The contribution of EEG to assess and treat motor disorders in multiple sclerosis.

OBJECTIVE: Electroencephalography (EEG) can highlight significant changes in spontaneous electrical activity of the brain produced by altered brain network connectivity linked to inflammatory demyelinating lesions and neuronal loss occurring in multiple sclerosis (MS). In this review, we describe the main EEG findings reported in the literature to characterize motor network alteration in term of local activity or functional connectivity changes in patients with MS (pwMS). METHODS: A comprehensive literature search was conducted to include articles with quantitative analyses of resting-state EEG recordings (spectrograms or advanced methods for assessing spatial and temporal dynamics, such as coherence, theory of graphs, recurrent quantification, microstates) or dynamic EEG recordings during a motor task, with or without connectivity analyses. RESULTS: In this systematic review, we identified 26 original articles using EEG in the evaluation of MS-related motor disorders. Various resting or dynamic EEG parameters could serve as diagnostic biomarkers of motor control impairment to differentiate pwMS from healthy subjects or be related to a specific clinical condition (fatigue) or neuroradiological aspects (lesion load). CONCLUSIONS: We highlight some key EEG patterns in pwMS at rest and during movement, both suggesting an alteration or disruption of brain connectivity, more specifically involving sensorimotor networks. SIGNIFICANCE: Some of these EEG biomarkers of motor disturbance could be used to design future therapeutic strategies in MS based on neuromodulation approaches, or to predict the effects of motor training and rehabilitation in pwMS.

Event-related desynchronization and synchronization in multiple sclerosis.

BACKGROUND: Motor preparation and execution can be impaired in patients with multiple sclerosis (pwMS). These neural processes can be assessed using electroencephalography (EEG). During a self-paced movement, EEG signal amplitude decreases before movement (event-related desynchronization, ERD) and increases after movement (event-related synchronization, ERS). OBJECTIVE: To reappraise ERD/ERS changes in pwMS compared to healthy controls (HC). METHODS: This single-center study included 13 pwMS and 10 sex/age-matched HC. 60-channel EEG was recorded during two self-paced movements of the right hand: a simple index finger extension task and a more complex finger tapping task. Clinical variables included MS type, sex, age, disease duration, disability, grip strength, fatigue and attentional performance. EEG variables included ERD and ERS onset latency, duration, and amplitude determined using two methods of signal analyses (based on visual or automated determination) in the alpha and beta frequency bands in five cortical regions: right and left frontocentral and centroparietal regions and a midline region. Neuroimaging variables included the volumes of four deep brain structures (thalamus, putamen, pallidum and caudate nucleus) and the relative lesion load. RESULTS: ERD/ERS changes in pwMS compared to HC were observed only in the beta band. In pwMS, beta-ERD had a delayed onset in the midline and right parietocentral regions and a shortened duration or increased amplitude in the parietocentral region; beta-ERS had a shorter duration, delayed onset, or reduced amplitude in the left parieto/frontocentral region. In addition, pwMS with a more delayed beta-ERD in the midline region had less impaired executive functions but increased caudate nuclei volume, while pwMS with a more delayed beta-ERS in the parietocentral region contralateral to the movement had less fatigue but increased thalami volume. CONCLUSION: This study confirms an alteration of movement preparation and execution in pwMS, mainly characterized by a delayed cortical activation (ERD) and a delayed and reduced post-movement inhibition (ERS) in the beta band. Compensatory mechanisms could be involved in these changes, associating more preserved clinical performance and overactivation of deep brain structures.

Rate and characteristics of inflammatory neuropathies associated with brentuximab vedotin therapy.

