LINAC) reporting long-term follow-up. METHODS: Between 2006 and 2015, 301 patients were treated by LINAC at our institution. The prescribed radiation dose was 90 Gy at the far anterior target. Clinical response was defined using the Barrow Neurological Institute scale. We considered grades I and IIIa as a successful response. Mean duration of follow-up was 54.6 months (range, 12-132 months). RESULTS: Two hundred and seventy-three patients (90.7%) were initially pain free, and 28 patients (9.3%) were unchanged. The actuarial probabilities of maintaining pain relief with or without medication (Barrow Neurological Institute grade I and IIIa) at 0.5, 1, 2, 4, 5, and 10 years were 88.7%, 85.0%, 76.1%, 68.8%, 65.8%, and 48.1%, respectively. Hypesthesia was present in only 26.2% of patients (very bothersome, 0.3%). No anesthesia dolorosa was reported. The actuarial probabilities of maintaining pain relief without further surgery at 0.5, 1, 2, 4, and 5 years were 99.3%, 98.3%, 95.8%, 91.0%, and 89.7%, respectively. Among all treated patients, 86.5% were satisfied by the procedure and would undergo stereotactic radiosurgery again. CONCLUSIONS: Stereotactic radiosurgery with dedicated LINAC is associated with high rates of long-term pain relief, with minimal invasiveness and rare complications. LINAC is a possible therapeutic alternative for drug-resistant trigeminal neuralgia and could be proposed to selected patients as the first intention therapy, among other surgical solutions.

Effect of subthalamic deep brain stimulation on pain in Parkinson's disease.

Painful sensations are common in Parkinson's disease. In many patients, such sensations correspond to neuropathic pain and could be related to central alterations of pain processing. Subthalamic nuclei deep brain stimulation improves motor function in Parkinson's disease. Several structures of the basal ganglia are involved in nociceptive function, and deep brain stimulation could thus also modify pain perception in Parkinson's disease. To test this hypothesis, we compared subjective heat pain thresholds, in deep brain stimulation OFF and ON conditions in 2 groups of Parkinson's disease patients with or without neuropathic pain. We also compared pain-induced cerebral activations during experimental nociceptive stimulations using H(2)(15)O positron emission tomography in both deep brain stimulation OFF and ON conditions. Correlation analyses were performed between clinical and neuroimaging results. Deep brain stimulation significantly increased subjective heat pain threshold (from 40.3 ± 4.2 to 41.6 ± 4.3, P=.03) and reduced pain-induced cerebral activity in the somatosensory cortex (BA 40) in patients with pain, whereas it had no effect in pain-free patients. There was a significant negative correlation in the deep brain stimulation OFF condition between pain threshold and pain-induced activity in the insula of patients who were pain free but not in those who had pain. There was a significant positive correlation between deep brain stimulation-induced changes in pain threshold and in pain-induced cerebral activations in the primary somatosensory cortex and insula of painful patients only. These results suggest that subthalamic nuclei deep brain stimulation raised pain thresholds in Parkinson's disease patients with pain and restored better functioning of the lateral discriminative pain system.

Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache.

Deep brain stimulation of the posterior hypothalamus is a therapeutic approach to the treatment of refractory chronic cluster headache, but the precise anatomical location of the electrode contacts has not been clearly assessed. Our aim was to study the location of the contacts used for chronic stimulation, projecting each contact centre on anatomic atlases. Electrodes were implanted in a series of 10 patients (prospective controlled trial) in the so-called 'posteroinferior hypothalamus' according to previously described coordinates, i.e. 2 mm lateral, 3 mm posterior and 5 mm below the mid-commissural point. The coordinates of the centre of each stimulating contact were measured on postoperative computed tomography or magnetic resonance imaging scans, taking into account the artefact of the electrode. Each contact centre (n=10; left and right hemispheres pooled) was displayed on the Schaltenbrand atlas and a stereotactic three dimensional magnetic resonance imaging atlas (4.7 tesla) of the diencephalon-mesencephalic junction for accurate anatomical location. Of the 10 patients with 1-year follow-up, 5 responded to deep brain stimulation (weekly frequency of attacks decrease >50%). In responders, the mean (standard deviation) coordinates of the contacts were 2.98 (1.16) mm lateral, 3.53 (1.97) mm posterior and 3.31 (1.97) mm below the mid-commissural point. All the effective contacts were located posterior to the hypothalamus. In responders, structures located <2 mm from the centres of effective contacts were: the mesencephalic grey substance (5/5), the red nucleus (4/5), the fascicle retroflexus (4/5), the fascicle longitudinal dorsal (3/5), the nucleus of ansa lenticularis (3/5), the fascicle longitudinal medial (1/5) and the thalamus superficialis medial (1/5). The contact coordinates (Wilcoxon test) and the structures (Fisher's exact test) were not significantly different between responders and non-responders. These findings suggest that failure of deep brain stimulation treatment in cluster headache may be due to factors unrelated to electrode misplacement. They also suggest that the therapeutic effect is probably not related to direct hypothalamic stimulation. Deep brain stimulation might modulate either a local cluster headache generator, located in the hypothalamus or in the mesencephalic grey substance, or non-specific anti-nocioceptive systems.

Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension.

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity,sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions.During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation(weekly frequency of attacks decrease [50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).

Chronic motor cortex stimulation for phantom limb pain: a functional magnetic resonance imaging study: technical case report.

OBJECTIVE AND IMPORTANCE: Chronic motor cortex stimulation has provided satisfactory control of pain in patients with central or neuropathic trigeminal pain. We used this technique in a patient who experienced phantom limb pain. Functional magnetic resonance imaging (fMRI) was used to guide electrode placement and to assist in understanding the control mechanisms involved in phantom limb pain. CLINICAL PRESENTATION: A 45-year-old man whose right arm had been amputated 2 years previously experienced phantom limb pain and phantom limb phenomena, described as the apparent possibility of moving the amputated hand voluntarily. He was treated with chronic motor cortex stimulation. INTERVENTION: Data from fMRI were used pre- and postoperatively to detect shoulder and stump cortical activated areas and the "virtual" amputated hand cortical area. These sites of preoperative fMRI activation were integrated in an infrared-based frameless stereotactic device for surgical planning. Phantom limb virtual finger movement caused contralateral primary motor cortex activation. Satisfactory pain control was obtained; a 70% reduction in the phantom limb pain was achieved on a visual analog scale. Postoperatively and under chronic stimulation, inhibiting effects on the primary sensorimotor cortex as well as on the contralateral primary motor and sensitive cortices were detected by fMRI studies. CONCLUSION: Chronic motor cortex stimulation can be used to relieve phantom limb pain and phantom limb phenomena. Integrated by an infrared-based frameless stereotactic device, fMRI data are useful in assisting the neurosurgeon in electrode placement for this indication. Pain control mechanisms and cortical reorganization phenomena can be studied by the use of fMRI.

The restore rechargeable, implantable neurostimulator: handling and clinical results of a multicenter study.

BACKGROUND: Spinal cord stimulation is an effective therapy for chronic, neuropathic pain refractory to medication. Use of a rechargeable neurostimulation system (Restore, Medtronic Inc) could provide greater longevity in the treatment of complex pain. However, patients' ability to successfully recharge a neurostimulation system has not yet been demonstrated. PRIMARY OBJECTIVE: Ability of patients to recharge the neurostimulator. SECONDARY OBJECTIVES: Patient and physician satisfaction with the system, pain relief, quality of life, functional status, adverse events. METHODS: Prospective, open-label, multicenter, European study in patients with long-term refractory neuropathic pain. Recharging ability was assessed 1-month postimplant. Patient and physician satisfaction, pain relief, quality of life, and functional status were assessed at scheduled follow-up visits through 12 months. Adverse events were monitored throughout. RESULTS: Primary end point: 100% of patients (n=41) successfully recharged the neurostimulator. Secondary end points at 1 month: 78.6% of patients found recharging easy. At 12 months: physicians were satisfied with the system for 92.7% of patients; pain intensity decreased significantly (P<0.001); mean self-reported pain relief was 62%; 80.5% of patients had more than 50% pain relief; quality of life and functional status improved significantly (P<0.001); 98% of patients would recommend spinal cord stimulation to others. Overall, 41 device-related complications (23 patients) were observed. CONCLUSIONS: Twelve-month experience indicates that the rechargeable neurostimulation system (Restore) was easy to use, with 100% of patients able to recharge successfully. Patient and physician satisfaction was high, with significant improvements in pain, quality of life, and functional status. Complications were comparable to prior experience with this therapy.

Does ageing influence deep brain stimulation outcomes in Parkinson's disease?

