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.

Occipital nerve stimulation improves the quality of life in medically-intractable chronic cluster headache: Results of an observational prospective study.

Background Occipital nerve stimulation (ONS) has been proposed to treat chronic medically-intractable cluster headache (iCCH) in small series of cases without evaluation of its functional and emotional impacts. Methods We report the multidimensional outcome of a large observational study of iCCH patients, treated by ONS within a nationwide multidisciplinary network ( https://clinicaltrials.gov NCT01842763), with a one-year follow-up. Prospective evaluation was performed before surgery, then three and 12 months after. Results One year after ONS, the attack frequency per week was decreased >30% in 64% and >50% in 59% of the 44 patients. Mean (Standard Deviation) weekly attack frequency decreased from 21.5 (16.3) to 10.7 (13.8) ( p = 0.0002). About 70% of the patients responded to ONS, 47.8% being excellent responders. Prophylactic treatments could be decreased in 40% of patients. Functional (HIT-6 and MIDAS scales) and emotional (HAD scale) impacts were significantly improved, as well as the health-related quality of life (EQ-5D). The mean (SD) EQ-5D visual analogic scale score increased from 35.2 (23.6) to 51.9 (25.7) ( p = 0.0037). Surgical minor complications were observed in 33% of the patients. Conclusion ONS significantly reduced the attack frequency per week, as well as the functional and emotional headache impacts in iCCH patients, and dramatically improved the health-related quality of life of responders.

Motor cortex stimulation modulates defective central beta rhythms in patients with neuropathic pain.

OBJECTIVE: Motor cortex stimulation therapy (MCS) is increasingly used to control refractory neuropathic pain. Post-movement beta synchronization (PMBS) is defined as a sharp increase in beta-frequency electroencephalographic power following movement offset and may reflect sensorimotor cortex inhibition induced, at least in part, by cortical processing of movement-related sensory afferent inputs. PMBS pattern is then often altered in case of neuropathic pain. The main objective of the present study was to test the hypothesis that implanted MCS modulates PMBS in patients presenting with neuropathic pain. METHODS: Using a high-resolution, 128-electrode electroencephalographic system, we recorded and compared, before and during MCS, PMBS patterns during brisk, unilateral right and left index finger extension in 8 patients presenting with neuropathic pain. RESULTS: The pre-operative PMBS patterns were altered in all cases. MCS increased the spatial distribution and amplitude of PMBS in most of cases and restored maximum-intensity of PMBS contralateral to the painful body side. These modifications appeared significantly correlated with the analgesic effect of MCS. CONCLUSION: This study provides evidence of central beta rhythms neuromodulation induced by MCS. SIGNIFICANCE: The restoration by MCS of defective cortical inhibition in patients with neuropathic pain is evoked.

MRI atlas of the human hypothalamus.

Gaining new insights into the anatomy of the human hypothalamus is crucial for the development of new treatment strategies involving functional stereotactic neurosurgery. Here, using anatomical comparisons between histology and magnetic resonance images of the human hypothalamus in the coronal plane, we show that discrete gray and white hypothalamic structures are consistently identifiable by MRI. Macroscopic and microscopic images were used to precisely annotate the MRI sequences realized in the coronal plane in twenty healthy volunteers. MRI was performed on a 1.5 T scanner, using a protocol including T1-weighted 3D fast field echo, T1-weighted inversion-recovery, turbo spin echo and T2-weighted 2D fast field echo imaging. For each gray matter structure as well as for white matter bundles, the different MRI sequences were analyzed in comparison to each other. The anterior commissure and the fornix were often identifiable, while the mammillothalamic tract was more difficult to spot. Qualitative analyses showed that MRI could also highlight finer structures such as the paraventricular nucleus, the ventromedial nucleus of the hypothalamus and the infundibular (arcuate) nucleus, brain nuclei that play key roles in the regulation of food intake and energy homeostasis. The posterior hypothalamic area, a target for deep brain stimulation in the treatment of cluster headaches, was readily identified, as was the lateral hypothalamic area, which similar to the aforementioned hypothalamic nuclei, could be a putative target for deep brain stimulation in the treatment of obesity. Finally, each of the identified structures was mapped to Montreal Neurological Institute (MNI) space.

External globus pallidus stimulation modulates brain connectivity in Huntington's disease.

