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.

Prognostic value of early EEG abnormalities in severe stroke patients requiring mechanical ventilation: a pre-planned analysis of the SPICE prospective multicenter study.

INTRODUCTION: Prognostication of outcome in severe stroke patients necessitating invasive mechanical ventilation poses significant challenges. The objective of this study was to assess the prognostic significance and prevalence of early electroencephalogram (EEG) abnormalities in adult stroke patients receiving mechanical ventilation. METHODS: This study is a pre-planned ancillary investigation within the prospective multicenter SPICE cohort study (2017-2019), conducted in 33 intensive care units (ICUs) in the Paris area, France. We included adult stroke patients requiring invasive mechanical ventilation, who underwent at least one intermittent EEG examination during their ICU stay. The primary endpoint was the functional neurological outcome at one year, determined using the modified Rankin scale (mRS), and dichotomized as unfavorable (mRS 4-6, indicating severe disability or death) or favorable (mRS 0-3). Multivariable regression analyses were employed to identify EEG abnormalities associated with functional outcomes. RESULTS: Of the 364 patients enrolled in the SPICE study, 153 patients (49 ischemic strokes, 52 intracranial hemorrhages, and 52 subarachnoid hemorrhages) underwent at least one EEG at a median time of 4 (interquartile range 2-7) days post-stroke. Rates of diffuse slowing (70% vs. 63%, p = 0.37), focal slowing (38% vs. 32%, p = 0.15), periodic discharges (2.3% vs. 3.7%, p = 0.9), and electrographic seizures (4.5% vs. 3.7%, p = 0.4) were comparable between patients with unfavorable and favorable outcomes. Following adjustment for potential confounders, an unreactive EEG background to auditory and pain stimulations (OR 6.02, 95% CI 2.27-15.99) was independently associated with unfavorable outcomes. An unreactive EEG predicted unfavorable outcome with a specificity of 48% (95% CI 40-56), sensitivity of 79% (95% CI 72-85), and positive predictive value (PPV) of 74% (95% CI 67-81). Conversely, a benign EEG (defined as continuous and reactive background activity without seizure, periodic discharges, triphasic waves, or burst suppression) predicted favorable outcome with a specificity of 89% (95% CI 84-94), and a sensitivity of 37% (95% CI 30-45). CONCLUSION: The absence of EEG reactivity independently predicts unfavorable outcomes at one year in severe stroke patients requiring mechanical ventilation in the ICU, although its prognostic value remains limited. Conversely, a benign EEG pattern was associated with a favorable outcome.

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.

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.

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.

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.

Bicentre, randomized, parallel-arm, sham-controlled trial of transcranial direct-current stimulation (tDCS) in the treatment of palliative care patients with refractory cancer pain.

BACKGROUND: Pain is a common symptom in palliative care cancer patients and is often insufficiently relieved. In recent years, transcranial direct-current stimulation (tDCS) of the motor cortex has been shown to be effective to treat chronic pain, essentially neuropathic pain. We propose to test the efficacy of tDCS in patients experiencing cancer pain in the palliative care setting. METHOD/DESIGN: This article describes the protocol of a bicentre, randomized, parallel-arm, sham-controlled clinical trial evaluating tDCS in the treatment of palliative care patients with refractory cancer pain. Seventy patients between the ages of 18 and 80 years experiencing refractory pain with a pain score of 4/10 on a numerical rating scale (NRS) ranging from 0 to 10 will be enrolled in this trial. The main exclusion criteria are patients unable to fill in the various rating scales and life expectancy less than 3 weeks. Treatment consists of 5 consecutive tDCS sessions targeting the motor cortex (one daily session for 5 days) on the contralateral side to the pain. After randomization (1:1 ratio), 35 patients will receive active stimulation and 35 patients will receive sham stimulation. The primary endpoint is the NRS score and the primary objective is a significant improvement of this score between the baseline score recorded between D-3 and D-1 and the score recorded 4 days after stopping treatment (D8). The secondary objectives are to evaluate whether this improvement is maintained 16 days after stopping treatment (D21) and whether the following scores are improved on D14 and D21: Brief Pain Inventory, Edmonton Symptom Assessment System, Hospital Anxiety and Depression scale, State-Trait Anxiety Inventory and Medication Quantification Scale. DISCUSSION: Positive results of this trial would indicate that tDCS can improve pain and quality of life of cancer patients in the palliative care setting. Reduction of analgesic consumption and improvement of activities of daily living should allow many patients to return home with a decreased workload for caregivers.