We sought to define the influence of ageing in clinical, cognitive, and quality-of-life outcomes after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). We performed motor assessment (UPDRS), mood tests, cognitive, and quality of life evaluation (PDQ-39) on PD patients before surgery, and 12 and 24 months after, and we recorded adverse events. The variations of these parameters after surgery were correlated with age using regression statistical tests. Cerebral bleeding risk was evaluated by a nonparametric test. We enrolled 45 patients (mean age 60 +/- 9 years, range 40-73). No significant correlation was found between age and motor scores and PDQ-39 improvements at 12 months. At 24 months, there was a significant negative correlation between age and the improvement of three dimensions of PDQ 39 (mobility, activities of daily life, and cognition). Cognitive impairment showed no correlation, but apathy and depression were positively correlated with age. Significant statistical difference was observed between cerebral bleeding and age. STN-DBS is an effective treatment for elderly patients with advanced PD. A longer follow-up duration and a larger population seem necessary to better assess the quality of life perception in elderly patients and to determinate the real risk of hemorrage.

Human fetal chromaffin cells: a potential tool for cell pain therapy.

Transplantation of adrenal medulla cells has been proposed in the treatment of various conditions. Indeed, these cells possess a bipotentiality: neural and neuroendocrine, which could be exploited for brain repair or pain therapy. In a previous study, we characterized these human cells in vitro over 7-10 gestational weeks (GW) [Zhou, H., Aziza, J., Sol, J.C., Courtade-Saidi, M., Chatelin, S., Evra, C., Parant, O., Lazorthes, Y., and Jozan, S., 2006. Cell therapy of pain: Characterization of human fetal chromaffin cells at early adrenal medulla development. Exp. Neurol. 198, 370-381]. We report here our results on the extension to 23 GW. This developmental period can be split into three stages. During the first stage (7-10 GW), we observed in situ that extra-adrenal surrounding cells display the same morphology and phenotype as the intra-adrenal chromaffin cells. We also found that the intra-adrenal chromaffin cells could be committed in vitro towards an adrenergic phenotype using differentiating agents. During the second stage (11 to 15-16 GW), two types of cells (Type 1 and Type 2 cells) were identified morphologically both inside and outside the gland. Interestingly, we noted that the Type 2 cells stem from the Type 1 cells. However, during this developmental period only the intra-adrenal Type 2 cells will evolve towards an adrenergic phenotype. In the third stage (17-23 GW), we observed the ultimate location of the medulla gland. Both the in situ results and the in vitro experiments indicate that particular procedures need to be implemented prior transplantation of chromaffin cells. First, in order to obtain a large number of immature chromaffin cells, they must be isolated from the intra and extra-adrenal gland and should then be committed towards an adrenergic phenotype in vitro for subsequent use in pain therapy. This strategy is under investigation in our laboratory.

Quantification of true in vivo (application) accuracy in cranial image-guided surgery: influence of mode of patient registration.

OBJECTIVE: Very few studies have attempted to quantify the true (application) accuracy of image-guidance systems during craniotomy. This is, in part, because of the lack of millimetric intraoperative targets to allow such measurements. Few in vivo studies have compared the influence of mode of patient registration on subsequent true accuracy. METHODS: Seven modes of patient registration (anatomic landmarks, 5 or 10 adhesive fiducials, bone-implanted fiducials [Stryker-Leibinger], surface matching using 45 or 100 points over scalp convexity or nose/auditory meatus contours) were compared. Thirty patients were involved in the study. Millimetric targets (bone drill holes or deep 1-mm titanium hemoclips) were placed then localized and saved at surgery. These targets were then identified on postoperative volumetric computed tomography fused with operative data sets. Localization errors of the targets were measured for each registration on an optical image-guidance system (StealthStation). RESULTS: Only implanted cranial fiducials had a statistically significant accuracy advantage (1.7 +/- 0.7 mm). All other registrations had similar accuracies (approximately 4.0 +/- 1.7 mm) except anatomic landmarks, which were worse (4.8 +/- 1.9 mm). Calculated accuracies (root mean squared) had no predictive value for true (application) accuracies. CONCLUSION: Not surprisingly, application accuracy of image-guidance is worse without implanted cranial markers. Unexpectedly, there was no major difference in localization of deep targets between the other registrations tested in this study. Care must be taken when using image-guidance tools to consider error introduced by registration. Cranium-implanted fiducials should be considered when high accuracy and reproducibility are needed.

