Search

Background and ObjectivesTo longitudinally investigate patients with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), quantifying timing and location of sensory involvements in motor onset patients, along with clinicohistopathologic and electrophysiologic findings to ascertain differences in patients with and without monoclonal gammopathy of uncertain significance (MGUS).MethodsPatients with MADSAM seen at Mayo Clinic and tested for monoclonal gammopathy and ganglioside antibodies were retrospectively reviewed (January 1, 2007–December 31, 2018).ResultsOf 76 patients with MADSAM, 53% had pure motor, 16% pure sensory, 30% sensorimotor, and 1% cranial nerve onsets. Motor-onset patients were initially diagnosed with multifocal motor neuropathy (MMN). MGUS occurred in 25% (89% immunoglobulin M [IgM] subtype), associating with ganglioside autoantibodies (p < 0.001) and higher IgM titers (p < 0.04). Median time to sensory involvements (confirmed by electrophysiology) in motor onset patients was 18 months (range 6–180). Compared to initial motor nerve involvements, subsequent sensory findings were within the same territory in 35% (14/40), outside in 20% (8/40), or both in 45% (18/40). Brachial and lumbosacral plexus MRI was abnormal in 87% (34/39) and 84% (21/25), respectively, identifying hypertrophy and increased T2 signal predominantly in brachial plexus trunks (64%), divisions (69%), and cords (69%), and intrapelvic sciatic (64%) and femoral (44%) nerves. Proximal fascicular nerve biopsies (n = 9) more frequently demonstrated onion-bulb pathology (p = 0.001) and endoneurial inflammation (p = 0.01) than distal biopsies (n = 17). MRI and biopsy findings were similar among patient subgroups. Initial Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores were higher in patients with MGUS relative to without (p = 0.02). Long-term treatment responsiveness by INCAT score reduction ≥1 or motor Neuropathy Impairment Score (mNIS) >8-point reduction occurred in 75% (49/65) irrespective of MGUS or motor onsets. Most required ongoing immunotherapy (86%). Patients with MGUS more commonly required dual-agent immunotherapy for stability (p = 0.02).DiscussionPure motor onsets are the most common MADSAM presentation. Long-term follow-up, repeat electrophysiology, and nerve pathology help distinguish motor onset MADSAM from MMN. Better long-term immunotherapy responsiveness occurs in motor onset MADSAM compared to MMN reports. Patients with MGUS commonly require dual immunotherapy.Classification of EvidenceThis study provides Class II evidence that most clinical, electrophysiologic, and histopathologic findings were similar between patients with MADSAM with and without MGUS.

ObjectiveSensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features.MethodsCISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986–2019).ResultsWe identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46).ConclusionThe recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.

ObjectiveTo determine whether patients in the community with lumbosacral radiculoplexus neuropathy (LRPN) have milder neuropathy than referral patients, we characterized the outcomes and survival of population-based compared to referral-based LRPN cohorts.BackgroundPreviously, we found that the incidence of LRPN is 4.16/100,000/y, a frequency greater than other inflammatory neuropathies. The survival of patients with LRPN is uncharacterized.MethodsSixty-two episodes in 59 patients with LRPN were identified over 16 years (2000–2015). Clinical findings were compared to previous referral-based LRPN cohorts. Survival data were compared to those of age- and sex-matched controls.ResultsAt LRPN diagnosis, median age was 70 years, median Neuropathy Impairment Score (NIS) 22 points, 92% had pain, 95% had weakness, 23% were wheelchair-bound, and median modified Rankin Scale score (mRS) was 3 (range 1–4). At last follow-up, median NIS improved to 17 points (p < 0.001) with 56% having ≥4 points improvement, 16% were wheelchair-bound, and median mRS was 2. Compared to referral-based LRPN cohorts, community patients with LRPN had less impairment, less bilateral disease (37% vs 92%), and less wheelchair usage (23% vs 49%). LRPN survival was 86% at 5 years and 55% at 10 years. Compared to age- and sex-matched controls, patients with LRPN had 76% increased risk of death (p = 0.016). In multivariate analysis, diabetes, age, stroke, chronic kidney disease, peripheral artery disease, and coronary artery disease were significant mortality risk factors but LRPN was not.ConclusionLRPN is a painful, paralytic, asymmetric, monophasic, sometimes bilateral pan-plexopathy that improves over time but leaves patients with impairment. Although having LRPN increases mortality, this increase is probably due to comorbidities (diabetes) rather than LRPN itself.

Introduction AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients. Methods/Design Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life—Diabetic Neuropathy questionnaire. Conclusion NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN. Trial Registration The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10). Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00235-6., Plain Language Summary Hereditary transthyretin amyloidosis with peripheral neuropathy (hATTR-PN for short) is a rare inherited condition.In hATTR-PN, a protein called transthyretin (TTR for short) builds up and damages nerves throughout the body.This neuropathy causes symptoms such as weakness, loss of sensation, and pain.Currently available medicines can slow disease progression, but researchers are looking for more effective treatments with fewer side effects.AKCEA-TTR-LRx is an investigational treatment for hATTR-PN.AKCEA-TTR-LRx prevents the liver from making TTR, reducing the amount that causes disease progression.It is similar to an existing treatment called inotersen, but designed for better delivery to the liver and is more potent.This article describes the NEURO-TTRansform study that will evaluate how effective AKCEA-TTR-LRx is for treating hATTR-PN.Around 140 adults with hATTR-PN from the USA, Canada, and Europe will be able to take part in this study.The study treatment period will be 85 weeks long. People will receive injections underneath the skin of either:AKCEA-TTR-LRx every 4 weeks, orInotersen once a week for 35 weeks, followed by a switch to AKCEA-TTR-LRx every 4 weeks.People may continue to receive AKCEA-TTR-LRx after the study treatment period ends.In this study, researchers will compare results from people who received AKCEA-TTR-LRx to results from people who received no active ingredients (called placebo) in a similar study (called NEURO-TTR).Researchers will measure the differences in peoples’:Neuropathy symptoms.Quality of life.TTR protein levels in the blood. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00235-6.

Introduction Inotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR‐mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test. Methods Adults with hATTR in the NEURO‐TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks. Results All major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS‐reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects. Discussion The results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy., See article on pages 509–515 in this issue.

Introduction Hereditary transthyretin‐mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO‐TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients’ neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score. Methods Stage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks. Results At 66 weeks, inotersen‐treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items. Discussion Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients’ neuropathy experience in clinical practice., See article on pages 502–508 in this issue.

Variable differences of nerve conduction amplitudes vs velocities and distal latencies (DLs) of healthy subjects assessed in ethnic cohorts. Introduction/aims The variables affecting reference compound muscle (CMAP) and sensory nerve action potential (SNAP) amplitudes as compared to ones affecting conduction velocities and DLs have not been adequately evaluated in previous studies. In this report, this subject is studied in healthy subject cohorts mainly of Northern European extraction, Northern Plains Indians, and Latinos. Methods Nineteen variables and 18 attributes of nerve conductions (NCs) were assessed using highly standard testing conditions and techniques. Classification and Regression Tree analyses were used to assess variable differences among amplitudes, conduction velocities, and DLs. Results The most important variable affecting CMAP and SNAP amplitudes was age. For conduction velocities (CVs) and DLs, the variables were height, ethnic cohort, and age. Discussion The variables affecting attributes of NCs were similar for the three ethnic cohorts evaluated. The differences of variables affecting amplitudes compared to CVs and DLs need to be taken into account in interpretation of NC results and in setting reference limits for use in medical practice, epidemiology surveys, and therapeutic trials. Scores of CMAP and SNAP amplitudes are suitable measures of sensorimotor polyneuropathy severity, whereas conduction velocities and DLs reflect physiologic/pathologic abnormality of nerve fibers.