Neuropathic Pain After Dental Implant Surgery: Literature Review and Proposed Algorithm for Medicosurgical Treatment.

The objective of this study is to establish an algorithm for the medicosurgical treatment of dental implant-induced neuropathic pain. The methodology was based on the good practice guidelines from the French National Authority for Health: the data were searched on the Medline database. A working group has drawn up a first draft of professional recommendations corresponding to a set of qualitative summaries. Consecutive drafts were amended by the members of an interdisciplinary reading committee. A total of 91 publications were screened, of which 26 were selected to establish the recommendations: 1 randomized clinical trial, 3 controlled cohort studies, 13 case series, and 9 case reports. In the event of the occurrence of post-implant neuropathic pain, a thorough radiological assessment by at least a panoramic radiograph (orthopantomogram) or especially a cone-beam computerized tomography scan is recommended to ensure that the tip of the implant is placed more than 4 mm from the anterior loop of the mental nerve for an anterior implant and 2 mm from the inferior alveolar nerve for a posterior implant. Very early administration of high-dose steroids, possibly associated with partial unscrewing or full removal of the implant preferably within the first 36-48 hours after placement, is recommended. A combined pharmacological therapy (anticonvulsants, antidepressants) could minimize the risk of pain chronicization. If a nerve lesion occurs in the context of dental implant surgery, treatment should be initiated within the first 36-48 hours after implant placement, including partial or full removal of the implant and early pharmacological treatment.

Resting-state electroencephalography (EEG) biomarkers of chronic neuropathic pain. A systematic review.

Diagnosis and management of chronic neuropathic pain are challenging, leading to current efforts to characterize 'objective' biomarkers of pain using imaging or neurophysiological techniques, such as electroencephalography (EEG). A systematic literature review was conducted in PubMed-Medline and Web-of-Science until October 2021 to identify EEG biomarkers of chronic neuropathic pain in humans. The risk of bias was assessed by the Newcastle-Ottawa-Scale. Experimental, provoked, or chronic non-neuropathic pain studies were excluded. We identified 14 studies, in which resting-state EEG spectral analysis was compared between patients with pain related to a neurological disease and patients with the same disease but without pain or healthy controls. From these heterogeneous exploratory studies, some conclusions can be drawn, even if they must be weighted by the fact that confounding factors, such as medication and association with anxio-depressive disorders, are generally not taken into account. Overall, EEG signal power was increased in the θ band (4-7Hz) and possibly in the high-ß band (20-30Hz), but decreased in the high-α-low-ß band (10-20Hz) in the presence of ongoing neuropathic pain, while increased γ band oscillations were not evidenced, unlike in experimental pain. Consequently, the dominant peak frequency was decreased in the θ-α band and increased in the whole-ß band in neuropathic pain patients. Disappointingly, pain intensity correlated with various EEG changes across studies, with no consistent trend. This review also discusses the location of regional pain-related EEG changes in the pain connectome, as the perspectives offered by advanced techniques of EEG signal analysis (source location, connectivity, or classification methods based on artificial intelligence). The biomarkers provided by resting-state EEG are of particular interest for optimizing the treatment of chronic neuropathic pain by neuromodulation techniques, such as transcranial alternating current stimulation or neurofeedback procedures.

3-T MR neurography of lumbo-sacral plexus in hereditary transthyretin-related amyloidosis with polyneuropathy.

