Efgartigimod in refractory autoimmune myasthenia gravis.

INTRODUCTION/AIMS: Efgartigimod, a neonatal Fc-receptor inhibitor, has recently been approved as treatment for myasthenia gravis (MG). In this retrospective cohort study, we aimed to systematically assess short- and long-term effectiveness of efgartigimod in patients with refractory MG. METHODS: Sixteen patients with refractory autoimmune acetylcholine receptor MG were treated with efgartigimod. Data were collected from January 2021 to March 2023 on Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis score (QMG), Myasthenia Gravis Composite score (MGC) and the 15-item revised version of the Myasthenia Gravis Quality of Life questionnaire (MG-QoL15r). RESULTS: A favorable outcome was seen in 56% of patients at the last measurement. Out of 16 patients, 50% were an MG-ADL responder after the first treatment cycle. After 4 weeks, a clinically meaningful improvement compared to baseline was seen on the MG-ADL, QMG, and MGC. There was a statistically significant improvement on the MGQoL15r from baseline to week 4. The improvement was maintained until the last measurement for the MGC and the MGQoL15r. At the last visit, all patients had discontinued 4-weekly dosages, shifting to administration frequencies of 1, 2, or 3 weeks. Drug doses could be decreased for prednisolone (n = 7), azathioprine (n = 2), and intravenous immunoglobulin (n = 9). Frequency of plasma exchange was decreased in nine patients. DISCUSSION: In patients with refractory MG, efgartigimod was effective for at least half of all patients. Patients required more frequent dosing compared to the ADAPT phase 3 trial. In 80% of the patients concurrent medication could be reduced or discontinued.

Diagnosing myasthenia gravis using orthoptic measurements: assessing extraocular muscle fatiguability.

INTRODUCTION: Diagnosing ocular myasthenia gravis (MG) can be challenging because serum antibodies are often not detected. We aimed to explore whether determining extraocular muscle (EOM) weakness using orthoptic measures, including an adapted Hess chart examination, can aid in diagnosing MG. METHODS: We conducted a prospective study among patients with acetylcholine receptor antibody positive MG (20 recently diagnosed, 19 chronic) and 14 seronegative MG patients. We compared orthoptic measures to 19 healthy and 18 disease controls with Graves orbitopathy, chronic progressive external ophthalmoplegia or oculopharyngeal muscular dystrophy. Maximal eye duction angles were measured using a synoptophore. Gaze deviations between eyes were measured using standard Hess chart examination with addition of 1 min persistent gaze to assess MG-associated fatiguability. Receiver operating characteristics curve analysis was performed. RESULTS: For duction angles, the area under the curve (AUC) was 0.73 comparing MG to healthy, and 0.69 comparing to patient controls. For the outer field of the Hess chart, the AUC was 0.89 comparing to healthy and 0.54 to patient controls. For drift, the AUC was 0.93 comparing to healthy and 0.93 to patient controls. The sensitivity and specificity of the presence of drift was 81% and 100%. DISCUSSION: Orthoptic measurements can be used to diagnose MG by quantifying EOM weakness and fatiguability. Drift during persistent gaze on a Hess chart is specific for MG and could be used for diagnostic purposes. The Hess chart examination is widely available, inexpensive and fast. Moreover, orthoptic measurements may be a clinically relevant outcome measure for clinical trials.

Optimal timing of needle electromyography to diagnose lesion severity in traumatic radial nerve injury.

