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Vasculitic neuropathies usually present acutely to subacutely, with an asymmetric pattern, involving multiple peripheral nerve territories. Drug-induced vasculitis is an often overlooked etiology of vasculitic neuropathy.We present the first reported case of nitrofurantoin-associated and an illustrative case of minocycline-associated vasculitic neuropathy, with a review of the literature.The first patient is a 60-year-old woman who developed axonal sensorimotor peripheral neuropathy after nitrofurantoin use, with a superficial radial nerve biopsy confirming vasculitis. The second patient is a 23-year-old woman, with a history of acne vulgaris treated with minocycline, who presented with a subacute right common peroneal mononeuropathy followed by a left deep peroneal mononeuropathy, with elevated antinuclear, perinuclear-antineutrophil cytoplasmic, and myleoperoxidase antibodies, and MPO titers, and a sural nerve biopsy showing large arteriole vasculitis. Finally, we provide a comprehensive review of previously published cases.Medications should be considered as a trigger for medication-induced vasculitic neuropathy. Accurate diagnosis would ensure timely treatment.

Recently, our group found an association between diabetes mellitus (DM) and lumbosacral radiculoplexus neuropathy (LRPN) in Olmsted County, Minnesota; we found a higher risk (odds ratio [OR], 7.91) for developing LRPN in diabetic compared with nondiabetic patients. However, the influence of other comorbidities and anthropomorphic variables was not studied.Demographic and clinical data from 59 LRPN patients and 177 age/sex-matched controls were extracted using the Rochester LRPN epidemiological study. Differences between groups were compared by chi-square/Fisher exact test or Wilcoxon rank-sum test. Uni- and multivariate logistic regression analysis were performed.Factors predictive of LRPN on univariate analysis were DM (OR, 7.91; 95% confidence interval [CI], 4.11-15.21), dementia (OR, 6.36; 95% CI, 1.13-35.67), stroke (OR, 3.81; 95% CI, 1.32-11.01), dyslipidemia (OR, 2.844; 95% CI, 1.53-5.27), comorbid autoimmune disorders (OR, 2.72; 95% CI, 1.07-6.93), hypertension (OR, 2.25; 95% CI, 1.2-4.13), obesity (OR, 2.05; 95% CI, 1.11-3.8), body mass index (BMI) (OR, 1.1; 95% CI, 1.04-1.15), and weight (OR, 1.02; 95% CI, 1.009-1.037). On multivariate logistic regression analysis only DM (OR, 8.03; 95% CI, 3.86-16.7), comorbid autoimmune disorders (OR, 4.58; 95% CI, 1.45-14.7), stroke (OR, 4.13; 95% CI, 1.2-14.25), and BMI (OR, 1.07; 95% CI, 1.01-1.13) were risk factors for LRPN.DM is the strongest risk factor for the development of LRPN, followed by comorbid autoimmune disorders, stroke, and higher BMI. Altered metabolism and immune dysfunction seem to be the most influential factors in the development of LRPN.

Introduction: Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study. Methods: Patients eligible for NEURO-TTRansform were 18–82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II. Results: The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0. Conclusion: The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice.