OBJECTIVES: Our aim was to evaluate the ability of magnetic resonance neurography (MRN) of the lumbo-sacral plexus (LSP) to distinguish patients with hereditary transthyretin-related amyloidosis with polyneuropathy (ATTRv-PN) from asymptomatic variant carriers (AVC) and healthy controls and to assess its prognostic value. METHODS: Three-Tesla MRN was performed in 25 consecutive ATTRv-PN patients, 18 AVC, and 10 controls including T2-w DIXON and DWI MR sequences. Two blinded readers independently assessed LSP root diameter and intraneural signal on the MRN images of each subject. MRN findings were compared between groups and correlated with clinical impairment scored on the Neuropathy Impairment Score (NIS) and the modified Polyneuropathy Disability score (mPND). RESULTS: The agreement between readers on MRN images was excellent (Cohen's kappa = 0.82). LSP root enlargement was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 4.38, p = 0.038). Increased LSP root intraneural signal on T2-w images was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 3.4, p = 0.016). In contrast, there were no MRN abnormalities in controls. In ATTRv-PN patients, LSP root enlargement was associated with higher mPND scores (p = 0.03) and increased intraneural signal on T2-w images was associated with significantly higher NIS and mPND scores (p = 0.004 and 0.02, respectively). CONCLUSIONS: MRN of the LSP can help differentiate ATTRv-PN patients from AVC. LSP root enlargement and increased intraneural signal are significantly associated with clinical impairment, suggesting potential implications for patient care. KEY POINTS: • ATTRv-PN patients showed abnormal LSP changes on MRN. • MRN of the LSP can help to differentiate ATTRv-PN patients from AVC and healthy controls. • LSP root enlargement and increased intraneural signal were significantly associated with clinical impairment in ATTRv-PN patients.

Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

Diffusion tensor imaging MR neurography in patients with acute or chronic plexopathy.

The nerve plexus is susceptible to various pathological processes. In addition to clinical and electrophysiological findings, magnetic resonance neurography (MRN) may contribute to characterize plexus involvement. Diffusion tensor imaging (DTI) was reported feasible for the nerve plexuses imaging but its value in the clinical practice remains uncertain. From 2014 to 2020, we routinely performed MRN including DTI at 3T in patients with acute or chronic plexopathy. DTI images were co-registered with conventional MRN images. MRN images including DTI were reviewed by consensus by two neuroradiologists and one neurologist. They retrospectively identified cases for whom the use of DTI had a potential impact on the diagnostic workup, seven of these clinical cases are presented here. Compared to conventional MRN, the added value of DTI consisted in: (i) improved detection of signal/morphological abnormalities of the plexus (due to removal of background structures, multiplanar reformatted views and large field of view), (ii) additional information regarding the microarchitecture of nerve fibers provided by DTI metrics, (iii) potential alternative for the use of gadolinium. This case series supports the implementation of DTI in MRN protocols.

Neurofeedback therapy for the management of multiple sclerosis symptoms: current knowledge and future perspectives.

Fatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Affective manifestations are also of high prevalence in this population and can drastically impact the patients' functioning. A considerable proportion of patients with MS suffer from cognitive deficits affecting general and social cognitive domains. In addition, pain in MS is commonly observed in neurology wards, could be of different types, and may result from or be exacerbated by other MS comorbidities. These complaints tend to cluster together in some patients and seem to have a complex pathophysiology and a challenging management. Exploring the effects of new interventions could improve these outcomes and ameliorate the patients' quality of life. Neurofeedback (NFB) might have its place in this context by enhancing or reducing the activity of some regions in specific electroencephalographic bands (i.e., theta, alpha, beta, sensorimotor rhythm). This work briefly revisits the principles of NFB and its application. The published data are scarce and heterogeneous yet suggest preliminary evidence on the potential utility of NFB in patients with MS (i.e., depression, fatigue, cognitive deficits and pain). NFB is simple to adapt and easy to coach, and its place in the management of MS symptoms merits further investigations. Comparing different NFB protocols (i.e., cortical target, specific rhythm, session duration and number) and performing a comprehensive evaluation could help developing and optimizing interventions targeting specific symptoms. These aspects could also open the way for the association of this technique with other approaches (i.e., brain stimulation, cognitive rehabilitation, exercise training, psychotherapies) that have proved their worth in some MS domains.

Extracardiac soft tissue uptake, evidenced on early 99mTc-HMDP SPECT/CT, helps typing cardiac amyloidosis and demonstrates high prognostic value.