BACKGROUND AND PURPOSE: Peripheral neuropathy is a frequent complication of brentuximab vedotin (BV), used in CD30+ lymphoma treatment. Classic BV-induced neuropathy (BV-CN) is a mild distal sensory axonal polyneuropathy. Severe BV-induced inflammatory neuropathies (BV-IN) have been described. BV-IN contribute to lymphoma-associated morbidity but might be immunotherapy-responsive. Our primary objective was to evaluate the rate of BV-IN. Our secondary objectives were to determine risk factors and warning signs. METHODS: We conducted a retrospective cohort study on all patients treated with BV at our center between April 2014 and September 2021. Clinical, biological, and electrophysiological data were collected. BV-induced neuropathy was defined as the occurrence of neuropathy up to 3 months after BV discontinuation. BV-IN was defined with criteria adapted from European Academy of Neurology/Peripheral Nerve Society 2021 electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. Other neuropathies were classified as BV-CN. RESULTS: Among 83 patients, 41 (49%) developed neuropathy: 35 BV-CN and 6 BV-IN. Thus, the rate of BV-IN was 7.2%. Compared to patients with BV-CN, no predisposing factor was identified. However, patients with BV-IN more frequently presented muscle weakness (67% vs. 5.7%, p < 0.05), gait disorders (83% vs. 20%, p < 0.05), or acute or subacute onset (67% vs. 14%, p < 0.05). BV-IN was frequently more severe (Common Terminology Criteria for Adverse Events grade ≥3; 50% vs. 0%, p < 0.05). Four patients were treated with immunotherapy. CONCLUSIONS: Brentuximab vedotin-induced neuropathy is an overlooked complication. Based on four easily identifiable "red flags", we provide an algorithm to help non-neurologist physicians that care for BV-treated patients to detect BV-IN. The aim of the algorithm is to decrease the diagnostic and management delay of this disabling neuropathy.

Impact of textured surfaces on the orthostatic balance of patients with multiple sclerosis.

OBJECTIVE: To perform posturographic measurements with eyes open or closed using floor coverings with different textured surfaces to study postural control in patients with multiple sclerosis (MS). METHODS: Static posturographic recordings were performed with eyes open and eyes closed on a forceplate with no covering (control condition) or covered by a textured mat with small pimples (height 2 mm) or large pimples (height 7 mm). Several posturographic variables were measured, focusing on displacements of the center of pressure (CoP) including the average velocity (Vav), the total length (L) of all displacements, and the surface (S) of the confidence ellipse. The recordings made with the textured mats were compared to the control condition with eyes open or closed. Then, the differences between the recordings made with large vs. small pimples on the one hand, and with eyes closed vs. open were calculated to assess the impact of pimple height or eye closure on posturographic measurements. Clinical assessment was based on the Expanded Disability Status Scale (EDSS) and its functional system (FS) subscores, the Modified Fatigue Impact Scale (MFIS), the Unipodal Stance test (UST), and the Timed Up-and-Go test (TUG). RESULTS: Forty-six MS patients (mean EDSS score: 3.6) completed the study. Several posturographic variables, including Vav and L, deteriorated when measured on a textured mat, especially with large pimples and in eyes open condition. In contrast, no difference was found with small pimples and eyes closed, as compared to the control condition (no covering). The deleterious impact of pimple height on posturography correlated positively with the alteration of balance and gait clinically assessed by the UST and the TUG, and also with the MFIS physical and cerebral EDSS-FS subscores, and negatively with the cerebellar and brainstem subscores. On the other hand, the impact of eye closure on posturography was negatively correlated with the visual EDSS-FS subscore. DISCUSSION: Static posturographic measurements made with different textured surfaces and visual conditions can be considered as a sensitive tool to measure "proprioceptive reserves". Actually, when cerebellar, brainstem, or visual functions are impaired, the resources of the sensory (proprioceptive) system, if preserved, can be recruited at a higher level and compensate for dysfunctions of other postural controls to maintain a satisfactory balance. In addition, this procedure of static posturographic examination can provide objective measurements correlated with clinical testing of balance and gait and could usefully complement EDSS scoring to assess disability affecting postural control and the risk of falling in MS patients.

Effect of exercise training on glycemic control in diabetic peripheral neuropathy: A GRADE assessed systematic review and meta-analysis of randomized-controlled trials.

