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Background and Purpose Methods Results Conclusions Small‐fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337‐18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group.In this retrospective single‐center study, we analyzed the frequency of the c.76G>A and c.337‐18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database.We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337‐18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database.The c.76G>A and c.337‐18G>C TTR gene variants are not associated with SFN. [ABSTRACT FROM AUTHOR]

Background: The factors underlying the topography of nitrous oxide (N2O)‐induced neurological complications are unknown. Methods: We included all consecutive patients admitted to the university hospital of Marseille for N2O‐induced neurological complications in a prospective observational study. Patients underwent neurological examination, spinal cord magnetic resonance imaging, and nerve conduction studies within the first 4 weeks after admission. Results: In total, 61 patients were included: 45% with myeloneuropathy, 34% with isolated myelopathy, and 21% with isolated neuropathy. On multivariable analysis, the odds of myelopathy were associated with the amount of weekly N2O consumption (~600 g cylinder per week, odds ratio [OR] = 1.11, 95% confidence interval [CI] = 1.001–1.24). The extent of the myelopathy (number of vertebral segments) was correlated with the number of ~600‐g cylinders consumed weekly (ρ = 0.40, p < 0.005). The odds of neuropathy were associated with the duration of consumption (per month; OR = 1.29, 95% CI = 1.05–1.58). Mean lower‐limb motor nerve amplitude was correlated with the duration of consumption (in months; ρ = −0.34, p < 0.05). Conclusions: The odds of myelopathy increased with the amount of N2O consumption, and the odds of neuropathy increased with the duration of N2O exposure, which suggests distinct pathophysiological mechanisms underlying these two neurological complications. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim of this study was to determine the prevalence of anti‐myelin‐associated glycoprotein (MAG) neuropathy and the current status of such patients in Japan. Methods: We conducted a nationwide survey in 2021 using established epidemiological methods. Questionnaires were sent to all neurology and pediatric neurology departments throughout Japan to identify patients with anti‐MAG neuropathy. An initial questionnaire was used to determine the number of patients, with a second one used to collect detailed clinical information. Results: The estimated number of patients with anti‐MAG neuropathy was 353, with a prevalence of 0.28 per 100,000 and an incidence of 0.05 per 100,000. The detailed clinical profiles of 133 patients were available. The median (range) age of onset was 67 (30–87) years, with a prominent peak in the age range 66–70 years, and the male‐to‐female ratio was 3.6. Most patients had distal sensory‐predominant polyneuropathy, and neuropathic pain (50%), or sensory ataxia (42%), while 18% had Waldenström's macroglobulinemia or multiple myeloma. Intravenous immunoglobulin was the most frequently used treatment (65%), but the response rate was <50%, whereas rituximab was given in 32% of patients, and 64% of these showed improvement. At the last visit, 27% of patients could not walk independently. Conclusions: This study on anti‐MAG neuropathy provides updated insights into the epidemiology of this disease, clinical profiles, and treatment approaches in Japan. Rituximab therapy, used for only one‐third of the patients, demonstrated efficacy. During the final visit, a quarter of the patients were unable to walk independently. Further studies are warranted to determine the optimal management of this rare and intractable disorder. [ABSTRACT FROM AUTHOR]

Background and purpose: Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to epidermal Aδ‐ and C‐fibers was tested. Methods: Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg. Results: Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment. Conclusion: Serum NfL levels cannot serve as a biomarker for small fiber damage. [ABSTRACT FROM AUTHOR]

Background: Anti‐myelin‐associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti‐MAG neuropathy. Methods: This phase 1b, open‐label, single‐arm, dose‐finding trial was conducted from 2019 through 2022. The original design included a dose‐escalation/extension phase followed by a dose‐expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. Results: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58–77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1–40 years). The study terminated early due to higher‐than‐expected non‐dose‐limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ‐5D (−0.95, 95% CI −1.81 to −0.09) and total IgM (−162 mg/dL, 95% CI −298 to −26) showed signs of improvement by month 12. Conclusions: Lenalidomide was associated with higher‐than‐expected VTE events in anti‐MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti‐MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. Trial Registration: Lenalidomide in Anti‐MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019. [ABSTRACT FROM AUTHOR]

Background and purpose: Despite thiamine deficiency being a lesser‐known entity in modern times, beriberi in various forms, including thiamine deficiency‐related neuropathy, remains endemic in Kashmir due to the consumption of polished rice as a staple food. This observational study investigates cases of peripheral neuropathy of unknown etiology and their potential responsiveness to thiamine administration. Methods: This prospective study enrolled adult patients presenting to the emergency department with weakness consistent with thiamine deficiency‐related neuropathy and conducted a therapeutic challenge with thiamine on 41 patients. Response to thiamine therapy was monitored based on subjective and objective improvements in weakness and power. Patients were divided into thiamine responders (n = 25) and nonresponders (n = 16) based on their response to thiamine therapy and nerve conduction studies. Results: Most of the baseline characteristics were similar between responders and nonresponders, except the responders exhibited lower thiamine levels and higher partial pressure of oxygen and lactate levels compared to nonresponders. All patients had a history of consuming polished rice and traditional salt tea. Although weakness in the lower limbs was present in both groups, nonresponders were more likely to exhibit weakness in all four limbs. Clinical improvement was observed within 24 h, but proximal muscle weakness persisted for an extended period of time. Conclusions: Thiamine deficiency‐related neuropathy presents with predominant lower limb weakness, exacerbated by vomiting, poor food intake, psychiatric illness, and pregnancy. Thiamine challenge should be followed by observation of clinical and biochemical response. [ABSTRACT FROM AUTHOR]

Background: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. Methods: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non‐caseating epithelioid cell granuloma in their sural nerve biopsy specimens. Results: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. Conclusions: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy. [ABSTRACT FROM AUTHOR]