Background and ObjectiveMultiple studies highlighting the diagnostic utility of neurofascin-155 (NF155)–immunoglobulin G4 (IgG4) in chronic demyelinating inflammatory polyradiculoneuropathy (CIDP) have been published. However, few studies comprehensively address the long-term outcomes or clinical utility of NF155–immunoglobulin M (IgM) or NF155–immunoglobulin G (IgG) in the absence of NF155-IgG4. We evaluated phenotypic and histopathologic specificity and differences in outcomes between these NF155 antibody isotypes or IgG subclasses. We also compare NF155-IgG4-seropositive cases to other seropositive demyelinating neuropathies.MethodsNeuropathy patient sera at Mayo Clinic were tested for NF155-IgG4, NF155-IgG, and NF155-IgM autoantibodies. Demographic and clinical data of all seropositive cases were reviewed.ResultsWe identified 32 NF155 cases (25 NF155-IgG-positive [20 NF155-IgG4-positive], 7 NF155-IgM-seropositive). NF155-IgG4-seropositive patients clinically presented with distal more than proximal muscle weakness, positive sensory symptoms (prickling, asymmetric paresthesia, neuropathic pain), and gait ataxia. Cranial nerve involvement (11/20 [55%]) and papilledema (4/12 [33%]) occurred in many. Electrodiagnostic testing (EDX) demonstrated demyelinating polyradiculoneuropathy (19/20 [95%]). Autonomic involvement occurred in 45% (n = 9, median composite autonomic scoring scale score 3.5, range 1–7). Nerve biopsies from the NF155-IgG4 patients (n = 11) demonstrated grouped segmental demyelination (50%), myelin reduplication (45%), and paranodal swellings (50%). Most patients needed second- and third-line immunosuppression but had favorable long-term outcomes (n = 18). Among 14 patients with serial EDX over 2 years, all except one demonstrated improvement after treatment. NF155-IgG-positive, NF155-IgG4-negative (NF155-IgG-positive) and NF155-IgM-positive patients were phenotypically different from NF155-IgG4-seropositive patients. Sensory ataxia, neuropathic pain, cerebellar dysfunction, and root/plexus MRI abnormalities were significantly more common in NF155-IgG4-positive compared to myelin-associated glycoprotein (MAG)–IgM neuropathy. Chronic immune sensory polyradiculopathy (CISP)/CISP-plus phenotype was more common among contactin-1 neuropathies compared to NF155-IgG4-positive cases. NF155-IgG4-positive cases responded favorably to immunotherapy compared to MAG-IgM-seropositive cases with distal acquired demyelinating symmetric neuropathy (p < 0.001) and had better long-term clinical outcomes compared to contactin-1 IgG (p = 0.04).DiscussionWe report long-term follow-up and clinical outcome of NF155-IgG4 cases. NF155-IgG4 but not IgM or IgG cases have unique clinical–electrodiagnostic signature. We demonstrate NF155-IgG4-positive patients, unlike classical CIDP with neuropathic pain and dysautonomia common at presentation. Long-term outcomes were favorable.Classification of EvidenceThis study provides Class III evidence that NF155-IgG4-seropositive patients, compared to patients with typical CIDP, present with distal more than proximal muscle weakness, positive sensory symptoms, and gait ataxia.

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.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study.Patients eligible for NEURO-TTRansform were 18-82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II.The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0.The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice.ClinicalTrials.gov identifier NCT04136184.Hereditary transthyretin amyloidosis, also called ATTRv amyloidosis, is a rare and serious disease that is passed down within families. People with ATTRv amyloidosis have a genetic variant that causes their liver to make abnormal versions of the transthyretin protein (also known as “TTR”), which clump together into “clusters” called amyloids. The amyloid clusters build up in various body tissues and organs such as the liver, nerves, heart, and kidney, causing damage that could ultimately lead to death. ATTRv amyloidosis is a progressive disease, meaning that it gets worse over time. Liver transplant has traditionally been the only treatment option. Recently, drugs that target TTR have been approved by the FDA, and potential drugs are being tested in clinical trials. Eplontersen is designed to degrade TTR mRNA in the liver and inhibit the production of TTR protein. NEURO-TTRansform is a global phase 3 study investigating the effectiveness and safety of eplontersen in 168 adults with ATTRv amyloidosis with polyneuropathy (ATTRv-PN), a disease in which amyloid accumulation in peripheral nerves causes multisystem damage and eventually death. This scientific article describes the characteristics of the patients at enrollment, including age, gender, geographic location, and disease-related information, to help improve the understanding of ATTRv-PN. NEURO-TTRansform is an ongoing study, and the results will be published at a later time as prespecified in the analysis plan.

