Intraputaminal Gene Delivery in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency.

Background: Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, early-onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). Objective: We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Methods: Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Results: Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l-6-[18F] fluoro-3, 4-dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Conclusion: Two patients with a severe form of AADCD had an objective motor and non-motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

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.

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.

Transcutaneous ventriculo-peritoneal shunt catheter extrusion with silent bowel perforation following digestive surgery: a case report.

This case report provides an account of transcutaneous ventriculo-peritoneal (VP) shunt extrusion with silent bowel perforation occurring 2 years post digestive surgery. A 22-year-old man treated since childhood for post-infectious hydrocephalus was referred to our neurosurgery department for an inflammatory wound to the right hypochondrium caused by an abandoned calcified VP shunt. This VP shunt was surgically removed without complications. The perforated bowel required no direct repair. Progress is favorable at 1 year follow-up.

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.

Task- and Rest-based Functional Brain Connectivity in Food-related Reward Processes among Healthy Adolescents.

It is known that the nucleus accumbens, orbitofrontal cortex and insula play a role in food-related reward processes. Although their interconnectedness would be an ideal topic for understanding food intake mechanisms, it nevertheless remains unclear especially in adolescent. Therefore, this study aims to investigate the effect of hunger on functional connectivity in healthy adolescents using task- and rest-based imaging. Fifteen participants underwent two MRI sessions, pre-lunch (hunger) and post-lunch (satiety), including food cue task and resting-state. During task- and rest-based imaging, functional connectivity was greater when hungry as opposed to satiated between the right posterior insula/nucleus accumbens, suggesting involvement of salient interoceptive stimuli signals. During task-based imaging, an increase was observed in functional connectivity when hungry as opposed to satiated between the medial and lateral orbitofrontal cortex which contributes to the perception of food deprivation as a frustration. A decrease was identified when hungry as opposed to satiated in functional connectivity in the right anterior orbitofrontal/accumbens and posterior insula/medial orbitofrontal cortices reflecting suppression of the affective and sensorial information. Conversely, functional connectivity was increased during aversive stimuli between the right medial orbitofrontal cortex and right posterior insula when hungry as opposed to satiated. This suggests that the value of valence could occur in the shift in connectivity between these two regions. In addition, during rest-based imaging, a left-sided lateralization was reported (accumbens/lateral orbitofrontal and accumbens/posterior insula) when hungry as opposed to satiated which may represent changes in internal state due to focus on the benefit of an upcoming meal.

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.

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.

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.

Secondary Worsening Following DYT1 Dystonia Deep Brain Stimulation: A Multi-country Cohort.

Objective: To reveal clinical characteristics of suboptimal responses to deep brain stimulation (DBS) in a multi-country DYT1 dystonia cohort. Methods: In this multi-country multi-center retrospective study, we analyzed the clinical data of DYT1 patients who experienced suboptimal responses to DBS defined as <30% improvement in dystonia scales at the last follow-up compared with baseline. We used a literature-driven historical cohort of 112 DYT1 patients for comparison. Results: Approximately 8% of our study cohort (11 out of 132) experienced suboptimal responses to DBS. Compared with the historical cohort, the multi-country cohort with suboptimal responses had a significantly younger age at onset (mean, 7.0 vs. 8.4 years; p = 0.025) and younger age at DBS (mean, 12.0 vs. 18.6 years; p = 0.019). Additionally, cranial involvement was more common in the multi-country cohort (before DBS, 64% vs. 45%, p = 0.074; before or after DBS, 91% vs. 47%, p = 0.001). Mean motor improvement at the last follow-up from baseline were 0% and 66% for the multi-country and historical cohorts, respectively. All 11 patients of the multi-country cohort had generalization of dystonia within 2.5 years after disease onset. All patients experienced dystonia improvement of >30% postoperatively; however, secondary worsening of dystonia commenced between 6 months and 3 years following DBS. The improvement at the last follow-up was less than 30% despite optimally-placed leads, a trial of multiple programming settings, and additional DBS surgeries in all patients. The on-/off-stimulation comparison at the long-term follow-up demonstrated beneficial effects of DBS despite missing the threshold of 30% improvement over baseline. Conclusion: Approximately 8% of patients represent a more aggressive phenotype of DYT1 dystonia characterized by younger age at onset, faster disease progression, and cranial involvement, which seems to be associated with long-term suboptimal responses to DBS (e.g., secondary worsening). This information could be useful for both clinicians and patients in clinical decision making and patient counseling before and following DBS implantations. Patients with this phenotype may have different neuroplasticity, neurogenetics, or possibly distinct neurophysiology.

