Deep brain stimulation effect in genetic dyskinetic cerebral palsy: The case of ADCY5- related disease.

BACKGROUND: Cerebral Palsy (CP) represents a frequent cause of disability in childhood. Early in life, genetic disorders may present with motor dysfunction and diagnosed as CP. Establishing the primary, genetic etiology allows more accurate prognosis, genetic counselling, and planning for symptomatic interventions in homogeneous etiological groups. Deep brain stimulation (DBS) is recommended in refractory movement disorders, including isolated pediatric dystonias. For dystonia evolving in more complex associations in genetic CP, the effect of DBS is still understudied and currently only sporadically described. OBJECTIVES: To report the effect of DBS applied to the globus pallidus pars interna (GPi) in children with complex movement disorders caused by pathogenic ADCY5 variants, diagnosed as dyskinetic CP previous to genetic diagnostic. METHODS: We conducted a retrospective study on evolution of treatment with DBS in ADCY5-related disease. A standardized proforma including the different type of movement disorders and associated neurological signs was completed at each follow-up time, based on video recordings, as well as functional assessments used in children with CP. RESULTS: Four children (mean of age, 13 ± 2.9 years) received GPi-DBS. The same de novo pathogenic missense variant (c.1252C > T, p.R418W) was identified in three out of four and a splice site variant (c.2088 + 2G > T) in one subject. Developmental delay and overlapping features including axial hypotonia, chorea, dystonic attacks, myoclonus, and cranial dyskinesia were present. The median age at DBS was 9 years and follow-up with DBS, 2.6 years. We identified a pattern of clinical response with early suppression of dystonic attacks, followed by improvement of myoclonus and facial dyskinesia. Effect on chorea was delayed and more limited. Two patients gained notable functional benefit related to sitting, standing, gait, use of upper limbs and speech. CONCLUSION: ADCY5-related disease may benefit from GPi-DBS. The most significant clinical response relates to the early and sustained benefit on dystonic attacks and a variable but still positive response on the other hyperkinetic features. Genetic etiology of CP will contribute to further elucidate genotype-phenotype correlations and to refine DBS indication as network-related symptomatic interventions.

Comparison between 1.5- and 3-T Magnetic Resonance Acquisitions for Direct Targeting Stereotactic Procedures for Deep Brain Stimulation: A Phantom Study.

INTRODUCTION: Deep brain stimulation (DBS) is a well-established treatment for movement disorders. High magnetic fields could have an impact on distortion. We evaluated 1.5- and 3-T magnetic resonance imaging (MRI) sequences for accuracy, precision, and trueness of our MRI-guided direct targeting protocol. METHODS: Effects of distortion on MR sequences (T1- and T2-weighted sequences) can be evaluated using a dedicated phantom (Elekta). Field strength capabilities were assessed on Siemens Avanto (1.5 T) and Skyra (3 T) scanners. We assessed the precision of our stereotactic MRI-guided procedure. RESULTS: We focused on the risk of error due to a high field strength. Error values on the localizer box were between 0.4 and 0.7 mm at 1.5 T and between 0.6 and 2 mm at 3 T. The most accurate 1.5-T sequence is the 3D FLASH T1-weighted sequence, which had an accuracy value of 0.6 mm. At 3 T, the accuracy value of the isotropic 3D FLASH T1-weighted sequence was 1.6 mm. CONCLUSION: Given the millimetric size of stereotactic targets and electrodes, lead implantation for neuromodulation therapy needs to be accurate. We demonstrate that 3-T imaging could not be used for stereotaxy in our MRI-guided direct targeting protocol because of a risk of error induced by distortion.

The enigma of multicentric glioblastoma: physiopathogenic hypothesis and discussion about two cases.

Two men were admitted following generalized seizures. Cerebral MRI-scans showed multiple independent enhancing lesions which were bilateral (first case) and unilateral but disseminated to the brainstem (second case). Whole-body CT-scans showed no primaries. Both cases were diagnosed by biopsy as IDH1 wild-type multicentric glioblastoma. Treatment of both was palliative. The natural history of this entity remains matter of debate but 2 genomic analysis strikingly revealed that foci from the same patient were of monoclonal origin. Consistently, these 2 cases could sustain the hypothesis that an anatomical connectivity exists between the different foci of a multicentric glioblastoma.

Rechargeable or Nonrechargeable Deep Brain Stimulation in Dystonia: A Cost Analysis.