Objective To evaluate the associated diseases, polyneuropathy correlates, and risk covariates of neuropathic plantar ulcers (PUs) and neuropathic arthropathies (NAs). Design The authors conducted a retrospective, observational study over 3.5 years of 69 patients with neuropathy, NA, or PU seen in a wound clinic who also had a comprehensive neurologic evaluation and neurophysiologic testing. Comparisons were made to a population representative cohort of patients with diabetes mellitus (DM; n = 259). Results Of the 69 wound clinic patients, 32 had PUs, 14 had NAs, and 23 had both. Of the 61 adequately assessed patients, 37 (61%) had DM, 22 (36%) had no known associated disease, and 2 (3%) had hereditary sensory and autonomic neuropathy. Of the 37 patients with DM, 35 had distal polyneuropathy, and 2 did not. In 22 patients with chronic idiopathic axonal polyneuropathy, 20 had distal polyneuropathy. Conclusions Although DM was the disease most commonly associated with PUs and NAs, chronic hyperglycemia may not have been the major underlying risk factor. The major risk covariates are sensation loss from polyneuropathy, old age, obesity, repetitive foot injury, and inadequate foot care or treatment. Physicians and other healthcare providers can help by identifying patients at risk and instituting measures such as adequate foot care to decrease these risks.

INTRODUCTION Onion-bulbs (OB) are concentrically layered Schwann-cell processes, surrounding nerve fibers, occurring in both inherited and acquired demyelinating polyneuropathies. We investigated whether OB patterns (generalized, mixed, or focal) correlate with acquired or inherited neuropathies. METHODS One hundred thirty-one OB-rich nerve biopsies were graded for OB pattern and inflammation without knowledge of clinical history. We classified inherited (n = 49) or acquired (n = 82) neuropathies based solely on clinical history. RESULTS Fifty-one biopsies had generalized (34 inherited vs. 17 acquired, P

Objective Report on the kind and distribution of somatotopic sensation loss and its utility in assessing severity of sensation loss in study of a large international cohort of patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN). Methods Smart Somatotopic Quantitative Sensation Testing (S ST QSTing) using Computer Assisted Sensation Evaluator IVc (CASE IVc) was used to assess the somatotopic distribution of touch pressure (TP) and heat pain (HP) sensation loss twice of untreated hATTR-PN patients in the Ionis NEURO-TTR trial ( www.clinicaltrials.gov , NCT01737398). Results Of the studied cohort of 169 patients, 163 (97%) had sensation loss, both TP and HP in 121/169 (75%), TP only in 39/169 (23%), and HP only in 3/169 (2%). Sensation loss typically affected both lower (152/169–90%) and upper limb (135/169–82%), and overall TP sensation loss was greater than HP loss, except for early-onset Val30Met patients in which HP exceeded TP loss. Conclusion Using S ST QSTing, a highly quantitated, standardized, referenced, and automated QSTing approach of the body's surface distribution of sensation loss we have shown that: 1) reliable and useful measurement of the body surface distribution of sensation loss is possible; 2) this measure is abnormal in most patients with hATTR-PN and is an indication of polyneuropathy severity; and 3) cutaneous sensation loss involves both large and small sensory fibers in this disease but slightly more small fibers in early onset Val30Met patients.

Context Reduced bone material strength index (BMSi) and increased cortical porosity (CtPo) have emerged as potentially contributing to fracture risk in type 2 diabetes mellitus (T2DM) patients. Objective To determine whether BMSi or CtPo are related to other diabetic complications. Design Cross-sectional observational study. Setting Subjects recruited from a random sample of southeast Minnesota residents. Participants A total of 171 T2DM patients (mean age, 68.8 years) and 108 age-matched nondiabetic controls (mean age, 67.3 years). Main Measures Bone material strength index was measured using microindentation, skin advanced glycation end-products (AGEs) measured using autofluorescence, high-resolution peripheral quantitative computed tomography at the distal radius and tibia, assessment of diabetic microvascular complications including urine microalbuminuria, retinopathy, neuropathy, and vascular disease (ankle brachial index and transcutaneous oxygen tension [TcPO2]). All analyses were adjusted for age, sex, and body mass index. Results Skin AGEs were negatively correlated with the BMSi in both T2DM (r = -0.30, P < 0.001) and control (r = -0.23, P = 0.020) subjects. In relating diabetic complications to CtPo, we found that T2DM patients with clinically significant peripheral vascular disease (TcPO2 ≤ 40 mm Hg) had higher (+21.0%, P = 0.031) CtPo at the distal tibia as compared to controls; in these subjects, CtPo was negatively correlated with TcPO2 at both the distal tibia (r = -0.39, P = 0.041) and radius (r = -0.41, P = 0.029). Conclusions Our findings demonstrate that bone material properties are related to AGE accumulation regardless of diabetes status, while CtPo in T2DM patients is linked to TcPO2, a measure of microvascular blood flow.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patients�� ability to walk and perform activities of daily living independently. With the lack of a diagnostic biomarker, the diagnosis relies on clinical suspicion, clinical findings, and the demonstration of demyelinating changes on electrodiagnostic (EDx) testing and nerve pathology. As a result, patients can often be misdiagnosed with CIDP and unnecessarily treated with immunotherapy. Interpreting the EDx testing and cerebrospinal fluid findings in light of the clinical phenotype, recognizing atypical forms of CIDP, and screening for CIDP mimickers are the mainstays of the approach to patients suspected of having CIDP, and are detailed in this review. We also review the currently available treatment options, including intravenous immunoglobulin (IVIg), corticosteroids (CCS), and plasma exchange (PE), and discuss how to approach treatment���refractory cases. Finally, we emphasize the need to adopt objective outcome measures to monitor treatment response.

