[Neurosurgical treatment of chronic pain]. / Traitement neurochirurgical de la douleur chronique.

Neurosurgical treatment of pain used two kind of techniques: 1) Lesional techniques interrupt the transmission of nociceptive neural input by lesionning the nociceptive pathways (drezotomy, cordotomy, tractotomy…). They are indicated to treat morphine-resistant cancer pain and few cases of selected neuropathic pain. 2) Neuromodulation techniques try to decrease pain by reinforcing inhibitory and/or to limit activatory mechanisms. Chronic electrical stimulation of the nervous system (peripheral nerve stimulation, spinal cord stimulation, motor cortex stimulation…) is used to treat chronic neuropathic pain. Intrathecal infusion of analgesics (morphine, ziconotide…), using implantable pumps, allows to increase their efficacy and to reduce their side effects. These techniques can improve, sometimes dramatically, selected patients with severe and chronic pain, refractory to all other treatments. The quality of the analgesic outcome depends on the relevance of the indications.

Anatomy of the pineal region applied to its surgical approach.

INTRODUCTION: The pineal region is situated in the posterior part of the incisural space. This region includes the pineal body inside the quadrigeminal arachnoidal cistern. This article reviews the anatomic features of this region, with particular emphasis on those aspects of importance for surgical access to the pineal region. MATERIAL & METHODS: Five cadaver heads fixed in 10% formalin and injected with colored latex were used for anatomic dissection (five other specimens were also prepared and dissected to illustrate the articles on surgical techniques and approaches presented elsewhere in this issue). RESULTS: The pineal body is surrounded by several important structures such as: posterior part of the third ventricle, tectum, the complex of the great cerebral vein of Galen, pulvinar nuclei of the thalamus and splenium of corpus callosum. CONCLUSION: The surgical approach of the pineal body, whatever the route or the technique used (microsurgical, endoscopic or stereotactic), creates a great challenge for the neurosurgeons due to its location in the deep part of the brain and its close relationships with complex surrounded vascular structures.

Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

Vitamin D and cardiovascular risk.

Vitamin D deficiency results in abnormal mineralization of bones and has resulted in prevention programs for children with supplementation when they are breast fed. Further activities of vitamin D relate to defence of microbial infections, e.g. tuberculosis, prevention of cancer, contractility of muscle cells and counteraction of congestive heart failure. Given early reports in the 1960s on deleterious effects of vitamin D supplementation in rodents, that is ectopic media ossification of arterial vessels, a pro-atherogenic function had been anticipated for humans as well. However, cross-sectional studies reveal that vitamin D deficiency in humans is associated with elevated blood pressure and propagation of atherogenesis. These contradictory findings on the progression of atherosclerosis may be reconciled by dissecting the activation mechanism(s) of vitamin D in rodents versus humans. Notably, novel findings convincingly indicate that vitamin D exerts anti-inflammatory effects. In conclusion, vitamin D supplementation in adults may be regarded as simple means with few potential side effects to prevent atherogenesis or halt its progression and combat arterial hypertension. Adjustment of vitamin D dosing regimens is required in patients with chronic kidney disease; however, prospective clinical trials are urgently needed to guide these recommendations with evidence.

Motor cortex stimulation for pain control induces changes in the endogenous opioid system.

BACKGROUND: Motor cortex stimulation (MCS) for neuropathic pain control induces focal cerebral blood flow changes involving regions with high density of opioid receptors. We studied the possible contribution of the endogenous opioid system to MCS-related pain relief. METHODS: Changes in opioid receptor availability induced by MCS were studied with PET scan and [(11)C]diprenorphine in eight patients with refractory neuropathic pain. Each patient underwent two preoperative (test-retest) PET scans and one postoperative PET scan acquired after 7 months of chronic MCS. RESULTS: The two preoperative scans, performed at 2 weeks interval, did not show significant differences. Conversely, postoperative compared with preoperative PET scans revealed significant decreases of [(11)C]diprenorphine binding in the anterior middle cingulate cortex (aMCC), periaqueductal gray (PAG), prefrontal cortex, and cerebellum. Binding changes in aMCC and PAG were significantly correlated with pain relief. CONCLUSION: The decrease in binding of the exogenous ligand was most likely explained by receptor occupancy due to enhanced secretion of endogenous opioids. Motor cortex stimulation (MCS) may thus induce release of endogenous opioids in brain structures involved in the processing of acute and chronic pain. Correlation of this effect with pain relief in at least two of these structures supports the role of the endogenous opioid system in pain control induced by MCS.