AIMS: We conducted a systematic review and meta-analysis to investigate the effect of exercise training on HbA1c, and on fasting and postprandial plasma glucose concentrations in patients with diabetic peripheral neuropathy (DPN). METHODS: Two independent researchers performed a systematic search in the electronic databases of PubMed, Web of Science and Scopus. Studies investigating the effect of exercise training on patients diagnosed with DPN using a randomized-controlled design were included in the meta-analysis. RESULTS: Of 1254 retrieved studies, 68 studies were identified to undergo full-text review; out of these a total of 13 randomized trials met the inclusion criteria. Eleven studies assessed HbA1c, 8 fasting plasma-glucose concentration, and 3 postprandial plasma-glucose concentration. Overall, exercise training significantly decreased HbA1c [-0.54% (95% CI -0.78 to -0.31%)], fasting plasma glucose [-32.6 mg/dl [-1.8 mmol/L] (-44.2 to -20.9 mg/dl [-2.4 to -1.1 mmol/L])] and postprandial plasma glucose [-67.5 mg/dl [-3.7 mmol/L] (-129.5 to -5.4 mg/dl [-7.1 to -0.3 mmol/L])]. Studies with aerobic training intervention yielded the largest significant mean reduction in HbA1c (-0.75%) and fasting plasma glucose concertation (34.0 mg/dl). CONCLUSIONS: aerobic training is the most effective modality to reduces HbA1c, fasting and postprandial plasma glucose concentration in patients with DPN. From a metabolic perspective, the magnitude precision range of the reduction in HbA1c is of clinical importance for patients with DPN. This area of research warrants further attention to investigate the impact of various exercise modalities on glycemic control. Registration number CRD42023413687.

Characterizing Acute-Onset Small Fiber Neuropathy.

BACKGROUND AND OBJECTIVES: Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable. METHODS: We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected. RESULTS: Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course. DISCUSSION: AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.

Neural Correlates of Pain-Autonomic Coupling in Patients With Complex Regional Pain Syndrome Treated by Repetitive Transcranial Magnetic Stimulation of the Motor Cortex.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a chronic pain condition involving autonomic dysregulation. In this study, we report the results of an ancillary study to a larger clinical trial investigating the treatment of CRPS by neuromodulation. This ancillary study, based on functional magnetic resonance imaging (fMRI), evaluated the neural correlates of pain in patients with CRPS in relation to the sympathetic nervous system and for its potential relief after repetitive transcranial magnetic stimulation of the motor cortex. MATERIALS AND METHODS: Eleven patients with CRPS at one limb (six women, five men, aged 52.0 ± 9.6 years) were assessed before and one month after the end of a five-month repetitive transcranial magnetic stimulation (rTMS) therapy targeting the motor cortex contralateral to the painful limb, by means of electrochemical skin conductance (ESC) measurement, daily pain intensity scores on a visual numerical scale (VNS), and fMRI with motor tasks (alternation of finger movements and rest). The fMRI scans were analyzed voxelwise using ESC and VNS pain score as regressors to derive their neural correlates. The criterion of response to rTMS therapy was defined as ≥30% reduction in VNS pain score one month after treatment compared with baseline. RESULTS: At baseline, ESC values were reduced in the affected limb vs the nonaffected limb. There was a covariance of VNS with brain activation in a small region of the primary somatosensory cortex (S1) contralateral to the painful side on fMRI investigation. After rTMS therapy on motor cortex related to the painful limb, the VNS pain scores significantly decreased by 22% on average. The criterion of response was met in six of 11 patients (55%). In these responders, at one month after treatment, ESC value increased and returned to normal in the CRPS-affected limb, and overall, the increase in ESC correlated with the decrease in VNS after motor cortex rTMS therapy. At one month after treatment, there also was a covariance of both variables (ESC and VNS) with fMRI activation of the S1 region previously mentioned. The fMRI activation of other brain regions (middle frontal gyrus and temporo-parietal junction) showed correlation with ESC values before and after treatment. Finally, we found a positive correlation at one month after treatment (not at baseline) between VNS pain score and fMRI activation in the temporo-parietal junction contralateral to painful side. CONCLUSIONS: This study first shows a functional pain-autonomic coupling in patients with CRPS, which could involve a specific S1 region. However, the modulation of sympathetic sudomotor activities expressed by ESC changes was rather correlated with functional changes in other brain regions. Finally, the pain relief observed at one month after rTMS treatment was associated with a reduced activation of the temporo-parietal junction on the side in which rTMS was performed. These findings open perspectives to define new targets or biomarkers for using rTMS to treat CRPS-associated pain. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02817880.

Validation of the Body Scan®, a new device to detect small fiber neuropathy by assessment of the sudomotor function: agreement with the Sudoscan®.