Patients with Type 2 Diabetes (T2D) are at higher fracture risk despite having relatively normal or even increased BMD by DXA. Increased cortical porosity has emerged as a potential factor contributing to fragility fractures in T2D. However, there is conflicting evidence whether T2D patients have increased cortical porosity. We hypothesized that microvascular complications have an important role in cortical porosity. Thus, we performed high-resolution peripheral quantitative computed tomography imaging at the distal radius and tibia to evaluate bone microarchitecture in men with T2DM age ≥ 50 yrs or postmenopausal women with T2DM and nondiabetic controls. Comprehensive diabetic complications were assessed in all patients including urine microalbuminuria, retinopathy, neuropathy (touch, temperature, and vibration sensation), ankle brachial index (ABI) and transcutaneous oxygen tension (TcPO2). Percent differences between groups were obtained from linear regression models adjusting for age, BMI, and sex. Relationships between variables were assessed using adjusted Spearman correlations. A total of 164 T2D patients (mean age 68.9 ±7.8 yrs.; 56.7% men; HbA1C=7.7 ±0.9%; mean diabetes duration 15.2 yrs.) and 107 nondiabetic controls (mean age 67.3±8.8 yrs.; 42.1% men; HbA1C =5.4 ±0.3%) were recruited to the study. Overall, there was a trend for increased cortical porosity at the distal tibia in the T2D group (+12.2%; p=0.063) compared with nondiabetic controls. Of note, TcPO2 was negatively correlated with cortical porosity at the distal radius (r= -0.17; p= 0.039) and distal tibia (r= -0.15; p= 0.073). In particular, the Low TcPO2 (≤40 mmHg) group (n=29) had greater cortical porosity at the distal tibia (+19.6 %; p=0.037) compared with the High TcPO2 (>40 mmHg) group (n=133). In addition, the low TcPO2 group had a significant increase in cortical porosity in the distal tibia (+24.8% p=0.020) compared with nondiabetic controls. In conclusion, this is the first evidence in humans indicating that TcPO2, a measure of microvascular blood flow, is linked to cortical porosity in the distal radius and tibia in T2D patients. Our findings may explain the conflicting findings regarding cortical porosity in T2D because only T2D patients with impaired microvascular blood flow have increased cortical porosity. Collectively, our data indicate that cortical porosity is a microvascular complication of longstanding T2D.

Background and purpose: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. Methods: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. Results: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. Conclusion: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed. info:eu-repo/semantics/publishedVersion

Hereditary transthyretin (ATTRm) amyloidosis is a rare, progressive and fatal disease with a range of clinical manifestations.This study comprehensively evaluates disease characteristics in a large, diverse cohort of patients with ATTRm amyloidosis.Adult patients (N = 172) with Stage 1 or Stage 2 ATTRm amyloidosis who had polyneuropathy were screened and enrolled across 24 investigative sites and 10 countries in the NEURO-TTR trial ( www.clinicaltrials.gov , NCT01737398). Medical and disease history, quality of life, laboratory data, and clinical assessments were analyzed.The NEURO-TTR patient population was diverse in age, disease severity, TTR mutation, and organ involvement. Twenty-seven different TTR mutations were present, with Val30Met being the most common (52%). One third of patients reported early onset disease (before age 50) and the average duration of neuropathy symptoms was 5.3 years. Symptoms affected multiple organs and systems, with nearly 70% of patients exhibiting broad involvement of weakness, sensory loss, and autonomic disturbance. Over 60% of patients had cardiomyopathy, with highest prevalence in the United States (72%) and lowest in South America/Australasia (33%). Cardiac biomarker NT-proBNP correlated with left ventricular wall thickness (p.001). Quality of life, measured by Norfolk QoL-DN and SF-36 patient-reported questionnaires, was significantly impaired and correlated with disease severity.Baseline data from the NEURO-TTR trial demonstrates ATTRm amyloidosis as a systemic disease with deficits in multiple organs and body systems, leading to decreased quality of life. We report concomitant presentation of polyneuropathy and cardiomyopathy in most patients, and early involvement of multiple body systems.

Introduction Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. Methods We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. Results The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. Conclusions Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.

Intraneural perineuriomas are benign peripheral nerve sheath tumors that cause progressive debilitating focal extremity weakness. The etiology of perineuriomas is largely unknown. We utilized whole exome sequencing, copy number algorithm evaluation and high-resolution whole genome microarray to investigate for a genetic causal link of intraneural perineuriomas. Ten of 16 (60%) tumor cases had mutations in the WD40 domain of TRAF7, the same location for causal mutations of meningiomas. Two additional perineurioma cases had large chromosomal abnormalities in multiple chromosomes, including chromosome 22q. This study identifies a common cause for intraneural perineuriomas and an unexpected shared pathogenesis with intracranial meningiomas. This article is protected by copyright. All rights reserved.

Introduction In severely affected inherited polyneuropathy patients, primary demyelination can be difficult to determine by routine extremity limb nerve conduction studies (NCS). Blink reflexes may help classify severe polyneuropathies as either axonal or demyelinating. However, blink reflex studies have not been studied systematically in any genetically confirmed cohort. Methods Patients with a genetic diagnosis who had undergone blink reflex testing and extremity NCS were identified retrospectively. Blink reflex R1 latency, extremity NCS, and severity were compared. Results We identified 26 demyelinating and 23 axonal, genetically confirmed cases, including 20 with PMP22 duplications. In 12 (25%), the ulnar CMAP amplitude was ≤0.5 mV making electrophysiological classification difficult. However, the R1-latency cutoff of >13 ms (demyelinating) robustly classified all patients regardless of severity. Conclusions We show that blink reflex studies are reliable for identification of inherited demyelinating polyneuropathy regardless of severity and can facilitate algorithmic decisions in genetic testing. Muscle Nerve 55: 316-322, 2017.

ObjectiveTo determine the previously unknown incidence of lumbosacral radiculoplexus neuropathy (LRPN) and its association with diabetes mellitus (DM).MethodsLRPN defined by clinical and electrophysiologic criteria was identified among Olmsted County, Minnesota, residents during a 16-year period (2000–2015) using the unique facilities of the Rochester Epidemiology Project. DM was ascertained using American Diabetes Association criteria.ResultsOf 1,892 medical records reviewed, 59 patients (33 men, 26 women) were identified as having LRPN. The median age was 70 years (range 24–88 years) and the median time of onset of symptoms to diagnosis was 2 months (range 1–72 months). DM was more frequent in patients with LRPN than in controls (39/59 vs 35/177, p < 0.001) but not in those with pre-DM (10/20 vs 55/142, p = 0.336). LRPN recurred in 3 patients with DM resulting in 62 LRPN episodes during the study period. The overall incidence of LRPN was 4.16/100,000/y (95% confidence interval [CI] 3.13–5.18). The incidences of LRPN among DM and non-DM groups were 2.79/100,000/y (95% CI 1.94–3.64) and 1.27/100,000/y (95% CI 0.71–1.83), respectively. The odds of LRPN among patients with DM and pre-DM was 7.91 (95% CI 4.11–15.21) and 1.006 (95% CI 1.004–1.012), respectively.ConclusionsLRPN incidence in Olmsted County of 4.16/100,000/y makes LRPN a common inflammatory neuropathy and is higher than that of other immune-mediated neuropathies (acute or chronic inflammatory demyelinating polyradiculoneuropathy, brachial plexus neuropathy) assessed within the same population. DM is a major risk factor for LRPN and thus justifies the continued classification of LRPN into diabetic and nondiabetic forms.

Transthyretin amyloidosis is a fatal disorder that is characterized primarily by progressive neuropathy and cardiomyopathy. It occurs in both a mutant form (with autosomal dominant inheritance) and a wild-type form (with predominant cardiac involvement). This article guides clinicians as to when the disease should be suspected, describes the appropriate diagnostic evaluation for those with known or suspected amyloidosis, and reviews the interventions currently available for affected patients.

Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, life-threatening disease, caused by point mutations in the transthyretin gene. It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction. Measures used to assess polyneuropathy in other diseases have been tested as endpoints in hATTR amyloidosis clinical trials (i.e. Neuropathy Impairment Score [NIS], NIS-lower limb, and NIS + 7), yet the unique nature of the polyneuropathy in this disease has necessitated modifications to these scales. In particular, the heterogeneous impairment and the aggressive disease course have been key drivers in developing scales that better capture the disease burden and progression of polyneuropathy in hATTR amyloidosis. The modified NIS + 7 (mNIS + 7) scale was specifically designed to assess polyneuropathy impairment in patients with hATTR amyloidosis, and has been the primary endpoint in two recent, phase III studies in this disease. The mNIS + 7 uses highly standardized, quantitative, and referenced assessments to quantify decreased muscle weakness, muscle stretch reflexes, sensory loss, and autonomic impairment. Physicians using this scale in clinical trials should be specifically trained and monitored to minimize variability. This article discusses the different scales that have been/are being used to assess polyneuropathy in patients with hATTR amyloidosis, their correlation with other disease assessments, and reflects on how and why scales have evolved to the latest iteration of mNIS + 7.

ObjectiveTo describe an expanded teased nerve fibre classification in disease association.MethodsWe reviewed four newly proposed teased nerve fibre types (Types J–M): Type J, rope-like fibres; K, fibril-like clumps of osmium positivity; L, cellular debris along and within nerve fibres; M, circular axonal inclusions surrounded by thin myelin. Different clinical pathological entities were studied for these fibre types including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP: N=20); amyloid polyneuropathy (N=20); intraneural B-cell lymphoma (N=20) or adult-onset polyglucosan body disease (APBD: N=6) in comparison with 112 disease controls. Student’s t-test was used to test significance of association between the identified fibre types and the specific clinical diagnosis.ResultsEach fibre type significantly associated (pType J, 60% of CIDP cases; Type K, 75% of amyloid cases; Type L, 75% of intraneural lymphoma cases; Type M, 100% of APBD cases. Rarely were these fibres found in the other disease control cases ≤3% of cases. In three cases, the teased fibre findings were so striking additional paraffin nerve preparations were made to make the pathological diagnosis when initial paraffin sections were non-diagnostic.ConclusionsTeased nerve fibre Types J–M associate with commonly seen pathological diagnosis and are helpful in the consideration of specific neuropathy diagnoses.

BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P

To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP).We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models.For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin (TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p0.0001) and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p0.0001). In addition, there was an association between NIS and TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8 points/year.In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion.

Diabetes mellitus is among the most common causes of peripheral neuropathy worldwide. Sensory impairment in diabetics is a major risk factor of plantar ulcers and neurogenic arthropathy (Charcot joints) causing severe morbidity and high health-care costs.To discuss the different patterns of sensory alterations in diabetic neuropathies and their anatomical basis.Literature review.Review of the literature discussing different patterns of sensory impairment in diabetic neuropathies.The different varieties of diabetic neuropathies include typical sensorimotor polyneuropathy (lower extremity predominant, length-dependent, symmetric, sensorimotor polyneuropathy presumably related to chronic hyperglycemic exposure, and related metabolic events), entrapment mononeuropathies, radiculoplexus neuropathies related to immune inflammatory ischemic events, cranial neuropathies, and treatment-related neuropathies (e.g. insulin neuritis). None of these patterns are unique for diabetes, and they can occur in nondiabetics. Sensory alterations are different among these prototypic varieties and are vital in diagnosis, following course, treatment options, and follow-up of treatment effects.Diabetic neuropathies can involve any segment of peripheral nerves from nerve roots to the nerve endings giving different patterns of abnormal sensation. It is the involvement of small fibers that causes positive sensory symptoms like pain early during the course of disease, bringing subjects to physician's care.This article emphasizes on the fact that diabetic neuropathies are not a single entity. They are rather different varieties of conditions with more or less separate pathophysiological mechanisms and anatomical localization. Clinicians should keep this in mind when assessing patients with diabetes on the first visit or follow-up.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a mutation in the alanine-glyoxalate aminotransferase (AGXT) gene which encodes the hepatic enzyme alanine-glyoxylate aminotransferase (AGT). AGT is responsible for converting glyoxylate into glycine. When the enzyme is deficient or defective, glyoxylate accumulates and is converted to oxalate. Oxalate cannot be metabolized and is excreted by the kidneys 4. In PH1, high urinary levels of oxalate lead to kidney stones and deposition of calcium oxalate crystals within the renal tubules and parenchyma, which results in progressive renal fibrosis. As kidney function declines, oxalate production increasingly exceeds renal oxalate clearance. Plasma oxalate levels rise, and insoluble calcium oxalate crystals are deposited in tissues throughout the body, including the kidney, heart, bone, blood vessels, retina, muscle, skin, and nerve. Hemodialysis is needed to remove oxalate from the body, but removal is incomplete, and even when it is intensive, dialysis is often insufficient to prevent progressive systemic oxalate deposition 5,6,7. Because oxalate removal with dialysis is incomplete, the treatment of choice for patients with PH1 and poor kidney function, is combined liver/ kidney transplantation. Liver transplantation is required in the majority of PH type 1 patients to restore the hepatic enzyme defect and protect the renal allograft from recurrent oxalate nephropathy. Significant neurologic improvement in patients with neuropathy has been noted following combined liver and kidney transplantation 8. Only a few case reports have described the nerve pathology associated with primary hyperoxaluria type 1. Demyelination (particularly at the internodes) and axonal degeneration have been reported,1 and some case reports describe crystals in nerve 1,3. The characterization and location of these crystals within nerve has not been well described, and their pathological significance has remained unclear 1,3. In each of these case reports, the patient had significant systemic oxalosis with deposition of oxalate into multiple tissues, whereas the patient we describe had oxalosis affecting peripheral nerve preferentially without other clinically discernible extrarenal manifestations. Approval by our Institutional Review Board and Biospecimens Committee was received for this study.

Background Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality. Methods Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18–85 years old with hATTR amyloidosis, investigator-estimated survival of ≥2 years, Neuropathy Impairment Score (NIS) of 5–130, and polyneuropathy disability score ≤IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study. Discussion APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease. Trial registration This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013.

Myelopathy is considered the most common neurological complication of copper deficiency. Concurrent peripheral neuropathy has been recognised in association with copper deficiency but has not been well characterised.To characterise the clinical, physiological and pathological features of copper-deficient peripheral neuropathy.Patients with simultaneous copper deficiency (0.78 μg/mL) and peripheral neuropathy seen at the Mayo Clinic from 1985 to 2005 were identified.34 patients were identified (median age 55 years, range 36-78) including 24 women and 10 men. Myelopathy was found in 21 patients. Median serum copper level was 0.11 μg/mL (range 0-0.58). The most frequent clinical and electrophysiological pattern of neuropathy was a sensory predominant length-dependent peripheral neuropathy (71%). Somatosensory evoked potentials demonstrated central slowing supporting myelopathy (96%). Quantitative sensory testing demonstrated both small and large fibre involvement (100%). Autonomic reflex screens (77%) and thermoregulatory sweat test (67%) confirmed sudomotor dysfunction. 14 cutaneous nerve biopsies revealed loss of myelinated nerve fibres (86%), increased regenerative clusters (50%), increased rates of axonal degeneration (91%) and increased numbers of empty nerve strands (73%). 71% of biopsies demonstrated epineurial perivascular inflammation.An axonal, length-dependent sensory predominant peripheral neuropathy causing sensory ataxia is characteristic of copper deficiency usually co-occurring with myelopathy. Neurophysiological testing confirms involvement of large, greater than small fibres. The pathological findings suggest axonal degeneration and repair. Inflammatory infiltrates are common but are small and of doubtful pathological significance.