Subthalamic nucleus stimulation in Parkinson's disease : anatomical and electrophysiological localization of active contacts.

OBJECTIVES: 1 - To assess the anatomical localization of the active contacts of deep brain stimulation targeted to the subthalamic nucleus (STN) in Parkinson's disease patients. 2 - To analyze the stereotactic spatial distribution of the active contacts in relation to the dorsal and the ventral electrophysiologically-defined borders of the STN and the stereotactic theoretical target. METHODS: Twenty-eight patients underwent bilateral high-frequency stimulation of the STN (HFS-STN). An indirect anatomical method based on ventriculography coupled to electrophysiological techniques were used to localize the STN. Clinical improvement was evaluated by Unified Parkinson's Disease Rating Scale motor score (UPDRS III). The normalized stereotactic coordinates of the active contact centres, dorsal and ventral electrophysiologically-defined borders of the STN were obtained from intraoperative X-rays images. These coordinates were represented in a three-dimensional stereotactic space and in the digitalized atlas of the human basal ganglia. RESULTS: HFS-STN resulted in significant improvement of motor function (62.8%) in off-medication state and levodopa-equivalent dose reduction of 68.7% (p < 0.05). Most of the active contacts (78.6%) were situated close to (+/- 1.6 mm) the dorsal border of the STN (STN-DB), while 16% were dorsal and 5.4% were ventral to it. Similar distribution was observed in the atlas. The euclidean distance between the STN-DB distribution center and the active contacts distribution center was 0.31 mm, while the distance between the active contacts distribution center and the stereotactic theoretical target was 2.15 mm. Most of the space defined by the active contacts distribution (53%) was inside that defined by the STN-DB distribution. CONCLUSION: In our series, most of the active electrodes were situated near the STN-DB. This suggests that HFS-STN could influence not only STN but also the dorsal adjacent structures (zona incerta and/or Fields of Forel).

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson's disease--A [(11)C]-raclopride PET study.

CONTEXT: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. OBJECTIVE: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [11C]-Raclopride, whether STN stimulation induces a striatal DA release. METHODS: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [11C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [11C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. RESULTS: For PD patients, the mean [(11C]-Raclopride BP (+/- SD) were, in Off stimulation condition: 1.7 +/- 0.3 for the right caudate nucleus, 1.8 +/- 0.4 for the left caudate nucleus, 2.6 +/- 0.5 for the right putamenand 2.6 +/- 0.5 for the left putamen. In On stimulation condition: 1.7 +/- 0.4 for the right caudate nucleus, 1.9 +/- 0.5 for the left caudate nucleus, 2.8 +/- 0.7 for the right putamen and 2.7 +/- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. CONCLUSION: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [11C]-Raclopride.

[Anatomical basis of motricity for the study of spasticity]. / Bases anatomiques de la motricité appliquées à l'étude de la spasticité.

The spinal motoneurone is under the permanent influence of peripheral afferent fibers, interneurons, and numerous descending projections from supraspinal structures. Motoneuronal activity summarizes these different and convergent modulations at one moment. Spasticity corresponds to exageration of monosynpatic reflex, from IA fiber to motoneuron alpha, associated with spinal hyperexitability. Various lesions of central nervous system give rise to spasticity, specially if they affect supra spinal descending controls, mainly reticulo-spinal tracts. The role of neuronal plasticity to explain the progressive time course of spasticity is also discussed.

The timing of antiparkinsonian treatment reduction after subthalamic nucleus stimulation.