INTRODUCTION/AIMS: In patients with traumatic radial nerve injury (RNI), the chance of spontaneous recovery must be balanced against the benefits of early surgical reconstruction. We aimed to explore the time-specific value of needle electromyography (NEMG) to diagnose nerve lesion severity. METHODS: In this retrospective diagnostic accuracy study at Leiden Nerve Center, patients at least 12 years of age with RNI caused by fractures or fracture treatment were included. The sensitivity and specificity of the patients' first NEMG examination were assessed, stratified by the timing after the nerve injury. The absence of motor unit potentials (MUPs) in muscles distal to the nerve lesion was considered a positive test result. Lesion severity was dichotomized to moderate injury (spontaneous Medical Research Council grade ≥3 recovery) or severe injury (poor spontaneous recovery or surgical confirmation of a mainly neurotmetic lesion). RESULTS: Ninety-five patients were included in our study. The sensitivity of NEMG to detect severe RNI was 75.0% (3 of 4) in the fourth, 66.7% (2 of 3) in the fifth, and 66.7% (2 of 3) in the sixth month after the nerve injury. The specificity in the first to the sixth month was 0.0% (0 of 1), 50.0% (2 of 4), 77.3% (17 of 22), 95.5% (21 of 22), 95.8% (23 of 24), and 100.0% (12 of 12), respectively. DISCUSSION: The specificity of NEMG is higher than 95% and therefore clinically relevant from the fourth month after the nerve injury onward. Absence of MUPs at this time can be considered an indication to plan nerve exploration. Moreover, the presence of MUPs on NEMG does not completely exclude the necessity for surgical reconstruction.

Warm ears, a red flag for sleepiness?

Core body and skin temperatures are intimately linked to sleep and alertness. The distal-to-proximal skin temperature gradient has been described as a good physiological predictor for sleep onset. Increased ear skin temperature is often caused by increased blood flow reflected in redness, which is commonly noticed in people who are sleepy, especially anecdotally in children. Nonetheless, no prior study investigated the possible relation between sleepiness and ear skin temperature as a separate measurement. We assessed the relation between ear skin temperature and sleepiness in patients undergoing regular electroencephalographic examinations, because of suspicion of epilepsy, both without and after sleep deprivation. Subjective sleepiness was measured using the Stanford Sleepiness Scale, and objective sleepiness by determining sleep onset with electroencephalography. Distal, proximal and ear skin temperature were measured repeatedly using wireless measurement devices (iButtons). Forty-four adult patients were included. Ear skin temperature correlates weakly with distal skin temperature (r = 0.174, p < 0.001) and distal-to-proximal gradient (r = 0.160, p < 0.001), but not with proximal skin temperature (r = -0.001, p = 0.975). Ear skin temperature increased significantly in a subgroup of 13 patients, between 5 and 1 min before sleep onset (p = 0.002; η2  = 0.059), even though this increase was also associated with supine posture. iButtons is a valid method to measure ear skin temperature, which appears to function partly like a distal and partly like a proximal skin temperature measurement. Change in ear skin temperature is associated with sleep onset and supine posture.

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra-ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye-motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2water ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2water values were determined in 12 HC (aged 22-65 years), 11 MG (aged 28-71 years) and six GO (aged 28-64 years) patients at 7 T using Dixon and multi-echo spin-echo sequences. The EOM were semi-automatically 3D-segmented by two independent observers. MANOVA and t-tests were used to assess differences in FF, T2water and volume of EOM between groups (P < .05). Bland-Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was -0.7% (LoA: ±2.1%) for the different observers; the bias in FF was -0.3% (LoA: ±2.8%) and 0.03 cm3 (LoA: ± 0.36 cm3 ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm3 ) and MG (0.8 ± 0.2 cm3 ) compared with HC (0.6 ± 0.2 cm3 ). The average T2water for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2water was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.

Preoperative Electroencephalography-Based Machine Learning Predicts Cognitive Deterioration After Subthalamic Deep Brain Stimulation.

