Improved Outcomes and Therapy Longevity after Salvage Using a Novel Spinal Cord Stimulation System for Chronic Pain: Multicenter, Observational, European Case Series.

Spinal cord stimulation (SCS) is proven to effectively relieve chronic neuropathic pain. However, some implanted patients may face loss of efficacy (LoE) over time, and conversion to more recent devices may rescue SCS therapy. Recent SCS systems offer novel stimulation capabilities, such as temporal modulation and spatial neural targeting, and can be used to replace previous neurostimulators without changing existing leads. Our multicenter, observational, consecutive case series investigated real-world clinical outcomes in previously implanted SCS patients who were converted to a new implantable pulse generator. Data from 58 patients in seven European centers were analyzed (total follow-up 7.0 years, including 1.4 years after conversion). In the Rescue (LoE) subgroup (n = 51), the responder rate was 58.5% at the last follow-up, and overall pain scores (numerical rating scale) had decreased from 7.3 ± 1.7 with the previous SCS system to 3.5 ± 2.5 (p < 0.0001). Patients who converted for improved battery longevity (n = 7) had their pain scores sustained below 3/10 with their new neurostimulator. Waveform preferences were diverse and patient dependent (34.4% standard rate; 44.8% sub-perception modalities; 20.7% combination therapy). Our results suggest that patients who experience LoE over time may benefit from upgrading to a more versatile SCS system.

Combining Awake Anesthesia with Minimal Invasive Surgery Optimizes Intraoperative Surgical Spinal Cord Stimulation Lead Placement.

Spinal cord stimulation (SCS) is an effective and validated treatment to address chronic refractory neuropathic pain in persistent spinal pain syndrome-type 2 (PSPS-T2) patients. Surgical SCS lead placement is traditionally performed under general anesthesia due to its invasiveness. In parallel, recent works have suggested that awake anesthesia (AA), consisting of target controlled intra-venous anesthesia (TCIVA), could be an interesting tool to optimize lead anatomical placement using patient intra-operative feedback. We hypothesized that combining AA with minimal invasive surgery (MIS) could improve SCS outcomes. The goal of this study was to evaluate SCS lead performance (defined by the area of pain adequately covered by paraesthesia generated via SCS), using an intraoperative objective quantitative mapping tool, and secondarily, to assess pain relief, functional improvement and change in quality of life with a composite score. We analyzed data from a prospective multicenter study (ESTIMET) to compare the outcomes of 115 patients implanted with MIS under AA (MISAA group) or general anesthesia (MISGA group), or by laminectomy under general anesthesia (LGA group). All in all, awake surgery appears to show significantly better performance than general anesthesia in terms of patient pain coverage (65% vs. 34-62%), pain surface (50-76% vs. 50-61%) and pain intensity (65% vs. 35-40%), as well as improved secondary outcomes (quality of life, functional disability and depression). One step further, our results suggest that MISAA combined with intra-operative hypnosis could potentialize patient intraoperative cooperation and could be proposed as a personalized package offered to PSPS-T2 patients eligible for SCS implantation in highly dedicated neuromodulation centers.

Efficacy and Safety of Electroconvulsive Therapy in Patients With Deep Brain Stimulation: Literature Review, Case Report for Patient With Essential Tremor, and Practical Recommendations.

AIM: Deep brain stimulation (DBS) has proven to be an effective therapy of some treatment-resistant psychiatric disorders and movement disorders. Comorbid depressive symptoms are common and difficult to manage. Treatment with electroconvulsive therapy (ECT) may be required. There are few published cases describing the safety and efficacy of ECT for patients with DBS implants, and there are no available guidelines for administration of ECT in patients with DBS and mood disorders. The current study had 3 aims: (i) to conduct a systematic review of case reports on patients with DBS implants who received ECT; (ii) to report the case of a 69-year-old man with a DBS implant for essential tremor, who required ECT; and (iii) to provide practical recommendations for ECT in patients with DBS implants. METHODS: We conducted a systematic review, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, of existing case reports on patients with DBS implants administered ECT for psychiatric disorders. RESULTS: Our search yielded 25 cases of ECT in patients implanted with DBS systems. In addition, we here describe successful ECT management of major depressive disorder in a patient treated by DBS. We also set forth ECT management guidelines based on points of consensus. The 2 most important practical recommendations are to make sure the DBS system is set to 0 V and turned off before ECT, and to avoid sites near the DBS electrodes. CONCLUSIONS: Electroconvulsive therapy may be an effective and safe treatment for DBS patients with MDD.