Among immune-mediated neuropathies, clinical-electrophysiological overlap exists between multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and multifocal motor neuropathy (MMN). Divergent immune pathogenesis, immunotherapy response, and prognosis exist between these two disorders. MRI reports have not shown distinction of these disorders, but biopsy confirmation is lacking in earlier reports. MADSAM nerves are hypertrophic with onion bulbs, inflammation, and edema, whereas MMN findings are limited to multifocal axonal atrophy.To understand if plexus MRI can distinguish MADSAM from MMN among pathologically (nerve biopsy) confirmed cases.Retrospective chart review and blinded plexus MRI review of biopsy-confirmed MADSAM and MMN cases at Mayo Clinic.Nine brachial plexuses (MADSAM-5, MMN-4) and 6 lumbosacral plexuses (MADSAM-4, MMN-2) had fascicular biopsies of varied nerves. Median follow-up in MADSAM was 93 months (range: 7-180) and 27 (range: 12-109) in MMN (p = 0.34). MRI hypertrophy occurred solely in MADSAM (89%, 8/9) with T2-hyperintensity in both. There was no correlation between time to imaging for hypertrophy, symptom onset age, or motor neuropathy impairments (mNIS). At last follow-up, on diverse immunotherapies mNIS improved in MADSAM (median - 4, range: -22 to 0), whereas MMN worsened (median 3, range: 0 to 6, p = 0.03) on largely IVIG.Nerve hypertrophy on plexus MRI helps distinguish MMN from MADSAM, where better immunotherapy treatment outcomes were observed. These findings are consistent with the immune pathogenesis seen on biopsies. Radiologic distinction is possible independent of time to imaging and extent of motor deficits, suggesting MRI is helpful in patients with uncertain clinical-electrophysiologic diagnosis, especially motor-onset MADSAM.

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.

Vasculitis is an uncommon but treatable and thus important cause of neuropathy. Vasculitic neuropathy can occur as an isolated entity (nonsystemic vasculitic neuropathy) but more frequently evolves in the setting of a systemic vasculitis. Polyarteritis nodosa, anti-neutrophil antibody-associated vasculitides (especially microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis), rheumatoid vasculitis, and cryoglobulinemic vasculitis are the systemic disorders most commonly associated with neuropathy. Both systemic vasculitic and nonsystemic vasculitic neuropathy usually present with a subacutely progressive, asymmetric/multifocal, painful, distal-predominant, axonal, sensory-motor phenotype. Available evidence suggests that nonsystemic and most systemic vasculitic neuropathies are mediated primarily by T-cell mechanisms, but immune complexes probably contribute. Evaluation of patients with suspected vasculitic neuropathy usually includes EMG, laboratory studies, and nerve/muscle biopsy. In patients lacking definite vasculitis in nerve biopsy, clinically probable vasculitic neuropathy can be diagnosed by recourse to supportive clinicopathologic findings. Vasculitic neuropathies occurring in the ANCA-associated vasculitides are treated in accordance with the underlying systemic vasculitis. About 50% of neuropathy-predominant primary systemic vasculitides are not controlled by initial corticosteroid monotherapy. IVIg or rituximab can induce remission in refractory or relapsing patients. Long-term outcome is reasonably good.

Background Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle). Methods The patient underwent magnetic resonance imaging (MRI) and whole body 18 F-florbetapir positron emission tomography (PET)/MRI. Results Whole body 18 F-florbetapir PET/MRI revealed abnormal low-level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis. Conclusions 18 F-florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

Objectives The objective of the study is to distinguish the mechanisms of disease for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN), which we believe to be fundamentally different. However, distinguishing the mechanisms is more difficult when the presentation of CIDP is motor-predominant, focal, or asymmetric. Methods We describe 3 focal, motor-predominant, representative cases that could be interpreted on clinical and/or electrophysiological grounds as either MMN or focal CIDP, and present pathological findings. Results We highlight pathological differences in these cases, and provide an argument that CIDP and MMN are distinct entities with different pathophysiological mechanisms-chronic demyelination for CIDP, and an immune-mediated attack on paranodal motor axons for MMN. Conclusions Based on clinical evaluation, electrophysiology, and nerve biopsy pathology, we can divide the conditions into inflammatory demyelinating neuropathy (focal CIDP) versus chronic axonal neuropathy (MMN). The divergent pathological findings provide further evidence that CIDP and MMN are fundamentally different disorders.