BACKGROUND: Subthalamic deep brain stimulation (STN DBS) may relieve refractory motor complications in Parkinson's disease (PD) patients. Despite careful screening, it remains difficult to determine severity of alpha-synucleinopathy involvement which influences the risk of postoperative complications including cognitive deterioration. Quantitative electroencephalography (qEEG) reflects cognitive dysfunction in PD and may provide biomarkers of postoperative cognitive decline. OBJECTIVE: To develop an automated machine learning model based on preoperative EEG data to predict cognitive deterioration 1 year after STN DBS. METHODS: Sixty DBS candidates were included; 42 patients had available preoperative EEGs to compute a fully automated machine learning model. Movement Disorder Society criteria classified patients as cognitively stable or deteriorated at 1-year follow-up. A total of 16,674 EEG-features were extracted per patient; a Boruta algorithm selected EEG-features to reflect representative neurophysiological signatures for each class. A random forest classifier with 10-fold cross-validation with Bayesian optimization provided class-differentiation. RESULTS: Tweny-five patients were classified as cognitively stable and 17 patients demonstrated cognitive decline. The model differentiated classes with a mean (SD) accuracy of 0.88 (0.05), with a positive predictive value of 91.4% (95% CI 82.9, 95.9) and negative predictive value of 85.0% (95% CI 81.9, 91.4). Predicted probabilities between classes were highly differential (hazard ratio 11.14 [95% CI 7.25, 17.12]); the risk of cognitive decline in patients with high probabilities of being prognosticated as cognitively stable (>0.5) was very limited. CONCLUSIONS: Preoperative EEGs can predict cognitive deterioration after STN DBS with high accuracy. Cortical neurophysiological alterations may indicate future cognitive decline and can be used as biomarkers during the DBS screening. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Combining timed GDNF and ChABC gene therapy to promote long-distance regeneration following ventral root avulsion and repair.

Ventral root avulsion leads to severe motoneuron degeneration and prolonged distal nerve denervation. After a critical period, a state of chronic denervation develops as repair Schwann cells lose their pro-regenerative properties and inhibitory factors such as CSPGs accumulate in the denervated nerve. In rats with ventral root avulsion injuries, we combined timed GDNF gene therapy delivered to the proximal nerve roots with the digestion of inhibitory CSPGs in the distal denervated nerve using sustained lentiviral-mediated chondroitinase ABC (ChABC) enzyme expression. Following reimplantation of lumbar ventral roots, timed GDNF-gene therapy enhanced motoneuron survival up to 45 weeks and improved axonal outgrowth, electrophysiological recovery, and muscle reinnervation. Despite a timed GDNF expression period, a subset of animals displayed axonal coils. Lentiviral delivery of ChABC enabled digestion of inhibitory CSPGs for up to 45 weeks in the chronically denervated nerve. ChABC gene therapy alone did not enhance motoneuron survival, but led to improved muscle reinnervation and modest electrophysiological recovery during later stages of the regeneration process. Combining GDNF treatment with digestion of inhibitory CSPGs did not have a significant synergistic effect. This study suggests a delicate balance exists between treatment duration and concentration in order to achieve therapeutic effects.

T2 relaxation-time mapping in healthy and diseased skeletal muscle using extended phase graph algorithms.

PURPOSE: Multi-echo spin-echo (MSE) transverse relaxometry mapping using multi-component models is used to study disease activity in neuromuscular disease by assessing the T2 of the myocytic component (T2water ). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T2fat calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice-selection flip angle profile, a through-plane chemical-shift displacement correction, and optimized calibration of T2fat . METHODS: Simulation experiments were used to study the influence of the slice flip-angle profile with chemical-shift and T2fat estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T2fat calibration methods and T2water estimations. RESULTS: Excluding slice flip-angle profiles or chemical-shift displacement resulted in a bias in T2water up to 10 ms. Furthermore, a wrongly calibrated T2fat caused a bias of up to 4 ms in T2water . For the in vivo data, one-component calibration led to a lower T2fat compared with a two-component method, and T2water decreased with increasing fat fractions. CONCLUSION: In vivo data showed a decline in T2water for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph-based model for fitting T2water from MSE sequences with two-component T2fat calibration. Moreover, we recommend including the slice flip-angle profile in the model with correction for through-plane chemical-shift displacements.

Lowering the cutoff value for increment increases the sensitivity for the diagnosis of Lambert-Eaton myasthenic syndrome.