Additional Benefit of Intraoperative Electroacupuncture in Improving Tolerance of Deep Brain Stimulation Surgical Procedure in Parkinsonian Patients.

BACKGROUND: Deep brain stimulation (DBS) is an effective technique to treat patients with advanced Parkinson's disease. The surgical procedure of DBS implantation is generally performed under local anesthesia due to the need for intraoperative clinical testing. However, this procedure is long (5-7 h on average) and, therefore, the objective that the patient remains co-operative and tolerates the intervention well is a real challenge. OBJECTIVE: To evaluate the additional benefit of electroacupuncture (EA) performed intraoperatively to improve the comfort of parkinsonian patients during surgical DBS implantation. METHODS: This single-center randomized study compared two groups of patients. In the first group, DBS implantation was performed under local anesthesia alone, while the second group received EA in addition. The patients were evaluated preoperatively, during the different stages of the surgery, and 2 days after surgery, using the 9-item Edmonton Symptom Assessment System (ESAS), including a total sum score and physical and emotional subscores. RESULTS: The data of nine patients were analyzed in each group. Although pain and tiredness increased in both groups after placement of the stereotactic frame, the ESAS item "lack of appetite", as well as the ESAS total score and physical subscore increased after completion of the first burr hole until the end of the surgical procedure in the control group only. ESAS total score and physical subscore were significantly higher at the end of the intervention in the control group compared to the EA group. After the surgical intervention (D2), anxiety and ESAS emotional subscore were improved in both groups, but the feeling of wellbeing improved in the EA group only. Finally, one patient developed delirium during the intervention and none in the EA group. DISCUSSION: This study shows that intraoperative electroacupuncture significantly improves the tolerance of DBS surgery in parkinsonian patients. This easy-to-perform procedure could be fruitfully added in clinical practice.

Occipital Nerve Stimulation for Refractory Chronic Cluster Headache: A Cost-Effectiveness Study.

INTRODUCTION: Occipital nerve stimulation (ONS) is proposed to treat refractory chronic cluster headache (rCCH), but its cost-effectiveness has not been evaluated, limiting its diffusion and reimbursement. MATERIALS AND METHODS: We performed a before-and-after economic study, from data collected prospectively in a nation-wide registry. We compared the cost-effectiveness of ONS associated with conventional treatment (intervention and postintervention period) to conventional treatment alone (preintervention period) in the same patients. The analysis was conducted on 76 rCCH patients from the French healthcare perspective at three months, then one year by extrapolation. Because of the impact of the disease on patient activity, indirect cost, such as sick leave and disability leave, was assessed second. RESULTS: The average total cost for three months was €7602 higher for the ONS strategy compared to conventional strategy with a gain of 0.07 quality-adjusted life-years (QALY), the incremental cost-effectiveness ratio (ICER) was then €109,676/QALY gained. The average extrapolated total cost for one year was €1344 lower for the ONS strategy (p = 0.5444) with a gain of 0.28 QALY (p < 0.0001), the ICER was then €-4846/QALY gained. The scatter plot of the probabilistic bootstrapping had 80% of the replications in the bottom right-hand quadrant, indicating that the ONS strategy is dominant. The average indirect cost for three months was €377 lower for the ONS strategy (p = 0.1261). DISCUSSION: This ONS cost-effectiveness study highlighted the limitations of a short-time horizon in an economic study that may lead the healthcare authorities to reject an innovative strategy, which is actually cost-effective. One-year extrapolation was the proposed solution to obtain results on which healthcare authorities can base their decisions. CONCLUSION: Considering the burden of rCCH and the efficacy and safety of ONS, the demonstration that ONS is dominant should help its diffusion, validation, and reimbursement by health authorities in this severely disabled population.

Long-Term Efficacy of Occipital Nerve Stimulation for Medically Intractable Cluster Headache.

