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.

[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.

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.

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.

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.

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.

Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF.

Huntington's disease (HD) is an autosomal dominant genetic disease with devastating clinical effects on cognitive, psychological, and motor functions. These clinical symptoms primarily relate to the progressive loss of medium-spiny GABA-ergic neurons of the striatum. There is no known treatment to date. Several neurotrophic factors have, however, demonstrated the capacity to protect striatal neurons in various experimental models of HD. This includes the ciliary neurotrophic factor (CNTF), the substance examined in this protocol. An ex vivo gene therapy approach based on encapsulated genetically modified BHK cells will be used for the continuous and long-term intracerebral delivery of CNTF. A device, containing up to 106 human CNTF-producing BHK cells surrounded by a semipermeable membrane, will be implanted into the right lateral ventricle of 6 patients. Capsules releasing 0.15-0.5 microg CNTF/day will be used. In this phase I study, the principal goal will be the evaluation of the safety and tolerability of the procedure. As a secondary goal, HD symptoms will be analyzed using a large battery of neuropsychological, motor, neurological, and neurophysiological tests and the striatal pathology monitored using MRI and PET-scan imaging. It is expected that the gene therapy approach described in this protocol will mitigate the side effects associated with the peripheral administration of recombinant hCNTF and allow a well-tolerated, continuous intracerebroventricular delivery of the neuroprotective factor.

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.

Thalamic stimulation and proximal tremor. A specific target in the nucleus ventrointermedius thalami.

The severe proximal cerebellar postural tremor (also called action or intention or hyperkinetic tremor) is barely influenced by thalamotomy or stimulation of the thalamus at the classic target in the lower part of the nucleus ventrointermedius thalami (VIM). In four patients with a severe postural distal and proximal tremor, an electrode fitted with four points of contact was introduced within the entire height of the VIM. In each patient, stimulation of the lower part of the VIM was most effective in the distal component of the tremor, whereas its proximal component was specifically reduced by stimulation of its upper part. These results indicate that (1) proximal postural tremors can be as much affected by stimulation of the VIM as distal tremors, (2) there is a somatotopy in the VIM that is similar to that in the nucleus ventralis posterolateralis thalami, and (3) it is possible with this technique to adjust the VIM stimulation site so as to obtain the maximum efficacy according to the locale of the tremor.

Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex.

Chronic electrical stimulation of the precentral (motor) cortex using surgically implanted electrodes is performed to treat medication-resistant neurogenic pain. The goal of this placebo-controlled study was to obtain such antalgic effects by means of a non-invasive cortical stimulation using repetitive transcranial magnetic stimulation (rTMS). Eighteen patients with intractable neurogenic pain of various origins were included and underwent a 20 min session of either 10 Hz, 0.5 Hz or* sham rTMS over the motor cortex in a random order. A significant decrease in the mean pain level of the series was obtained only after 10 Hz rTMS. This study shows that a transient pain relief can be induced by 10 Hz rTMS of the motor cortex in some patients suffering from chronic neurogenic pain.

A technique for stereotactic aspiration of deep intracerebral hematomas under computed tomographic control using a new device.

A new device, modified from the Nucleotome (Surgical Dynamics, Alameda, CA), was used for stereotactic aspiration of deep brain hematomas. Real-time monitoring by computed tomography allows a very safe procedure, and the risk of aspirating the surrounding brain is avoided. The technique was applied in 13 cases of deep brain hematomas. The intraoperative computed tomographic scan demonstrated that the mass effect was always immediately improved. Aspiration was stopped when the midline shift disappeared or was dramatically reduced. For most of the cases, a total aspiration of the hematoma was not needed (mean value of the aspiration rate of 71, 5%). No rebleeding and no complication related to the technique was observed. This technique was easily performed in emergency conditions.

Soleus neurotomy for treatment of the spastic equinus foot. Groupe d'Evaluation et de Traitement de la Spasticité et de la Dystonie.