Introduction The Cl. NPhys Trial 3 showed that attributes of nerve conduction (NC) were without significant intraobserver differences, although there were significant interobserver differences. Methods: Trial 4 tested whether use of written instructions and pretrial agreement on techniques and use of standard reference values, diagnostic percentile values, or broader categorization of abnormality could reduce significant interobserver disagreement and improve agreement among clinical neurophysiologists. Results: The Trial 4 modifications markedly decreased, but did not eliminate, significant interobserver differences of measured attributes of NC. Use of standard reference values and defined percentile values of abnormality decreased interobserver disagreement and improved agreement of judgment of abnormality among evaluators. Therefore, the same clinical neurophysiologist should perform repeat NCs of therapeutic trial patients. Conclusions: Differences in interobserver judgment of abnormality decrease with use of common standard reference values and a defined percentile level of abnormality, providing a rationale for their use in therapeutic trials and medical practice. Muscle Nerve 50: 900–908, 2014

Introduction: We assessed proficiency (accuracy and intra- and intertest reproducibility) of smart quantitative sensation tests (smart QSTs) in subjects without and with diabetic sensorimotor polyneuropathy (DSPN). Methods: Technologists from 3 medical centers using different but identical QSTs independently assessed 6 modalities of sensation of the foot (or leg) twice in patients without (n = 6) and with (n = 6) DSPN using smart computer assisted QSTs. Results: Low rates of test abnormalities were observed in health and high rates in DSPN. Very high intraclass correlations were obtained between continuous measures of QSTs and neuropathy signs, symptoms, or nerve conductions (NCs). No significant intra- or intertest differences were observed. Conclusions: These results provide proof of concept that smart QSTs provide accurate assessment of sensation loss without intra- or intertest differences useful for multicenter trials. Smart technology makes possible efficient testing of body surface area sensation loss in symmetric length-dependent sensorimotor polyneuropathies. Muscle Nerve 49: 645–653, 2014

Importance Erythromelalgia is a clinical diagnosis based on intermittent warmth, erythema, and pain in the distal extremities. One problem facing physicians is how to objectively test for this disease. Given that other painful conditions of the distal extremities (ie, neuropathy related to human immunodeficiency virus, diabetes, or Fabry disease) can be evaluated with a skin biopsy to visualize pathologically decreased densities of the small nerve fibers that innervate the epidermis, one hypothesis is that erythromelalgia could similarly be associated with a loss of epidermal nerve fiber density (ENFD). Objectives To examine whether erythromelalgia is associated with a structural loss of small fibers using the ENFD technique and to compare this with functional studies of small nerve fibers. Design, Setting, and Participants In a retrospective study of 52 consecutive patients with erythromelalgia who were seen between September 1, 2010, and September 22, 2015, patients were interviewed and examined and their conditions clinically diagnosed by a board-certified dermatologist at a large tertiary referral center, where ENFD testing became a routine part of evaluating erythromelalgia in 2010. Thus, all 52 consecutive patients were included solely based on their clinical diagnosis of erythromelalgia. For quantification of ENFD, observers were masked to all patient information except for name and clinic number. Main Outcomes and Measures The hypothesis that patients with erythromelalgia would have decreased ENFD was formulated before data collection. Epidermal nerve fiber density, the primary outcome, is a measurement of the density of small nerve fibers within the epidermis. Secondary measures included functional small fiber evaluation, such as autonomic (heart rate, blood pressure, and sweat testing) and subjective testing of pain. Results In this cohort study, 52 consecutively seen patients were identified (female, 42 [80%]; median age, 44 years; age range, 13-82 years). Whereas only 5 of 52 patients (10%) had ENFD at or below the fifth percentile of healthy control individuals, most patients had functional abnormalities of these small fibers; 29 patients (60%) had abnormal sweat test results, 21 (42%) had abnormal pain thresholds, and 20 (38%) had abnormal blood pressure or heart rate control. Conclusions and Relevance Unlike other diseases of the small nerve fibers that cause acral pain syndromes, erythromelalgia is not characterized by loss of ENFD. However, most patients have impaired function of these small fibers. Physicians would benefit from performing functional rather than structural small fiber studies when evaluating erythromelalgia.

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis a hereditary, multi-systemic and life-threatening disease resulting in neuropathy and cardiomyopathy. In the APOLLO study, patisiran, an investigational RNAi therapeutic targeting hepatic TTR production resulted in significant improvement in neuropathy and QoL compared to placebo and was generally well tolerated. Methods: APOLLO, a Phase 3 study of patisiran vs. placebo (NCT01960348) prespecified a cardiac subpopulation (n=126 of 225 total) that included patients with baseline left ventricular (LV) wall thickness ≥ 13mm and no medical history of aortic valve disease or hypertension. Cardiac measures included structure and function by electrocardiography, changes in NT-proBNP and 10-MWT gait speed. Results: At 18 months, patisiran treatment resulted in a mean reduction in LV wall thickness of 1 mm (p=0.017) compared to baseline, which was associated with significant improvements relative to placebo in LV end diastolic volume (+8.31 mL, p=0.036), global longitudinal strain (-1.37%, p=0.015) and NT-proBNP (55% reduction, p=7.7 x 10-8) (Figure 1). Gait speed was also improved relative to placebo (+0.35 m/sec, p=7.4 x 10-9). Rate of death or hospitalization was lower with patisiran. mNIS+7 results in the cardiac subpopulation will also be presented. Conclusions: These data suggest patisiran has the potential to halt or reverse cardiac manifestations of hATTR amyloidosis.

Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive, and fatal disease caused by the buildup of transthyretin-derived amyloid protein in major organs, predominantly affecting the peripheral nerves and heart. Inotersen, a second-generation antisense oligonucleotide targeting TTR mRNA, has shown efficacy and safety in patients with hATTR in a randomized, double-blind, placebo-controlled, phase 3 study, NEURO-TTR (ClinicalTrials.gov, NCT01737398; Benson NEJM 2018). Patients with hATTR amyloidosis who completed the NEURO-TTR study were eligible to receive inotersen for up to 5 years in a phase 3 open-label extension study (ClinicalTrials.gov, NCT02175004). Methods: In NEURO-TTR, patients were randomized 2:1 to receive inotersen (300-mg weekly subcutaneous doses) or placebo. In the open-label extension, patients continued inotersen (inotersen-inotersen) or switched from placebo to inotersen (placebo-inotersen). Evaluations included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7; higher scores indicate worse neuropathy), Norfolk Quality of Life-Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN; higher scores indicate worse QoL), and adverse events (AEs). Cardiomyopathy (CM) was defined by a diagnosis of hATTR-CM at trial entry or by an interventricular wall thickness of 13 mm or more on transthoracic echocardiography at baseline, as ascertained by a central reader, or no known history of persistent hypertension (systolic blood pressure, ≥150 mm Hg) within 12 months before screening. Results : In the placebo-controlled, double-blind, phase 3 NEURO-TTR study, 112/172 patients were randomized and received inotersen. At baseline, patients were predominantly white (91.9%) males (68.6%) with a mean age of 59.2 years. A total of 67.4% had stage I (ambulatory) and 32.6% had stage II (ambulatory with assistance) disease. Inotersen-treated patients who had stage II disease had a longer duration of disease from diagnosis (40.9 vs 24.8 months, respectively) and from onset (72.6 vs 63.2 months, respectively) of hATTR polyneuropathy symptoms compared with placebo-treated patients who had stage II disease, indicating more advanced disease. A higher proportion of inotersen-treated patients had CM at baseline (67% vs 55%, respectively), and more severe CM, measured by higher NT-proBNP levels and longer duration of disease from hATTR-CM symptom onset, compared with placebo-treated patients. In the phase 3 open-label extension study as of Sept 15, 2017, 134 of 135 patients enrolled received ≥1 dose of inotersen. The mean age was 60.4 years and most patients were male (69.4%). Extended dosing with inotersen up to 27 months continued to improve mNIS+7 and Norfolk QoL-DN in the open-label extension compared to placebo-treated patients at week 66 in the double-blind NEURO-TTR study; mean changes from open-label extension baseline to open-label extension week 52 in the inotersen-inotersen group were 5.1 points for mNIS+7 (vs 25.5 for placebo-treated patients in the double-blind NEURO-TTR study) and 3.9 points for Norfolk QoL-DN (vs 10.7 for placebo-treated patients in the double-blind NEURO-TTR study). Initiation of inotersen in placebo-treated patients (placebo-inotersen) resulted in improvement in mNIS+7 and Norfolk QoL-DN by week 26. Few patients discontinued treatment because of AEs (inotersen-inotersen, 9%; placebo-inotersen, 4%). The rate of treatment-related serious AEs was low in both treatment groups (2% each). There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure. We will present 2-year follow-up results from the open-label extension study. Conclusions: Results of the open-label extension show continued benefit, measured by mNIS+7 and Norfolk QoL-DN, and confirmed that earlier initiation of treatment is important for optimal clinical outcomes. No new safety concerns were identified. Results from the longer-term follow-up for the open-label extension will further elucidate how inotersen may benefit patients with hATTR amyloidosis. Disclosures Brannagan: Alnylam: Honoraria, Other: Investigator, Speakers Bureau; Ionis: Other: Investigator. Wang:Ionis: Other: Investigator, Speakers Bureau. Coelho:Prothena: Consultancy, Honoraria; Ionis: Consultancy, Other: Investigator; Alnylam: Consultancy, Honoraria, Other: Investigator; Pfizer: Consultancy, Honoraria, Other: Investigator. Waddington Cruz:Ionis: Honoraria; Genzyme/Sanofi: Honoraria; Pfizer: Honoraria. Polydefkis:Pfizer: Honoraria; Alnylam: Honoraria. Dyck:Ionis: Consultancy; Alnylam: Consultancy. Plante-Bordeneuve:Alnylam: Consultancy; Pfizer: Consultancy, Other: reimbursement for travel and meeting; Ionis: Other: reimbursement for travel and meeting. Berk:Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator. Barroso:Pfizer: Consultancy, Honoraria, Other: Thaos registry, Speakers Bureau; Alnylam: Honoraria, Other: Investigator. Conceição:Alnylam: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hughes:Ionis: Employment. Kwoh:Ionis: Employment. Jung:Ionis: Employment. Guthrie:Akcea: Employment. Pollock:Akcea: Employment. Benson:Ionis: Other: Investigator, Research Funding. Gertz:janssen: Consultancy; Teva: Consultancy; spectrum: Consultancy, Honoraria; Alnylam: Honoraria; Ionis: Honoraria; Amgen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; celgene: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; Physicians Education Resource: Consultancy.

Background and objectives The association between prediabetes and distal polyneuropathy (DPN) remains controversial. Here we test whether the prevalence of small fiber sensory distal polyneuropathy is increased in prediabetes. Methods Prospectively recruited cohorts of healthy subjects and those with prediabetes from Olmsted County, Minnesota, were assessed for positive neuropathic sensory symptoms, or pain symptoms characteristic of small fiber sensory DPN. Hyperalgesia and hypoalgesia were assessed by “smart” quantitative sensation testing (QST). The prevalence of symptoms and QST abnormalities were compared among the groups. Results There was no significant increase in the prevalence of positive neuropathic sensory or pain symptoms, nor of hyper- or hypoalgesia in the prediabetes group. There was an increased prevalence of hypoalgesia of the foot only in newly diagnosed diabetes. Conclusions Based on positive sensory and pain symptoms and QSTs, we did not find an increase in small fiber sensory DPN in prediabetes. Recognizing that obesity and diabetes mellitus are implicated in macro- and microvessel complications, physicians should encourage healthy living and weight loss in patients with prediabetes. In medical practice, alternate causes should be excluded before concluding that small fiber sensory distal neuropathy is secondary to prediabetes.

Loss of sensation and increased sensory phenomena are major expressions of varieties of diabetic polyneuropathies needing improved assessments for clinical and research purposes. We provide a neurobiological explanation for the apparent paradox between decreased sensation and increased sensory phenomena. Strongly endorsed is the use of the 10-g monofilaments for screening of feet to detect sensation loss, with the goal of improving diabetic management and prevention of foot ulcers and neurogenic arthropathy. We describe improved methods to assess for the kind, severity, and distribution of both large- and small-fiber sensory loss and which approaches and techniques may be useful for conducting therapeutic trials. The abnormality of attributes of nerve conduction may be used to validate the dysfunction of large sensory fibers. The abnormality of epidermal nerve fibers/1 mm may be used as a surrogate measure of small-fiber sensory loss but appear not to correlate closely with severity of pain. Increased sensory phenomena are recognized by the characteristic words patients use to describe them and by the severity and persistence of these symptoms. Tests of tactile and thermal hyperalgesia are additional markers of neural hyperactivity that are useful for diagnosis and disease management.