BACKGROUND: Occipital nerve stimulation (ONS) has been proposed to treat refractory chronic cluster headache (rCCH) but its efficacy has only been showed in small short-term series. OBJECTIVE: To evaluate ONS long-term efficacy in rCCH. METHODS: We studied 105 patients with rCCH, treated by ONS within a multicenter ONS prospective registry. Efficacy was evaluated by frequency, intensity of pain attacks, quality of life (QoL) EuroQol 5 dimensions (EQ5D), functional (Headache Impact Test-6, Migraine Disability Assessment) and emotional (Hospital Anxiety Depression Scale [HAD]) impacts, and medication consumption. RESULTS: At last follow-up (mean 43.8 mo), attack frequency was reduced >50% in 69% of the patients. Mean weekly attack frequency decreased from 22.5 at baseline to 9.9 (P < .001) after ONS. Preventive and abortive medications were significantly decreased. Functional impact, anxiety, and QoL significantly improved after ONS. In excellent responders (59% of the patients), attack frequency decreased by 80% and QoL (EQ5D visual analog scale) dramatically improved from 37.8/100 to 73.2/100. When comparing baseline and 1-yr and last follow-up outcomes, efficacy was sustained over time. In multivariable analysis, low preoperative HAD-depression score was correlated to a higher risk of ONS failure. During the follow-up, 67 patients experienced at least one complication, 29 requiring an additional surgery: infection (6%), lead migration (12%) or fracture (4.5%), hardware dysfunction (8.2%), and local pain (20%). CONCLUSION: Our results showed that long-term efficacy of ONS in CCH was maintained over time. In responders, ONS induced a major reduction of functional and emotional headache-related impacts and a dramatic improvement of QoL. These results obtained in real-life conditions support its use and dissemination in rCCH patients.

How Should we Use Multicolumn Spinal Cord Stimulation to Optimize Back Pain Spatial Neural Targeting? A Prospective, Multicenter, Randomized, Double-Blind, Controlled Trial (ESTIMET Study).

BACKGROUND: Recent studies have highlighted multicolumn spinal cord stimulation (SCS) efficacy, hypothesizing that optimized spatial neural targeting provided by new-generation SCS lead design or its multicolumn programming abilities could represent an opportunity to better address chronic back pain (BP). OBJECTIVE: To compare multicolumn vs. monocolumn programming on clinical outcomes of refractory postoperative chronic BP patients implanted with SCS using multicolumn surgical lead. MATERIALS AND METHODS: Twelve centers included 115 patients in a multicenter, randomized, double-blind, controlled trial. After randomization, leads were programmed using only one or several columns. The primary outcome was change in BP visual analogic scale (VAS) at six months. All patients were then programmed using the full potential of the lead up until 12-months follow-up. RESULTS: At six months, there was no significant difference in clinical outcomes whether the SCS was programmed using a mono or a multicolumn program. At 12 months, in all patients having been receiving multicolumn SCS for at least six months (n = 97), VAS decreases were significant for global pain (45.1%), leg pain (55.8%), and BP (41.5%) compared with baseline (p < 0.0001). CONCLUSION: The ESTIMET study confirms the significant benefit experienced on chronic BP by patients implanted with multicolumn SCS, independently from multicolumn lead programming. These good clinical outcomes might result from the specific architecture of the multicolumn lead, giving the opportunity to select initially the best column on a multicolumn grid and to optimize neural targeting with low-energy requirements. However, involving more columns than one does not appear necessary, once initial spatial targeting of the "sweet spot" has been achieved. Our findings suggest that this spatial concept could also be transposed to cylindrical leads, which have drastically improved their capability to shape the electrical field, and might be combined with temporal resolution using SCS new modalities.

Efficacy of Occipital Nerve Stimulation to Treat Refractory Occipital Headaches: A Single-Institution Study of 60 Patients.