BACKGROUND: Increment of compound muscle action potential amplitude is a diagnostic hallmark of Lambert-Eaton myasthenic syndrome (LEMS). Making a diagnosis can be challenging, therefore, a proper cutoff for abnormal increment is highly relevant for improved recognition of this rare disease. METHODS: We determined the sensitivity and specificity of 60% and 100% cutoff values in all consecutive patients who underwent increment testing in our hospital from 1999 to 2016. RESULTS: We included 156 patients, 63 with LEMS and 93 without LEMS. Sensitivity of a 60% cutoff for increment testing was 77.8% (95% confidence interval 65.5%-87.3%) and 58.7% (45.6%-71.0%) for 100%. Specificity was 98.9% (94.2%-100%) and 100% (96.1%-100%) using a threshold of 60% and 100%, respectively. CONCLUSIONS: Lowering the cutoff value for abnormal increment to 60% greatly increases sensitivity to diagnose LEMS without an overt loss in specificity.

Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration.

Neurosurgical repair in patients with proximal nerve lesions results in unsatisfactory recovery of function. Gene therapy for neurotrophic factors is a powerful strategy to promote axon regeneration. Glial cell line-derived neurotrophic factor (GDNF) gene therapy promotes motor neuron survival and axon outgrowth; however, uncontrolled delivery of GDNF results in axon entrapment. We report that time-restricted GDNF expression (1 month) using an immune-evasive doxycycline-inducible gene switch attenuated local axon entrapment in avulsed reimplanted ventral spinal roots, was sufficient to promote long-term motor neuron survival (24 weeks) and facilitated the recovery of compound muscle action potentials by 8 weeks. These improvements were associated with an increase in long-distance regeneration of motor axons. In contrast, persistent GDNF expression impaired axon regeneration by inducing axon entrapment. These findings demonstrate that timed expression can resolve the deleterious effect of uncontrolled growth factor delivery and shows that inducible growth factor gene therapy can be employed to enhance the efficacy of axon regeneration after neurosurgical repair of a proximal nerve lesion in rats. This preclinical study is an important step in the ongoing development of a neurotrophic factor gene therapy for patients with severe proximal nerve lesions.

A systematic review of MEG-based studies in Parkinson's disease: The motor system and beyond.

Parkinson's disease (PD) is accompanied by functional changes throughout the brain, including changes in the electromagnetic activity recorded with magnetoencephalography (MEG). An integrated overview of these changes, its relationship with clinical symptoms, and the influence of treatment is currently missing. Therefore, we systematically reviewed the MEG studies that have examined oscillatory activity and functional connectivity in the PD-affected brain. The available articles could be separated into motor network-focused and whole-brain focused studies. Motor network studies revealed PD-related changes in beta band (13-30 Hz) neurophysiological activity within and between several of its components, although it remains elusive to what extent these changes underlie clinical motor symptoms. In whole-brain studies PD-related oscillatory slowing and decrease in functional connectivity correlated with cognitive decline and less strongly with other markers of disease progression. Both approaches offer a different perspective on PD-specific disease mechanisms and could therefore complement each other. Combining the merits of both approaches will improve the setup and interpretation of future studies, which is essential for a better understanding of the disease process itself and the pathophysiological mechanisms underlying specific PD symptoms, as well as for the potential to use MEG in clinical care.

Outcome of Carpal Tunnel Release and the Relation With Depression.