Background: Sudomotor dysfunction is one of the earliest manifestations of small fiber neuropathy (SFN), reflecting the alteration of sympathetic C fiber innervation of the sweat glands. Among other techniques, such innervation can be assessed by measuring electrochemical skin conductance (ESC) in microsiemens (µS). In this study, ESC was measured at the feet to detect distal SFN. For this objective, the performance of a new device, the Body Scan® (Withings, France), intended for home use, was compared with that of a reference device, the Sudoscan® (Impeto Medical, France), which requires a hospital setting. Methods: In patients with diabetes with or without neuropathy or non-diabetic patients with lower-limb neuropathy, the diagnostic performance of the Body Scan® measurement was assessed by calculating its sensitivity (Se) and specificity (Sp) to detect at least moderate SFN (Se70 and Sp70), defined by a value of feet ESC ≤ 70 µS and > 50 µS on the Sudoscan® measure, or severe SFN (Se50 and Sp50), defined by a value of feet ESC ≤ 50 µS on the Sudoscan® measure. The agreement between the two devices was assessed with the analysis of Bland-Altman plots, mean absolute error (MAE), and root mean squared error (RMSE) calculations. The repeatability of the measurements was also compared between the two devices. Results: A total of 147 patients (52% men, mean age 59 years old, 76% diabetic) were included in the analysis. The sensitivity and specificity to detect at least moderate or severe SFN were: Se70 = 0.91 ([0.83, 0.96]), Sp70 = 0.97 ([0.88, 0.99]), Se50 = 0.91 ([0.80, 0.98]), and Sp50 = 0.99 ([0.94, 1]), respectively. The bias and 95% limits of agreement were 1.5 [-5.4, 8.4]. The MAE was 2.9 and the RMSE 3.8. The intra-sample variability was 2.0 for the Body Scan® and 2.3 for the Sudoscan®. Conclusion: The ESC measurements provided by the Body Scan® were in almost perfect agreement with those provided by the reference device, the Sudoscan®, which validates the accuracy of the Body Scan® for the detection of SFN. By enabling simple, rapid, and autonomous use by the patient at home, this new technique will facilitate screening and monitoring of SFN in daily practice. Clinical trial registration: ClinicalTrials.gov, identifier NCT05178459.

Treatment of cognitive and mood disorders secondary to traumatic brain injury by the association of bilateral occipital nerve stimulation and a combined protocol of multisite repetitive transcranial magnetic stimulation and cognitive training: A case report.

Purpose: Cognitive impairment secondary to traumatic brain injury (TBI) is difficult to treat and usually results in severe disability. Method: A 48-year-old man presented with chronic refractory headaches and persistent disabling cognitive impairment after TBI. He was first treated with occipital nerve stimulation (ONS) implanted bilaterally to relieve headaches (8 years after the head trauma). Two years later, he was treated with a 6-week protocol combining repetitive transcranial magnetic stimulation (rTMS) delivered to multiple cortical sites (prefrontal cortex, language areas, and areas involved in visuo-spatial functions) and computerized cognitive training (CogT) (targeting memory, language, and visuo-spatial functions) to improve cognitive performance. Results: Executive and cognitive functions (attention, ability to perform calculations, and verbal fluency) improved in association with pain relief after ONS (33-42% improvement) and then improved even more after the rTMS-CogT protocol with an additional improvement of 36-40% on apathy, depression, and anxiety, leading to a significant reduction in caregiver burden. The functional improvement persisted and even increased at 6 months after the end of the rTMS-CogT procedure (10 years after the onset of TBI and 2 years after ONS implantation). Conclusion: This is the first observation describing sustained improvement in post-TBI refractory headache, depression, and cognitive impairment by the association of bilaterally implanted ONS and a combined procedure of multisite rTMS and CogT to target various brain functions.

High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study.

BACKGROUND: We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept. METHODS: Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables. RESULTS: The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product. CONCLUSIONS: Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

Comparison of the analgesic effects of "superficial" and "deep" repetitive transcranial magnetic stimulation in patients with central neuropathic pain: a randomized sham-controlled multicenter international crossover study.

