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INTRODUCTION: The revised international standards for neurological classification of spinal cord injury (ISNCSCI) have facilitated the documentation of non-spinal cord injury-related impairments, such as chronic peripheral nerve injuries and muscle weakness due to immobility. This advancement addresses potential biases in muscle strength examinations. Utilizing electrically evoked contractions from paralyzed muscles, enhanced by electrodiagnosis, holds promise in identifying false-negative diagnoses of non-responsiveness to neuromuscular electrical stimulation. This concept prompts the exploration of polyneuromyopathy arising from nonuse in paralyzed muscles. CASE SERIES PRESENTATION: To substantiate our hypothesis, we recruited nine participants for a case series aimed at elucidating the potential benefits of incorporating the stimulus electrodiagnostic test (SET) to mitigate non-responsiveness during preparation for functional electrical stimulation (FES)-assisted cycling. In our convenience sample (n = 5), we conducted neurological mapping based on ISNCSCI and applied SET on the quadriceps. The SET guided optimal dosimetry for evoking contractions and revealed responses similar to those observed in peripheral neuropathies, with α coefficients equal to or lower than 2.00. This observation is likely attributable to nonuse of paralyzed muscles, indicative of an ongoing polyneuropathy in individuals with chronic spinal cord injury (SCI). DISCUSSION: Among the nine initially recruited subjects, seven exhibited responsiveness to neuromuscular electrical stimulation (78% responsiveness), with two participants excluded based on exclusion criteria. In the final five reported cases, all displayed α coefficient values indicating impaired neuromuscular accommodation, and one presented no α coefficient within the normal range. The inclusion of electrodiagnosis appears effective in averting non-responsiveness, suggesting the presence of ongoing polyneuropathies in paralyzed muscles.

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BACKGROUND: Increasing evidence indicates a higher prevalence of polyneuropathy (PNP) in Parkinson's disease (PD). However, the involvement of large fiber neuropathy in PD still remains poorly understood. Given the lack of longitudinal data, we investigated the course of PNP associated with PD. METHODS: In total, 41 PD patients underwent comprehensive clinical evaluation including motor and non-motor assessments as well as nerve conduction studies at baseline and at 2 years of follow-up. The definition of PNP was based on electrophysiological standard criteria. Common causes of PNP were excluded. RESULTS: At baseline, PNP was diagnosed in 65.85% of PD patients via electroneurography. Patients with PNP presented with higher age (p = 0.019) and PD motor symptom severity (UPDRS III; p < 0.001). Over the course of 2 years, PNP deteriorated in 21.95% of cases, and 26.83% remained without PNP. Deterioration of nerve amplitude was most prevalent in the median sensory nerve affecting 57.58% of all PD cases with an overall reduction of median sensory nerve amplitude of 45.0%. With regard to PD phenotype, PNP progression was observed in 33.33% of the tremor dominant and 23.81% of the postural instability/gait difficulties subtype. Decrease of sural nerve amplitude correlated with lower quality of life (PDQ-39, p = 0.037) and worse cognitive status at baseline (MoCA, p = 0.042). CONCLUSION: The study confirms the high PNP rate in PD, and demonstrates a significant electrophysiological progression also involving nerves of the upper extremities. Longitudinal studies with larger cohorts are urgently needed and should elucidate the link between PD and PNP with the underlying pathomechanisms.

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AIMS: The aim of this study was to assess associations between neurological biomarkers and distal sensorimotor polyneuropathy (DSPN). MATERIALS AND METHODS: Cross-sectional analyses were based on 1032 participants aged 61-82 years from the population-based KORA F4 survey, 177 of whom had DSPN at baseline. The prevalence of type 2 diabetes was 20%. Prospective analyses used data from 505 participants without DSPN at baseline, of whom 125 had developed DSPN until the KORA FF4 survey. DSPN was defined based on the examination part of the Michigan Neuropathy Screening Instrument. Serum levels of neurological biomarkers were measured using proximity extension assay technology. Associations between 88 biomarkers and prevalent or incident DSPN were estimated using Poisson regression with robust error variance and are expressed as risk ratios (RR) and 95% CI per 1-SD increase. Results were adjusted for multiple confounders and multiple testing using the Benjamini-Hochberg procedure. RESULTS: Higher serum levels of CTSC (cathepsin C; RR [95% CI] 1.23 (1.08; 1.39), pB-H = 0.044) and PDGFRα (platelet-derived growth factor receptor A; RR [95% CI] 1.21 (1.08; 1.35), pB-H = 0.044) were associated with prevalent DSPN in the total study sample. CDH3, JAM-B, LAYN, RGMA and SCARA5 were positively associated with DSPN in the diabetes subgroup, whereas GCP5 was positively associated with DSPN in people without diabetes (all pB-H for interaction <0.05). None of the biomarkers showed an association with incident DSPN (all pB-H>0.05). CONCLUSIONS: This study identified multiple novel associations between neurological biomarkers and prevalent DSPN, which may be attributable to functions of these proteins in neuroinflammation, neural development and myelination.

