Characterization of pulmonary immune responses to hyperoxia by high-dimensional mass cytometry analyses.

Prolonged exposure to hyperoxia has deleterious effects on the lung, provoking both inflammation and alveolar injury. The elements of hyperoxic injury, which result in high rates of lethality in experimental models, are thought to include multicellular immune responses. To characterize these alterations in immune cell populations, we performed time-of-flight mass cytometry (CyTOF) analysis of CD45-expressing immune cells in whole lung parenchyma and the bronchoalveolar space of mice, exposed to 48 hours of hyperoxia together with normoxic controls. At the tested time point, hyperoxia exposure resulted in decreased abundance of immunoregulatory populations (regulatory B cells, myeloid regulatory cells) in lung parenchyma and markedly decreased proliferation rates of myeloid regulatory cells, monocytes and alveolar macrophages. Additionally, hyperoxia caused a shift in the phenotype of alveolar macrophages, increasing proportion of cells with elevated CD68, CD44, CD11c, PD-L1, and CD205 expression levels. These changes occurred in the absence of histologically evident alveolar damage and abundance of neutrophils in the parenchyma or alveolar space did not change at these time points. Collectively, these findings demonstrate that pulmonary response to hyperoxia involves marked changes in specific subsets of myeloid and lymphoid populations. These findings have important implications for therapeutic targeting in acute lung injury.

[Familial colloid cyst of the third ventricle: case report and review of the literature]. / Kystes colloïdes familiaux du troisième ventricule : cas clinique et revue de la littérature.

Colloid cysts of the third ventricle are rare benign lesions. We report here an exceptional familial case defined by the evidence of two colloid cysts in two relatives of the first degree, a mother and her daughter in our description. Only 15 cases are reported in the literature. The main differences compared with sporadic cases are an earlier age of discovery and a female predominance. In case of familial colloid cyst, we have to recover a brain MRI screening of all the relatives of the first degree.

Chronic neuropathic pain in spinal cord injury: efficiency of deep brain and motor cortex stimulation therapies for neuropathic pain in spinal cord injury patients.

OBJECTIVES: In spite of all the scientific advances in pharmacological research, a great number of patients cannot efficiently manage their chronic pain with conventional pharmacological treatments. Brain stimulation techniques have considerably improved these last 10 years. These techniques could be an interesting option after a rigorous selection of patients. We aim to evaluate the efficacy of brain stimulation (deep brain stimulation [DBS] and motor cortex stimulation [MCS]) within the framework of neuropathic pain management in spinal cord injury (SCI) patients and elaborate some recommendations. MATERIAL AND METHOD: The methodology used, proposed by the French Society of Physical Medicine and Rehabilitation (SOFMER), includes a systematic review of the literature, the gathering of information regarding current clinical practices and a validation by a multidisciplinary panel of experts. RESULTS: DBS is more effective on nociceptive pain than deafferentation pain. For the central pain of SCI patients, the long-term efficacy of DBS is quite low (three patients out of 19, amounting to 16%). MCS seems to have an interesting potential with a long-term efficacy of 57% (four patients out of seven), with less complications than DBS. CONCLUSION: For central pain in SCI patients, there is no sufficient level of evidence to validate the use of DBS. There is however a low level of evidence for MCS. These results must be validated by larger comparative or controlled versus placebo clinical studies.

[Treatment of trigeminal neuropathic pain by motor cortex stimulation]. / Traitement des douleurs trigéminales neuropathiques par stimulation corticale.

The neurosurgical procedures currently available for the treatment of trigeminal neuralgia can induce trigeminal neuropathic pain. Severe forms of trigeminal neuropathic pain correspond to the classical facial anesthesia dolorosa, whose treatment is known to be very difficult. Chronic stimulation of the ventral posterolateral nucleus (VPL) of the thalamus was, in the past, the only neurosurgical therapy available to treat this complication. The long-term results have been disappointing, which opened the field to the development of other techniques, including stimulation of the motor cortex for which there is now sufficient experience showing long-term results that are satisfactory in more than 70% of patients. Meanwhile, some authors have proposed directly stimulating the nerve branches concerned, such as the supraorbital nerve, or discussing indications for thalamic stimulation. In this chapter, only the cortical stimulation procedure will be developed.

Involvement of electrophysiological localization of the subthalamic nucleus in deep brain stimulation for Parkinson's disease.