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.

A 51-year-old healthy man sought care for a 6-month history of progressive, distal, lower extremity weakness, imbalance, and numbness in the feet. Neurologic examination showed a steppage gait, upper and lower extremity weakness, distal greater than proximal, absent tendon reflexes, and large fiber–predominant sensation loss in the feet. Nerve conduction studies showed marked temporal dispersion and slowed conductions. Cerebrospinal fluid analysis showed an increased protein concentration, 1 white blood cell/µL, and normal glucose level. Lumbar spine magnetic resonance imaging showed enlargement and enhancement of the nerve roots in the cauda equina, along with hypointensity in lumbar vertebral bodies. He underwent right sural nerve biopsy that showed an inflammatory demyelinating process. The patient was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and started on intravenous immunoglobulin. He was markedly worse at 12-week follow-up, with severe proximal and distal weakness and requiring the use of a walker. The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy was revisited. Lumbar spine magnetic resonance imaging again showed enhancement of the nerve roots. Because of concern for neurolymphomatosis, a proximal fascicular nerve biopsy of the right sciatic nerve was performed. It showed the hallmark pathologic features of chronic inflammatory demyelinating polyradiculoneuropathy: endoneurial inflammation and signs of long-standing demyelination and remyelination with stacks on Schwann cell processes. The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy was confirmed. Intravenous immunoglobulin was stopped, and the patient was started on an aggressive plasma exchange regimen. He had modest improvement. Azathioprine was also started. The patient continued to improve. He remained on this regimen for 2 years. Over the next year, the intravenous methylprednisolone dose was reduced. He was weaned off plasma exchange and intravenous methylprednisolone. At the last follow-up the disease was still in remission. Chronic inflammatory demyelinating polyradiculoneuropathy was described and named in 1975. It is a fairly symmetric peripheral neuropathy that usually presents with proximal and distal weakness, imbalance, and large fiber sensory dysfunction. Cerebrospinal fluid analysis shows albuminocytologic dissociation in 80% to 95% of those with typical chronic inflammatory demyelinating polyradiculoneuropathy.

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.

While thrombotic microangiopathy (TMA) can commonly affect the kidney, peripheral nerve involvement has not been reported to date. A 56-year-old man, recipient of a kidney allograft, reported severe headaches, tremors, and diarrhea followed by sudden-onset right foot drop after increasing his dose of tacrolimus. He then developed acute right hand pain, numbness, and weakness. At presentation, neurological examination and electroneuromyography confirmed the presence of right worse than left, sciatic and ulnar mononeuropathies. Kidney biopsy showed evidence of a thrombotic microangiopathy. Similarly, nerve biopsy showed thrombosis of epineurial blood vessels with minimal inflammation. Herein, we demonstrated that thrombotic microangiopathy can involve the peripheral nerves, resulting in major morbidity. Distinguishing TMA from vasculitis is important because it has major treatment implications.

Single-organ vasculitis of the peripheral nervous system (PNS) is often designated nonsystemic vasculitic neuropathy (NSVN). Several variants or subtypes have been distinguished, including migratory sensory neuropathy, postsurgical inflammatory neuropathy, diabetic radiculoplexus neuropathies, skin-nerve vasculitides, and, arguably, neuralgic amyotrophy. NSVN often presents as nondiabetic lumbosacral radiculoplexus neuropathy (LRPN). This review updates classification, clinical features, epidemiology, and imaging of these disorders.A recent study showed the annual incidence of LRPN in Olmstead County, Minnesota to be 4.16/100 000:2.79/100 000 diabetic and 1.27/100 000 nondiabetic. This study was the first to determine the incidence or prevalence of any vasculitic neuropathy. In NSVN, ultrasonography shows multifocal enlargement of proximal and distal nerves. In neuralgic amyotrophy, MRI and ultrasound reveal multifocal enlargements and focal constrictions in nerves derived from the brachial plexus. Histopathology of these chronic lesions shows inflammation and rare vasculitis. Diffusion tensor imaging of tibial nerves in NSVN revealed decreased fractional anisotropy in one study.Single-organ PNS vasculitides are the most common inflammatory neuropathies. Neuralgic amyotrophy might result from PNS vasculitis, but further study is necessary. The usefulness of focal nerve enlargements or constrictions in understanding pathological mechanisms, directing biopsies, and monitoring disease activity in NSVN should be further investigated.