ABSTRACT: We directly compared the analgesic effects of "superficial" and 'deep" repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex in patients with central neuropathic pain. Fifty-nine consecutive patients were randomly assigned to active or sham "superficial" (using a figure-of-8 [F8]-coil) or "deep" (using a Hesed [H]-coil) stimulation according to a double-blind crossover design. Each treatment period consisted of 5 daily stimulation sessions and 2 follow-up visits at 1 and 3 weeks after the last stimulation session. The primary outcome was the comparison of the mean change in average pain intensity over the course of the treatment (group × time interaction). Secondary outcomes included neuropathic symptoms (NPSI), pain interference, patient global impression of change (PGIC), anxiety, depression, and catastrophizing. In total, 51 patients participated in at least one session of both treatments. There was a significant interaction between "treatment" and "time" (F = 2.7; P = 0.0024), indicating that both figure-8 (F8-coil) and H-coil active stimulation induced significantly higher analgesic effects than sham stimulation. The analgesic effects of both types of coils had a similar magnitude but were only moderately correlated (r = 0.39, P = 0.02). The effects of F8-coil stimulation appeared earlier, whereas the effects of H-coil stimulation were delayed, but tended to last longer (up to 3 weeks) as regards to several secondary outcomes (PGIC and total NPSI score). In conclusion, "deep" and "superficial" rTMS induced analgesic effects of similar magnitude in patients with central pain, which may involve different mechanisms of action.

Impact of five floor coverings on the orthostatic balance of healthy subjects.

Plantar skin sensitivity contributes to the regulation of postural control and, therefore, changing the characteristics of the plantar support surface can modify this control. This study aimed at assessing the impact of five different floor coverings on the orthostatic balance in 48 healthy subjects. Static posturography was performed with eyes open or closed on a platform in a control condition (no covering) and with five different covering surfaces: foam, silicone, ethyl vinyl acetate, and two textured mats with small (height 2 mm) or large pimples (7 mm). The average velocity of center of pressure (CoP) displacement was the primary endpoint measure and ten other posturographic variables were assessed. Comfort and pain produced by the covering were also scored. In eyes open condition, the average velocity of CoP displacement was increased when subjects stood on the foam mat, the silicone mat, and especially the textured mat with large pimples. Several other posturographic variables showed significant changes with different types of floor coverings with eyes open. These changes were not correlated to the comfort or pain scores associated with the different surfaces. In contrast, no difference was observed compared to the control condition (no covering) with eyes closed. This study shows that adding smooth or textured floor covering can alter balance in eyes open condition. In eyes closed condition, although more disturbing for balance, healthy subjects achieved better postural adaptation, probably by mobilizing more of their proprioceptive resources. This posturographic examination procedure could, therefore, be used to assess "proprioceptive reserve" capacities in clinical practice.

Surgical treatment of hemifacial spasms: how to predict failure and complications through a series of 200 patients.

Primary hemifacial spasm (pHFS) is a benign but disabling movement disorder caused by a neurovascular conflict involving the facial nerve. Surgical treatment by microvascular decompression (MVD) is the most effective therapeutic. Predictors of surgical failure and surgical complications are still lacking. The aim of this study is to identify such predictors through the retrospective analysis of a series of 200 consecutive patients. All patients who underwent MVD for pHFS from January 1991 to December 2017 were included. All patients had at least two years follow-up. In addition to the demographic data, the outcome and the complications were collected. The primary outcome analysis showed that 7.5% of patients had a recurrence. Multiple and AICA related neurovascular conflicts were statistically associated to a higher recurrence rate after MVD (respectively p < 0.001 and p = 0.02). Permanent facial palsy occurred in 2.5% of patients, hearing loss in 9.0% (2.0% of complete unilateral impairment) and dizziness in 2.5%. The risk of each of these peripheral neurological impairments was statistically increased by a long duration between the first pHFS symptom and the MVD (p < 0.001). In case of recurrence, a second MDV was offered. Long term follow-up showed that all patients had a complete resolution of the HFS. Post-operative complication rate was not significantly increased after a second MVD. Multiple and AICA related neurovascular conflicts are associated to a higher risk of surgical failure. When a pHFS recurrence occurs, a second surgical procedure is associated with excellent outcome without significant increase of post-operative complications and should therefore be recommended.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Long-term analgesic effect of trans-spinal direct current stimulation compared to non-invasive motor cortex stimulation in complex regional pain syndrome.