PURPOSE: To examine the relation between depressive symptoms and outcome of carpal tunnel release (CTR). METHODS: Prospective study in a general hospital with data collection at baseline and 3 and 12 months after CTR. We quantified depressive symptoms using the Center for Epidemiologic Studies Depression (CES-D) scale and performed multivariable analyses on 2 outcome measures: (1) carpal tunnel syndrome (CTS) symptoms (Boston Carpal Tunnel Questionnaire [BCTQ]) and (2) palmar pain, focusing on preoperative CES-D and BCTQ score, sex, age, alcohol use, diabetes, and severity of nerve conduction abnormalities. RESULTS: We included 227 patients. Before surgery, patients with depression had a higher BCTQ score than patients without depression. After 1 year, depressed patients had a higher BCTQ score and more palmar pain. The CES-D decreased by a median of 2 points from baseline to 1 year. This correlated with the decrease in BCTQ score. Multivariable analyses showed that preoperative depression had a small but statistically significant influence on palmar pain, but not on postoperative BCTQ score. CONCLUSIONS: Depression is not an independent predictor of residual CTS symptoms 1 year after CTR. Depressive symptoms in patients with CTS decrease after CTR, along with a decrease in CTS symptoms. The nature of this relationship is unknown. Patients with CTS and depression may expect a somewhat higher degree of palmar pain after CTR, the clinical relevance of which is small. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Activity limitations in myasthenia gravis and relation to clinical variables.

INTRODUCTION: It is unknown how fluctuations in muscle weakness affect activity limitations in myasthenia gravis patients and how the severity of these limitations compares with published data on other neuromuscular disorders (NMD). METHODS: In this study we analyzed ACTIVLIM (acronym of "ACTIVity LIMitations") and quantitative myasthenia gravis (QMG) scores. We assessed the impact of QMG and other clinical variables on ACTIVLIM, using B coefficients. RESULTS: The mean ACTIVLIM score in 118 MG patients was 3.3. There was a correlation between QMG and ACTIVLIM (B coefficient = -0.206, P < 0.001) and between changes in both scores (B coefficient = -0.175, P = 0.002). Men and patients without another autoimmune disease had a better ACTIVLIM score (B coefficient = 0.785, P = 0.015 and B coefficient = 0.998, P = 0.008, respectively). CONCLUSIONS: The ACTIVLIM score in MG is higher than in other NMD. Fluctuations in QMG correlated significantly with changes in ACTIVLIM. Muscle Nerve 56: 64-70, 2017.

Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion.

Root avulsions due to traction to the brachial plexus causes complete and permanent loss of function. Until fairly recent, such lesions were considered impossible to repair. Here we review clinical repair strategies and current progress in experimental ventral root avulsion lesions. The current gold standard in patients with a root avulsion is nerve transfer, whereas reimplantation of the avulsed root into the spinal cord has been performed in a limited number of cases. These neurosurgical repair strategies have significant benefit for the patient but functional recovery remains incomplete. Developing new ways to improve the functional outcome of neurosurgical repair is therefore essential. In the laboratory, the molecular and cellular changes following ventral root avulsion and the efficacy of intervention strategies have been studied at the level of spinal motoneurons, the ventral spinal root and peripheral nerve, and the skeletal muscle. We present an overview of cell-based pharmacological and neurotrophic factor treatment approaches that have been applied in combination with surgical reimplantation. These interventions all demonstrate neuroprotective effects on avulsed motoneurons, often accompanied with various degrees of axonal regeneration. However, effects on survival are usually transient and robust axon regeneration over long distances has as yet not been achieved. Key future areas of research include finding ways to further extend the post-lesion survival period of motoneurons, the identification of neuron-intrinsic factors which can promote persistent and long-distance axon regeneration, and finally prolonging the pro-regenerative state of Schwann cells in the distal nerve.

The Tinel sign has no diagnostic value for nerve entrapment or neuropathy in the legs.

INTRODUCTION: The presence of a Tinel sign in leg nerves has been proposed as a criterion for decompressive surgery in polyneuropathy. We investigated the diagnostic yield of the Tinel sign for nerve entrapment and for distal symmetrical peripheral neuropathy (DSPN). METHODS: We prospectively tested for the Tinel sign at 3 sites of possible nerve entrapment per leg in 91 patients. Entrapment was defined using nerve conduction data. We also investigated whether the number of sites at which the Tinel sign was present identified patients with DSPN. RESULTS: Sensitivity of the Tinel sign for nerve entrapment was low (29%, 44%, and 17%) for the 3 sites, and specificity was moderate (86%, 75%, and 81%). In the subgroup with DSPN, sensitivity was extremely low (0%, 20%, and 8%), and specificity was moderate (91%, 79%, and 73%). The number of sites with a Tinel sign did not identify patients with DSPN. CONCLUSION: The Tinel sign does not reliably indicate nerve entrapment or DSPN. Muscle Nerve 54: 25-30, 2016.