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OBJECTIVE: To establish a simple electrophysiological scale for patients with distal symmetric axonal polyneuropathy, in order to promote standardized and informative electrodiagnostic reporting, and understand the complex relationship between electrophysiological and clinical polyneuropathy severity. METHODS: We included 76 patients with distal symmetric axonal polyneuropathy, from a cohort of 151 patients with polyneuropathy prospectively recruited from November 2016 to May 2017. Patients underwent nerve conduction studies (NCS), were evaluated by the Toronto Clinical Neuropathy Score (TCNS), and additional tests. The number of abnormal NCS parameters was determined, within the range of 0-4, considering low amplitude or conduction velocity in the sural and peroneal nerve. RESULTS: Higher number of NCS abnormalities was associated with higher TCNS, indicating more severe polyneuropathy. Polyneuropathy severity per the TCNS was most frequently (63%-70%) mild in patients with a low (0-1) number of NCS abnormalities, and most frequently (57%-67%) severe in patients with a high number (3-4) of NCS abnormalities, while patients with an intermediate (2) number of NCS abnormalities showed mainly mild and moderate severity with equal distribution (40%). CONCLUSIONS: A simple NCS classification system can objectively grade polyneuropathy severity, although significant overlap exists especially at the intermediate range, underscoring the importance of clinical based scoring.

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Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.

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OBJECTIVE: To determine whether single fibre electromyography and motor unit number index can distinguish between axonal and myelin lesions in polyneuropathies. METHODS: This case-control study was conducted at the Department of Medical Physiology, School of Medicine, University of Duhok, Iraq, and the Neurophysiology Department, Hawler Teaching Hospital, Erbil, Iraq, from January 2021 to March 2022. Group A had patients diagnosed with polyneuropathy regardless of the aetiology, while group B had age-matched healthy controls. Both groups were subjected to single fibre electromyography and motor unit number index as well as conventional nerve conduction study and concentric needle electromyography. Data was analysed using SPSS 26. RESULTS: Of the 140 subjects, 60(43%) were patients in group A; 40(67%) males and 20(33%) females with mean age 55.3±7.2 years. There were 80(57%) controls in group B; 43(54%) females and 37(46%) males with mean age 53.81±7.15. Group A had significantly higher single fibre electromyography jitter, and mean consecutive difference (MCD) values than group B (p<0.05). Group A patients with axonal polyneuropathy had a higher mean jitter (MCD) value (36.476.7ms) than those with demyelinating polyneuropathy (23.262.31 ms) (P <0.05). Patients in group A had a motor unit number index value with a significantly lower mean value (p<0.05) when compared to the controls. Axonal polyneuropathy patients had a lower MUNIX value (99.612.8) than demyelinating polyneuropathy patients (149.845.7) (P< 0.05). CONCLUSIONS: Single fibre electromyography and motor unit number index could help differentiate between the pathophysiology of axonal and demyelinating polyneuropathy.