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Motor cortex electric stimulation for the treatment of neuropathic pain / Estimulação elétrica do córtex motor no tratamento da dor neuropática

OBJECTIVE: Motor cortex stimulation (MCS) is considered to be an effective treatment for chronic neuropathic pain. The aim of the present study was to assess the efficacy of MCS for treating neuropathic pain. METHOD: 27 patients with chronic neuropathic pain were operated. Electrodes were implanted with the use of an stereotactic frame. Electrophysiological evaluations (motor stimulation and somatosensory evoked potentials) were performed, with guidance by means of three-dimensional reconstruction of magnetic resonance images of the brain. 10 patients (37 percent) presented central neuropathic pain (post-stroke pain) and 17 others (63 percent) presented peripheral neuropathic pain (brachial plexus avulsion, phantom limb pain or trigeminal pain). RESULTS: In 15 patients (57.7 percent) the pain relief was 50 percent or more; while in ten patients (38.5 percent), more than 60 percent of the original pain was relieved. No differences were found in relation to central and peripheral neuropathic pain (p=0.90), pain location (p=0.81), presence of motor deficit (p=0.28) and pain duration (p=0.72). No major complications were observed. CONCLUSION: MCS was efficient for treating patients presenting chronic central or peripheral neuropathic pain.

OBJETIVO: A estimulação do córtex motor (ECM) é método considerado eficaz no tratamento da dor neuropática crônica rebelde. O presente estudo avaliou a eficácia da ECM no tratamento de pacientes portadores de dor neuropática crônica. MÉTODO: 27 doentes foram avaliados; 10 (37,0 por cento) apresentavam dor neuropática de origem central, enquanto 17 (63,0 por cento), dor neuropática periférica. Avulsão de raízes do plexo braquial, dor no membro fantasma, dor decorrente de doença cerebrovascular isquêmica ou hemorrágica ou neuropatia trigeminal foram as causas mais freqüentes da dor. Os doentes foram operados com uso da técnica de localização estereotáctica do córtex motor associadamente a estudo eletroneurofisiológico (estimulação motora e potencial evocado somatossensitivo) ou ainda com uso de imagens de ressonância magnética do encéfalo reconstruídas tridimensionalmente. RESULTADOS: O alívio da dor foi igual ou superior a 50 por cento em 15 doentes (57,7 por cento), sendo em 10 (38,5 por cento), superior a 60 por cento. Não houve diferença nos resultados quanto a origem central ou periférica (p=0,90) da dor, localização da dor (p=0,81), ocorrência ou não de déficit motor (p=0,28) e duração da sintomatologia (p=0,72). Não foram observadas complicações graves. CONCLUSÃO: A estimulação do córtex motor foi útil no tratamento da dor neuropática crônica rebelde tanto de origem central como periférica.

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

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

Motor cortex electric stimulation for the treatment of neuropathic pain.

OBJECTIVE: Motor cortex stimulation (MCS) is considered to be an effective treatment for chronic neuropathic pain. The aim of the present study was to assess the efficacy of MCS for treating neuropathic pain. METHOD: 27 patients with chronic neuropathic pain were operated. Electrodes were implanted with the use of an stereotactic frame. Electrophysiological evaluations (motor stimulation and somatosensory evoked potentials) were performed, with guidance by means of three-dimensional reconstruction of magnetic resonance images of the brain. 10 patients (37%) presented central neuropathic pain (post-stroke pain) and 17 others (63%) presented peripheral neuropathic pain (brachial plexus avulsion, phantom limb pain or trigeminal pain). RESULTS: In 15 patients (57.7%) the pain relief was 50% or more; while in ten patients (38.5%), more than 60% of the original pain was relieved. No differences were found in relation to central and peripheral neuropathic pain (p=0.90), pain location (p=0.81), presence of motor deficit (p=0.28) and pain duration (p=0.72). No major complications were observed. CONCLUSION: MCS was efficient for treating patients presenting chronic central or peripheral neuropathic pain.

Differential erbB signaling in astrocytes from the cerebral cortex and the hypothalamus of the human brain.

Studies in rodents have shown that astroglial erbB tyrosine kinase receptors are key regulatory elements in neuron-glia communication. Although both astrocytes and deregulation of erbB functions have been implicated in the pathogenesis of many common human brain disorders, erbB signaling in native human brain astrocytes has never been explored. Taking advantage of our ability to perform primary cultures from the cortex and the hypothalamus of human fetuses, we conducted a thorough analysis of erbB signaling in human astrocytes. We showed that human cortical astrocytes express erbB1, erbB2, and erbB3, whereas human hypothalamic astrocytes express erbB1, erbB2, and erbB4 receptors. Ligand-dependent activation of different erbB receptor heterodimeric complexes in these two populations of astrocytes translated into different morphological and proliferative responses. Although morphological plasticity was more pronounced in hypothalamic astrocytes than in cortical astrocytes, the former showed a lower mitogenic potential. Decreasing erbB4 expression via siRNA-mediated gene knockdown revealed that erbB4 constitutively restrains basal proliferative activity in hypothalamic astrocytes. We further show that treatment of human astrocytes with a protein kinase C activator results in rapid tyrosine phosphorylation of erbB receptors that involves cleavage of endogenous membrane bound erbB ligands by metalloproteinases. Together, these results indicate that erbB signaling in primary human brain astrocytes is functional, region-specific, and can be activated in a paracrine and/or autocrine manner. In addition, by revealing that some aspects of astroglial erbB signaling are different between human and rodents, our results provide a molecular framework to explore the potential involvement of astroglial erbB signaling deregulation in human brain disorders.