The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes.

Syncope is defined as transient loss of consciousness as a result of cerebral hypoperfusion. Electroencephalography during syncope shows either a 'slow-flat-slow' or a 'slow' pattern. The first is believed to denote more severe hypoperfusion. Although the diagnosis of vasovagal syncope relies primarily on history taking, there is limited evidence regarding the relative importance of various clinical features, and none that relate them to the severity of electroencephalographic changes. The aim of this investigation was to study symptoms, signs and electroencephalographic changes with a 1 s resolution using electroencephalography and video data in 69 cases of tilt-induced vasovagal syncope. The main finding was that flattening of the electroencephalograph indicated more profound circulatory changes: the 'slow-flat-slow' group had a lower minimum blood pressure, longer maximum RR-interval, contained more cases with asystole and had a longer duration of loss of consciousness than the 'slow' group. Second, we describe a range of signs, including some that have rarely been reported in syncope, e.g. oral automatisms. Third, signs occurred at different rates depending on electroencephalographic flattening, suggesting a classification of syncopal signs. Type A signs (e.g. loss of consciousness, eye opening and general stiffening) develop during the first slow phase, stay present during flattening and stop in the second slow phase. Type B (particularly myoclonic jerks) occur when the electroencephalograph is slow but not flat: their abolition with electroencephalographic flattening suggests dependence on cortical activity. Type C signs (making sounds, roving eye movements and stertorous breathing) occur only in the flat phase, whereas type D (dropping the jaw and snoring) may occur either in slow or flat phases. In conclusion, our findings provide a detailed assessment of clinical symptoms in relation to electroencephalographic (EEG) changes during tilt-induced syncope.

Myasthenia gravis-Pathophysiology, diagnosis, and treatment.

Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction of the neuromuscular junction resulting in skeletal muscle weakness. It is equally prevalent in males and females, but debuts at a younger age in females and at an older age in males. Ptosis, diplopia, facial bulbar weakness, and limb weakness are the most common symptoms. MG can be classified based on the presence of serum autoantibodies. Acetylcholine receptor (AChR) antibodies are found in 80%-85% of patients, muscle-specific kinase (MuSK) antibodies in 5%-8%, and <1% may have low-density lipoprotein receptor-related protein 4 (Lrp4) antibodies. Approximately 10% of patients are seronegative for antibodies binding the known disease-related antigens. In patients with AChR MG, 10%-20% have a thymoma, which is usually detected at the onset of the disease. Important differences between clinical presentation, treatment responsiveness, and disease mechanisms have been observed between these different serologic MG classes. Besides the typical clinical features and serologic testing, the diagnosis can be established with additional tests, including repetitive nerve stimulation, single fiber EMG, and the ice pack test. Treatment options for MG consist of symptomatic treatment (such as pyridostigmine), immunosuppressive treatment, or thymectomy. Despite the treatment with symptomatic drugs, steroid-sparing immunosuppressants, intravenous immunoglobulins, plasmapheresis, and thymectomy, a large proportion of patients remain chronically dependent on corticosteroids (CS). In the past decade, the number of treatment options for MG has considerably increased. Advances in the understanding of the pathophysiology have led to new treatment options targeting B or T cells, the complement cascade, the neonatal Fc receptor or cytokines. In the future, these new treatments are likely to reduce the chronic use of CS, diminish side effects, and decrease the number of patients with refractory disease.

New phenotyping questionnaire for diagnosing sarcoidosis-associated small fiber neuropathy.