Cortical areas involved in virtual movement of phantom limbs: comparison with normal subjects.

OBJECTIVE: To demonstrate that amputees performing "virtual" movements of their amputated limb activate cortical areas previously devoted to their missing limb, we studied amputees with functional magnetic resonance imaging (fMRI) and positron emission tomographic (PET) scans and compared the results with those of normal volunteers performing imaginary movements during fMRI acquisitions. METHODS: Ten amputees (age range, 33-92 yr; average age, 49 yr; six men and four women; eight upper-limb and two lower-limb amputations) able to move their phantom limb at will were studied by fMRI (all patients) and PET scan (seven patients). The time between amputation and fMRI and PET studies ranged from 1 to 27 years (average, 13 yr). Patients were asked to perform virtual movements of the amputated limb and normal movements of the contralateral normal limb according to the functional images acquisition procedure. Movements of the stump were also used to differentiate stump cortical areas from virtual movement-activated areas. Ten right-handed volunteers, age- and sex-matched to the amputees, were also studied by fMRI. All volunteers were asked to perform four tasks during their fMRI study: imaginary movements of their right arm (1 task) and foot (1 task) and real movements of their left arm (1 task) and foot (1 task). RESULTS: In amputees, virtual movements of the missing limbs produced contralateral primary sensorimotor cortex activation on both fMRI and PET scans. These activation areas, different from the stump activation areas, were similar in location to contralateral normal limb-activated areas. Quantitatively, in two amputees who claimed to be able to perform both slow and fast virtual movements, regional cerebral blood flow measured by PET scan in the precentral gyrus increased significantly during fast movements in comparison with slow virtual movements. In normal subjects, significant differences between real versus imaginary fMRI activations were found (for both foot and hand movements); imaginary right hand and foot tasks activated primarily the contralateral supplementary motor areas, with no significant activation detected in the contralateral precentral or postcentral gyri. CONCLUSION: Primary sensorimotor cortical areas can be activated by phantom-limb movements and thus can be considered functional for several years or decades after amputation. In this study, we found that the location of the activation of these areas is comparable to that of activations produced by normal movements in control subjects or in amputees.

Human chromaffin cell graft into the CSF for cancer pain management: a prospective phase II clinical study.

A number of pre-clinical studies have demonstrated the value of adrenal medullary allografts in the management of chronic pain. The present longitudinal survey studied 15 patients transplanted for intractable cancer pain after failure of systemic opioids due to the persistence of undesirable side-effects. Before inclusion, all the patients had their pain controlled by daily intrathecal (I-Th) morphine administration. The main evaluation criteria of analgesic activity of the chromaffin cell allograft was the complementary requirement of analgesics and in particular the consumption of I-Th morphine required to maintain effective pain control. Out of the 12 patients who profited from enhanced analgesia with long-term follow-up (average 4.5 months), five no longer required the I-Th morphine (with prolonged interruption of systemic opioids as well), two durably decreased I-Th morphine intake and five were stabilized until the end of their follow-up. Durable decline and stabilization were interpreted as indicative of analgesic activity by comparison with the usual dose escalation observed during disease progression. In most cases, we noted a relationship between analgesic responses and CSF met-enkephalin levels. The results of this phase II open study demonstrate the feasibility and the safety of this approach using chromaffin cell grafts for long-term relief of intractable cancer pain. However, while analgesic efficacy was indicated by the reduction or stabilization in complementary opioid intake, these observations will need to be confirmed in a controlled trial in a larger series of patients.

Acupuncture meridians and radiotracers.

Acupuncture is frequently used and in particular for the treatment of pain. One of the cornerstones of its use, at least in Western countries, is the concept of the acupuncture meridian. Yet, their existence has never actually been proven. Recently, a report was published stating that injection of a radiotracer at an acupuncture point allows the visualization of the corresponding meridian in the shape of a radioactive path which is apparent on scintiscans. The present work confirms the appearance of radioactive paths after the injection of a radiotracer at acupuncture points. However, the cross-checks made with the method used (counting the radioactivity of the venous blood, studying radioactivity of the organs which normally take up the tracer, scintiscan study of the complete meridian paths as they are described in traditional Chinese medicine and studying the effect of venous blockade on the observed radioactive paths) show that the radioactive paths in fact correspond to vascular drainage of the radiotracer.