Background and purpose: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate generating amyloid fibrils. Methods: A prospective systematic genetic screening for ATTRv‐PN was proposed in patients presenting with a sensory–motor idiopathic polyneuropathy and two or more "red flags" among the following: family history of polyneuropathy or cardiopathy, bilateral carpal tunnel syndrome, cardiac insufficiency, renal amyloidosis, lumbar tract stenosis, autonomic dysfunction, idiopathic gastrointestinal disease, amyloid deposits on biopsy, and vitreous opacities. The detection rate was calculated, and nonparametric analyses were carried out to underline differences among screened positive versus negative patients. Results: In the first step, 145 suspected patients underwent genetic testing, revealing a diagnosis of ATTRv‐PN in 14 patients (10%). Then, cascade screening allowed early recognition of 33 additional individuals (seven symptomatic ATTRv‐PN patients and 26 presymptomatic carriers) among 84 first‐degree relatives. Patients with a positive genetic test presented a higher frequency of unexplained weight loss, gastrointestinal symptoms, and family history of cardiopathy. Conclusions: A systematic screening for ATTRv‐PN yielded an increased recognition of the disease in our neurological clinic. Unexplained weight loss associated with axonal polyneuropathy had the highest predictive value in the guidance of clinical suspicion. A focused approach for the screening of ATTRv‐PN could lead to an earlier diagnosis and identification of asymptomatic carriers, who will be promptly treated after a strict follow‐up at the clinical onset. [ABSTRACT FROM AUTHOR]

Background and purpose: Biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages. Methods: RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs). Results: Forty patients, median age at onset 54 years (interquartile range [IQR] 49–61) and disease duration 10 years (IQR 6–16), were enrolled. Mild‐to‐moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5–22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7–44.3) were frequently reported and showed scarce correlation with disease duration. A non‐length‐dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5, p < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1, p < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. Conclusions: RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder. [ABSTRACT FROM AUTHOR]

Background: Recreational use of nitrous oxide (N2O) has dramatically increased in recent years, resulting in numerous cases of acute sensorimotor tetraparesis secondary to nitrous oxide‐induced neuropathy (N2On). Challenging clinical features can mimic Guillain‐Barré syndrome (GBS), the main differential diagnosis upon admission. The most sensitive biomarkers for distinguishing between these two conditions remain to be determined. Methods: Fifty‐eight N2On patients from three referral centers were retrospectively included over a 2‐year period and compared to GBS patients hospitalized during the same timeframe (47 patients). Collected demographic, clinical, biological, and electrophysiological data were compared between the two groups. Results: The typical N2On clinical pattern included distal sensorimotor deficit in lower limbs with absent reflexes, proprioceptive ataxia, and no cranial involvement (56.7% of our cohort). Misleading GBS‐like presentations were found in 14 N2On patients (24.1%), and 13 patients (22.4%) did not report N2O use during initial interview. Only half the N2On patients presented with reduced vitamin B12 serum levels upon admission. A slightly increased cut‐off (<200 pmol/L) demonstrated 85.1% sensitivity and 84.5% specificity in distinguishing N2On from GBS. Only 6.9% of N2On patients met the criteria for primary demyelination (p < 0.01), with only one presenting conduction blocks. A diagnostic algorithm combining these two biomarkers successfully classified all GBS‐like N2On patients. Conclusions: Vitamin B12 serum level < 200 pmol/L cut‐off and conduction blocks in initial electrophysiological study are the two most sensitive biomarkers for rapidly distinguishing N2On from GBS patients. These two parameters are particularly useful in clinically atypical N2On with GBS‐like presentation. [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to determine the association of hospital‐diagnosed morbidity and recent surgery with risk of subsequent Guillain–Barré syndrome (GBS) development. Methods: We conducted a nationwide population‐based case–control study of all patients with first‐time hospital‐diagnosed GBS in Denmark between 2004 and 2016 and 10 age‐, sex‐, and index date‐matched population controls per case. Hospital‐diagnosed morbidities included in the Charlson Comorbidity Index were assessed as GBS risk factors up to 10 years prior to the GBS index date. Incident major surgery was assessed within 5 months prior. Results: In the 13‐year study period, there were 1086 incident GBS cases, whom we compared with 10,747 matched controls. Any pre‐existing hospital‐diagnosed morbidity was observed in 27.5% of GBS cases and 20.0% of matched controls, yielding an overall matched odds ratio (OR) of 1.6 (95% confidence interval [CI] = 1.4–1.9). The strongest associations were found for leukemia, lymphoma, diabetes, liver disease, myocardial infarction, congestive heart failure, and cerebrovascular disease, with 1.6‐ to 4.6‐fold increased risks of subsequent GBS. GBS risk was strongest for morbidities newly diagnosed during the past 5 months (OR = 4.1, 95% CI = 3.0–5.6). Surgical procedures within 5 months prior were observed in 10.6% of cases and 5.1% of controls, resulting in a GBS OR of 2.2 (95% CI = 1.8–2.7). Risk of developing GBS was highest during the first month following surgery (OR = 3.7, 95% CI = 2.6–5.2). Conclusions: In this large nationwide study, individuals with hospital‐diagnosed morbidity and recent surgery had a considerably increased risk of GBS. [ABSTRACT FROM AUTHOR]

Background and purpose: The modified Toronto Clinical Neuropathy Score (mTCNS) is a valid and reliable scale for the diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). The aim of this study was to determine the optimal diagnostic cut‐off value of the mTCNS in diverse polyneuropathies (PNPs). Methods: Demographics and mTCNS values were retrospectively extracted from an electronic database of 190 patients with PNP and 20 normal controls. Sensitivity, specificity, and likelihood ratios and area under the receiver‐operating characteristic (ROC) curve were determined for each diagnosis and different cut‐off values of the mTCNS. Patients underwent clinical, electrophysiological and functional assessments of their PNP. Results: Forty‐three percent of PNP was related to diabetes or impaired glucose tolerance. mTCNS was significantly higher in patients with PNP than in those without (15.27 ± 8 vs. 0.79 ± 1.4; p = 0.001). The cut‐off value for diagnosing PNP was ≥3 (sensitivity 98.4%, specificity 85.7%, positive likelihood ratio 6.88). The area under the ROC curve was 0.987. Conclusion: A value of 3 or more on the mTCNS is recommended for the diagnosis of PNP. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the neuroretinal structure of young patients with Leber hereditary optic neuropathy (LHON). Methods: For this retrospective cross‐sectional analysis, the peripapillary retinal nerve fiber layer (pRNFL) thickness and the macular retinal layer volumes were measured by optical coherence tomography. Patients aged 12 years or younger at disease onset were assigned to the childhood‐onset (ChO) group and those aged 13–16 years to the early teenage‐onset (eTO) group. All patients received treatment with idebenone. The same measurements were repeated in age‐matched control groups with healthy subjects. Results: The ChO group included 11 patients (21 eyes) and the eTO group 14 patients (27 eyes). Mean age at onset was 8.6 ± 2.7 years in the ChO group and 14.8 ± 1.0 years in the eTO group. Mean best‐corrected visual acuity was 0.65 ± 0.52 logMAR in the ChO group and 1.60 ± 0. 51 logMAR in the eTO group (p < 0.001). Reduced pRNFL was evident in the eTO group compared to the ChO group (46.0 ± 12.7 μm vs. 56.0 ± 14.5 μm, p = 0.015). Additionally, a significantly lower combined ganglion cell and inner plexiform layer volume was found in the eTO compared to the ChO group (0.266 ± 0.0027 mm3 vs. 0.294 ± 0.033 mm3, p = 0.003). No difference in these parameters was evident between the age‐matched control groups. Conclusion: Less neuroaxonal tissue degeneration was observed in ChO LHON than in eTO LHON, a finding that may explain the better functional outcome of ChO LHON. [ABSTRACT FROM AUTHOR]