Small fiber neuropathy is a common complication in patients with sarcoidosis and its prevalence is estimated at 40-86%. The underlying mechanism influences the presentation of small fiber neuropathy. For example, patients with metabolic diseases are often associated with a classic length-dependent small fiber neuropathy pattern, while patients with inflammatory diseases are more often present with a non-length-dependent small fiber neuropathy. Detailed phenotyping may be useful to improve diagnostic efficiency, as a clue to underlying mechanisms and as a precondition for personalized medicine. This study examined four phenotypes distinguishing between length-dependent and non-length-dependent presentation with a new subdivision for continuous and intermittent presentation. Forty-eight sarcoid patients with symptoms and at least two clinical signs of small fiber neuropathy and normal nerve conduction studies were classified as having probable small fiber neuropathy. A new small fiber neuropathy phenotyping questionnaire has been developed that allows patients to mark the anatomical locations of pain at three different levels: the skin, muscles, and joints. The location of symptoms was used to define length dependence, and two colors were used to distinguish continuous (red) from intermittent (blue) symptoms. In addition, skin biopsy, corneal confocal microscopy, Sudoscan and water immersion skin wrinkling were used to investigate a correlation between the four phenotypes, sensory function, nerve fiber density, and autonomic nerve function. Overall, 35% of patients with probable small fiber neuropathy showed length-dependent symptoms and 44% showed non-length-dependent symptoms while 21% suffered from non-neuropathic musculoskeletal pain. The distinction between intermittent and continuous symptoms showed significantly less continuous than intermittent non-length-dependent symptoms (odds ratio = 0.3, P = 0.01). Moreover, continuous length-dependent symptoms were the only phenotype that correlated with thermal threshold testing (R = 0.3; P = 0.02) and the small fiber neuropathy screening list (R = 0.3; P = 0.03). In addition, thermal threshold testing (TTT) also correlated with the small fiber neuropathy (SFN) screening list (R = 0.3; P = 0.03). Other diagnostic methods showed no correlation with any of the four defined phenotypes. A novel finding is that TTT is only associated with continuous length-dependent pain, suggesting that TTT could result in more false negatives in patients with other pain phenotypes. Determining the pathophysiologic mechanisms could help develop new diagnostic methods. If patients suspected of SFN show symptoms without a length-dependent continuous presentation, the diagnosis should focus less on the diagnostic methods used.

ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density.

Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD.

Fully Automatic, Semiautomatic, and Manual Corneal Nerve Fiber Analysis in Patients With Sarcoidosis.

Purpose: No guidelines are available on the preferred method for analyzing corneal confocal microscopy (CCM) data. Manual, semiautomatic, and automatic analyzes are all currently in use. The purpose of the present study was threefold. First, we aimed to investigate the different methods for CCM analysis in patients with and without small fiber neuropathy (SFN). Second, to determine the correlation of different methods for measuring corneal nerve fiber length (CNFL) and nerve fiber area (NFA). Finally, we investigated the added value of automatic NFA analysis. Methods: We included 20 healthy controls and 80 patients with sarcoidosis, 31 with established SFN and 49 without SFN. The CNFL was measured using CCMetrics, ACCMetrics, and NeuronJ. NFA was measured with NFA FIJI and ACCMetrics NFA. Results: CNFL and NFA could not distinguish sarcoidosis with and without SFN or healthy controls. CCMetrics, NeuronJ, and ACCMetrics CNFL highly correlated. Also, NFA FIJI and ACCMetrics NFA highly correlated. Reproducing a nonlinear formula between CNFL and NFA confirmed the quadratic relation between NFA FIJI and ACCMetrics CNFL. CCMetrics and NeuronJ instead showed a square root relationship and seem to be less comparable owing to differences between automatic and manual techniques. Conclusions: ACCMetrics can be used for fully automatic analysis of CCM images to optimize efficiency. However, CNFL and NFA do not seem to have a discriminatory value for SFN in sarcoidosis. Further research is needed to determine the added value and normative values of NFA in CCM analysis. Translational Relevance: Our study improves the knowledge about CCM software and pathophysiology of SFN.