OBJECTIVE: This prospective, nonrandomized, noncontrolled study was performed to evaluate the results of a new type of neurotomy, namely the soleus neurotomy, for treatment of the spastic equinus foot. METHODS: Between May 1996 and March 1998, 46 patients were treated for a spastic equinus foot. Clinical status, spasticity (Ashworth Scale score), and kinematic parameters of the gait were determined before and after surgery. The neurotomy was performed on the upper nerve of the soleus in all cases and was associated with other neurotomies (lower nerve of the soleus, 21 patients; gastrocnemius, 9 patients, tibialis posterior, 18 patients; flexor hallucis longus, 16 patients; and flexor digitorum longus, 17 patients). RESULTS: The mean follow-up period was 15 months (range, 8-28 mo). The equinus deformity disappeared clinically in all patients. Before the operation, all patients had an Ashworth Scale score of 2, with an inexhaustible clonus present on knee extension and persisting with knee flexion (Tardieu Scale score, 4), which was abolished in 95% of the patients after surgery. Two patients still had some clonus on knee extension; this did not interfere with their clinical improvement. Knee recurvatum disappeared in eight patients. Analysis of kinematic parameters demonstrated a statistically significant increase in joint motion of the second rocker (P = 0.0026) of the ankle during stance. The duration of the stance or swing phase, length of the walking cycle, and velocity or rate of spontaneous walking were not significantly modified. CONCLUSION: The study demonstrated that soleus neurotomy is effective for the treatment of spastic equinus foot, leading to abolition of spasticity and improvement in the range of ankle motion during the stance phase of gait.

Cortical stimulation and epileptic seizure: a study of the potential risk in primates.

OBJECTIVE: The recent successful development of chronic stimulation of the motor cortex as a treatment for neuropathic and central pain does not exclude the possibility of eventual side effects, such as epileptic seizure or a lowering of the epileptic threshold. This study evaluates the behavioral and electroencephalographic impact of this treatment in three normal monkeys. RESULTS: None of the monkeys presented epileptic behavior or abnormal electroencephalographic activity at parameters of stimulation currently used in clinical series, i.e., frequency and pulse duration of approximately 40 Hz and 90 microseconds, respectively, and an intensity just under the threshold for inducing muscle twitch in painful areas. Higher intensities did, however, induce reversible epileptic seizure. There was, nonetheless, no modification of the epileptic threshold, because even after these seizures, intermittent light stimulation elicited no abnormal electroencephalographic activity. CONCLUSION: It thus seems that motor cortex stimulation does not induce epileptic complications when the classic clinical criteria of stimulation are respected. Nevertheless, it would be wise to subject candidates for implantation to intermittent light stimulation before and after a period of stimulation to ascertain the innocuousness of the cortical stimulation.

Endoscopic management of colloid cysts.

OBJECTIVE: Several surgical approaches have been proposed for the treatment of colloid cysts, which still remains controversial. The most recent technique used is endoscopy. By its nature, endoscopy cannot offer complete removal, as compared to microsurgical techniques, but can do more than puncture. To evaluate the usefulness of endoscopy for colloid cyst surgery, a series of 15 patients who were operated on for colloid cysts under endoscopic control since 1994 was reviewed. METHODS: The presenting symptoms of our patients (10 men and 5 women) were intermittent headache (10 patients), nausea (3 patients), short-term memory loss (4 patients), coma (2 patients), gait disturbance (3 patients), blurred vision (2 patients), and mental status changes (3 patients). The sizes of the cysts ranged from 4 to 50 mm (median, 22.93 mm). Depending on the radiological appearance, the procedure was performed via a right (10 patients) or left (5 patients) precoronal burr hole. A rigid neuroendoscope was used. Initial stereotactic placement of the neuroendoscope was used in two patients who had moderate hydrocephalus. In the other patients, hand-guided endoscopy was performed using an articulated arm. The cysts were perforated with a needle. The opening was enlarged with microscissors. The cyst material was aspirated, and the remaining capsule was coagulated. RESULTS: The average follow-up was 15.26 months (range, 1-28 mo). Total aspiration of the cysts was achieved in 12 patients, as revealed by normal postoperative magnetic resonance imaging. Control magnetic resonance imaging revealed residual cysts in three patients. One patient presented with an asymptomatic recurrence at 1 year. Resolution of the symptoms was obtained in all patients except for two of the four patients with preoperative memory deficit (improvement without complete recovery). There was no mortality or morbidity. CONCLUSION: These results show that endoscopy is a safe and promising percutaneous technique for the treatment of colloid cysts of the third ventricle. Longer follow-up is, however, still required.

Multiple vertebral hemangiomas with neurological signs. Case report.