Background and purpose: Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot–Marie–Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD‐related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. Methods: Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. Results: Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. Conclusions: This SORD‐inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22‐fold) compared to controls, with both diagnostic and potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Background and purpose: Intramuscular blood flow increases during physical activity and may be quantified immediately following exercise using power Doppler sonography. Post‐exercise intramuscular blood flow is reduced in patients with muscular dystrophy, associated with disease severity and degenerative changes. It is not known if intramuscular blood flow is reduced in patients with neuropathy, nor if it correlates with muscle strength and structural changes. The aim was to determine whether blood flow is reduced in patients with polyneuropathy due to Charcot–Marie–Tooth disease type 1 (CMT1) and to compare more affected distal to less affected proximal muscles. Methods: This was a cross‐sectional study including 21 healthy volunteers and 17 CMT patients. Power Doppler ultrasound was used to quantify post‐exercise intramuscular blood flow in distal (gastrocnemius) and proximal (elbow flexor) muscles. Intramuscular blood flow was compared to muscle echo intensity, muscle strength, disease severity score, patient age and electromyography. Results: Polyneuropathy patients showed reduced post‐exercise blood flow in both gastrocnemius and elbow flexors compared to controls. A more prominent reduction was seen in the gastrocnemius (2.51% vs. 10.34%, p < 0.0001) than in elbow flexors (4.48% vs. 7.03%, p < 0.0001). Gastrocnemius intramuscular blood flow correlated with muscle strength, disease severity and age. Receiver operating characteristic analysis showed that quantification of intramuscular blood flow was superior to echo intensity for detecting impairment in the gastrocnemius (area under the curve 0.962 vs. 0.738, p = 0.0126). Conclusion: Post‐exercise intramuscular blood flow is reduced in CMT1 polyneuropathy. This reduction is present in both impaired distal and minimally affected proximal muscles, indicating it as an early marker of muscle impairment due to neuropathy. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim was to characterize the phenotypic and genotypic features of myelin protein zero (MPZ) related neuropathy and provide baseline data for longitudinal natural history studies or drug clinical trials. Method: Clinical, neurophysiological and genetic data of 37 neuropathy patients with MPZ mutations were retrospectively collected. Results: Nineteen different MPZ mutations in 23 unrelated neuropathy families were detected, and the frequency of MPZ mutations was 5.84% in total. Mutations c.103_104InsTGGTTTACACCG, c.513dupG, c.521_557del and c.696_699delCAGT had not been reported previously. Hot spot mutation p.Thr124Met was detected in four unrelated families, and seven patients carried de novo mutations. The onset age indicated a bimodal distribution: prominent clustering in the first and fourth decades. The infantile‐onset group included 12 families, the childhood‐onset group consisted of two families and the adult‐onset group included nine families. The Charcot–Marie–Tooth Disease Neuropathy Score ranged from 3 to 25 with a mean value of 15.85 ± 5.88. Mutations that changed the cysteine residue (p.Arg98Cys, p.Cys127Trp, p.Ser140Cys and p.Cys127Arg) in the extracellular region were more likely to cause severe early‐onset Charcot–Marie–Tooth disease type 1B (CMT1B) or Dejerine–Sottas syndrome. Nonsense‐mediated mRNA decay mutations p.Asp35delInsVVYTD, p.Leu174Argfs*66 and p.Leu172Alafs*63 were related to severe infantile‐onset CMT1B or Dejerine–Sottas syndrome; however, mutation p.Val232Valfs*19 was associated with a relatively milder childhood‐onset CMT1 phenotype. Conclusion: Four novel MPZ mutations are reported that expand the genetic spectrum. De novo mutations accounted for 30.4% and were most related to a severe infantile‐onset phenotype. Genetic and clinical data from this cohort will provide the baseline data necessary for clinical trials and natural history studies. [ABSTRACT FROM AUTHOR]

Background and purpose: Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP‐related tremor is more variable than other tremor disorders. Methods: Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross‐sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t‐test was used for comparisons between groups. Results: Twenty‐four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high‐frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F‐wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor. Conclusions: Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat‐to‐beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor. [ABSTRACT FROM AUTHOR]

Background and purpose: Ehlers–Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers–Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood. Study Purpose: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers‐Danlos Syndromes. Methods: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt‐table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS‐31 (Composite Autonomic Symptom Score 31) questionnaire. Results: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions. Conclusion: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism. [ABSTRACT FROM AUTHOR]

Background and purpose: A diagnostic score was developed to discriminate anti‐myelin‐associated‐glycoprotein (MAG) neuropathy from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and applied it to patients with atypical anti‐MAG neuropathy. Methods: The clinical and electrophysiological features of patients with a diagnosis of typical anti‐MAG neuropathy were compared to those of patients with a diagnosis of CIDP. The association of each feature with the diagnosis was assessed in the two groups. Features showing a significant association with the diagnosis were included in a multivariable logistic regression model and adjusted odds ratios were estimated for each feature. A score ranging from 1 to 3 was applied to each feature based on the magnitude of the estimated odds ratios. The score was then applied to patients with a clinical diagnosis of CIDP who also had high anti‐MAG antibody titers (CIDP‐MAG). Results: Thirty‐one anti‐MAG neuropathy patients, 45 typical CIDP patients and 16 CIDP‐MAG patients were included. Scores in anti‐MAG antibody patients ranged from 1 to 5 and in CIDP patients from −7 to −1. Using the score, 4/16 CIDP‐MAG patients were diagnosed to have anti‐MAG neuropathy and 12/16 patients to have CIDP. Response to intravenous immunoglobulin in the CIDP‐MAG patients classified as CIDP was similar to that of definite CIDP patients and higher than that of anti‐MAG neuropathy patients. Conclusions: Our score allowed an accurate discrimination to be made, amongst patients with anti‐MAG antibodies, of those affected by CIDP and the patients with anti‐MAG neuropathy. This score may help proper treatment to be chosen for patients with anti‐MAG antibodies with a CIDP‐like presentation. [ABSTRACT FROM AUTHOR]