OBJECTIVE: Deep brain stimulation of the internal Globus Pallidus (GPi DBS) delivered by an implantable neurostimulator (INS) is an established, effective, and safe treatment option for patients with medically refractory primary dystonia. Compared to other DBS targets, the battery life of the INS is substantially shorter due to the higher energy demands required to penetrate the GPi resulting in faster battery depletion and more frequent hospitalizations for INS replacement. We, therefore, performed a cost analysis to compare a rechargeable DBS system, Activa®RC, with nonrechargeable systems, from the perspective of the French public health insurer. MATERIALS AND METHODS: To estimate the cost of INS replacement in the nonrechargeable cohort, and costs potentially avoided in the hypothetical Activa® RC cohort, the medical records of patients who had undergone GPi DBS with a nonrechargeable INS between 1996 and 2010 at a center in France were accessed. Replacement rates were estimated for up to nine years. RESULTS: With Activa® RC, a total of 315 hospitalizations for replacement procedures would have been avoided over nine years compared with a nonrechargeable INS, resulting in a discounted mean direct medical cost per patient over nine years of €50,119 with a nonrechargeable INS and €33,306 with Activa® RC, a reduction of 34%. CONCLUSIONS: The adoption of a rechargeable instead of a nonrechargeable INS for eligible patients with dystonia may provide substantial savings to the public health insurer in France.

Robot-assisted spine surgery: feasibility study through a prospective case-matched analysis.

PURPOSE: While image guidance and neuronavigation have enabled a more accurate placement of pedicle implants, they can inconvenience the surgeon. Robot-assisted placement of pedicle screws appears to overcome these disadvantages. However, recent data concerning the superiority of currently available robots in assisting spinal surgeons are conflicting. The aim of our study was to evaluate the percentage of accurately placed pedicle screws, inserted using a new robotic-guidance system. METHOD: 20 Patients were operated on successively by the same surgeon using robotic assistance (ROSA™, Medtech) (Rosa group 10 patients, n = 40 screws) or by the freehand conventional technique (Freehand group 10 patients, n = 50 screws). Patient characteristics as well as the duration of the operation and of exposure to X rays were recorded. RESULTS: The mean age of patients in each group (RG and FHG) was 63 years. Mean BMI and operating time among the RG and FHG were, respectively, 26 and 27 kg/m(2), and 187 and 119 min. Accurate placement of the implant (score A and B of the Gertzbein Robbins classification) was achieved in 97.3% of patients in the RG (n = 36) and in 92% of those in the FHG (n = 50). Four implants in the RG were placed manually following failed robotic assistance. CONCLUSION: We report a higher rate of precision with robotic as compared to the FH technique. Providing assistance by permanently monitoring the patient's movements, this image-guided tool helps more accurately pinpoint the pedicle entry point and control the trajectory. Limitations of the study include its small sized and non-randomized sample. Nevertheless, these preliminary results are encouraging for the development of new robotic techniques for spinal surgery.

Submammary Implantation of Internal Pulse Generators for Deep Brain Stimulation: Long-Term Follow-up of Device Acceptance and Quality of Life in Women.

BACKGROUND: A submammary approach to implanting pulse generators is innovative and has yielded good aesthetic results in the current literature. It was our aim to make a comparison of patient device acceptance, tolerance, and complications between submammary and abdominal device locations in deep brain stimulation. METHODS: Twenty-five and 28 patients were included in the submammary and abdominal groups, respectively. Our primary criterion was patient acceptance that was calculated using total Florida Patient Acceptance Survey (FPAS) scores in each group. Secondarily, tolerance was assessed in the submammary group by means of a specific questionnaire. RESULTS: Total FPAS scores from the submammary group [total FPAS: 77.1 versus 74.7, P = 0.29] revealed no significant difference when compared with the abdominal group. The same similarities were observed regarding the 4 subscales: return to function [16.3 versus 15.8, P = 0.53], device-related distress [22.0 versus 21.3, P = 0.31], body image concerns [9.2 versus 8.6, P = 0.14], and positive appraisal [17.8 versus 17.4, P = 0.58]. Tolerance was reported as good by the majority of the women from the submammary group. There was no evidence of higher infection rates in the submammary implantation (SMI) group. CONCLUSIONS: SMI is a satisfactory alternative to other deep brain stimulation locations. SMI is a feasible option for any young woman who is eligible for deep brain stimulation.

Deep Brain Stimulation and Hypoxemic Perinatal Encephalopathy: State of Art and Perspectives.