BACKGROUND: Occipital nerve stimulation (ONS) is shown to be effective in treating various forms of headache. Most studies describe the treatment of occipital neuralgia (ON), but in many patients, the clinical description could also correspond to cervicogenic headache (CGH) or occipital migraine (OM). These different entities (ON, CGH, and OM) may be grouped together under the term occipital headaches. OBJECTIVE: To assess the efficacy of ONS to treat occipital headaches in a large series of patients with a long-term follow-up. MATERIALS AND METHODS: We performed a retrospective review of data on 60 patients with intractable occipital headaches treated with occipital nerve stimulation (ONS), who were referred to our center between October 2008 and October 2014. Details of pain evaluation, location, duration, cause and previous treatment were analyzed. Evaluations included the visual analog scale (VAS), the number of headache days per month (NHD), and the Medication Quantification Scale (MQS). Trials with transcutaneous electrical nerve stimulation (TENS-ONS) were performed and served as a guide for surgery indication (see Patients and Method section). RESULTS: After one year of ONS, mean VAS had decreased from 8.4/10 to 2.8/10 (72.2% reduction [p < 0.001]), and 76% of patients had at least a 50% decrease in mean VAS score. The mean MQS score decreased from 18 to 8.8, corresponding to a reduction of pain medication by an average of 50%. Adverse events concerned 12 patients (20%). Six patients presented with electrode displacement or fracture (10%) and six patients presented with cases of infection (10%) associated with the pulse generator. CONCLUSIONS: The results of this large series confirm that ONS is an effective treatment option for patients with intractable occipital headaches, but the frequency of complications remains quite high and must be taken into account in the surgical decision.

Treatment of refractory headache secondary to intracranial endovascular procedure by transcutaneous electrical nerve stimulation of the occipital nerve.

This pilot study aimed at assessing the effect of transcutaneous electrical nerve stimulation (TENS) of the occipital nerve (ON) to treat chronic refractory headache secondary to intracranial endovascular procedures (iEVP) in 4 patients. The duration of ON-TENS therapy was only 1 month (n=2) or longer than 4 months (n=2). Overall, pain intensity decreased from 7.8 (on a 0-10 scale) at baseline to 0.8 at 6 months after ON-TENS therapy initiation (-90%), while drug treatment was reduced from 34.3 to 0.8 (-98%) on the medication quantification scale. ON-TENS is a simple technique that may benefit patients with post-iEVP refractory headache.

Long-Term Follow-Up Comparative Study of Hydroxyapatite and Autologous Cranioplasties: Complications, Cosmetic Results, Osseointegration.

OBJECTIVE: A three-dimensional reconstruction technique using the CustomBone (CB) prosthesis allows custom-made cranioplasty (CP) possessing osseointegration properties owing to its porous hydroxyapatite (HA) composition. This reconstruction technique has replaced less expensive techniques such as subcutaneously preserved autologous bone (SP). Our primary objective was to evaluate complications between CB and SP CP techniques. A secondary objective was to assess cosmetic results and osseointegration of CPs. METHODS: This single-center study comprised patients undergoing delayed CB or SP CP after craniectomy between 2007 and 2014. A prospective interview was conducted to collect all data, including 2-year follow-up clinical and radiologic data. Cosmetic results were assessed by a qualitative score, and osseointegration was assessed by measuring relative fusion at the CP margins. RESULTS: Of 100 patients undergoing CB or SP CP between 2007 and 2014, 92 (CB, n = 44; SP, n = 48) participated in the prospective interview. No significant difference in complication rates was observed between the 2 groups. The main complication specific to the CB group was fracture of the prosthesis observed in 20.8% patients. A higher rate of good cosmetic results was observed in the CB group (92.5% vs. 74.3%, P = 0.031). In the CB group, 51% of patients demonstrated no signs of bone fusion of the CP. CONCLUSIONS: Although the CB prosthesis is associated with cosmetic advantages, the porous hydroxyapatite composition makes it fragile in the short-term and long-term, and effective osseointegration remains uncertain.

Anterior pallidal deep brain stimulation for Tourette's syndrome: a randomised, double-blind, controlled trial.

BACKGROUND: Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. METHODS: In this randomised, double-blind, controlled trial, we recruited patients aged 18-60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. FINDINGS: Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR -23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [-10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). INTERPRETATION: 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. FUNDING: French Ministry of Health.

A good preoperative response to transcutaneous electrical nerve stimulation predicts a better therapeutic effect of implanted occipital nerve stimulation in pharmacologically intractable headaches.