The objective of this work was to precisely analyse the reduction of the antiparkinsonian treatment in 18 consecutive patients with Parkinson's disease (PD) operated on for bilateral subthalamic nucleus (STN) stimulation, first after 1 month of follow-up, then at 1 year postoperatively. Trihexyphenidyle, selegiline, entacapone, apomorphine and lisuride could be withdrawn shortly after starting STN electrical stimulation. The levodopa mean daily dose was reduced by 57% at 1 month after surgery and remained stable at 1 year. The mean ropinirole and bromocriptine daily dose decrements after surgery corresponded to 54 and 63%, respectively, at 1 month and to 77 and 40% at 1 year. At 12 months postoperatively, one third of the patients no longer received any antiparkinsonian drugs and the others were on monotherapy of either levodopa or dopamine agonists or received a combined treatment of a dopaminergic agonist and levodopa. In conclusion, STN stimulation allows a major reduction and simplification of antiparkinsonian treatment which can usually be achieved during the early postoperative period.

Cognitive effects of precentral cortical stimulation for pain control: an ERP study.

Electrical stimulation of the motor cortex (MCS) is a promising and increasingly used neurosurgical technique for the control of refractory neuropathic pain. Although its mechanisms of action remain unknown, recent functional imaging data suggest involvement of the thalamus, brainstem and anterior cingulate/orbitofrontal cortex. Since some of these areas are also implicated in higher cognitive functions, notably attentional processes, we analysed cognitive ERPs and behavioural performance during an "oddball" auditory detection task in patients submitted to this procedure. Eleven consecutive patients undergoing MCS because of neuropathic refractory pain, ranging in age from 25 to 71 years, were included in the study. ERPs were obtained in all cases both during the application ("MCS-on") and within the 10 min that followed discontinuation of the procedure ("MCS-off"). In five patients, ERPs could also be obtained just before the start of MCS. When the patients' sample was taken as a whole, there were no consistent effects of MCS on the ERPs. There was, however, a significant interaction of MCS action with the patients' age, reflecting a significant delay during MCS of the cognitive responses N2 and P3 (N200 and P300) in the group of patients older than 50 years exclusively. This effect was rapidly reversible after MCS discontinuation. No MCS-related changes were observed in the N1 component. At the individual level, the effect of MCS on the endogenous ERPs was highly variable, ranging from a total stability of ERPs (mostly in younger subjects) to latency differences of tens of milliseconds in the older group. These results, together with recent experiments showing P300 alteration during repetitive transcranial stimulation, suggest that motor cortex stimulation may interfere with relatively simple cognitive processes such as those underlying target detection, and that the risk of abnormal cognitive effects related to cortical stimulation may increase with age. Although the procedure appears on the whole remarkably safe, complementary neuropsychological studies in this category of patients are advised, as well as caution to possible adverse cognitive effects when using MCS in the elderly, notably in the presence of pre-existent cerebral lesions.

Subthalamic nucleus stimulation in Parkinson's disease: clinical evaluation of 18 patients.

The aim of the present study was to assess the efficacy and safety of chronic subthalamic nucleus deep-brain stimulation (STN-DBS) in patients with Parkinson's disease (PD). 18 consecutive severely affected PD patients were included (mean age, SD: 56.9+/-6 years; mean disease duration: 13.5+/-4.4 years). All the patients were evaluated clinically before and 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS). Additionally, a 12 months follow-up was available in 14 patients. The target coordinates were determined by ventriculography under stereotactic conditions, followed by electrophysiology and intraoperative stimulation. After surgery, continuous monopolar stimulation was applied bilaterally in 17 patients at 2.9+/-0.4 V through 1 (n = 31) or 2 contacts (n = 3). One patient had bilateral bipolar stimulation. The mean frequency of stimulation was 140+/-16 Hz and pulse width 68+/-13 micros. Off medication, the UPDRS part III score (max = 108) was reduced by 55 % during on stimulation (score before surgery: 44.9+/-13.4 vs at 6 months: 20.2+/-10; p < 0.001). In the on medication state, no difference was noted between the preoperative and the postoperative off stimulation conditions (scores were respectively: 17.9+/-9.2 and 23+/-12.6). The severity of motor fluctuations and dyskinesias assessed by UPDRS IV was reduced by 76 % at 6 months (scores were respectively: 10.3+/-3 and 2.5+/-3; p < 0.001). Off medication, the UPDRS II or ADL score was reduced by 52.8 % during on stimulation (26.9+/-6.5 preop versus 12.7+/-7 at 6 months). The daily dose of antiparkinsonian treatment was diminished by 65.5 % (levodopa equivalent dose -- mg/D -- was 1045 +/- 435 before surgery and 360 +/- 377 at 6 months; p < 0.01). These results remained stable at 12 months for the 14 patients studied. Side effects comprised lower limb phlebitis (n = 2), pulmonary embolism (n = 1), depression (n = 6), dysarthria and freezing (n = 1), sialorrhea and drooling (n = 1), postural imbalance (n = 1), transient paresthesias and dyskinesias. This study confirms the great value of subthalamic nucleus stimulation in the treatment of intractable PD. Some adverse events such as depression may be taken into account in the inclusion criteria and also in the post-operative outcome.