PURPOSE: Increased cardiac uptake (CU) on early-phase 99mTc-HMDP scintigraphy has demonstrated diagnostic and prognostic values in amyloid transthyretin (ATTR) cardiac amyloidosis (CA). Extracardiac uptake (ECU) has been poorly studied. We assessed the clinical value of ECU, in combination with CU, on 99mTc-HMDP scintigraphy using a novel Methodological Amyloidosis Diagnostic Index (MADI). METHODS: We reviewed all patients referred for suspicion of CA, who underwent 99mTc-HMDP scintigraphy over an 8-year period. ECU, CU, and MADI were determined: MADI0 = neither ECU or CU, MADI1 = ECU alone, MADI2 = CU alone, and MADI3 = ECU + CU. RESULTS: Of 308 eligible patients, 247 had CA, including 75 ATTRv, 107 ATTRwt, and 65 light-chain (AL), while 61 had another cardiopathy (controls). ECU was observed in 29% of CA and 3% of controls. Most frequent sites of ECU were pleuropulmonary (16% of CA, 3% of controls) followed by the digestive tract and subcutaneous tissues. The liver and spleen ECU was only observed in AL-CA (n = 8). CU was only observed in CA patients (n = 187), of whom 182 had ATTR-CA vs. 5 AL-CA, P < 0.001. MADI0 was only observed in controls (97%) and in AL-CA (60%). MADI1 was mainly observed in AL-CA (positive predictive value, PPV = 91%) while MADI2/3 were more frequent in ATTR-CA (PPV = 97%), P < 0.0001. MADI > 0 vs. MADI0 in AL and MADI3 vs. MADI2 in ATTR were associated with a worse prognosis (P = 0.03 and P = 0.002, respectively). CONCLUSIONS: ECU combined with CU demonstrates high diagnostic and prognostic values in CA patients. MADI seems an easy and reliable score in clinical practice.

Phosphorus magnetic resonance spectroscopy and fatigue in multiple sclerosis.

Fatigue stands among the most debilitating multiple sclerosis (MS) manifestations. Several pathophysiological mechanisms have been proposed at its origin. However, unmet needs still exist, and further investigations are required to better understand and manage this complaint. A new imaging modality-the phosphorous magnetic resonance spectroscopy (31P-MRS)-might help studying fatigue by allowing the measurement of energy metabolites of various cerebral regions. Therefore, this work aimed to explore the association between fatigue and brain energy status. Thirty MS patients with progressive disease forms completed the study. Their sociodemographic and clinical data including fatigue and disability scores [i.e., Fatigue Severity Scale (FSS) and Expanded Disability Status Scale (EDSS)] were collected. 31P-MRS spectra of (1) bilateral frontoparietal area and (2) centrum semiovale normal appearing white matter (NAWM) were obtained. Percentages of phosphocratine and ß-adenosine triphosphate (ß-ATP) were calculated. FSS scores were found to be directly correlated with the frontoparietal ß-ATP % (p < 0.05). However, there were no significant correlations between FSS scores and NAWM energy metabolites or clinical data (i.e., age, EDSS scores or disease duration). These findings point toward the existence of a link between fatigue severity and the amount of cerebral ATP metabolites. Such a link might reflect either a high production or low utilization of ATP, both of which were paralleled with increased fatigue perception. While the former would be due to a redistribution of ion channels along demyelinated axons and subsequent changes in mitochondrial activity; the latter could be interpreted in the light of neuronal loss which would lead to a decrease in ATP utilization and accumulation of its metabolites.

Characterization of Neuropathic Pain in Primary Sjögren's Syndrome with Respect to Neurophysiological Evidence of Small-Fiber Neuropathy.

OBJECTIVE: To determine whether clinical features of neuropathic pain differ with respect to the presence of small-fiber neuropathy (SFN) in patients with primary Sjögren's syndrome (pSS). METHODS: We compared the clinical presentation of neuropathic pain between 15 patients with pSS and SFN detected by neurophysiological tests (laser-evoked potentials, cold and warm detection thresholds, sympathetic skin responses, and electrochemical skin conductance) and 15 patients with pSS but no neurophysiological evidence of SFN. RESULTS: The patients with SFN had more intense squeezing and pressure sensations and more frequent dynamic mechanical allodynia (pain provoked by brushing) than the patients without SFN. Restless leg syndrome was also more frequently observed in patients with SFN, who had pain aggravated at rest that improved by moving. CONCLUSIONS: These findings are in favor of the sensitization of relatively spared large Aß-fibers and second-order nociceptive neurons in patients with SFN. On the other hand, burning sensations, which rather reveal sensitization of small nociceptive fibers, were observed whether SFN was present or not. Thus, some discriminating clinical features may help to suggest the presence of SFN in patients with pSS and chronic neuropathic pain.