We studied the involvement of the electrophysiological localization of the subthalamic nucleus (NST) using a multi-unit recording technique by means of semi-microelectrode in a set of thirty Parkinson's patients who benefited from a bilateral stimulation of the NST and who were operated on under local or general anesthesia. The multi-unit recording technique by means of semi-microelectrodes appeared efficient, capable of improving the localization of the NST and leading to improvement in clinical results. We believe that the use of our technique will allow for time savings while providing good results, and that the choice of the angle of the trajectory will allow for improved localization of the NST and thus improved clinical results.

Attempted and completed suicides after subthalamic nucleus stimulation for Parkinson's disease.

A higher than expected frequency of suicide has been reported among patients undergoing subthalamic nucleus deep brain stimulation (STN DBS) for advanced Parkinson's disease (PD). We conducted a retrospective survey of 200 patients with PD who underwent STN DBS. Two patients (1%) committed suicide and four (2%) attempted suicide, despite clear motor improvements. Suicidal patients did not differ from non-suicidal patients with respect to age, disease duration or preoperative depressive and cognitive status. Suicidal behaviour was associated with postoperative depression and/or altered impulse regulation. Suicidal behaviour is a potential hazard of STN DBS, calling for careful preoperative assessment and close postoperative psychiatric and behavioural follow-up.

Motor cortex rTMS in chronic neuropathic pain: pain relief is associated with thermal sensory perception improvement.

BACKGROUND: Improvement in sensory detection thresholds was found to be associated with neuropathic pain relief produced by epidural motor cortex stimulation with surgically implanted electrodes. OBJECTIVE: To determine the ability of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex to produce similar sensory changes. METHODS: In 46 patients with chronic neuropathic pain of various origins, first-perception thresholds for thermal (cold, warm) and mechanical (vibration, pressure) sensations were quantified in the painful zone and in the painless homologue contralateral territory, before and after rTMS of the motor cortex corresponding to the painful side. Ongoing pain level was also scored before and after rTMS. Three types of rTMS session, performed at 1 Hz or 10 Hz using an active coil, or at 10 Hz using a sham coil, were compared. The relationships between rTMS-induced changes in sensory thresholds and in pain scores were studied. RESULTS: Subthreshold rTMS applied at 10 Hz significantly lowered pain scores and thermal sensory thresholds in the painful zone but did not lower mechanical sensory thresholds. Pain relief correlated with post-rTMS improvement of warm sensory thresholds in the painful zone. CONCLUSIONS: Thermal sensory relays are potentially dysfunctioning in chronic neuropathic pain secondary to sensitisation or deafferentation-induced disinhibition. By acting on these structures, motor cortex stimulation could relieve pain and concomitantly improve innocuous thermal sensory discrimination.

Subthalamic nucleus stimulation in Parkinson's disease: postoperative CT-MRI fusion images confirm accuracy of electrode placement using intraoperative multi-unit recording.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is increasingly used to treat advanced Parkinson's disease (PD). The optimal method for targeting the STN before implanting the definitive DBS electrode is still a matter of debates. Beside methods of direct visualization of the nucleus based on stereotactic magnetic resonance imaging (MRI), the most often used technique for targeting STN consists in recording single-cell activity along exploratory tracks of 10-15mm in length, centered on the theoretical or MRI-defined target coordinates. Single-unit recordings with a microelectrode present various drawbacks. They are time-consuming if correctly performed and a single-cell precision is probably superfluous, taking into account the size of the implanted electrode. In this study, we present an original method of recording and quantification of a multi-unit signal recorded intraoperatively with a semi-microelectrode for targeting the STN. Twelve patients with advanced PD have been included and assessed clinically before and one year after bilateral STN-DBS electrode implantation guided by multi-unit electrophysiological recordings. After one year of chronic stimulation, all patients showed a marked clinical improvement. The motor score of the unified Parkinson's disease rating scale decreased by more than 57% and the required levodopa-equivalent daily dose by 59.5% in on-stimulation off-medication condition compared to off-stimulation off-medication condition. The accuracy of STN-DBS lead placement was confirmed on postoperative computed tomography (CT) scans, which were fused to preoperative T2-weighted MRI. The boundaries of the STN were easily determined by an increase in multi-unit signal amplitude, which was observed on average from 0.492mm below the rostral border of the STN down to 0.325mm above its caudal border. Signal amplitude significantly increased at the both rostral and caudal STN margins (P<0.05) and the level of neuronal activity easily distinguished inside from outside the nucleus. This study showed that STN boundaries could be adequately determined on the basis of intraoperative multi-unit recording with a semi-microelectrode. The accuracy of our method used for positioning DBS electrodes into the STN was confirmed both on CT-MRI fusion images and on the rate of therapeutic efficacy.