Objective To characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. Methods Patients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient‐derived dermal fibroblast cultures for collagen XII. Results Four independent families with childhood‐onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal‐predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in‐frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient‐derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns. Interpretation This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1‐related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele‐specific knockdown using siRNAs specifically designed to target a patient’s dominant COL12A1 disease allele.

"The vasculitic neuropathies encompass a wide range of disorders characterized by ischemic injury to the vasa nervorum. Patients with vasculitic neuropathies develop progressive, painful sensory or sensorimotor deficits that are typically multifocal or asymmetric. Depending on the underlying etiology, the vasculitis may be confined to the peripheral nervous system; may be one manifestation of a primary systemic vasculitis; or one manifestation of a systemic vasculitis that is secondary to underlying connective tissue disease, drug exposure, viral infection, or paraneoplastic syndrome. This article reviews the classification, clinical presentation, diagnostic approach, etiologies, and treatment of the vasculitic neuropathies."

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.

Background and ObjectivesThere are limited population-based data on small fiber neuropathy (SFN). We wished to determine SFN incidence, prevalence, comorbid conditions, longitudinal impairments, and disabilities.MethodsTest-confirmed patients with SFN in Olmsted, Minnesota, and adjacent counties were compared 3:1 to matched controls (January 1, 1998–December 31, 2017).ResultsNinety-four patients with SFN were identified, with an incidence of 1.3/100,000/y that increased over the study period and a prevalence of 13.3 per 100,000. Average follow-up was 6.1 years (0.7–43 years), and mean onset age was 54 years (range 14–83 years). Female sex (67%), obesity (body mass index mean 30.4 vs 28.5 kg/m2), insomnia (86% vs 54%), analgesic-opioid prescriptions (72% vs 46%), hypertriglyceridemia (180 mg/dL mean vs 147 mg/dL), and diabetes (51% vs 22%, p < 0.001) were more common (odds ratio 3.8–9.0, all p < 0.03). Patients with SFN did not self-identify as disabled with a median modified Rankin Scale score of 1.0 (range 0–6) vs 0.0 (0–6) for controls (p = 0.04). Higher Charlson comorbid conditions (median 6, range 3–9) occurred vs controls (median 3, range 1–9, p < 0.001). Myocardial infarctions occurred in 46% vs 27% of controls (p < 0.0001). Classifications included idiopathic (70%); diabetes (15%); Sjögren disease (2%); AL-amyloid (1%); transthyretin-amyloid (1%); Fabry disease (1%); lupus (1%); postviral (1%); Lewy body (1%), and multifactorial (5%). Foot ulcers occurred in 17, with 71% having diabetes. Large fiber neuropathy developed in 36%, on average 5.3 years (range 0.2–14.3 years) from SFN onset. Median onset Composite Autonomic Severity Score (CASS) was 3 (change per year 0.08, range 0–2.0). Median Neuropathy Impairment Scale (NIS) score was 2 at onset (range 0–8, change per year 1.0, range −7.9 to +23.3). NIS score and CASS change >1 point per year occurred in only AL-amyloid, hereditary transthyretin-amyloid, Fabry, uncontrolled diabetes, and Lewy body. Death after symptom onset was higher in patients with SFN (19%) vs controls (12%, p < 0.001), 50% secondary to diabetes complications.DiscussionIsolated SFN is uncommon but increasing in incidence. Most patients do not develop major neurologic impairments and disability but have multiple comorbid conditions, including cardiovascular ischemic events, and increased mortality from SFN onsets. Development of large fiber involvements and diabetes are common over time. Targeted testing facilitates interventional therapies for diabetes but also rheumatologic and rare genetic forms.