Assessment of signs, symptoms, functional impairments, and nerve tests are the the main clinical measures used for diagnosing and characterizing peripheral nerve disease. Among tests, nerve conduction (NC) has increasingly been advocated for objective electrodiagnosis and characterization of focal, multifocal, or generalized polyneuropathies.1–4 NC is also being used for conducting epidemiological surveys5–7 and therapeutic trials.8,9 For the latter purposes, NC has gained consensus approval,10–13 because its results are considered sensitive, objective, quantitative, and reproducible indications of nerve dysfunction that correlate with clinical signs and symptoms and with neurophysiological and neuropathological abnormalities.14,15 In knowing that assessment of attributes of NC can provide sensitive and quantitative diagnostic and characterizing information about diabetic sensorimotor polyneuropathy (DSPN) for use in medical practice and therapeutic trials, it would also be helpful to learn how accurately and reproducibly within and among clinical neurophysiologists this assessment is done (proficiency). There is already considerable information about test–retest reproducibility of individual attributes of NC focusing mainly on which attributes show the greatest reproducibility and, with this criterion, are suitable for therapeutic trials (albeit test–retest reproducibility is only 1 criterion for such selection). Reproducibility studies have not addressed the issue of proficiency—that is, the variability of NC results among different clinical neurophysiologists without retraining, consensus development, or quality control of their evaluations. Two previous studies have assessed intra- and interobserver variability of measured attributes of NC. In the first study, electromyographers from 1 medical center studied healthy subjects,16 and in a second they studied patients with diabetes mellitus (DM).17 They found no significant intraobserver differences, but significant interobserver differences. They concluded that, for therapeutic trials, it may be advisable to have the same electromyographers perform the sequential NCs over time on patients in the trial. The present trial, Clinical vs. Neurophysiology Trial 3 (Cl vs. NPhys Trial 3) had each group of clinical neurophysiologists and their associate technologist perform NC assessment of 8 attributes of NC of the leg of 24 masked patients with DM without and with DSPN on consecutive days. The expert clinical neurophysiologists were asked to make independent measurements of the attributes without any clinical information, record whether their values were normal or abnormal, and finally make a judgment of whether the abnormalities were diagnostic of DSPN. Thus, these studies specifically addressed 3 questions: (1) Did expert neurophysiologists obtain the same measured values of the 8 attributes of NC without intra- or interobserver differences? (2) Assuming that they did, did they judge abnormality of attributes without intraor interobserver differences? (3) Did they judge DSPN as present or not without intra- or interobserver differences? It was recognized prior to the study that if the first question could not be answered affirmatively, it may not be possible to adequately assess questions (2) and (3). This trial also addresses the broader question of whether further standardization of NC assessment is needed and possible, or whether it is really necessary to have the same electromyographer perform serial evaluations of individual patients. This trial is part of a series of studies organized by Cl vs. NPhys Trial investigators to assess the proficiency of assessment of signs, symptoms, and clinical diagnosis,18,19 attributes of NC (the present Trial 3) and other nerve tests for the diagnosis and characterization of polyneuropathies, especially DSPN. The overall goal is to improve the quality of these evaluations of measures of polyneuropathy in medical practice, medical education, and the conduct of therapeutic trials.

Introduction: Surgery and childbirth can trigger attacks of hereditary brachial plexus neuropathy (HBPN), and inflammation was suggested as a component of the pathogenesis. Methods: HBPN patients who underwent surgery or parturition from January 1, 1996 to December 31, 2009 were studied. Results: Twenty-five HBPN patients underwent 48 surgeries or parturitions. Seventeen patients (68%) had attacks, including 13 periprocedural and 7 postpartum by varied anesthesia types. Three patients who had 8 earlier combined attacks (after thyroidectomy, laminectomy, and Caesarean section) were given prophylactic immunosuppressive therapy (corticosteroids ± immunoglobulin). None suffered postoperative attacks, which is uncharacteristic of their prior experience. Five had perioperative attacks as their first HBPN manifestation. Median follow-up was 11 months (3–48 months). Attacks occurred in the operated limb (n = 6) or distant (n = 7) to surgical sites. All attacks interfered with daily living, with frequent incomplete recovery. Five patients had a SEPT9 mutation. Conclusions: Corticosteroids may prevent parturition and surgical HBPN attacks in some patients. Diverse surgeries, anesthesia, and childbirth frequently trigger HBPN attacks. Muscle Nerve, 2013

Objectives: Autonomic deficits in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have not been adequately quantitated. The Composite Autonomic Severity Score (CASS) is a validated instrument for laboratory quantitation of autonomic failure derived from standard autonomic reflex tests. We characterized dysautonomia in CIDP using CASS. Methods: Autonomic function was retrospectively analyzed in 47 patients meeting CIDP criteria. CASS ranges from 0 (normal) to 10 (pandysautonomia), reflecting summation of sudomotor (0–3), cardiovagal (0–3), and adrenergic (0–4) subscores. Severity of neurologic deficits was measured with Neuropathy Impairment Score (NIS). Degree of small fiber involvement was assessed with quantitative sensation testing. Thermoregulatory sweat test (TST) was available in 8 patients. Results: Patients (25 men) were middle-aged (45.0 ± 14.9 years) with longstanding CIDP (3.5 ± 4.3 years) of moderate severity (NIS, 46.5 ± 32.7). Autonomic symptoms were uncommon, mainly gastrointestinal (9/47; 19%) and genitourinary (8/47; 17%). Autonomic deficits (CASS ≥1) were frequent (22/47; 47%) but very mild (CASS, 0.8 ± 0.9; CASS ≤3, all cases). Deficits were predominantly sudomotor (16/47; 34%) and cardiovagal (10/47; 21%) with relative adrenergic sparing (4/47; 9%). TST was abnormal in 5 of 8 patients (anhidrosis range, 2%–59%). Sudomotor impairment was predominantly distal and postganglionic. Somatic deficits (disease duration, severity, small fiber deficits) did not predict presence of autonomic deficits. Conclusion: Our data characterize the autonomic involvement in classic CIDP as mild, cholinergic, and predominantly sudomotor mainly as a result of lesions at the distal postganglionic axon. Extensive or severe autonomic involvement (CASS ≥4) in suspected CIDP should raise concern for an alternative diagnosis.

OBJECTIVE To test whether diabetic polyneuropathies (DPNs), retinopathy, or nephropathy is more prevalent in subjects with impaired glycemia (IG) (abnormality of impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or impaired HbA1c [IA1C]) than in healthy subjects (non-IG). RESEARCH DESIGN AND METHODS Matched IG and non-IG volunteers were randomly identified from population-based diagnostic and laboratory registries, restudied, and reclassified as non-IG (n = 150), IG (n = 174), or new diabetes (n = 218). RESULTS Frequency (%) of DPN in non-IG, IG, and new diabetes was 3 (2.0%), 3 (1.7%), and 17 (7.8%) narrowly defined (no other cause for polyneuropathy) and 19 (12.7%), 22 (12.6%), and 38 (17.4%) broadly defined. Mean and frequency distribution of composite scores of nerve conduction and quantitative sensation tests were not significantly different between IG and non-IG but were worse in new diabetes. Frequency of retinopathy and nephropathy was significantly increased only in new diabetes. In secondary analysis, small but significant increases in retinopathy and nephropathy were found in IGT, IFG, and IGT combined groups. CONCLUSIONS In population studies of Olmsted County, Minnesota, inhabitants, prevalence of typical DPN, retinopathy, and nephropathy was significantly increased only in subjects with new diabetes—not in subjects with IG as defined by American Diabetes Association (ADA) criteria of abnormality of IFG, IGT, or IA1C. For atypical DPN, such an increase was not observed even in subjects with new diabetes. In medical practice, explanations other than IG should be sought for patients with atypical DPN (chronic idiopathic axonal polyneuropathy) who have IG.