Functional imaging and neurophysiological assessment of spinal and brain therapeutic modulation in humans.

We summarize here our experience in the neurophysiological and neuroimaging assessment of spinal and brain neuromodulation for pain relief. Techniques reviewed include somatosensory evoked potentials (SEPs), nociceptive spinal (RIII) reflexes, and positron emission tomography (PET), which have been applied both to investigate the mechanisms and to optimize the application of neurostimulation procedures. SEPs are especially useful in the preoperative assessment of patients with neuropathic pain, as they allow the establishment of the functional state of the dorsal column system. Patients with strongly abnormal SEPs due to ganglionic or preganglionic pathology are not likely to benefit from spinal (SCS) or peripheral (TENS) neurostimulation, because ascending fibers disconnected from their soma will undergo rapid degeneration and not be excitable. In the postoperative period, nociceptive spinal reflexes yield objective data concerning the effects of neurostimulation on spinal circuitry. In our experience, the best clinical results are achieved in patients with preserved preoperative SEPs, in whom neurostimulation entails profound attenuation of nociceptive reflexes.PET-scan imaging techniques have recently been used to demonstrate changes in cerebral blood flow during new neuromodulation schemes such as motor cortex stimulation for pain control (MCS). PET studies highlight the thalamus as the key structure mediating functional MCS effects. Thalamic activation would trigger a cascade of synaptic events influencing activity in other pain-related structures including the anterior cingulate gyrus, insula, and upper brainstem. The combination of clinical electrophysiology and functional neuroimaging provides insight into the mechanisms of action of neuromodulation procedures, guides clinical decision, and contributes to optimize patient selection.

Neurosurgical management of neuropathic pain.

Neuropathic pain is a very difficult problem with which the neurosurgeon frequently must deal. The neurosurgical methods to be considered are: (1) modulative, by using neurostimulation or implanted drug delivery systems, and (2) ablative, by making selective therapeutic lesions in well-defined and identified targets proven to sustain pain mechanisms (especially DREZotomy).

Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study.

Although electrical stimulation of the precentral gyrus (MCS) is emerging as a promising technique for pain control, its mechanisms of action remain obscure, and its application largely empirical. Using positron emission tomography (PET) we studied regional changes in cerebral flood flow (rCBF) in 10 patients undergoing motor cortex stimulation for pain control, seven of whom also underwent somatosensory evoked potentials and nociceptive spinal reflex recordings. The most significant MCS-related increase in rCBF concerned the ventral-lateral thalamus, probably reflecting cortico-thalamic connections from motor areas. CBF increases were also observed in medial thalamus, anterior cingulate/orbitofrontal cortex, anterior insula and upper brainstem; conversely, no significant CBF changes appeared in motor areas beneath the stimulating electrode. Somatosensory evoked potentials from SI remained stable during MCS, and no rCBF changes were observed in somatosensory cortex during the procedure. Our results suggest that descending axons, rather than apical dendrites, are primarily activated by MCS, and highlight the thalamus as the key structure mediating functional MCS effects. A model of MCS action is proposed, whereby activation of thalamic nuclei directly connected with motor and premotor cortices would entail a cascade of synaptic events in pain-related structures receiving afferents from these nuclei, including the medial thalamus, anterior cingulate and upper brainstem. MCS could influence the affective-emotional component of chronic pain by way of cingulate/orbitofrontal activation, and lead to descending inhibition of pain impulses by activation of the brainstem, also suggested by attenuation of spinal flexion reflexes. In contrast, the hypothesis of somatosensory cortex activation by MCS could not be confirmed by our results.

