Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase–Associated Neurodegeneration

Fosmetpantotenate; Randomized controlled trialFosmetpantotenato; Ensayo controlado aleatorizadoFosmetpantotenat; Assaig controlat aleatoritzatBackground Pantothenate kinase–associated neurodegeneration (PKAN) currently has no approved treatments. Objectives The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. Methods This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. Results Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was −0.09 (−1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. Conclusions Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN.The FORT trial was supported by Retrophin, Inc

Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

BackgroundGNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD.ObjectivesThis study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies.MethodsA Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise.ResultsConsensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis.ConclusionThis consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Thirty Years of Global Deep Brain Stimulation : ;plus ça change, plus c'est la même chose;?

Background: The advent of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease 30 years ago has ushered a global breakthrough of DBS as a universal method for therapy and research in wide areas of neurology and psychiatry. The literature of the last three decades has described numerous concepts and practices of DBS, often branded as novelties or discoveries. However, reading the contemporary publications often elicits a sense of déjà vu in relation to several methods, attributes, and practices of DBS. Here, we review various applications and techniques of the modern-era DBS and compare them with practices of the past. Summary: Compared with modern literature, publications of the old-era functional stereotactic neurosurgery, including old-era DBS, show that from the very beginning multidisciplinarity and teamwork were often prevalent and insisted upon, ethical concerns were recognized, brain circuitries and rational for brain targets were discussed, surgical indications were similar, closed-loop stimulation was attempted, evaluations of surgical results were debated, and controversies were common. Thus, it appears that virtually everything done today in the field of DBS bears resemblance to old-Time practices, or has been done before, albeit with partly other tools and techniques. Movement disorders remain the main indications for modern DBS as was the case for lesional surgery and old-era DBS. The novelties today consist of the STN as the dominant target for DBS, the tremendous advances in computerized brain imaging, the sophistication and versatility of implantable DBS hardware, and the large potential for research. Key Messages: Many aspects of contemporary DBS bear strong resemblance to practices of the past. The dominant clinical indications remain movement disorders with virtually the same brain targets as in the past, with one exception: The STN. Other novel brain targets-that are so far subject to DBS trials-are the pedunculopontine nucleus for gait freezing, the anteromedial internal pallidum for Gilles de la Tourette and the fornix for Alzheimer's disease. The major innovations and novelties compared to the past concern mainly the unmatched level of research activity, its high degree of sponsorship, and the outstanding advances in technology that have enabled multimodal brain imaging and the miniaturization, versatility, and sophistication of implantable hardware. The greatest benefit for patients today, compared to the past, is the higher level of precision and safety of DBS, and of all functional stereotactic neurosurgery

A target-specific electrode and lead design for internal globus pallidus deep brain stimulation.

In nearly all deep brain stimulation (DBS) applications, the same quadripolar electrode design is used for different anatomical targets even if shape and volume differences exist between nuclei. Taking into account the electrode location within the internal globus pallidus (GPi) and the size of the GPi, 2 electrodes were designed in order to improve the therapeutic benefit, to minimize side effects from DBS and to obtain a more homogeneous electric field distribution. The electrodes were evaluated numerically by using a stereotactic model measuring the correlation between the electric field and the GPi. The model was applied to 26 dystonodyskinetic patients who underwent surgery for a bilateral lead implantation into the posteroventral part of the GPi. The designed electrodes produced a more homogeneous distribution of the electric field than the quadripolar electrode

Morphological Neuron Classification Using Machine Learning

Classification and quantitative characterization of neuronal morphologies from histological neuronal reconstruction are challenging since still unclear how to delineate a neuronal cell class and which would be the best features to define them. The morphological neuron characterization represents primary sources to address anatomical comparisons, morphometric analysis of cells or brain modeling. The objective of this paper are i), to develop and integrate a pipeline that goes from morphological features extraction to classification and ii), to assess and compare the accuracy of machine learning algorithms to classify neuron morphologies. The algorithms were trained on 430 digitally reconstructed neurons subjectively classified into layers and/or m-types using young and/or adult development state population of the somatosensory cortex in rats. For supervised algorithms, Linear Discriminant Analysis provided better classification results by comparison with others. For unsupervised, algorithms providing slightly better results are the affinity propagation and the Ward algorithms

Neural Oscillatory Correlates for Conditioning and Extinction of Fear

The extinction of conditioned-fear represents a hallmark of current exposure therapies as it has been found to be impaired in people suffering from post-traumatic stress disorder (PTSD) and anxiety. A large body of knowledge focusing on psychophysiological animal and human studies suggests the involvement of key brain structures that interact via neural oscillations during the acquisition and extinction of fear. Consequently, neural oscillatory correlates of such mechanisms appear relevant regarding the development of novel therapeutic approaches to counterbalance abnormal activity in fear-related brain circuits, which, in turn, could alleviate fear and anxiety symptoms. Here, we provide an account of state-of-the-art neural oscillatory correlates for the conditioning and extinction of fear, and also deal with recent translational efforts aimed at fear extinction by neural oscillatory modulation

Prognostic value of globus pallidus internus volume in primary dystonia treated by deep brain stimulation.

OBJECT: Given that improvement is variable from one patient to another, the authors analyzed the impact of globus pallidus internus (GPi) volume on the result of deep brain stimulation (DBS) by comparing highly and less improved patients with primary dystonodyskinetic syndromes. METHODS: A stereotactic model was developed to visualize and quantify the relationship between the isofield lines generated by the DBS lead and GPi target. The model was used in 30 right-handed selected patients with primary dystonodyskinetic syndromes who had been treated using bilateral stimulation of the sensorimotor GPi. Ten healthy control individuals were also included in the study. First, the authors compared the GPi volumes between patients and healthy controls. Second, the stimulated GPi volumes, that is, the intersection between the volume of each isofield value and the GPi volumes, were compared between less improved and highly improved patients. RESULTS: Improvement in the Burke-Fahn-Marsden Dystonia Rating Scale's motor score was rated > 90% in 20 patients (97 +/- 4.6%) and < 60% in 10 patients (56.9 +/- 6%). The mean volume of the right (461.8 +/- 81.8 mm(3)) and left (406.6 +/- 113.2 mm(3)) GPi in patients showing less response to DBS was significantly smaller than the GPi volume of patients who responded well (right 539.9 +/- 86.6 mm(3), left 510.6 +/- 88.7 mm(3)) and healthy controls (right 557.8 +/- 109.1 mm(3), left 525.1 +/- 40.8 mm(3)). CONCLUSIONS: On the left side, the mean stimulated volumes (isofield line range 0.2-1 V/mm) were significantly larger in highly improved than in less improved patients. In this model, the threshold for functional effect was calculated at 0.2 V/mm

Stereotactic model of the electrical distribution within the internal globus pallidus during deep brain stimulation.

International audienceDeep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established surgical technique for the treatment of movement disorders. The objective of this study was to propose a computational stereotactic model of the electrical distribution around the electrode within the targeted GPi in order to optimize parameter adjustment in clinical practice. The outline of the GPi can be defined precisely by using stereotactic magnetic resonance imaging (MRI) and from this it is possible to model its three-dimensional structure. The electrode and the distribution of the patient-specific parameters can then be co-registered with the GPi volume. By using this methodology, it is possible to visualize and measure the relationship between the electrical distribution of patient-specific parameters and the morphology of the GPi. The model could be applied in clinical practice to help determine the threshold for achieving a therapeutic effect and consequently may aid in optimizing parameter settings for individual patients