Cathodal, anodal or bifocal stimulation of the motor cortex in the management of chronic pain?

The conditions of motor cortex stimulation (MCS) applied with epidural electrodes, in particular monopolar (cathodal or anodal) and bipolar stimulation, are discussed. The results of theoretical studies, animal experiments and clinical studies lead to similar conclusions. Basically, cortical nerve fibres pointing at the epidural electrode and those normal to this direction are activated by anodal and cathodal stimulation, respectively. Because MCS for the relief of chronic pain is generally applied bipolarly with electrodes at a distance of at least 10 mm, stimulation may actually be bifocal. The polarity and magnitude of a stimulus needed to recruit cortical nerve fibres varies with the calibre and shape of the fibres, their distance from the electrode and their position in the folded cortex (gyri and sulci). A detailed analysis of intra-operative stimulation data suggests that in bipolar MCS the anode of the bipole giving the largest motor response in the pain region is generally the best electrode for pain management as well, when connected as a cathode. These electrode positions are most likely confined to area 4.

Somatotopic organization of the analgesic effects of motor cortex rTMS in neuropathic pain.

BACKGROUND: Motor cortex repetitive transcranial magnetic stimulation (rTMS) was found to relieve chronic neuropathic pain, but the optimal parameters of stimulation remain to be determined, including the site of stimulation. OBJECTIVE: To determine the relationship between cortical stimulation site and pain site regarding the analgesic efficacy of rTMS of motor cortex in chronic neuropathic pain. METHODS: Thirty-six patients with unilateral chronic neuropathic pain located at the face or the hand were enrolled. Motor cortex rTMS was applied at 10 Hz over the area corresponding to the face, hand, or arm of the painful side, whatever pain location. Analgesic effects were daily assessed on visual analogue scale for the week that followed each rTMS session. RESULTS: All types of rTMS session, whatever the target, significantly relieved pain, compared with baseline. However, analgesic effects were significantly better after hand than face area stimulation in patients with facial pain and after face than hand or arm area stimulation in patients with hand pain. CONCLUSION: Repetitive transcranial magnetic stimulation was more effective for pain relief when the stimulation was applied to an area adjacent to the cortical representation of the painful zone rather than to the motor cortical area corresponding to the painful zone itself. This result contradicts the somatotopic efficacy observed for chronic epidural motor cortex stimulation with surgically implanted electrodes.

Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain.

OBJECTIVE: To assess cortical excitability changes in patients with chronic neuropathic pain at baseline and after repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. METHODS: In 22 patients with unilateral hand pain of various neurologic origins and 22 age-matched healthy controls, we studied the following parameters of cortical excitability: motor threshold at rest, motor evoked potential amplitude ratio at two intensities, cortical silent period (CSP), and intracortical inhibition (ICI) and intracortical facilitation. We compared these parameters between healthy subjects and patients at baseline. We also studied excitability changes in the motor cortex corresponding to the painful hand of patients after active or sham rTMS of this cortical region at 1 or 10 Hz. RESULTS: At baseline, CSP was shortened for the both hemispheres of patients vs healthy subjects, in correlation with pain score, while ICI was reduced only for the motor cortex corresponding to the painful hand. Regarding rTMS effects, the single significant change was ICI increase in the motor cortex corresponding to the painful hand, after active 10-Hz rTMS, in correlation with pain relief. CONCLUSION: Chronic neuropathic pain was associated with motor cortex disinhibition, suggesting impaired GABAergic neurotransmission related to some aspects of pain or to underlying sensory or motor disturbances. The analgesic effects produced by motor cortex stimulation could result, at least partly, from the restoration of defective intracortical inhibitory processes.

Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study.

Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.

[Cost-benefit evaluation of spinal cord stimulation treatment for failed-back surgery syndrome patients]. / Evaluation coût/bénéfice du traitement des lombosciatalgies post-operatoires par stimulation médullaire.