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OBJECTIVE: To evaluate the performance of serum neurofilament light chain (NfL) and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNfH) as diagnostic biomarkers for the differentiation between motor neuron disease (MND) and multifocal motor neuropathy (MMN). METHODS: This retrospective, monocentric study included 16 patients with MMN and 34 incident patients with MND. A subgroup of lower motor neuron (MN) dominant MND patients (n = 24) was analyzed separately. Serum NfL was measured using Ella automated immunoassay, and CSF pNfH was measured using enzyme-linked immunosorbent assay. Area under the curve (AUC), optimal cutoff values (Youden's index), and correlations with demographic characteristics were calculated. RESULTS: Neurofilament concentrations were significantly higher in MND compared to MMN (p < 0.001), and serum NfL and CSF pNfH correlated strongly with each other (Spearman's rho 0.68, p < 0.001). Serum NfL (AUC 0.946, sensitivity and specificity 94%) and CSF pNfH (AUC 0.937, sensitivity 90.0%, specificity 100%) performed excellent in differentiating MND from MMN. Optimal cutoff values were ≥ 44.15 pg/mL (serum NfL) and ≥ 715.5 pg/mL (CSF pNfH), respectively. Similar results were found when restricting the MND cohort to lower MN dominant patients. Only one MMN patient had serum NfL above the cutoff. Two MND patients presented with neurofilament concentrations below the cutoffs, both featuring a slowly progressive disease. CONCLUSION: Neurofilaments are valuable supportive biomarkers for the differentiation between MND and MMN. Serum NfL and CSF pNfH perform similarly well and elevated neurofilaments in case of diagnostic uncertainty underpin MND diagnosis.

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INTRODUCTION: Critical illness polyneuropathy and myopathy (CIP/CIM) are frequent complications in the intensive care unit (ICU) with major consequences for the progress and outcome of subjects. CIP/CIM delays the weaning process, prolongs the hospital stay and increases the mortality rate. Additionally, it may have long-term consequences beyond the hospitalisation phase with prolonged disability. Even though there is growing interest in CIP/CIM, research about the clinical and post-clinical course as well as the middle-term and long-term outcomes of subjects with CIP/CIM is scarce. A large prospective study of critically ill subjects is needed with accurate diagnosis during the acute stage and comprehensive assessment during long-term follow-up. METHODS AND ANALYSIS: This prospective observational cohort study aims to compare the clinical and post-clinical course of chronically critically ill subjects with and without the diagnosis of CIP/CIM and to determine predictors for the middle-term and long-term outcomes of subjects with CIP/CIM. In addition, the influence of the preclinical health status and the preclinical frailty on the long-term outcome of subjects with CIP/CIM will be investigated.This single-centre study will include 250 critically ill patients who were invasively ventilated for at least 5 days at the ICU and show reduced motor strength. At five study visits at admission and discharge to neurological rehabilitation, and 12, 18 and 24 months after disease onset, a comprehensive test battery will be applied including assessments of functioning and impairment, independence, health-related quality of life, activity and participation, cognition, gait and balance, fatigue, mental health and frailty.Secondary objectives are the documentation of therapy goals, therapy content and achieved milestones during the rehabilitation, to evaluate the clinimetric properties of the Mini-BESTest in critically ill patients, and to evaluate the time course and outcome of subjects with CIP/CIM after SARS-CoV-2 infection. ETHICS AND DISSEMINATION: The study was approved by the ethical committee of the Ludwig-Maximilians University Munich. Participants will be included in the study after having signed informed consent.Results will be published in scientific, peer-reviewed journals and at national and international conferences. TRIAL REGISTRATION NUMBER: German Clinical Trial Register (DRKS00021753).

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A 63-year-old man with type 2 diabetes mellitus, alcohol consumption in moderation, and three episodes of hepatic encephalopathy presented with symmetrical lower limb distal weakness, sensory ataxia, thickened palpable nerves, mood disturbances for seven years, and a family history of schizophreniform disorders. Nerve conduction studies showed demyelinating sensorimotor polyradiculoneuropathy. CSF analysis showed mild albumino-cytological dissociation. MRI brain and lumbosacral plexus showed thickened fifth cranial nerves and lumbosacral roots. He was treated with steroids for a provisional diagnosis of chronic inflammatory polyneuropathy and became encephalopathic. EEG showed triphasic waves. Serum ammonia was 201 micrograms/dL. Further evaluation suggested ornithine transcarbamylase (OTC) deficiency. The patient underwent hemodialysis with a low protein diet, rifaximin, and sodium benzoate, with subsequent recovery.

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Polyneuropathy is a disease of the peripheral nervous system that usually results in distally emphasized, often symmetrical sensory and motor stimulation and deficits. These are often extremely painful. They can be divided into hereditary and acquired causes; inflammatory and infectious causes should be further differentiated among the acquired causes. A careful diagnostic workup is essential. Clinical signs and distribution patterns of symptoms can often already provide clues to the underlying aetiology. This review describes this workup, which in addition to the medical history and clinical examination always includes thorough laboratory diagnostics, electrophysiological examination and cerebrospinal fluid diagnostics. In individual cases, further diagnostic steps may be necessary in order to make the correct diagnosis.