Immune checkpoint inhibitor (ICI) indications have broadened considerably in the last few years.1 The aim of this study is to provide an update on clinical presentations, serological associations and outcomes of ICI-related neuropathy (irNeuropathy) in the context of expanding use of cancer immunotherapy for neuroendocrine tumours. All patients with irNeuropathy who were evaluated at Mayo Clinic from 01 January 2015 to 10 October 2020 were identified by electronic medical record search. Patients with neuropathies secondary to cytotoxic chemotherapy, radiation, diabetes, structural or compressive aetiologies, prior to administration of ICIs were excluded. Clinical presentations, electrodiagnostic features, autoantibody profiles and clinical outcomes were reviewed. Twenty patients (13 males) with irNeuropathy were identified. Median age was 64 (range 31–81) years. Two patients (10%) had a diagnosis of autoimmune disorders prior to ICI initiation; one with Graves’ disease and the other with rheumatoid arthritis. ICI regimens included programmed cell death-1 receptor (PD-1) or programmed death-ligand 1 inhibitors (n=15, 75%), cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor (n=2, 10%) and a combination of PD-1 and CTLA-4 (n=3, 15%). The median number of ICI cycles and median time from ICI initiation to onset of irNeuropathy symptoms were 2.5 cycles (range 1–20) and 9 weeks (range 1–56), respectively. ICIs were discontinued for all patients after diagnosis of irNeuropathy. Two non-neuroendocrine patients were restarted on different type of ICIs after irNeuropathy had resolved; one of these patients developed recurrent ICI-related phrenic neuropathy. ### Neuroendocrine tumour associated irNeuropathies All neuroendocrine tumour patients (small cell lung cancer, n=3; Merkel cell cancer, n=1) with irNeuropathies were seropositive for onconeural antibodies (type 1 antineuronal nuclear antibody (ANNA1, anti-Hu), n=2; ANNA1 and collapsin response …

Amyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases, pathologically characterized by extracellular amyloid fibrils producing congophillic amorphous deposits in organs and tissues, which may lead to severe organ dysfunction and mortality. Clinical presentations vary and are often nonspecific, depending on what organs or tissues are affected. In systemic amyloidosis, the peripheral nervous system is commonly affected, whereas the skeletal muscles are only rarely involved. Immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin (ATTRv) amyloidosis are the most frequent types of systemic amyloidosis involving the neuromuscular system. Localized amyloidosis can occur in skeletal muscle, so-called isolated amyloid myopathy. Amyloid neuropathy typically involves small myelinated and unmyelinated sensory and autonomic nerve fibers early in the course of the disease, followed by large myelinated fiber sensory and motor deficits. The relentlessly progressive nature with motor, painful sensory and severe autonomic dysfunction, profound weight loss, and systemic features are distinct characteristics of amyloid neuropathy. Amyloid myopathy presentation differs between systemic amyloidosis and isolated amyloid myopathy. Long-standing symptoms, distal predominant myopathy, markedly elevated creatine kinase level, and lack of peripheral neuropathy or systemic features are highly suggestive of isolated amyloid myopathy. In ATTR and AL amyloidosis, early treatment correlates with favorable outcomes. Therefore, awareness of these disorders and active screening for amyloidosis in patients with neuropathy or myopathy are crucial in detecting these patients in the everyday practice of neuromuscular medicine. Herein, we review the clinical manifestations of neuromuscular amyloidosis and provide a diagnostic approach to this disorder.

Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle).The patient underwent magnetic resonance imaging (MRI) and whole bodyWhole body

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.

Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by mutations of the NF2 tumor suppressor gene that predisposes patients to develop multiple tumors in the peripheral and central nervous system. The most common neoplasms associated with the disease are schwannomas and meningiomas. Both have been shown to contain abnormalities in chromosome 22 and the NF2 gene, suggesting a genetic component to their pathogenesis. Perineuriomas are rare benign tumors arising from the perineural cells. They are commonly classified as intraneural and soft tissue perineuriomas. Several studies have reported mutations in genes on chromosome 22 in both types of perineuriomas, and there are reports of soft tissue perineuriomas associated with NF2 gene mutations. Despite this, perineuriomas are not considered as part of the NF2 constellation of tumors. The electronic medical records were searched for patients with a radiologic or pathologic diagnosis of intraneural perineurioma. Patients with clinical signs and genetic testing consistent with a diagnosis of NF2 were further evaluated. Of 112 patients meeting inclusion criteria, there were two cases of intraneural perineurioma in patients with NF2 treated at our institution (1.8%). We include a third patient treated at another facility for whom we performed a virtual consultation. The rarity of both NF2 and perineuriomas could explain the rarity of perineuriomas in the setting of NF2. Furthermore, there is divergent intraneural and soft tissue perineurioma somatic mutation pathogenesis, and there may be cytogenetic overlap between perineuriomas and multiple tumor syndromes. Our observed occurrence of intraneural perineurioma in the setting of NF2 in several patients provides further evidence of a potential link between the NF2 gene and the development of intraneural perineurioma.

Objective To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo. Methods Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures—the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)—were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66. Results Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm. Conclusion Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.

There are many causes for brachial and lumbosacral plexopathies including stretch, compression, traumatic, lymphomatous, tumor infiltration, radiation, necrotizing vasculitis, and inflammatory damage, among others. Cervical and lumbosacral radiculoplexus neuropathies (CRPN and LSRPN) refer to inflammatory neurologic disorders affecting predominantly the brachial and lumbosacral plexus, respectively. As cervical and lumbosacral roots, the plexus proper and the peripheral nerves coming from the plexus are often involved; the terms CRPN and LSRPN are used to describe these conditions. These illnesses usually present with abrupt onset of pain, followed by weakness and numbness that has unilateral or asymmetrical bilateral involvement often associated with weight loss. The pathogenesis of CRPN and LSRPN usually is ischemic nerve injury from microvasculitis. The clinical symptoms and signs depend on the anatomy of the plexus involved. The best treatment for the inflammatory plexopathies is unclear due to few controlled trials, but given that the pathogenesis is likely inflammatory/microvasculitis, immunotherapy seems desirable. The prognosis is usually good with most patients having spontaneous improvement or recovery, although residual deficits can occur. In this chapter, we discuss CRPN and LSRPN as well as the other causes of brachial and lumbosacral plexopathies.

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.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is probably the best recognized progressive immune-mediated peripheral neuropathy. It is characterized by a symmetrical, motor-predominant peripheral neuropathy that produces both distal and proximal weakness. Large-fiber abnormalities (weakness and ataxia) predominate, whereas small-fiber abnormalities (autonomic and pain) are less common. The pathophysiology of CIDP is inflammatory demyelination that manifests as slowed conduction velocities, temporal dispersion, and conduction block on nerve conduction studies and as segmental demyelination, onion-bulb formation, and endoneurial inflammatory infiltrates on nerve biopsies. Although spinal fluid protein levels are generally elevated, this finding is not specific for the diagnosis of ClDP. Other neuropathies can resemble CIDP, and it is important to identify these to ensure correct treatment of these various conditions. Consequently, metastatic bone surveys (for osteosclerotic myeloma), serum electrophoresis with immunofixation (for monoclonal gammopathies), and human immunodeficiency virus testing should be considered for testing in patients with suspected CIDP. Chronic inflammatory demyelinating polyradiculoneuropathy can present as various subtypes, the most common being the classical symmetrical polyradiculoneuropathy and the next most common being a localized asymmetrical form, multifocal CIDP. There are 3 well-established, first-line treatments of CIDP-corticosteroids, plasma exchange, and intravenous immunoglobulin-with most experts using intravenous immunoglobulin as first-line therapy. Newer immune-modulating drugs can be used in refractory cases. Treatment response in CIDP should be judged by objective measures (improvement in the neurological or electrophysiological examination), and treatment needs to be individualized to each patient.