Precentral cortex stimulation for the treatment of central neuropathic pain: results of a prospective study in a 20-patient series.

The authors report a series of 23 patients with central neuropathic pain who were treated with the recently developed technique of precentral cortex stimulation (PCS). Of the 20 patients with a follow-up of more than 1 year (mean of 23 months) 25% had an excellent, 35% a good and 15% a fair relief of pain. In 25% the method failed. On the basis of these findings and the literature data (127 reported cases), the authors advocate PCS in patients with severe and medically refractory poststroke pain.

Positron emission tomography during motor cortex stimulation for pain control.

We studied regional changes in cerebral flood flow (rCBF) in 9 patients undergoing motor cortex stimulation (MCS) for pain control. Significant increase in rCBF was observed in the lateral thalamus ipsilateral to MCS probably reflecting corticothalamic connections from motor/premotor areas. Subsignificant increases were observed in the anterior cingulate, left insula and upper brainstem. Mean rCBF in the anterior cingulate increased during MCS in patients with good analgesic efficacy, while it decreased in those with poor clinical outcome; conversely, thalamic rCBF increased in the two groups, albeit to a greater extent in patients with good clinical results. Our results support a model of MCS action whereby activation of thalamic nuclei directly connected with motor and premotor cortices would entail a cascade of synaptic events in other pain-related structures, including the anterior cingulate and the periaqueductal gray. MCS could influence the affective-emotional component of chronic pain by way of cingulate activation, and lead to descending inhibition of pain impulses by activation of the brainstem. Such effects may be obtained only if thalamic activation reaches a 'threshold' level, below which the analgesic cascade would not be successfully triggered.

[Neurosurgical treatments of chronic pain]. / Traitements neurochirurgicaux de la douleur chronique.

During these last years the methods and the indications of analgesic neurosurgery have respectively changed toward greater multiplicity and more selectivity. The conservative methods of neurostimulation have acquired a prominent place in some types of pain from neuropathic origin. Their aim is to reinforce inhibitory fibre function. Whatever the technique used, stimulation of peripheral nerves, of posterior funiculi of the spinal cord, of the thalamus or the cerebral cortex, it will be effective only if the target structures are not totally, anatomically and functionally, destroyed. Intrathecal morphine administration, has been shown to be useful to control some cancer-induced pain. Lastly, the techniques of interrupting the pathways of pain, achieving greater selectivity in their effects, remain the preferred treatment for some types of localised pain having precise mechanisms.

Effect of antibiotic therapy on the antibiotic resistance of faecal Escherichia coli in patients attending general practitioners.

To analyse the influence of antibiotic therapy on the faecal flora of patients from general practice with complaints of a respiratory tract infection (RTI), 189 paired faecal specimens were collected, before and after completing antibiotic treatment (n = 129) and symptomatic treatment (n = 60). Faecal specimens were examined for the prevalence and degree of resistance to amoxycillin, apramycin, ciprofloxacin, nalidixic acid, neomycin, nitrofurantoin, oxytetracycline, sulphamethoxazole and trimethoprim. In the antibiotic-treated group a significant increase in the prevalence of resistance to amoxycillin post-treatment from 50% to 64% (P < 0.05, Wilcoxon) was observed. In the symptomatic treated group no significant differences in the prevalence of resistance were found. Using discriminant analysis, amoxycillin and doxycycline therapy contributed to an increased prevalence of resistance to amoxycillin and oxytetracycline, respectively. In the antibiotic-treated group Escherichia coli isolates post-treatment had a significantly increased resistance rate to amoxycillin (15%-23%) and to neomycin (2%-6%) (P < 0.05, Wilcoxon). Logistic regression analysis showed a cross resistance to neomycin and kanamycin, and for kanamycin cross-resistance to apramycin, neomycin and streptomycin occurred.