Occipital nerve stimulation (ONS) is a surgical approach to treat patients with medically intractable chronic headache disorders. However, no preoperative test has been yet validated to allow candidates to be selected for implantation. In this study, the analgesic efficacy of transcutaneous electrical nerve stimulation (TENS) was tested for 1 to 3 months in 41 patients with pharmacologically intractable headache disorders of various origins, using a new technique of electrode placement over the occipital nerve. ONS electrodes were subsequently implanted in 33 patients (occipital neuralgia [n=15], cervicogenic headache [n=7], cluster headache [n=6], chronic migraine [n=5]) who had responded at least moderately to TENS. Assessment was performed up to five years after implantation (three years on average), based on the mean and maximum daily pain intensity scored on a 0-10 visual analogue scale and the number of headache days per month. Both TENS and chronic ONS therapy were found to be efficacious (57-76% improvement compared to baseline on the various clinical variables). The efficacy of ONS was better in cases of good or very good preoperative response to TENS than in cases of moderate response to TENS. Implanted ONS may be a valuable therapeutic option in the long term for patients with pharmacologically intractable chronic headache. Although we cannot conclude in patients with poor or no response to TENS, a good or very good response to TENS can support the indication of ONS therapy. This preoperative test could particularly be useful in patients with chronic migraine, in whom it may be difficult to indicate an invasive technique of cranial neurostimulation.

Long-term efficacy and tolerability of bilateral pallidal stimulation to treat tardive dyskinesia.

OBJECTIVE: To confirm the efficacy and safety of deep brain stimulation (DBS) of the internal part of the globus pallidus in improving severe tardive dyskinesia (TD). METHODS: Nineteen patients with severe pharmacoresistant TD were included. All were assessed at baseline and at 3, 6 (main outcome measure), and 12 months, and in the long term (6-11 years) for 14 patients, after bilateral pallidal DBS, using motor scales (Extrapyramidal Symptoms Rating Scale [ESRS], Abnormal Involuntary Movement Scale [AIMS]), cognitive scales, and a psychiatric assessment. At 6 months, a double-blind ESRS evaluation was performed in the stimulation "on" and stimulation "off" conditions. RESULTS: At 6 months, all patients had a decrease of more than 40% on the ESRS. The efficacy of the procedure was confirmed by a double-blind evaluation. This improvement was maintained at 12 months (ESRS: decrease of 58% [21%-81%]; AIMS: decrease of 50% [7%-77%]) and in the long term (ESRS: decrease of 60% [22%-90%]; AIMS: decrease of 63% [14%-94%], n = 14). All the subscores of the ESRS (parkinsonism, dystonia, and chorea) and of the AIMS (facial, oral, extremities, and trunk movements) improved. Despite psychiatric comorbidities at baseline, cognitive and psychiatric tolerability of the procedure was excellent. No cognitive decline was observed and mood was improved in most of the patients. CONCLUSIONS: Pallidal DBS procedure should be considered as a therapeutic option in disabling TD refractory to medical treatment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with severe pharmacoresistant TD with implanted pallidal leads, the stimulation "on" condition significantly improved ESRS scores compared to the stimulation "off" condition.

Interest of repetitive transcranial magnetic stimulation of the motor cortex in the management of refractory cancer pain in palliative care: Two case reports.

BACKGROUND: Non-drug treatments should be systematically associated to the medical analgesic treatment during the terminal phase of cancer. CASES PRESENTATION: Patient 1, a 23-year-old woman, presented an adenocarcinoma of the rectum, with liver and lung metastases. Pain was initially treated by oral morphine and a combination of pregabalin and amitriptyline. Ketamine and intrathecal administration of morphine were both ineffective. Patient 2, a 69-year-old woman, presented a cutaneous T-cell lymphoma. She was admitted to the palliative care unit with mixed pain related to cutaneous lymphomatous infiltration. World Health Organization (WHO) step 3 analgesics had not been tolerated. CASES MANAGEMENT: Both patients received five consecutive 20-min sessions of repetitive transcranial magnetic stimulation to the right motor cortex. CASES OUTCOME: Patient 1 experienced a marked improvement of her pain over the days following the first repetitive transcranial magnetic stimulation session. Medical treatment was able to be rapidly decreased by about 50%, which restored an almost normal level of consciousness and lucidity. Patient 2's pain was also markedly decreased over the days following these five consecutive sessions, and repetitive transcranial magnetic stimulation also appeared to have had a beneficial effect on the patient's anxiety and mood. CONCLUSION: In the context of palliative care of cancer patients experiencing refractory pain that is difficult to control by the usual treatments, motor cortex repetitive transcranial magnetic stimulation, due to its noninvasive nature, can be used as an adjuvant therapy to improve various components of pain, including the emotional components. By reducing the doses of analgesics, repetitive transcranial magnetic stimulation decreases the severity of their adverse effects and improves the patient's quality of life.