A case of multiple vertebral hemangiomas with progressive neurological deficit is presented. Successful treatment was accomplished using preoperative embolization, palliative surgical decompression, and postoperative radiation therapy. The patient has remained asymptomatic for 6 years. The authors review the role of current imaging modalities and options for therapeutic intervention. Preoperative embolization, palliative surgical decompression, and postoperative radiotherapy appear to provide a satisfactory outcome in patients with multiple hemangiomas and may represent an effective alternative to more aggressive surgical intervention.

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.

Percutaneous endoscopic treatment of suprasellar arachnoid cysts: ventriculocystostomy or ventriculocystocisternostomy? Technical note.

The use of an endoscope in the treatment of suprasellar arachnoid cysts provides an opening of the upper and lower cyst walls, thereby allowing the surgeon to perform a ventriculocystostomy (VC) or a ventriculocystocisternostomy (VCC). To discover which procedure is appropriate, magnetic resonance (MR)-imaged cerebrospinal fluid (CSF) flow dynamics in two patients were analyzed, one having undergone a VC and the other a VCC using a rigid endoscope. Magnetic resonance imaging studies were performed before and after treatment, with long-term follow-up periods (18 months and 2 years). The two patients were reoperated on during the follow-up period because of slight headache recurrence in one case and MR-imaged CSF flow dynamics modifications in the other. In each case surgery confirmed the CSF flow dynamics modifications appearing on MR imaging. In both cases, long-term MR imaging follow-up studies showed a secondary closing of the upper wall orifice. After VCC, however, the lower communication between the cyst and the cisterns remained functional. The secondary closure of the upper orifice may be explained as follows: when opened, the upper wall becomes unnecessary and tends to return to a normal shape, leading to a secondary closure. The patent sylvian aqueduct aids the phenomenon, as observed after ventriculostomy when the aqueduct is secondarily functional. The simplicity of the VCC performed using endoscopic control, which is the only procedure to allow the opening in the cyst's lower wall to remain patent, leads the authors to advocate this technique in the treatment of suprasellar arachnoid cysts.

A new device for endoscopic third ventriculostomy.

Since its description by Dandy in 1922, several techniques have been used to perform third ventriculostomy under endoscopic control. Except for the blunt technique, in which the endoscope is used by itself to create the opening in the floor of the third ventricle, the other techniques require more than one instrument to perforate the floor of the ventricle and enlarge the ventriculostomy. The new device described is a sterilizable modified forceps that allows both the opening of the floor and the enlargement of the ventriculostomy in a simple and effective way. The new device has the following characteristics: 1) the tip of the forceps is thin enough to allow the easy perforation of the floor of the ventricle; 2) the inner surface of the jaws is smooth to avoid catching vessels of the basal cistern; and 3) the outer surface of the jaws has indentations that catch the edges of the opening to prevent them from slipping along the instrument's jaws. The ventricle floor is opened by gentle pressure of the forceps, which is slowly opened so that the edges of the aperture are caught by the distal outer indentation of the jaws, leading to an approximately 4-mm opening of the floor. This device has been used successfully in 10 consecutive patients. This new device allows surgeons to perform third ventriculostomy under endoscopic control in a very simple, quick, and effective way, avoiding the need for additional single-use instruments.

Motor cortex stimulation in the treatment of central and neuropathic pain.

BACKGROUND: Motor cortex stimulation has been proposed for the treatment of central pain. METHODS: Thirty-two patients with refractory central and neuropathic pain of peripheral origin were treated by chronic stimulation of the motor cortex between May 1993 and January 1997. The mean follow-up was 27.3 months. The first 24 patients were operated on according to the technique described by Tsubokawa. The last 13 cases (8 new patients and 5 reinterventions) were operated on by a technique including localization by superficial CT reconstruction of the central region and neuronavigator guidance. The position of the central sulcus was confirmed by the use of intraoperative somatosensory evoked potentials. The somatotopic organization of the motor cortex was established preoperatively by studying the motor responses at stimulation of the motor cortex through the dura. RESULTS: Ten of the 13 patients with central pain (77%) and 10 of the 12 patients with neuropathic facial pain experienced substantial pain relief (83.3%). One of the three patients with post-paraplegia pain was clearly improved. A satisfactory result was obtained in one patient with pain related to plexus avulsion and in one patient with pain related to intercostal herpes zoster. None of the patients developed epileptic seizures. CONCLUSIONS: Our results confirm that chronic stimulation of the motor cortex is an effective method in treating certain forms of refractory pain.