This document is a reply to a comment made by Drs Plantone and Primiano on a study regarding serum neurofilament light chain (NfL) and small fiber neuropathy (SFN). The authors of the reply agree that having a marker specific for peripheral nerve damage would be beneficial, but they do not believe that NfL is solely a marker for central nervous system damage. They discuss the correlation between NfL levels and sensory nerve action potential amplitude in SFN, as well as the potential use of peripherin as another marker for peripheral nerve damage. The authors suggest further studies to confirm these findings and explore the dynamics of NfL and peripherin blood levels during and after nerve damage. They also acknowledge that factors such as age, chronic kidney disease, and body mass index can impact NfL measurements. The authors conclude by stating their contributions to the study. [Extracted from the article]

The article discusses a study that explored the potential use of serum neurofilament light chain (NfL) as a biomarker for small fiber neuropathy (SFN). The study compared the serum NfL levels of 30 SFN patients with those of 19 healthy individuals and found no significant difference between the two groups. However, the authors did observe a negative correlation between sural sensory nerve action potential (SNAP) and serum NfL in the patient group. The article also highlights the challenges of using NfL as a biomarker for peripheral nerve diseases and suggests that other neurofilament proteins, such as peripherin (PRPH), may be more suitable biomarkers for SFN. The authors also propose considering factors like body mass index (BMI) as potential confounding factors in NfL analysis. [Extracted from the article]

Background and purpose: Influenza vaccination may increase the risk of developing Guillain–Barré syndrome (GBS) due to an elicited immune response, but the exact magnitude and duration of risk is unclear and hence the aim of this study. Methods: We conducted a retrospective nationwide population‐based case–control study of prospectively collected data on all patients with first‐time hospital‐diagnosed GBS in Denmark between 2002 and 2016 and 10 age‐, sex‐ and index date‐matched population controls per case. The primary exposure was incident influenza vaccination 1 month prior to admission with GBS. We used medical registries to ascertain a complete hospital contact history of pre‐existing morbidities. To examine duration of GBS risk, we repeated the analysis for five consecutive 1‐month risk periods following vaccination. Results: Of the 1295 GBS cases and 12,814 controls, 20 cases (1.5%) and 119 controls (0.9%) had received an influenza vaccination within the last month, yielding a comorbidity‐adjusted odds ratio of 1.9 (95% confidence interval 1.1–3.2) for GBS. Stratified analyses by calendar time, gender and age showed similar results. The increased risk of GBS was largely confined to 1 month following influenza vaccination. The population‐attributable fraction of GBS from influenza vaccination in Denmark was 0.4%. Conclusions: Influenza vaccination was associated with a slightly elevated risk of GBS occurrence within 1 month after vaccination. However, only 1.5% of GBS cases in Denmark are associated with recent influenza vaccination. Thus, the benefit of influenza vaccines in preventing influenza infections and associated morbidity and mortality needs to be weighed against the small absolute risk of GBS. [ABSTRACT FROM AUTHOR]

Background and purpose: Although several case series have described nitrous‐oxide‐associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level of exposure) in substance abusers has not been performed. The aim of this study was to describe the onset patterns of recreational use of nitrous‐oxide‐induced neurological disorders. Methods: All cases of neurological disorders related to nitrous oxide recreational use reported to the Hauts‐de‐France addictovigilance center between January 2019 and August 2020 were selected. Only cases requiring hospitalization with informative data to perform the nitrous oxide causality assessment were included. Results: A total of 20 cases from five hospitals were included. The male‐to‐female ratio was 6:1 and the median age was 19 years (range 16–34). The neurological presentation (myeloneuropathy 64%, 7/11; sensorimotor neuropathy 36%, 4/11) included for all patients gait disorders due to proprioceptive ataxia and limb hypoesthesia. The median dose used per occasion was 100 cartridges (range 5–960; n = 19). The median time from the start of nitrous oxide use to the onset of neurological symptoms was 6 months (range 0.7–54; n = 16). The cumulative dose was significantly higher in patients with damage to all four limbs than in patients with lower limb symptoms only (p = 0.042). Conclusions: A low intermittent exposure may be sufficient to cause neurological damage in some subjects, suggesting that, at the population level, there is no safe exposure to nitrous oxide in recreational settings. The severity of neurological impairment could increase once used at high doses and for prolonged durations of nitrous oxide. [ABSTRACT FROM AUTHOR]

Background and purpose: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. Methods: This study was performed within the population‐based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6–78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome‐wide association studies. Results: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR]diabetes, p < 1.0 = 1.21, 95% confidence interval [CI] = 1.05–1.39 and ORBMI, p < 1.0 = 1.21, 95% CI = 1.04–1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR vitamin B12, p < 5e‐6 = 0.79, 95% CI = 0.68–0.92 and ORalcohol, p < 5e‐8 = 1.17, 95% CI = 1.02–1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGSp < 5e‐8 and polyneuropathy. Conclusions: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well‐known clinical risk factors and polyneuropathy. [ABSTRACT FROM AUTHOR]

Background and purpose: Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients. Methods: After unremarkable whole‐exome sequencing (WES) analysis, we performed repeat‐primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough. Results: In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1−/− cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). Conclusions: We demonstrate that RFC1 is a frequent cause of (WES‐negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat‐primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy‐ataxia spectrum. [ABSTRACT FROM AUTHOR]

Background and purpose: Hereditary amyloidosis related to transthyretin (ATTR) is a rare and progressive disease that, despite the phenotypic heterogeneity, a length‐dependent sensorimotor axonal neuropathy (ATTR‐PN) is the classic hallmark. Timely diagnosis is paramount for early treatment implementation. Methods: Sixty‐nine asymptomatic gene carriers (Val30Met) were assessed during a 4‐year period to identify those remaining asymptomatic versus those converting to ATTRV30M‐PN. Conversion to symptomatic was defined as presenting with two definite symptoms of ATTRV30M‐PN. Composite neurophysiological scores of sensory (SNS), motor (MNS), and sympathetic skin response (SSRS) amplitudes were used to assess neuropathy progression. We used mixed‐effects modeling and ordinal logistic regression to assess neurophysiological evolution over time. Results: Of all asymptomatic gene carriers, 55.1% (n = 38/69) converted over the period of this analysis. The progression of the SNS relative to baseline was different between groups (asymptomatic gene carriers vs. converters), the decline being greater in the converter group (time × group interaction p = 0.040), starting about 2 years before symptom onset. No significant change occurred regarding MNS or SSRS. Moreover, the percentage of cases with an annual decline on the SNS of at least 25%, gradually and significantly increased in the converter group, representing a 1.92 increase in risk of developing symptoms for those with such reduction on the last evaluation. Conclusions: A simple composite neurophysiological sum score can predict the onset of ATTRV30M‐PN symptoms by as much as 2 years, highlighting the importance of a systematic follow‐up of asymptomatic gene carriers, allowing a timely diagnosis, and management of symptomatic disease. [ABSTRACT FROM AUTHOR]