Differential effects of hunger on cerebral blood flow in healthy adolescents.

Adolescence represents a key developmental period in terms of both mood and overweight and is linked to disturbed eating behavior. Therefore, it is essential to investigate the basis of food intake in healthy adolescents by considering mood impacts which remain largely unexplored. Hence this study aims to investigate the impact of hunger and mood on cerebral blood flow (CBF) changes in healthy adolescents. Fifteen participants underwent two MRI sessions including a 3D pseudo-continuous arterial spin labeling sequence: pre-lunch (hunger) and post-lunch (satiety). Mood was assessed using the Multiscore Depression Inventory for Children. We found higher CBF values in the posterior insula in response to hunger compared to satiety, an area of the brain which contributes to the anticipation and motivation of feeding. In response to satiation, we observed higher CBF values in the precuneus, lingual gyrus and cuneus which are involved in the aspects of response inhibition related to food intake. Furthermore, we show that correlation between mood assessment and CBF is modulated by appetite in the precuneus, anterior cingulate gyrus, anterior orbitofrontal gyrus, occipital gyrus and cuneus, suggesting that participants affected by depressed mood could use ruminative processing in order to evaluate the reward of an upcoming meal.

Pallidal Deep Brain Stimulation in DYT6 Dystonia: Clinical Outcome and Predictive Factors for Motor Improvement.

Pallidal deep brain stimulation is an established treatment in dystonia. Available data on the effect in DYT-THAP1 dystonia (also known as DYT6 dystonia) are scarce and long-term follow-up studies are lacking. In this retrospective, multicenter follow-up case series of medical records of such patients, the clinical outcome of pallidal deep brain stimulation in DYT-THAP1 dystonia, was evaluated. The Burke Fahn Marsden Dystonia Rating Scale served as an outcome measure. Nine females and 5 males were enrolled, with a median follow-up of 4 years and 10 months after implant. All benefited from surgery: dystonia severity was reduced by a median of 58% (IQR 31-62, p = 0.001) at last follow-up, as assessed by the Burke Fahn Marsden movement subscale. In the majority of individuals, there was no improvement of speech or swallowing, and overall, the effect was greater in the trunk and limbs as compared to the cranio-cervical and orolaryngeal regions. No correlation was found between disease duration before surgery, age at surgery, or preoperative disease burden and the outcome of deep brain stimulation. Device- and therapy-related side-effects were few. Accordingly, pallidal deep brain stimulation should be considered in clinically impairing and pharmaco-resistant DYT-THAP1 dystonia. The method is safe and effective, both short- and long-term.

Deep brain stimulation is effective in pediatric patients with GNAO1 associated severe hyperkinesia.

BACKGROUND: Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication. OBJECTIVE: The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations. METHODS: We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS. RESULTS: The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723+1G>T) in patient 1, a new missense mutation (c.610G>C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625>T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G>A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation. CONCLUSION: In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.

Deep brain stimulation treated dystonia-trajectory via status dystonicus.

BACKGROUND: Status dystonicus (SD) is a life-threatening condition. OBJECTIVE AND METHODS: In a dystonia cohort who developed status dystonicus, we analyzed demographics, background dystonia phenomenology and complexity, trajectory previous to-, via status dystonicus episodes, and evolution following them. RESULTS: Over 20 years, 40 of 328 dystonia patients who were receiving DBS developed 58 status dystonicus episodes. Dystonia was of pediatric onset (95%), frequently complex, and had additional cognitive and pyramidal impairment (62%) and MRI alterations (82.5%); 40% of episodes occured in adults. Mean disease duration preceding status dystonicus was 10.3 ± 8 years. Evolution time to status dystonicus varied from days to weeks; however, 37.5% of patients exhibited progressive worsening over years. Overall, DBS was efficient in resolving 90% of episodes. CONCLUSION: Status dystonicus is potentially reversible and a result of heterogeneous conditions with nonuniform underlying physiology. Recognition of the complex phenomenology, morphological alterations, and distinct patterns of evolution, before and after status dystonicus, will help our understanding of these conditions. © 2018 International Parkinson and Movement Disorder Society.