Introduction Multifocal motor neuropathy (MMN) is a motor only, asymmetric onset neuropathy that is relatively treatment-refractory compared with classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. Methods We reviewed 35 patients seropositive for GM1 (monosialo-asialo [immunoglobulin M, IgM; immunoglobulin G, IgG]) and/or GD1b (disialo [IgG, IgM]) autoantibodies having MMN, classic CIDP, or MADSAM. Immune-treatment responsiveness and clinical course was compared with antibody negative disease controls. Results Seventy-nine percent of seropositives with an initial diagnosis of MMN were immunotherapy responsive compared with 46% of seronegatives (P = 0.045). Eight ganglioside antibody positive MMN patients of 19 (42%) developed sensory findings consistent with MADSAM compared with 3 of 41 (7%) seronegative MMN patients (P = 0.003). MMN and MADSAM patients with ganglioside antibody positivity had more sustained treatment responses (P = 0.03). Discussion Patients initially diagnosed with MMN seropositive for diverse GM1 autoantibodies appear more likely to have sustained treatment response and evolution to MADSAM. Muscle Nerve 57: 1000-1005, 2018.

We report a 73-year-old man with Val142Ile transthyretin (TTR) amyloidosis and an atypical clinical presentation of upper-extremity-predominant neuropathy without significant autonomic or cardiac involvement. TTR familial amyloid polyneuropathy commonly presents as length-dependent sensorimotor polyneuropathy with marked and early autonomic involvement. Multiple pathogenic mutations in TTR gene have been identified, of which Val50Met is commonly associated with TTR familial amyloid polyneuropathy, and Val142Ile is commonly associated with familial amyloid cardiomyopathy. Our patient is from a nonendemic region, without family history for amyloidosis. Predominant upper-extremity neuropathy, without significant cardiac or autonomic involvement, distinguishes this case from previously reported Val142Ile-mutated TTR amyloidosis.

Silver is known to be a potent bactericidal agent. It has a proinflammatory effect by inducing inflammatory cytokines and reactive oxygen species. Silver can also have a direct cytotoxic effect on immune cells and can cause endothelial cell injury.1 At low levels, silver is thought to be nontoxic. It only deposits in the skin and causes a silver-blue discoloration called argyria. Lately, there has been an increase in the use of silver nanoparticles as antimicrobial agents or via alternative medicine, which reignited interest in further studying silver toxicity. In the CNS, silver can disrupt the blood–brain barrier and be toxic to neurons and astrocytes.1 There have been case reports of silver toxicity associated with seizures, cortical basal degeneration, and psychosis.2–4 On the other hand, the effect of silver on the peripheral nervous system remains poorly explored. In this report, we present a case of a peripheral neuropathy associated with argyria with detailed clinical, laboratory, and histopathologic findings.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired autoimmune demyelinating polyneuropathy characterized by symmetrical diffuse weakness that also can rarely affect bulbar and respiratory muscles. The study objective was to describe perioperative outcomes of patients with CIDP who received general anesthesia. This retrospective observational study evaluated patients with active (diagnosed or treated within the previous year) CIDP who underwent general anesthesia at our institution between January 1, 2010, and December 31, 2015. Medical records were reviewed for perioperative outcomes with emphasis on respiratory complications or unexpected reactions to muscle relaxants. Seventeen patients with CIDP underwent general anesthesia, of whom 16 had muscle weakness. Succinylcholine was used in 5 cases (29.4%) and nondepolarizing muscle relaxants in 11 cases (64.7%). Two patients required postoperative mechanical ventilation; one was critically ill and the other had open heart surgery. One patient had aspiration on the second postoperative day and required endotracheal intubation and mechanical ventilation for 3 days. Three patients had worsening CIDP symptoms: 1 acutely after surgery; 1 several months later; and 1 who died in the hospital. The patient who died underwent lengthy abdominal exploration, had acute worsening of neurologic symptoms, and died after 46 days of malnutrition. Anesthetic concerns of patients with CIDP include frailty, bulbar dysfunction, and the effects of immunosuppressive therapy. Although our patients tolerated neuromuscular drugs, substantial theoretical concerns with these medications in patients with demyelinating neuropathies preclude safety in this population without further study.

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.