Background and purpose: Nitrous oxide misuse is a recognized issue worldwide. Prolonged misuse inactivates vitamin B12, causing a myeloneuropathy. Methods: Twenty patients presenting between 2016 and 2020 to tertiary hospitals in Sydney with myeloneuropathy due to nitrous oxide misuse were reviewed. Results: The average age was 24 years, and mean canister consumption was 148 per day for 9 months. At presentation, paresthesias and gait unsteadiness were common, and seven patients were bedbound. Mean serum B12 was normal (258 pmol/L, normal range [NR] = 140–750) as was active B12 (87 pmol/L, normal > 35). In contrast, mean serum homocysteine was high (51 μmol/L, NR = 5–15). Spinal magnetic resonance imaging (MRI) showed characteristic dorsal column T2 hyperintensities in all 20 patients. Nerve conduction studies showed a predominantly axonal sensorimotor neuropathy (n = 5). Patients were treated with intramuscular vitamin B12, with variable functional recovery. Three of the seven patients who were bedbound at presentation were able to walk again with an aid at discharge. Of eight patients with follow‐up data, most had persistent paresthesias and/or sensory ataxia. Mobility scores at admission and discharge were not significantly correlated with the serum total and active B12 levels or cumulative nitrous oxide use. There were no significant trends between serum active B12 level and cumulative nitrous oxide use (Spearman rho = −0.331, p = 0.195). Conclusions: Nitrous oxide misuse can cause a severe but potentially reversible subacute myeloneuropathy. Serum and active B12 can be normal, while elevated homocysteine and dorsal column high T2 signal on MRI strongly suggest the diagnosis. Neurological deficits can improve with abstinence and B12 supplementation, even in the most severely affected patients. [ABSTRACT FROM AUTHOR]

Background and purpose: Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot–Marie–Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials. Methods: Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers. Results: Forty‐four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23–47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients. Conclusions: To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time. [ABSTRACT FROM AUTHOR]

Background and purpose: Antiganglioside antibodies have been implicated in several autoimmune‐mediated neuropathies, and binding of these antibodies can result in inflammatory changes of the nerves. Diaphragmatic paralysis is a rare condition, mostly arising from diseases affecting the phrenic nerve, neuromuscular junction, or skeletal muscle. Objectives: In this case series, we identified five patients with diaphragmatic paralysis due to unilateral or bilateral neuropathy of the phrenic nerve associated with the presence of antiganglioside antibodies (immunoglobulin G anti‐GT1a antibodies and immunoglobulin M anti‐GM1 antibodies). Discussion: The combination of an isolated phrenic nerve palsy with anti‐GM1 antibodies has only once been described. On the other hand, the association of anti‐GT1a antibodies with phrenic nerve palsy has never been reported before. Conclusions: We report an association between phrenic nerve palsy and the presence of antiganglioside antibodies, but it remains unclear if there is a causal relationship. Further studies are needed to explore this matter. [ABSTRACT FROM AUTHOR]

Background and purpose: Chronic axonal polyneuropathy is a common, usually multifactorial, disease for which there is no treatment yet available. We investigated the association between cardiovascular health, defined by the health score of the American Heart Association, and chronic axonal polyneuropathy. Methods: Between June 2013 and January 2017, we investigated participants of the Rotterdam Study, a population‐based cohort study. Participants were screened for polyneuropathy and categorized as having no, possible, probable or definite polyneuropathy. The cardiovascular health score (range 0–14; higher score reflecting better health) consisted of four health behaviours (diet, physical activity, smoking and body mass index) and three health factors (blood pressure, serum cholesterol and fasting glucose level). Results: We included 1919 participants, of whom 120 (6.3%) had definite polyneuropathy. The median (interquartile range [IQR]) age was 69.0 (58.6–73.7) years and 53.4% were women. A higher cardiovascular health score was associated with a lower prevalence of definite polyneuropathy (per point increase: odds ratio [OR] 0.90, 95% confidence interval [CI] 0.84–0.96). Optimal cardiovascular health (score≥10) was strongly associated with a lower prevalence of definite polyneuropathy (OR 0.55, 95% CI 0.32–0.90). An increase in health factors and health behaviour scores separately was associated with a lower prevalence of polyneuropathy (per point increase: OR 0.82, 95% CI 0.71–0.95 and OR 0.86, 95% CI 0.78–0.96, respectively). The association between a lower cardiovascular health score and lower sural nerve amplitude was not significant after correction for covariates (difference 0.07µV, 95% CI −0.02–0.17). Conclusions: Better cardiovascular health, consisting of both modifiable health behaviours and health factors, is associated with a lower prevalence of chronic axonal polyneuropathy. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy (PN) is common in patients with diseases that are in turn associated with deficiency of the B‐vitamins, and vitamin treatment has shown mixed results. Methods: This systematic review and meta‐analysis studied the association between PN/pain and B‐vitamin biomarkers and investigated whether vitamin treatment can ameliorate the symptoms. PubMed and Web of Science were searched according to the study protocol. Results: A total of 46 observational and seven interventional studies were identified and included in the data synthesis. The presence of PN was associated with lowered B12 levels (pooled estimate [95% CIs] = 1.51 [1.23–1.84], n = 34, Cochran Q Test I2 = 43.3%, p = 0.003) and elevated methylmalonic acid (2.53 [1.39–4.60], n = 9, I2 = 63.8%, p = 0.005) and homocysteine (3.48 [2.01–6.04], n = 15, I2 = 70.6%, p < 0.001). B12 treatment (vs. the comparators) showed a non‐significant association with symptom improvement (1.36 (0.66–2.79), n = 4, I2 = 28.9%). Treatment with B1 was associated with a significant improvement in symptoms (5.34 [1.87–15.19], n = 3, I2 = 64.6%, p = 0.059). Analysis of seven trials combined showed a non‐significant higher odds ratio for improvement under treatment with the B‐vitamins (2.58 [0.98–6.79], I2 = 80.0%, p < 0.001). Conclusions: PN is associated with lowered plasma vitamin B12 and elevated methylmalonic acid and homocysteine. Overall, interventional studies have suggested that B‐vitamins could improve symptoms of PN. Available trials have limitations and generally did not investigate vitamin status prior to treatment. Well‐designed studies, especially in non‐diabetes PN, are needed. This meta‐analysis is registered at PROSPERO (ID: CRD42020144917). [ABSTRACT FROM AUTHOR]