BACKGROUND AND PURPOSE: Spinal cord stimulation is a well-known treatment of rigorously selected failed-back surgery syndrome patients. Efficacy levels over 50% of pain relief have been reported in long-term studies. The objective of this multicenter prospective evaluation was to analyze the cost to benefit ratio of spinal cord stimulation treatment for failed back surgery syndrome patients. METHODS: Nine hospitals (pain evaluation and treatment centers) were involved in the study. Forty-three patients were selected and implanted between January 1999 and January 2000. For each patient, pre- and post-operative evaluations (6, 12 and 24 months after implantation) were performed to assess pain relief and economical impact on pain treatment costs. RESULTS: After 24 months, mean 60% pain relief was achieved as assessed with the neuropathic pain score using a Visual Analog Scale (success rate=70%), whereas low-back pain was moderately reduced (29%). The Oswestry Disability questionnaire score was improved by a mean 39%. Costs of pain treatment (medication, consultation, other) are reduced by a mean 64% (1705 Euro) per patient per year. CONCLUSIONS: This study confirms a clear analgesic effect on neuropathic sciatalgia, and moderate attenuation of low-back pain. One particular interest of this study is the medico-economic prospective evaluation showing that the initial cost of the implanted device is compensated by a significant, early, and stable reduction in the cost of associated pain therapies.

Low-frequency repetitive TMS of premotor cortex can reduce painful axial spasms in generalized secondary dystonia: a pilot study of three patients.

Dystonia is associated with excessive corticospinal motor output. Motor cortex excitability may be reduced by low-frequency repetitive transcranial magnetic stimulation (rTMS) of premotor cortical areas. We report the effects of 1 Hz rTMS applied at 90% of resting motor threshold over the left premotor cortex in an open pilot study of three patients with severe, generalized, secondary dystonia including painful spasms in the proximal and axial musculature. A 20-min session of premotor rTMS was daily performed during 5 consecutive days. The series of rTMS sessions dramatically reduced the painful spasms, for 3-8 days after the last session, without any other significant beneficial effects. However, a slight reduction of the Movement score of the Burke, Fahn and Marsden rating scale was observed for two patients, and of the Disability score for the third one. Low-frequency rTMS of the premotor cortex may improve some specific motor symptoms in severe, generalized dystonia. These results should prompt confirmation in a larger placebo-controlled study.

Neuropathic pain controlled for more than a year by monthly sessions of repetitive transcranial magnetic stimulation of the motor cortex.

Neuropathic pain can be controlled by motor cortex stimulation using surgically-implanted electrodes in a majority of selected patients. Analgesic effects were also found to result from repetitive transcranial magnetic stimulation (rTMS) of the cortex. We report the case of a woman, in whom drug-resistant peripheral pain was controlled for 16 months by monthly sessions of motor cortex rTMS until a durable pain relief was obtained after surgical implantation of a cortical stimulator. This case illustrates the value of rTMS in helping patients to wait for surgery.

Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain.

OBJECTIVE: Drug resistant neurogenic pain can be relieved by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. This study was designed to assess the influence of pain origin, pain site, and sensory loss on rTMS efficacy. PATIENTS AND METHODS: Sixty right handed patients were included, suffering from intractable pain secondary to one of the following types of lesion: thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion, or trigeminal nerve lesion. The pain predominated unilaterally in the face, the upper limb, or the lower limb. The thermal sensory thresholds were measured within the painful zone and were found to be highly or moderately elevated. Finally, the pain level was scored on a visual analogue scale before and after a 20 minute session of "real" or "sham" 10 Hz rTMS over the side of the motor cortex corresponding to the hand on the painful side, even if the pain was not experienced in the hand itself. RESULTS: and discussion: The percentage pain reduction was significantly greater following real than sham rTMS (-22.9% v -7.8%, p = 0.0002), confirming that motor cortex rTMS was able to induce antalgic effects. These effects were significantly influenced by the origin and the site of pain. For pain origin, results were worse in patients with brainstem stroke, whatever the site of pain. This was consistent with a descending modulation within the brainstem, triggered by the motor corticothalamic output. For pain site, better results were obtained for facial pain, although stimulation was targeted on the hand cortical area. Thus, in contrast to implanted stimulation, the target for rTMS procedure in pain control may not be the area corresponding to the painful zone but an adjacent one. Across representation plasticity of cortical areas resulting from deafferentation could explain this discrepancy. Finally, the degree of sensory loss did not interfere with pain origin or pain site regarding rTMS effects. CONCLUSION: Motor cortex rTMS was found to result in a significant but transient relief of chronic pain, influenced by pain origin and pain site. These parameters should be taken into account in any further study of rTMS application in chronic pain control.