Cerebral palsy (CP) is a heterogeneous group of non-progressive syndromes with lots of clinical variations due to the extent of brain damages and etiologies. CP is majorly defined by dystonia and spasticity. The treatment of acquired dystonia in CP is very difficult. Many pharmacological treatments have been tried and surgical treatment consists of deep brain stimulation (continuous electrical neuromodulation) of internal globus pallidus (GPi). A peculiar cause of CP is neonatal encephalopathy due to an anoxic event in the perinatal period. Many studies showed an improvement of dystonia in CP patients with bilateral GPi DBS. However, it remains a variability in the range of 1% to 50%. Published case-series concerned mainly small population with a majority of adult patients. Selection of patients according to the clinical pattern, to the brain lesions observed on classical imaging and to DTI is the key of a high success rate of DBS in children with perinatal hypoxemic encephalopathy. Only a large retrospective study with a high number of patients in a homogeneous pediatric population with a long-term follow-up or a prospective multicenter trial investigation could answer with a high degree of certitude of the real interest of this therapeutic in children with hypoxemic perinatal encephalopathy.

Does pallidal neuromodulation influence cognitive decline in Huntington's disease?

OBJECTIVE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder associated with motor, psychiatric and cognitive deterioration over time. To date, Continuous Electrical Neuromodulation (CEN) of the globus pallidus internus (GPi) has been reported to improve chorea but little is known about cognitive progression in these patients. We propose to examine CEN impact on expected cognitive decline throughout long-term neuropsychological assessment of a cohort of HD patients. METHOD: 13 consecutive HD patients underwent GPi neuromodulation between January 2008 and February 2019. Over a 5-year follow-up period, they received systematic pre- and post-operative assessment according to the existing protocol in our unit. The main outcome measure was the total score obtained on the Mattis Dementia Rating Scale (MDRS) as an indicator of global cognitive function. RESULTS: Chorea decreased in all patients postoperatively with a mean improvement of 56% despite disease progression over time, according to previous studies. Moreover we found that the global cognitive profile of HD patients treated with CEN was stable during the first 3 years of treatment. CONCLUSION: We report an unexpected positive influence of GPi continuous electrical neuromodulation on the progression of global cognitive functioning in operated HD patients. This is the most important group of patients treated with this method to our knowledge whatever the sample size remains small. This result provides promising evidence of GPi-CEN efficacy not only in reducing chorea, but also in delaying cognitive decline in HD patients operated at an early stage of the disease.

Spinal cord injury induces astroglial conversion towards neuronal lineage.

BACKGROUND: Neurons have intrinsic capability to regenerate after lesion, though not spontaneously. Spinal cord injury (SCI) causes permanent neurological impairments partly due to formation of a glial scar that is composed of astrocytes and microglia. Astrocytes play both beneficial and detrimental roles on axonal re-growth, however, their precise role after SCI is currently under debate. METHODS: We analyzed molecular changes in astrocytes at multiple stages after two SCI severities using cell-specific transcriptomic analyses. RESULTS: We demonstrate that astrocyte response after injury depends on both time after injury and lesion severity. We then establish that injury induces an autologous astroglial transdifferentiation where over 10 % of astrocytes express classical neuronal progenitor markers including ßIII-tubulin and doublecortin with typical immature neuronal morphology. Lineage tracing confirmed that the origin of these astrocytes is resident mature, rather than newly formed astrocytes. Astrocyte-derived neuronal progenitors subsequently express GABAergic, but not glutamatergic-specific markers. Furthermore, we have identified the neural stem cell marker fibroblast growth factor receptor 4 (Fgfr4) as a potential autologous modulator of astrocytic transdifferentiation following SCI. Finally, we establish that astroglial transdifferentiation into neuronal progenitors starts as early as 72 h and continues to a lower degrees up to 6 weeks post-lesion. CONCLUSION: We thus demonstrate for the first time autologous injury-induced astroglial conversion towards neuronal lineage that may represent a therapeutic strategy to replace neuronal loss and improve functional outcomes after central nervous system injury.

Correlation of in vivo and ex vivo (1)H-MRI with histology in two severities of mouse spinal cord injury.