Intracerebral Gene Therapy Using AAVrh.10-hARSA Recombinant Vector to Treat Patients with Early-Onset Forms of Metachromatic Leukodystrophy: Preclinical Feasibility and Safety Assessments in Nonhuman Primates.

No treatment is available for early-onset forms of metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by autosomal recessive defect in arylsulfatase A (ARSA) gene causing severe demyelination in central and peripheral nervous systems. We have developed a gene therapy approach, based on intracerebral administration of AAVrh.10-hARSA vector, coding for human ARSA enzyme. We have previously demonstrated potency of this approach in MLD mice lacking ARSA expression. We describe herein the preclinical efficacy, safety, and biodistribution profile of intracerebral administration of AAVrh.10-hARSA to nonhuman primates (NHPs). NHPs received either the dose planned for patients adjusted to the brain volume ratio between child and NHP (1×dose, 1.1×10(11) vg/hemisphere, unilateral or bilateral injection) or 5-fold this dose (5×dose, 5.5×10(11) vg/hemisphere, bilateral injection). NHPs were subjected to clinical, biological, and brain imaging observations and were euthanized 7 or 90 days after injection. There was no toxicity based on clinical and biological parameters, nor treatment-related histological findings in peripheral organs. A neuroinflammatory process correlating with brain MRI T2 hypersignals was observed in the brain 90 days after administration of the 5×dose, but was absent or minimal after administration of the 1×dose. Antibody response to AAVrh.10 and hARSA was detected, without correlation with brain lesions. After injection of the 1×dose, AAVrh.10-hARSA vector was detected in a large part of the injected hemisphere, while ARSA activity exceeded the normal endogenous activity level by 14-31%. Consistently with other reports, vector genome was detected in off-target organs such as liver, spleen, lymph nodes, or blood, but not in gonads. Importantly, AAVrh.10-hARSA vector was no longer detectable in urine at day 7. Our data demonstrate requisite safe and effective profile for intracerebral AAVrh.10-hARSA delivery in NHPs, supporting its clinical use in children affected with MLD.

scAAV9 intracisternal delivery results in efficient gene transfer to the central nervous system of a feline model of motor neuron disease.

On the basis of previous studies suggesting that vascular endothelial growth factor (VEGF) could protect motor neurons from degeneration, adeno-associated virus vectors (serotypes 1 and 9) encoding VEGF (AAV.vegf) were administered in a limb-expression 1 (LIX1)-deficient cat-a large animal model of lower motor neuron disease-using three different delivery routes to the central nervous system. AAV.vegf vectors were injected into the motor cortex via intracerebral administration, into the cisterna magna, or intravenously in young adult cats. Intracerebral injections resulted in detectable transgene DNA and transcripts throughout the spinal cord, confirming anterograde transport of AAV via the corticospinal pathway. However, such strategy led to low levels of VEGF expression in the spinal cord. Similar AAV doses injected intravenously resulted also in poor spinal cord transduction. In contrast, intracisternal delivery of AAV exhibited long-term transduction and high levels of VEGF expression in the entire spinal cord, yet with no detectable therapeutic clinical benefit in LIX1-deficient animals. Altogether, we demonstrate (i) that intracisternal delivery is an effective AAV delivery route resulting in high transduction of the entire spinal cord, associated with little to no off-target gene expression, and (ii) that in a LIX1-deficient cat model, however, VEGF expressed at high levels in the spinal cord has no beneficial impact on the disease course.

Invasive stimulation therapies for the treatment of refractory pain.