Objective: To report 3 patients with minocycline-induced autoimmunity resulting in peripheral nerve vasculitis. Methods: We report 3 patients who, during minocycline treatment for acne vulgaris, developed subacute onset of pain and weakness caused by vasculitis in single and multiple mononeuropathy patterns. Results: Each patient underwent either a nerve or muscle biopsy that confirmed vasculitis. One patient additionally developed systemic symptoms (including fever, fatigue, and night sweats) and another had a posterior circulation stroke. Symptoms developed with either early or prolonged use of minocycline. Despite withdrawal of minocycline, patients needed long-term immunotherapy to gain neurologic improvement. Conclusions: Our findings suggest that the typical neuropathy associated with minocycline use is painful single or multiple mononeuropathy due to peripheral nerve vasculitis, which may also be accompanied by presumed CNS vasculitis (presenting as stroke).

Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13-18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long-standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease-but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small-fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre-specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject- and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN.

OBJECTIVE To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

Introduction: In this study we aimed to deter- mine which criteria are valid for nerve conduction (NC) diagno- sis of typical diabetic sensorimotor polyneuropathy (DSPN). Methods: Eight criteria were assessed from among diabetes databases, the Rochester Diabetic Neuropathy Study (RDNS, N ¼ 456), and in healthy subjects (RDNS-HS, N ¼ 330). Results: In the RDNS, the most frequent abnormal attributes (� 2.5th/� 97.5th percentile) are: fibular motor nerve conduction velocity (MNCV; 26.3%); sural sensory nerve conduction veloc- ity (SNAP; 25.4%); tibial MNCV (24.8%); ulnar MNCV (21.3%); fibular F latency (16.9%); and ulnar F latency (16.0%). Normal deviate (from percentiles) composite scores of NC included: representative of neurophysiological abnormalities; sensitive and specific for diagnosis and useful for epidemiological sur- veys; randomized trials; and medical practice. By contrast, abnormality of one or more attributes in any nerve or abnormally of two most sensitive attributes performed poorly. Conclusions: Composite sum scores of normal deviates (from percentiles corrected for applicable variables) of sensitive NC attributes and with modifications, RDNS and AAN criteria per- formed acceptably for diagnosis of DSPN. Muscle Nerve 44: 340-345, 2011

Introduction Minocycline is an antibiotic used for the treatment of acne. It has been associated with several autoimmune syndromes, including drug-induced lupus, autoimmune hepatitis, and vasculitis. Method and results We report a case of a 28-year-old previously healthy woman who developed a left sciatic mononeuropathy 2 weeks after starting minocycline for acne. Magnetic resonance imaging studies supported the localization. A biopsy of the left sural nerve revealed acute nerve large arteriole necrotizing vasculitis. Her condition improved after the withdrawal of minocycline and a course of treatment with methylprednisolone. Conclusion This case provides further evidence that minocycline may induce a nonsystemic necrotizing vasculitis.

In the evaluation of a patient with peripheral neuropathy the discovery of a serum monoclonal protein has implications for the neurologic and hematologic diagnosis, prognosis and treatment1. Among such patients the type of neuropathy may suggest the specific underlying hematologic process. To illustrate, in a patient with a monoclonal protein having subacute painful multiple mononeuropathies the diagnosis of mixed cryoglobulinemia is likely and evaluation for viral hepatitis should be emphasized. In another patient, also with a monoclonal protein and with insidious onset of a symmetric painful autonomic, sensory motor polyneuropathy, primary amyloid light chain (AL) amyloidosis should be suspected. In a third example a monoclonal protein with insidious demyelinating polyradiculoneuropathy occurs in POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M spike and Skin changes) and should lead to search of treatable osteosclerotic myeloma2. Familiarity of these patterns, and others, leads to correct diagnosis and treatment. Among persons having IgM-MGUS an insidious painless distal sensory ataxic neuropathy with demyelination has been felt to be so characteristic as to coin the acronym DADS (Distal, Acquired, Demyelinating, Sensory-neuropathy)3. By contrast descriptions of the neuropathy features occurring in another IgM condition, namely Waldenstrom’s macroglobulinemia (WM) are limited4,5. Waldenstrom’s macroglobulinemia is defined by the Revised European American Lymphoma (REAL) and World Health Organization (WHO) as having a bone marrow (BM) infiltrated lymphoplasmacytic lymphoma and IgM paraproteinemia6. In WM the hematologic features of anemia, hepatosplenomegaly, lymphadenopathy, and hyperviscosity have previously been reported but are variably present with current requirement of BM diagnosis7. Some investigators have suggested there are more axonal features in the nerve conduction studies (NCS) in WM, but the diagnosis of WM did not appear to be based on current BM criteria4,5. By contrast, distal, symmetric, chronic demyelinating neuropathy is more commonly described in IgM-MGUS neuropathy patients3,8 including the reports of reduced terminal latency index (TLI), indicating relative slowing in distal motor nerve segments9–11. Tremor has also been described to be one of the possible clinical stigmata of the IgM-MGUS neuropathy12. Some studies have suggested that the existence of myelin-associated glycoprotein antibodies (anti-MAG) may explain the clinical, electrophysiologic, and histologic features of the DADS-IgM-MGUS neuropathy13–15. However, other studies of IgM neuropathy have found little or no difference between the type and severity of neuropathies in IgM patients with or without anti-MAG antibodies16,17. The MAG antibodies are commonly present in IgM amyloid neuropathy and IgM patients without neuropathy and therefore are not routinely used for diagnosis at many institutions including our own18. We conducted this retrospective review to characterize the neuropathies associated with WM and IgM-MGUS to answer whether there are clinical, electrophysiologic and nerve biopsy findings that distinguish the neuropathies associated with WM from IgM-MGUS. In an attempt to study distal predominant involvements we use the previously published formulas to calculate the residual latency (RL) and TLI from routine NCS. The RL19 is a subtraction of the calculated latency from the measured latency. It evaluates the distal segment of the motor nerves and has been reported to be associated with the neuropathy associated with IgM-MGUS20. The TLI is the ratio between the calculated latency [distance/motor conduction velocity (MCV)] and the measured latency, i.e. distal motor latency (DML) and also assesses for selective distal conduction velocity slowing9–11,21.

Item does not contain fulltext Nerve biopsy is often the final step in the diagnostic work-up of neuropathies of unknown origin. The aim of this guideline was to prepare an evidence-based guideline on the methods for performing and evaluating nerve biopsy. The panel performed a search of MEDLINE, hand search of bibliographies of the references retrieved, review of the evidence, and reached agreement by consensus. There were not enough formal studies of diagnostic test accuracy to allow evidence-based recommendations of levels A-C for most questions. The panel summarized the class IV evidence and reached agreement by consensus on the following recommendations: (1) Nerve biopsy should not be performed before adequate clinical, electrophysiological, and laboratory investigation and only be performed with appropriate informed consent. (2) An interactive working relationship with the relevant disciplines involved and the provision of sufficient clinical information is encouraged. (3) Biopsies should be processed and read by professionals with adequate training and experience. (4) Optimal analysis of nerve biopsy is best performed by laboratories that have the facilities and expertise to prepare and evaluate frozen and fixed sections (cryostat, paraffin, and epoxy sections). (5) Immunohistochemistry, teased fiber analysis, electron microscopy, and morphometry may help clarify the diagnosis in some conditions and should be considered as additional studies. 01 september 2010