Background and purpose: To investigate prion protein (PrP) deposits in cutaneous tissues of patients of glycosylphosphatidylinositol (GPI)‐anchorless prion diseases with neuropathy. Methods: Cutaneous tissue samples from three patients with GPI‐anchorless prion diseases were obtained, two cutaneous biopsy samples from the lower leg of Case 1 (Y162X) and Case 3 (D178fs25), and a cutaneous sample taken from the abdomen during an autopsy of Case 2 (D178fs25). We performed immunohistochemistry for PrP to look for abnormal PrP deposits. Results: PrP deposits were observed in the dermal papilla, the sweat glands, the hair follicles, the arrector pili muscles, and peripheral nerves of all examined cases of GPI‐anchorless prion disease with neuropathy. The abnormal PrP accumulation was frequently localized at the basement membrane, and colocalized with laminin. Conclusion: Immunohistochemical detection of PrP in cutaneous samples could be used to definitively diagnose GPI‐anchorless PrP disease with neuropathy. [ABSTRACT FROM AUTHOR]

Background and purpose: Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA‐binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. Methods: Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of EGR2 were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two‐hybrid assay. Results: A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the EGR2 gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB‐EGR2 protein interactions can result in dramatic neuropathy. Conclusion: Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission. [ABSTRACT FROM AUTHOR]

Background and purpose: Charcot–Marie–Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families. Methods: Individuals with FBLN5‐associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites. Results: Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. Conclusions: Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work‐up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5‐associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme. [ABSTRACT FROM AUTHOR]

Guillain‐Barré syndrome (GBS) incidence can increase during outbreaks of infectious illnesses. A few cases of GBS associated with coronavirus disease 2019 (COVID‐19) infection have been reported. The aim was to identify specific clinical features of GBS associated with COVID‐19. PubMed, Embase and Cochrane were searched from 1 November 2019 to 17 May 2020 and included all papers with full text in English, Spanish, French or Italian, reporting original data of patients with GBS and COVID‐19. Data were extracted according to a predefined protocol. A total of 18 patients reported in 14 papers were included in this review. All the patients were symptomatic for COVID‐19, with cough and fever as the most frequently reported symptoms. The interval between the onset of symptoms of COVID‐19 and the first symptoms of GBS ranged from −8 to 24 days (mean 9 days; median 10 days). Most of the patients had a typical GBS clinical form predominantly with a demyelinating electrophysiological subtype. Mechanical ventilation was necessary in eight (44%) patients. Two (11%) patients died. Published cases of GBS associated with COVID‐19 report a sensorimotor, predominantly demyelinating GBS with a typical clinical presentation. Clinical features and disease course seem similar to those observed in GBS related to other etiologies. These results should be interpreted with caution since only 18 cases have been heterogeneously reported so far. [ABSTRACT FROM AUTHOR]

Background and purpose: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. Methods: Ninety‐four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. Results: Twenty‐one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage‐mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage‐gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5–5.1 times) and/or distal (1.2–3.4 times) compound muscle action potential in at least two nerves. Conclusion: Antibody‐ and macrophage‐mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker. [ABSTRACT FROM AUTHOR]

Background and purpose: Muscle‐strengthening, stretching or proprioceptive treatments may slow symptom progression in Charcot—Marie–Tooth (CMT) neuropathy. The aim of the study was to evaluate safety and efficacy of treadmill training in CMT1A. Methods: We planned a multicenter, prospective, randomized, single‐blind, controlled study. We recruited 53 outpatients affected by CMT1A and randomized them into two treatment groups: one underwent stretching and proprioceptive exercise, whereas the other was additionally treated with treadmill training (TreSPE). Primary outcome measures (OMs) were the walking evaluations and secondary OM was the balance assessment. All participants were assessed at baseline and after 3 and 6 months of treatment. Results: Most patients showed an improvement in at least one OM after 3 months [42/47 (89.4%)] and 6 months [38/40 (95%)] of treatment. No adverse events were reported in either group. Conclusions: The most important finding was that both stretching and proprioceptive exercise and treadmill training had an objective benefit on patients affected by CMT disease, without causing overwork weakness. We had a low rate of drop out and did not find deterioration in motor performance. Our results also confirm that applying evidence‐based medicine methods to rehabilitative research is the correct way to test the efficacy of a treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Conduction block is a pathognomonic feature of immune‐mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Methods: A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. Results: Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. Conclusions: The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody‐mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block. [ABSTRACT FROM AUTHOR]

Background and purpose: We aimed to test the clinical utility of the leg:thigh intraepidermal nerve‐fiber (IENF) density ratio as a parameter to discriminate between length‐dependent small‐fiber neuropathy (SFN) and small‐fiber sensory ganglionopathy (SFSG) in subjects with signs and symptoms of small‐fiber pathology. Methods: We retrospectively evaluated thigh and leg IENF density in 314 subjects with small‐fiber pathology (173 with distal symmetrical length‐dependent SFN and 141 with non‐length‐dependent SFSG). A group of 288 healthy subjects was included as a control group. The leg:thigh IENF density ratio was calculated for all subjects. We used receiver operating characteristic curve analyses to assess the ability of this parameter to discriminate between length‐dependent SFN and SFSG, and the decision curve analysis to estimate its net clinical benefit. Results: In patients with neuropathy, the mean IENF density was 14.8 ± 6.8/mm at the thigh (14.0 ± 6.9/mm in length‐dependent SFN and 15.9 ± 6.7/mm in patients with SFSG) and 7.5 ± 4.5/mm at the distal leg (5.4 ± 3.2/mm in patients with length‐dependent SFN and 10.1 ± 4.6/mm in patients with SFSG). The leg:thigh IENF density ratio was significantly (P < 0.01) lower in patients with length‐dependent SFN (0.44 ± 0.23) compared with patients with SFSG (0.68 ± 0.28). The area under the curve of the receiver operating characteristic analysis to discriminate between patients with length‐dependent SFN and SFSG was 0.79. The decision curve analysis demonstrated the clinical utility of this parameter. Conclusions: The leg:thigh IENF ratio represents a valuable tool in the differential diagnosis between SFSG and length‐dependent SFN. [ABSTRACT FROM AUTHOR]