Invasive neurostimulation therapies may be proposed to patients with neuropathic pain refractory to conventional medical management, in order to improve pain relief, functional capacity, and quality of life. In this review, the respective mechanisms of action and efficacy of peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS) are discussed. PNS appears to be useful in various refractory neuropathic pain indications (as long as there is some preservation of sensation in the painful area), such as intractable chronic headache, pelvic and perineal pain, and low back pain, but evidence for its efficacy is not strongly conclusive, and large-scale randomized controlled studies are necessary to confirm the efficacy in the long term. Spinal cord stimulation (SCS) has been validated for the treatment of selected types of chronic pain syndromes, such as Failed Back Surgery Syndrome, and Complex Regional Pain Syndrome type I. When neuropathic pain is secondary to a brain lesion (especially following stroke) or a trigeminal lesion, stimulation of brain structures is required. Deep brain stimulation (DBS), which can be proposed with targets like the periventricular/periaqueductal gray matter or the sensory thalamus, is increasingly replaced by motor cortex stimulation (MCS), mainly because it is safer, more easily performed, and probably more effective in a wider range of indications (including central post-stroke pain). The respective places of DBS and MCS in some selected indications, such as peripheral neuropathic pain and phantom limb pain, have yet to be clearly delineated. Controlled trials, with the stimulator switched ON or OFF in a double-blind procedure, have demonstrated the efficacy of MCS in the treatment of peripheral and central neuropathic pain, although these trials included a limited number of patients and need to be confirmed by large, controlled, multicenter studies. Despite technical progress in neurosurgical navigation, guided by neuroimaging and intraoperative electrophysiology to optimize electrode positioning, MCS results are still variable, and validated criteria for selecting good candidates for implantation are lacking, except clinical response to preoperative rTMS, which showed correlations with a good response to MCS-induced analgesia. However, the evidence in favor of this technique is sufficient to include it in the range of treatment options for refractory neuropathic pain.

Subthalamic nucleus stimulation reverses spinal motoneuron activity in parkinsonian patients.

Although a cardinal symptom of Parkinsonian disease, up to now, rigidity has been investigated much less than spasticity in hemiplegic patients. Many pathophysiological mechanisms may at least theoretically contribute to Parkinsonian rigidity, from altered viscoelastic muscle properties to inability of parkinsonian patients to relax. However, as demonstrated many years ago, motoneuron responses to muscle afferent volleys are involved in rigidity since afferent volleys are suppressed after dorsal root section. To our knowledge, homosynaptic depression (i.e. the fact that motoneuron responses to Ia afferent volleys exhibit a frequency-related depression) has not been studied in parkinsonian disease, despite the fact that in spastic patients, changes in homosynaptic depression are significantly correlated at wrist and ankle levels with the severity of spasticity. Thus, in the present series of experiments, we investigated in parkinsonian patients with chronic implantation of both subthalamic motor nuclei, the amount of homosynaptic depression at wrist and ankle levels on and off deep brain stimulation. Off deep brain stimulation, the frequency-related depression disappeared, the patients became rigid and the amount of homosynaptic depression was significantly correlated with the severity of rigidity. On deep brain stimulation, the frequency-related depression was restored and the rigidity suppressed, suggesting that homosynaptic depression is one of the mechanisms underlying rigidity in Parkinson's disease. Moreover, the unexpected finding that changes in the rigidity score and the amount of homosynaptic depression are time-locked to the onset of deep brain stimulation leads us to reconsider the mechanisms underlying changes in homosynaptic depression.

Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation.

BACKGROUND: Greater occipital nerve stimulation (ONS) has been recently proposed to treat severe chronic cluster headache patients (CCH) refractory to medical treatment. We report the results of a French multidisciplinary cohort study. METHODS: Thirteen CCH patients were operated and data were collected prospectively. All of them suffered from CCH according to the International Headache Society classification, lasting for more than 2 years, refractory to pharmacological prophylactic treatment with adequate trials, with at least one daily attack. Chronic ONS was delivered through a subcutaneous occipital electrode connected to an implanted generator, in order to induce paraesthesias perceived locally in the lower occipital region. RESULTS: After surgery (mean follow-up 14,6 months), the mean attack frequency and intensity decreased by 68% and 49%, respectively. At last follow-up, 10/13 patients were considered as responders (improvement >50%). Prophylactic treatment could be stopped or reduced in 8/13 cases. Local infection occurred in one patient, leading to hardware removal. CONCLUSIONS: Our data confirmed the results of the 36 similar cases reported in the literature, suggesting that ONS may act as a prophylactic treatment in chronic CH. Considering their respective risks, ONS should be proposed before deep brain stimulation in severe refractory CCH patients.