[Neural transplantation for the treatment of Parkinson's disease. Update and future]. / Greffe neuronale dans le traitement de la maladie de Parkinson. Mise au point et perspectives d'avenir.

Cell transplantation to replace lost neurons is a recent approach to the treatment of progressive neurodegenerative diseases. Replacement of dopaminergic neurons in patients with Parkinson's disease (PD) was the first transplantation therapy to be tested in the clinical setting. In PD, cell replacement strategy has been based on the idea that neural graft-induced restoration of dopamine neurotransmission in the striatum could lead to substantial and long-lasting functional recovery. Since transplantation of embryonic dopaminergic cells was first reported in the early 1990s, several open-label clinical trials have confirmed the benefits of transplantation. But, the validity of these studies has been uncertain because of small patient numbers, variable inclusion criteria, and the absence of control groups. Two controlled trials have been recently designed and performed. Their designs incorporated a "sham-operated" versus a transplant group. The conclusions drawn by both teams are that fetal mesencephalic allograft can not, at present, be recommended as a treatment for severe PD. However, several lessons can be learnt and the efficacy can be improved employing more neurons and better targets, and/or neurotrophic factors.

Low levels of ventricular CSF orexin/hypocretin in advanced PD.

The origins of excessive daytime sleepiness in Parkinson disease (PD) are unclear. The authors hypothesize that orexin neurons, a recently identified wake promoting system, could contribute to its pathophysiology. They measured orexin-A/hypocretin-1 concentration in ventricular CSF in 19 parkinsonian patients and compared it with neurologic controls. Orexin levels were lower in patients and decreased with the severity of the disease. The authors suggest that orexin neurons contribute to daytime sleepiness in late stage PD.

Chiari I malformation: a rare cause of noncommunicating hydrocephalus treated by third ventriculostomy.

OBJECT: Hydrocephalus associated with Chiari I malformation is a rare entity related to an obstruction in the flow of cerebrospinal fluid (CSF) in the foramen of Magendie. Like all forms of noncommunicating hydrocephalus. it can be treated by endoscopic third ventriculostomy (ETV). The object of this study is to report a series of five cases of hydrocephalus associated with Chiari I malformation and to evaluate the use of ETV in the treatment of this anomaly. METHODS: Five patients (four women and one man with a mean age of 29.6 years) underwent ETV for hydrocephalus associated with Chiari I malformation between April 1991 and February 1997. All patients had presented with paroxysmal headaches, which in two cases were associated with visual disorders. All patients had also presented with hydrocephalus (mean transverse diameter of the third ventricle 12.79 mm; mean sagittal diameter of the fourth ventricle 18.27 mm) with a mean herniation of the cerebellar tonsils at 13.75 mm below the basion-opisthion line. Surgery was performed in all patients by using a rigid endoscope. No complications occurred either during or after the procedure, except in one patient who experienced a wound infection that was treated by antibiotic medications. The mean duration of follow up in this study was 50.39 months. Four patients became completely asymptomatic and remained stable throughout the follow-up period. One patient required an additional third ventriculostomy after I year, due to secondary closure, and has remained stable since that time. Postoperative magnetic resonance images demonstrated a significant reduction in the extent of hydrocephalus in all patients (mean transverse diameter of the third ventricle 6.9 mm [p = 0.0035]; mean sagittal diameter of the fourth ventricle 10.32 mm [p = 0.007]), with a mean ascent of the cerebellar tonsils from 13.75 mm below the basion-opisthion line to 7.76 mm below it (p = 0.01). In addition, CSF flow was identified on either side of the orifice of the third ventriculostomy in all patients postoperatively. CONCLUSIONS: Results in this series confirm the efficacy of ETV in the treatment of hydrocephalus associated with Chiari I malformation. It is a reliable, minimally invasive technique that also provides a better understanding of the pathophysiology of this malformation.