The aim of the present study was to compare the analgesic effect of motor cortex stimulation using high-frequency repetitive transcranial magnetic stimulation or transcranial direct current stimulation and transcutaneous spinal direct current stimulation in patients with complex regional pain syndrome. Thirty-three patients with complex regional pain syndrome were randomized to one of the three treatment groups (repetitive transcranial magnetic stimulation, n = 11; transcranial direct current stimulation, n = 10; transcutaneous spinal direct current stimulation, n = 12) and received a series of 12 sessions of stimulation for 3 weeks (induction phase) and 11 sessions for 4 months (maintenance therapy). The primary end-point was the mean pain intensity assessed weekly with a visual numerical scale during the month prior to treatment (baseline), the 5-month stimulation period and 1 month after the treatment. The weekly visual numerical scale pain score was significantly reduced at all time points compared to baseline in the transcutaneous spinal direct current stimulation group, at the last two time points in the repetitive transcranial magnetic stimulation group (end of the 5-month stimulation period and 1 month later), but at no time point in the transcranial direct current stimulation group. A significant pain relief was observed at the end of induction phase using transcutaneous spinal direct current stimulation compared to repetitive transcranial magnetic stimulation (P = 0.008) and to transcranial direct current stimulation (P = 0.003). In this trial, transcutaneous spinal direct current stimulation was more efficient to relieve pain in patients with complex regional pain syndrome compared to motor cortex stimulation techniques (repetitive transcranial magnetic stimulation, transcranial direct current stimulation). This efficacy was found during the induction phase and was maintained thereafter. This study warrants further investigation to confirm the potentiality of transcutaneous spinal direct current stimulation as a therapeutic option in complex regional pain syndrome.

Targeting Lower Limb, Upper Limb, and Face Representation in the Primary Motor Cortex for the Practice of Neuronavigated Transcranial Magnetic Stimulation.

OBJECTIVE: The primary motor cortex (M1) is a usual target for therapeutic application of repetitive transcranial magnetic stimulation (rTMS), especially the region of hand motor representation. However, other M1 regions can be considered as potential rTMS targets, such as the region of lower limb or face representation. In this study, we assessed the localization of all these regions on magnetic resonance imaging (MRI) with the aim of defining three standardized M1 targets for the practice of neuronavigated rTMS. MATERIALS AND METHODS: A pointing task of these targets was performed by three rTMS experts on 44 healthy brain MRI data to assess interrater reliability (including the calculation of intraclass correlation coefficients [ICCs] and coefficients of variation [CoVs] and the construction of Bland-Altman plots). In addition, two "standard" brain MRI data were randomly interspersed with the other MRI data to assess intrarater reliability. A barycenter was calculated for each target (with x-y-z coordinates provided in normalized brain coordinate systems), in addition to the geodesic distance between the scalp projection of the barycenters of these different targets. RESULTS: Intrarater and interrater agreement was good, according to ICCs, CoVs, or Bland-Altman plots, although interrater variability was greater for anteroposterior (y) and craniocaudal (z) coordinates, especially for the face target. The scalp projection of the barycenters between the different cortical targets ranged from 32.4 to 35.5 mm for either the lower-limb-to-upper-limb target distance or the upper-limb-to-face target distance. CONCLUSIONS: This work clearly delineates three different targets for the application of motor cortex rTMS that correspond to lower limb, upper limb, and face motor representations. These three targets are sufficiently spaced to consider that their stimulation can act on distinct neural networks.

Reference-free Bayesian model for pointing errors of typein neurosurgical planning.

PURPOSE: Many neurosurgical planning tasks rely on identifying points of interest in volumetric images. Often, these points require significant expertise to identify correctly as, in some cases, they are not visible but instead inferred by the clinician. This leads to a high degree of variability between annotators selecting these points. In particular, errors of type are when the experts fundamentally select different points rather than the same point with some inaccuracy. This complicates research as their mean may not reflect any of the experts' intentions nor the ground truth. METHODS: We present a regularised Bayesian model for measuring errors of type in pointing tasks. This model is reference-free; in that it does not require a priori knowledge of the ground truth point but instead works on the basis of the level of consensus between multiple annotators. We apply this model to simulated data and clinical data from transcranial magnetic stimulation for chronic pain. RESULTS: Our model estimates the probabilities of selecting the correct point in the range of 82.6[Formula: see text]88.6% with uncertainties in the range of 2.8[Formula: see text]4.0%. This agrees with the literature where ground truth points are known. The uncertainty has not previously been explored in the literature and gives an indication of the dataset's strength. CONCLUSIONS: Our reference-free Bayesian framework easily models errors of type in pointing tasks. It allows for clinical studies to be performed with a limited number of annotators where the ground truth is not immediately known, which can be applied widely for better understanding human errors in neurosurgical planning.

Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee.

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.