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OBJECTIVE: To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and TTR variant (TTRv) carriers. METHODS: sNfL levels were assessed longitudinally in persistently asymptomatic TTRv carriers (N = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) (N = 8), in TTRv carriers who developed polyneuropathy (N = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser (N = 20) or TTR-silencer (N = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay. RESULTS: sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic TTRv carriers. In all TTRv carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment. CONCLUSION: sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic TTRv carriers and in monitoring of disease progression and treatment effect.

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BACKGROUND AND PURPOSE: This study aimed to assess the diagnostic criteria, ancillary investigations and treatment response using real-life data in multifocal motor neuropathy (MMN) patients. METHODS: Clinical and laboratory data were collected from 110 patients enrolled in the Italian MMN database through a structured questionnaire. Twenty-six patients were excluded due to the unavailability of nerve conduction studies or the presence of clinical signs and symptoms and electrodiagnostic abnormalities inconsistent with the MMN diagnosis. Analyses were conducted on 73 patients with a confirmed MMN diagnosis and 11 patients who did not meet the diagnostic criteria. RESULTS: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria were variably applied. AUTHOR: When applying the American Association of Electrodiagnostic Medicine criteria, an additional 17% of patients fulfilled the criteria for probable/definite diagnosis whilst a further 9.5% missed the diagnosis. In 17% of the patients only compound muscle action potential amplitude, but not area, was measured and subsequently recorded in the database by the treating physician. Additional investigations, including anti-GM1 immunoglobulin M antibodies, cerebrospinal fluid analysis, nerve ultrasound and magnetic resonance imaging, supported the diagnosis in 46%-83% of the patients. Anti-GM1 immunoglobulin M antibodies and nerve ultrasound demonstrated the highest sensitivity. Additional tests were frequently performed outside the EFNS/PNS guideline recommendations. CONCLUSIONS: This study provides insights into the real-world diagnostic and management strategies for MMN, highlighting the challenges in applying diagnostic criteria.

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INTRODUCTION/AIMS: The clinical presentation of multifocal motor neuropathy (MMN) may mimic early amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron (LMN) involvement, posing a diagnostic challenge. Both diseases have specific treatments and prognoses, highlighting the importance of early diagnosis. The aim of this study was to assess the diagnostic value of serum neurofilament light chain (NfL) in differentiating MMN from LMN dominant ALS. METHODS: NfL was measured in serum in n = 37 patients with MMN and n = 37 age- and sex-matched patients with LMN dominant ALS, to determine the diagnostic accuracy. Clinical and demographic data were obtained at the time of NfL sampling. RESULTS: Serum NfL concentration was significantly lower in MMN patients compared to ALS patients (mean 20.7 pg/mL vs. 59.4 pg/mL, p < .01). NfL demonstrated good diagnostic value in discriminating the two groups (AUC 0.985 [95% CI 0.963-1.000], sensitivity 94.6%, specificity 100%, cut-off 44.00 pg/mL). DISCUSSION: NfL could be a helpful tool in differentiating MMN from LMN dominant ALS in those patients in whom electrophysiological and clinical examinations remain inconclusive early in the diagnostic process.

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Polyneuropathy is a frequently encountered clinical presentation where peripheral nerves are affected due to the same cause and physiopathological processes. We report a case of acute sensorimotor polyneuropathy in a patient with Tangier disease (TD) who was treated with miglustat which is a glycosphingolipid synthesis inhibitor. TD is a very rare genetic disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene which encodes the cholesterol efflux regulatory protein. It leads to accumulation of cholesterol esters within various tissues and affects lipid metabolism by deficiency of high-density lipoprotein (HDL) in the blood. Due to the accumulation of cholesterol esters in Schwann cells, it could provoke polyneuropathy in TD. Our case presented to our clinic with quadriparesis and after treated with miglustat therapy his weakness regressed.