Spinal cord injury (SCI) is a debilitating neuropathology with no effective treatment. Magnetic resonance imaging (MRI) technology is the only method used to assess the impact of an injury on the structure and function of the human spinal cord. Moreover, in pre-clinical SCI research, MRI is a non-invasive method with great translational potential since it provides relevant longitudinal assessment of anatomical and structural alterations induced by an injury. It is only recently that MRI techniques have been effectively used for the follow-up of SCI in rodents. However, the vast majority of these studies have been carried out on rats and when conducted in mice, the contusion injury model was predominantly chosen. Due to the remarkable potential of transgenic mice for studying the pathophysiology of SCI, we examined the use of both in and ex vivo (1)H-MRI (9.4 T) in two severities of the mouse SCI (hemisection and over-hemisection) and documented their correlation with histological assessments. We demonstrated that a clear distinction between the two injury severities is possible using in and ex vivo (1)H-MRI and that ex vivo MR images closely correlate with histology. Moreover, tissue modifications at a remote location from the lesion epicenter were identified by conventional ex vivo MRI analysis. Therefore, in vivo MRI has the potential to accurately identify in mice the progression of tissue alterations induced by SCI and is successfully implemented by ex vivo MRI examination. This combination of in and ex vivo MRI follow-up associated with histopathological assessment provides a valuable approach for further studies intended to evaluate therapeutic strategies on SCI.

Awake mapping for low-grade gliomas involving the left sagittal stratum: anatomofunctional and surgical considerations.

OBJECT: Preserving function while optimizing the extent of resection is the main goal in surgery for diffuse low-grade glioma (DLGG). This is particularly relevant for DLGG involving the sagittal stratum (SS), where damage can have severe consequences. Indeed, this structure is a major crossroad in which several important fascicles run. Thus, its complex functional anatomy is still poorly understood. Subcortical electrical stimulation during awake surgery provides a unique opportunity to investigate white matter pathways. This study reports the findings on anatomofunctional correlations evoked by stimulation during resection for gliomas involving the left SS. Surgical outcomes are also detailed. METHODS: The authors performed a review of patients who underwent awake surgery for histopathologically confirmed WHO Grade II glioma involving the left SS in the neurosurgery department between August 2008 and August 2012. Information regarding clinicoradiological features, surgical procedures, and outcomes was collected and analyzed. Intraoperative electrostimulation was used to map the eloquent structures within the SS. RESULTS: Eight consecutive patients were included in this study. There were 6 men and 2 women, whose mean age was 41.7 years (range 32-61 years). Diagnosis was made because of seizures in 7 cases and slight language disorders in 1 case. After cortical mapping, subcortical stimulation detected functional fibers running in the SS in all patients: semantic paraphasia was generated by stimulating the inferior frontooccipital fascicle in 8 cases; alexia was elicited by stimulating the inferior longitudinal fascicle in 3 cases; visual disorders were induced by stimulating the optic radiations in 5 cases. Moreover, in front of the SS, phonemic paraphasia was evoked by stimulating the temporal part of the arcuate fascicle in 5 patients. The resection was stopped according to these functional limits in the 8 patients. After a transient postsurgical worsening, all patients recovered to normal results on examination, except for the persistence of a right superior quadrantanopia in 5 cases, with no consequences for quality of life. The 8 patients returned to a normal social and professional life. Total or subtotal resection was achieved in all cases but one. CONCLUSIONS: The authors suggest that the use of intrasurgical electrical mapping of the white matter pathways in awake patients opens the door to extensive resection of DLGG within the left SS while preserving the quality of life. Further anatomical, clinical, radiological, and electrophysiological studies are needed for a better understanding of the functional anatomy of this complex region.

Spinal metastases in breast cancer: single center experience.

OBJECTIVE: Metastases to the spine are a common manifestation of breast cancer leading to considerable reduction in the patient's quality of life. Physicians must consider the different treatments available to decrease pain, reduce tumor burden, and ensure spinal stability to prevent neurological compromises. The first objective of this study is to analyze the epidemiology and outcomes of patients with spinal metastases from breast cancer and describe changes over time in these lesions. The second objective is to establish the current treatment of spinal metastases in this type of cancer. METHODS: A total of 140 patients with breast cancer and spinal metastasis involvement were studied retrospectively. Demographic, clinical, and radiologic parameters were assessed, and the effects of systemic and local treatments on spinal metastasis were analyzed. RESULTS: Median patient age at diagnosis of breast cancer was 50 years (19-86 years) and average follow-up was 100 months (4-384 months). Median overall survival after diagnosis of spinal metastasis was 18.6 months. Fractures were present in 24 patients (19.3%) at diagnosis and in up to 60 cases (48.6%) by the end of the study period. CONCLUSIONS: The survival rate was better in patients with spinal metastases who received specific treatment. The evolution from lytic spinal metastasis to mixed and blastic subtypes is observed with adjunctive therapy for spinal metastases (bisphosphonates, radiotherapy). Increased attention must be given for high-grade breast cancer, as spinal metastases declare faster for these stages. This study provides evidence that a multidisciplinary tumor board specifically focusing on bone metastasis is essential to effectively manage patients with breast cancer and spinal metastasis.