Background and purpose: Many epidemiological studies of Guillain−Barré syndrome (GBS) and Fisher syndrome (FS) have been conducted in Europe and America. In contrast, epidemiological studies are rare in Asia where the GBS subtypes differ from those in Western countries. This study was undertaken to clarify the incidence of GBS and FS in a local area in Japan as well as their seasonal trends. Method: Seventy‐one GBS and 37 FS patients were recorded from 2006 to 2015 in an area of approximately 1.5 million inhabitants in Japan. The incidence, seasonal trends and clinical features of GBS and FS were examined. Results: The incidence rate of GBS was 0.42 cases per 100 000 person‐years and that of FS was 0.22 cases per 100 000 person‐years. The incidence of GBS increased with age and FS affected predominantly patients aged from 45 to 64 years old. There was some seasonal clustering of acute motor axonal neuropathy (AMAN) and FS in spring and summer, but it was not significant. AMAN and FS patients had a high frequency of preceding infection (AMAN, 68% gastrointestinal infection; FS, 65% upper respiratory infection). Antecedent respiratory infection was significantly associated with FS as an outcome. Serum antibodies to ganglioside GM1 were detected in 71% of AMAN patients and antibodies to GQ1b were detected in 81% of FS patients. Conclusions: Our study offers evidence of a lower incidence of GBS and a higher incidence of FS in a local area in Japan than in Western countries. [ABSTRACT FROM AUTHOR]

Background and purpose: Sensory neuronopathy is a cardinal feature of cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS). Having observed that two patients with CANVAS had small median and ulnar nerves on ultrasound, we set out to examine this finding systematically in a cohort of patients with CANVAS, and compare them with both healthy controls and a cohort of patients with axonal neuropathy. We have previously reported preliminary findings in seven of these patients with CANVAS and seven healthy controls. Methods: We compared the ultrasound cross‐sectional area of median, ulnar, sural and tibial nerves of 14 patients with CANVAS with 14 healthy controls and 14 age‐ and gender‐matched patients with acquired primarily axonal neuropathy. We also compared the individual nerve cross‐sectional areas of patients with CANVAS and neuropathy with the reference values of our laboratory control population. Results: The nerve cross‐sectional area of patients with CANVAS was smaller than that of both the healthy controls and the neuropathy controls, with highly significant differences at most sites (P < 0.001). Conversely, the nerve cross‐sectional areas in the upper limb were larger in neuropathy controls than healthy controls (P < 0.05). On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one patient with CANVAS. Discussion: Small nerves in CANVAS probably reflect nerve thinning from loss of axons due to ganglion cell loss. This is distinct from the ultrasound findings in axonal neuropathy, in which nerve size was either normal or enlarged. Our findings indicate a diagnostic role for ultrasound in CANVAS sensory neuronopathy and in differentiating neuronopathy from neuropathy. [ABSTRACT FROM AUTHOR]

Background and purpose: The Toronto Clinical Neuropathy Score (TCNS) is a valid and reliable scale for the diagnosis and staging of diabetic sensorimotor polyneuropathy. In this study, we aimed to explore the performance of the TCNS in non‐diabetic polyneuropathies. Methods: We performed a prospective study from November 2016 to May 2017 of patients with non‐diabetic polyneuropathy. Patients had clinical, electrophysiological and functional assessments of their polyneuropathy, and the findings were correlated with the TCNS. Results: The TCNS correlated with all clinical, electrophysiological and disability measures of polyneuropathy, mostly at a moderate level (e.g. r = −0.58 for sural nerve action potential amplitude). Higher TCNS severity grades were associated with worse polyneuropathy on all measures in the lower limbs, and with worse electrophysiological parameters and vibration perception thresholds in the upper limbs. The scale also showed excellent reliability and accuracy (kappa, 0.92–0.93 for inter‐ and intra‐observer reliability; area under the receiver operating characteristics curve, 0.93). Conclusion: The TCNS is a valid and reliable scale for a wide spectrum of polyneuropathies, and might be useful in clinical practise and research for the diagnosis and staging of polyneuropathy. [ABSTRACT FROM AUTHOR]

Background and purpose: To better characterize the effects of tafamidis in non‐Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12‐month, open‐label study of non‐Val30Met versus Val30Met patients at month 12 from the 18‐month, double‐blind, placebo‐controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity. Methods: Neurological function was assessed using the Neuropathy Impairment Score – Lower Limbs (NIS‐LL) in three cohorts: Val30Met tafamidis (n = 64), Val30Met placebo (n = 61) and non‐Val30Met tafamidis (n = 21). The change in NIS‐LL from baseline to month 12 for Val30Met and non‐Val30Met tafamidis‐treated patients was compared with the change from baseline at month 12 for Val30Met placebo‐treated patients using a mixed‐effects model for repeated measures (MMRM). Results: The baseline adjusted mean (standard error) change in NIS‐LL values at month 12 was similar for Val30Met [1.60 (0.78)] and non‐Val30Met [1.62 (1.43)] tafamidis‐treated patients and less than that observed in the Val30Met placebo‐treated group [4.72 (0.77); P = 0.0055 for Val30Met and P = 0.0592 for non‐Val30Met]. Based on the MMRM, the magnitude of change in both tafamidis‐treated cohorts was similar across the range of observed baseline NIS‐LL values, and was consistently less than that observed in the Val30Met placebo‐treated group at month 12. Conclusions: This baseline‐adjusted analysis demonstrated that tafamidis treatment delayed neurological progression comparably in Val30Met and non‐Val30Met patients across a range of baseline NIS‐LL values. Neurological progression in these two genotype groups may be more similar than previously considered. [ABSTRACT FROM AUTHOR]