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AIMS/INTRODUCTION: This prospective cohort study aims to identify the optimal measure of glycated hemoglobin (HbA1c) variability and to explore its relationship with the development of new diabetic sensorimotor polyneuropathy (DSPN) in individuals with type 2 diabetes mellitus, building upon previous cross-sectional studies that highlighted a significant association between HbA1c visit-to-visit variability and DSPN. MATERIALS AND METHODS: In a prospective study, 321 participants diagnosed with type 2 diabetes mellitus underwent comprehensive clinical assessments, neurophysiologic studies, and laboratory evaluations at enrollment and follow-up. Various indices, including HbA1c standard deviation (HbA1c SD), coefficient of variation (HbA1c CV), HbA1c change score (HbA1c HVS), and average real variability (HbA1c ARV), were employed to calculate the visit-to-visit variability HbA1c based on 3 month intervals. The investigation focused on examining the associations between these indices and the development of new DSPN. RESULTS: The average follow-up duration was 16.9 ± 6.9 months. The Cox proportional hazards model identified age (P = 0.001), diabetes duration (P = 0.024), and HbA1C ARV (P = 0.031) as the sole factors associated with the development of new DSPN. Furthermore, the cumulative risk of developing DSPN over 1 year demonstrated a significant association with HbA1C ARV (P = 0.03, log-rank test). CONCLUSIONS: Apart from age and diabetes duration, HbA1c variability emerged as a robust predictor for the occurrence of new DSPN. Among the various measures of HbA1c variability evaluated, HbA1c ARV demonstrated the highest potential as a reliable indicator for anticipating the onset of new DSPN.

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BACKGROUND: PHARC syndrome (MIM:612674) is a rare neurodegenerative disorder characterized by demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts (PHARC). The syndrome is caused by mutations in the ABHD12 gene, which encodes αß-hydrolase domain-containing protein 12 related to endocannabinoid metabolism. PHARC syndrome is one of the rare diseases; so far, only 51 patients have been reported in the literature. METHODS: We evaluated the 25-year-old male patient referred to us due to vision loss, cataracts, and hearing loss. Ophthalmological examinations and genetic analyses were performed using targeted next-generation sequencing. RESULTS: In the genetic analysis, the patient was diagnosed with PHARC syndrome by detecting homozygous (NM_001042472.3): c.871del (p.Tyr291IlefsTer28) novel pathogenic variation in the ABHD12 gene. Following the molecular diagnosis, he was referred to the neurology department for reverse phenotyping and sensorimotor demyelinating polyneuropathy was detected in the neurological evaluation. CONCLUSIONS: In this study, we report a novel variation in ABHD12 gene in the first Turkish-origin PHARC patient. We present this study to contribute genotype-phenotype correlation of PHARC syndrome and emphasize the importance of molecular genetic diagnosis in order to determine the appropriate clinical approach. This report is essential for expanding the phenotypic spectrum in different populations and understanding the genotype-phenotype correlation of PHARC syndrome via novel pathogenic variation in the ABHD12 gene.

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Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)-specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US-based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium-based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene-silencing therapeutics recommended as a first-line option. Consensus is lacking on what represents "disease progression" during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy.

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BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is an adult-onset autosomal dominant disease resulting from TTR gene pathogenic variants. ATTRv often presents as a progressive polyneuropathy, and effective ATTRv treatments are available. METHODS: In this 5 year-long (2017-2021) nationwide prospective study, we systematically analysed the TTR gene in French patients with age >50 years with a progressive idiopathic polyneuropathy. RESULTS: 553 patients (70% males) with a mean age of 70 years were included. A TTR gene pathogenic variant was found in 15 patients (2.7%), including the Val30Met TTR variation in 10 cases. In comparison with patients with no TTR gene pathogenic variants (n = 538), patients with TTR pathogenic variants more often presented with orthostatic hypotension (53 vs. 21%, p = .007), significant weight loss (33 vs 11%, p = .024) and rapidly deteriorating nerve conduction studies (26 vs. 8%, p = .03). ATTRv diagnosis led to amyloid cardiomyopathy diagnosis in 11 cases, ATTRv specific treatment in all cases and identification of 15 additional ATTRv cases among relatives. CONCLUSION: In this nationwide prospective study, we found ATTRv in 2.7% of patients with age >50 years with a progressive polyneuropathy. These results are highly important for the early identification of patients in need of disease-modifying treatments.

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