The Clinical Features of Painful Small-Fiber Neuropathy Suggesting an Origin Linked to Primary Sjögren's Syndrome.

OBJECTIVE: We attempted to determine whether clinical features could differentiate painful small-fiber neuropathy related to primary Sj€ogren's syndrome (pSS-SFN) from idiopathic SFN (idio-SFN). METHODS: Validated clinical questionnaires and neurophysiological investigations specific for pain and SFN assessment were performed in 25 patients with pSS-SFN and 25 patients with idio-SFN. RESULTS: Patients with idio-SFN had more frequent severe burning sensations and higher mean anxiety scores and daily pain intensity compared to patients with pSSSFN. Conversely, patients with pSS-SFN had reduced electrochemical skin conductance measured by Sudoscan_, and almost half of them had the sensation of walking on cotton wool. CONCLUSION: Our results suggest that idio-SFN more specifically involved small sensory fibers than pSS-SFN, in which subtle dysfunction of larger sensory fibers and damage of distal autonomic sudomotor innervation may occur. A practical algorithm is proposed to help to differentiate SFN associated with pSS from idio-SFN, based on information very easy to obtain by clinical interview.

N-hexane exposure: a cause of small fiber neuropathy.

A 59-year-old woman presented with progressive paresthesias of all of her limbs for 4 years, associated with neuropathic pain, tingling in the tongue and allodynia, consistent with small fiber neuropathy (SFN). Several systemic symptoms and signs were found on clinical examination and laboratory work-up. Neurological investigations including neurophysiologic test and skin biopsy supported the diagnosis of SFN. Chronic exposure to N-hexane was then disclosed and suspected to be the cause of the disease. Following the discontinuation of chronic N-hexane exposure, the patient had a progressive improvement of all signs and symptoms, reinforcing the correlation between exposure to N-hexane, and development of SFN. Exposure to N-hexane may be considered as a novel reversible cause of SFN, which underlines the need to look for toxic etiologies in the diagnosis of SFN.

Face transplant: long-term follow-up and results of a prospective open study.

BACKGROUND: More than 30 face transplantations have been done worldwide since 2005 but no documented long-term follow-up has been reported in the literature. We aimed to answer remaining question about the long-term risks and benefits of face transplant. METHODS: In this single-centre, prospective, open study, we assessed 20 patients presenting with facial defects. Ten patients were selected, and, after three were secondarily excluded, seven were transplanted: two with neurofibromatosis 1, one with a burn, and four with self-inflicted facial gunshot injuries. We report the long-term outcomes of six face allotransplant recipients at an average of 6 years (range 3·4-9 years) after the transplantation. All admissions to hospital except for planned revisions and immunosuppressive follow-up therapy were reported as adverse events (safety endpoint). Predefined immunological, metabolic, surgical, and social integration endpoints were collected prospectively. Patients underwent quantitative health-related quality of life assessments through Short Form 36 health questionnaires. This study was registered with ClinicalTrials.gov, number NCT00527280. FINDINGS: Two of seven patients died: one at 65 days due to transplant destruction with concomitant pseudomonas infection and the second at 3·4 years after transplantation by suicide. The six patients alive at long-term follow-up presented with functional transplants. Safety endpoints were related to infection in the first month, acute rejection from 1 day to 7 years after transplantation, or side-effects of immunosuppressive therapy. Recurrent rejection episodes justified maintenance therapy with high-dose steroids at high levels in all patients at last follow-up, yet none of the patients developed diabetes. Three patients were found to have hypertension with one requiring therapy. All patients had a noticeable reduction in glomerular filtration rate. All recipients and their families accepted their transplant. Improvements in social integration and quality of life were highly variable among the patients and depended on baseline levels and psychiatric comorbidities. INTERPRETATION: These long-term results show the crucial effect of patients' social support and pre-existing psychiatric conditions on the risk-benefit ratio of facial transplantation. Careful preoperative patient selection and long-term postoperative follow-up programmes under strict institutional review board controls should be used for any future grafts of this type. FUNDING: Protocole Hospitalier de Recherche Clinique (PHRC) National.

Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial.

LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. METHODS: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. RESULTS: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.