Background and purpose: Distal hereditary motor neuropathy (dHMN) due to sigma non‐opioid intracellular receptor 1 (SIGMAR1) gene mutation (OMIM 601978.0003) is a rare neuromuscular disorder characterized by prominent amyotrophic distal limb weakness and co‐existing pyramidal signs initially described in a Chinese family recently. We report an extended consanguineous Omani family segregating dHMN with pyramidal signs in an autosomal recessive pattern and describe a novel mutation in the SIGMAR1 gene underlying this motor phenotype. We also provide an update on the reported phenotypic profile of SIGMAR1 mutations. Methods: We utilized homozygosity mapping and whole‐exome sequencing of leucocyte DNA obtained from three affected members of an Omani family who manifested with a length‐dependent motor neuropathy and pyramidal signs. Results: We identified a novel C>T transition at nucleotide position 238 (c.238C>T) in exon 2 of the SIGMAR1 gene. Sanger sequencing and segregation analysis confirmed the presence of two copies of the variant in the affected subjects, unlike the unaffected healthy parents/sibling who carried, at most, a single copy. The T allele is predicted to cause a truncating mutation (p.Gln80*), probably flagging the mRNA for nonsense‐mediated decay leading to a complete loss of function, thereby potentially contributing to the disease process. Conclusions: Our finding expands the spectrum of SIGMAR1 mutations causing recessive dHMN and indicates that this disorder is pan‐ethnic. SIGMAR1 mutation should be included in the diagnostic panel of a dHMN, especially if there are co‐existing pyramidal signs and autosomal recessive inheritance. [ABSTRACT FROM AUTHOR]

Background and purpose: Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. Methods: A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. Results: No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. Conclusions: Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral. [ABSTRACT FROM AUTHOR]

Background and purpose: The frequency of pain and cramps is uncertain in anti-myelin associated glycoprotein antibody (anti-MAG) neuropathy. Whether these symptoms may affect function/quality of life is unknown. Methods: A cross-sectional study of the prevalence, correlates and impact of pain, pain subtypes and cramps, their severity, frequency and anatomical distribution was performed for 55 clinically stable patients with anti-MAG neuropathy. Results: Pain of any type was reported by 80% of subjects. The most common subtype was paraesthesiae and dysaesthesiae (70%). Cramps were reported by >60% of patients, with lower limb cramps in all and upper limb cramps in about 20%. Cramps affected daily activities in >30% of these subjects, sleep in 60%, ability to exercise in >30%. Total pain score correlated with several Short Form 36 health-related quality of life (SF-36 HR-QoL) measures (P < 0.05), with Inflammatory Rasch-built Overall Disability Scale (I-RODS) (P = 0.006) and 10-m timed walk (P = 0.019). An independent association was ascertained with I-RODS (P = 0.002). Different pain subtypes showed multiple associations with SF-36 HR-QoL measures and/or functional scales. Upper limb cramps had multiple SF-36 HR-QoL functional correlates, with an independent association with the Overall Neuropathy Limitation Score (ONLS) (P = 0.004). Cramp severity correlated with ONLS (P = 0.04) and I-RODS (P = 0.028) and inversely with level of physiotherapy input (P = 0.009). Cramp frequency was associated with tremor score (P = 0.004) and multiple SF-36 HR-QoL subsections. Conclusions: Neuropathic pain and cramps may affect function and quality of life in anti-MAG neuropathy. Optimizing treatments of these symptoms, including by adequate levels of physiotherapy, may be beneficial in affected patients and requires further research. [ABSTRACT FROM AUTHOR]

Background and purpose: Mutations in the small heat-shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. The aim was to report a novel family with HSPB8K141E-related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. Methods: We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by reverse transcriptase-polymerase chain reaction. Results: The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in three out of four TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. Conclusions: Our study confirmed the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathological mechanism of HSPB8K141E toxicity, leading to muscle and nerve degeneration. [ABSTRACT FROM AUTHOR]

Background and purpose Anti-sulfatide antibodies have been observed in heterogeneous neuropathies and their clinical relevance is still controversial. Whether the combination of sulfatide with galactocerebroside would increase sensitivity or specificity of enzyme-linked immunosorbent assay testing compared to sulfatide alone was assessed. Methods Immunoglobulin M (IgM) antibodies to sulfatides, galactocerebroside and combined sulfatide and galactocerebroside (Sulf/GalC) were measured in 229 neuropathy patients, including 73 with IgM paraproteinemic neuropathy [62 with anti-myelin-associated glycoprotein (anti-MAG) antibody] and 156 with other neuropathies. Results from 27 patients with IgM monoclonal gammopathy without neuropathy and 28 healthy subjects served as control. Results Thirty-three patients showed increased titers of anti-sulfatide antibodies, 28 of whom had an IgM paraproteinemic neuropathy ( P < 0.0001). When evaluating the reactivity for the combination Sulf/GalC, 57/229 patients were found to be positive, including 36/73 (49%) with IgM paraproteinemic neuropathy ( P < 0.0001). Patients with known anti-sulfatide antibodies also showed anti-Sulf/GalC reactivity, with increased titers in 48.5% of the cases. Testing for anti-Sulf/GalC antibodies allowed 24 additional patients to be detected (eight with IgM paraproteinemic neuropathies), who had no reactivity to the individual glycolipids. Amongst the 11 subjects with IgM paraproteinemic neuropathy who were negative for anti- MAG antibodies, only two were reactive to sulfatide, whilst six (55%) were found to be positive when tested against the combination of sulfatide and galactocerebroside. Conclusions Testing for both sulfatide and galactocerebroside in IgM paraproteinemic neuropathies seems to increase the sensitivity compared to anti-sulfatide antibodies alone (49% and 39%, respectively, with a slightly reduced specificity, from 97% to 87%), helping the characterization of otherwise undefined neuropathy that could benefit from immunomodulatory therapy. [ABSTRACT FROM AUTHOR]

Background and purpose To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound ( HRUS) and magnetic resonance imaging ( MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy ( CIDP) and multifocal motor neuropathy ( MMN). Methods Fifty-one incident, treatment-naive patients with CIDP ( n = 23) or MMN ( n = 28) underwent imaging of the brachial plexus using (i) a standardized MRI protocol to assess enlargement or T2 hyperintensity and (ii) bilateral HRUS to determine the extent of nerve (root) enlargement. Results We found enlargement of the brachial plexus in 19/51 (37%) and T2 hyperintensity in 29/51 (57%) patients with MRI and enlargement in 37/51 (73%) patients with HRUS. Abnormal results were only found in 6/51 (12%) patients with MRI and 12/51 (24%) patients with HRUS. A combination of the two imaging techniques identified 42/51 (83%) patients. We found no association between age, disease duration or Medical Research Council sum-score and sonographic nerve size, MRI enlargement or presence of T2 hyperintensity. Conclusions Brachial plexus sonography could complement MRI in the diagnostic work-up of patients with suspected CIDP and MMN. Our results indicate that combined imaging studies may add value to the current diagnostic consensus criteria for chronic inflammatory neuropathies. [ABSTRACT FROM AUTHOR]