Effects of subthalamic nucleus stimulation on parkinsonian dysarthria and speech intelligibility.

Subthalamic stimulation is known to improve tremor, akinesia and rigidity in Parkinson's disease. However, other signs such as hypophonia and swallowing disorders can be relatively resistant to this technique. The effect on dysarthria remains unclear. The aim of this study was to investigate the effects of implantation of electrode and stimulation of the subthalamic nucleus (STN) on parkinsonian dysarthria. Seven patients were prospectively included. Electrodes (Medtronic) were implanted in both STN. The electrode contacts and stimulation parameters were adjusted to provide best relief of symptoms with fewest side effects. Assessment used global scales (Unified Parkinson Disease Rating Scale, UPDRS II and III), dyskinesia scale, exhaustive dysarthria assessment (bucco-facial movements, voice, articulation, intelligibility) and the 'dysarthria' item from the UPDRS III. Evaluations were performed in six conditions: before and three months after surgery (pre-op, post-op) stimulation turned off or on (off-stim, onstim), and without or with a suprathreshold levodopa dose (offdrug, on-drug). Performance level on the UPDRS III significantly improved following electrode implantation and stimulation. For dysarthria, modest beneficial effects were observed on several motor parameters, especially lip movements. Voice mildly improved, especially for the modulation in loudness and pitch. Articulation was not affected. Furthermore, intelligibility was slightly reduced in the on-stimulation condition, especially when patients received levodopa. At an individual level, negative effects on intelligibility were observed in two patients, and this was associated with a discrete increase in facial and trunk dyskinesias, but not with the electrode position or stimulation parameters. In conclusion, surgery had weak effects on dysarthria. Intelligibility can be worsened, especially in the on-drug condition. Thus, adaptation of the stimulation parameters can be difficult.

Effects of subthalamic nucleus stimulation and levodopa treatment on gait abnormalities in Parkinson disease.

BACKGROUND: Stimulation of the subthalamic nucleus is proposed for the treatment of patients presenting with severe Parkinson disease. The effect on gait is not clearly established. OBJECTIVES: To evaluate objectively the influence of bilateral subthalamic nucleus stimulation on gait in Parkinson disease and to compare it with the effects of levodopa treatment. METHODS: Ten patients underwent bilateral subthalamic nucleus stimulation. The preoperative and postoperative (3 months after surgery) clinical gait disturbances, as well as spatial and temporal gait parameters, were analyzed in off and on-drug conditions. The gait analysis was performed using a video motion analysis system (optoelectronic VICON system; Oxford Metrics, Oxford, England). RESULTS: In the off condition, there was an improvement after surgery for the total motor score and the gait subscore. In the on-drug condition, there was an improvement in levodopa-induced dyskinesias and the motor score, whereas the gait subscore was unchanged. For the gait parameters measured by the video motion analysis system system, there was also an improvement in the off condition and to a lesser extent in the on-drug condition. CONCLUSIONS: Our method allowed exact quantification of the benefit of surgery on gait parameters. Compared with the levodopa treatment, the effect of stimulation on gait kinematic parameters seems to be qualitatively similar but quantitatively different with a lower benefit on gait velocity and stride length. Concerning the pathophysiology of gait troubles in Parkinson disease, the deficit in control of stride length would be the fundamental deficit. The study underlines the possible role of the subthalamic nucleus on the stride length regulation.

Influence of pallidal stimulation and levodopa on gait and preparatory postural adjustments in Parkinson's disease.

In order to assess the influence of the bilateral internal globus pallidus (GPi) stimulation on gait and postural instability in Parkinson's disease (PD), we compared gait kinematic parameters and preparatory postural adjustments before and 3 months after stimulation in off- and on-drug conditions for seven patients. Gait kinematic parameters and displacements of centre of pressure (CP) and shoulder computed before a lateral raising task of the leg, were recorded using optoelectric Vicon system. Levodopa (L-dopa) induced a clear benefit for gait velocity (related to an increase of stride length) and also an increase of swing phase duration. GPi stimulation had a limited effect, since the increase of gait velocity was induced by a concomitant increase of stride length and cadence corresponding to a compensatory mechanism. The benefit on swing phase duration was also moderate. Displacements of CP were improved mainly by L-dopa. GPi stimulation and L-dopa had the same beneficial effect on the speed at which the CP was transferred back towards the support side, the ankle velocity, the onset time for ankle displacement, and the decrease of shoulder amplitude towards the support side, which reflects a better postural adjustment phase. This study, based on an objective method, revealed that chronic bilateral GPi stimulation may improve gait and preparatory postural adjustments in severe PD patients with a more limited effect than L-dopa.