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To identify clinical factors and biomarkers that could contribute to early differential diagnosis of acute inflammatory demyelinating polyneuropathy (AIDP) and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) in the pediatric population, with limited evidence. We conducted an observational retrospective study of children diagnosed with AIDP and A-CIDP between January 2014 and December 2022. Demographic data, clinical features, and routine biomarkers were also analyzed. Statistical analysis was used to identify significant features with high sensitivity and specificity. We included 91 AIDP and 17 A-CIDP patients. The A-CIDP group had an older median age (6.33 vs. 4.33 years, p = 0.017), required more complex immunotherapies (p < 0.001), and showed a longer time to nadir over 2 weeks (76.5 % vs. 7.7 %, p < 0.001). Gastrointestinal dysfunction (29.4 % vs. 6.59 %, p = 0.014) and numbness (35.3 % vs. 12.1 %, p = 0.027) were more prevalent in A-CIDP. The AIDP patients had a longer median hospitalization stays (13 vs. 11 days, p < 0.05), more prodromal events (90.1 % vs. 64.7 %, p = 0.013), and more frequent cranial nerve palsy (61.5 % vs. 5.88 %, p < 0.001). The disability scores on admission, discharge, and peak were worse in the AIDP group (p < 0.001). AIDP patients showed higher cerebrospinal fluid protein (p = 0.039), albumin quotient (p = 0.048), leukocytes (p = 0.03), neutrophils (p = 0.010), platelet count (p = 0.005), systemic inflammatory index (SII) (p = 0.009), and gamma-glutamyl transferase (p = 0.039). Multivariable regression identified two independent predictors of early A-CIDP detection: time from onset to peak beyond 2 weeks (OR = 37.927, 95%CI = 7.081–203.15) and lower modified Rankin Scale score on admission (OR = 0.308, 95%CI = 0.121–0.788). Our study found that when the condition continued to deteriorate beyond two weeks with a lower mRS on admission and possibly less cranial nerve involvement, we may favor the diagnosis of pediatric A-CIDP rather than AIDP. • The time to nadir beyond 2 weeks and lower mRS on admission are the strongest predictors of A-CIDP compared to AIDP. • A-CIDP were older, needed complex immunotherapies, showed slower progression, and had more gastrointestinal issues and numbness. • AIDP showed more cranial nerve palsy and higher CSF protein, Qalb, leukocytes, neutrophils, platelet count, SII, and GGT. • The disability scores on admission, discharge, and peak were worse in the AIDP group. [ABSTRACT FROM AUTHOR]

• Increased intraneural microvascular could be detected in patients with peripheral neuropathies using sonography. • Intraneural hypervascularization was frequently observed in patients with inflammatory neuropathies. • Superb microvascular imaging is the most sensitive technique for evaluating microvessel flow within peripheral nerves. We assessed microvessel flow within peripheral nerves using nerve sonography in patients with peripheral neuropathy. This study included consecutive patients with peripheral neuropathy who were admitted to our hospital. The patients were divided into two groups: inflammatory neuropathies for immune-mediated neuropathies, such as Guillain − Barré syndrome and chronic inflammatory demyelinating polyneuropathy, and the rest were defined as non-inflammatory neuropathies. We assessed nerve size and intraneural blood flow at four sites on each median and ulnar nerve. Blood flow was evaluated using color Doppler imaging, advanced dynamic flow (ADF), and superb microvascular imaging (SMI) techniques. Thirty-nine patients (median age, 60.0 years; 20 male) were enrolled in this study. An increase in intraneural blood flow was observed in five patients when evaluated by color Doppler, five patients by ADF, and 13 patients by SMI. An overall analysis of the three methods showed that intraneural blood flow was significantly higher in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy (54.2% vs. 0%, p = 0.0005). Intraneural hypervascularization is more frequent in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy. Evaluation of microvessel flow within peripheral nerves may contribute to the diagnosis of peripheral neuropathy. [ABSTRACT FROM AUTHOR]

• TIA1/SQSTM1 myopathy is one of the few digenic myopathies. • All patients carry the TIA1 p.Asn357Ser variant and four different SQSTM1 variants have been reported. • Patients present with asymmetric ankle dorsiflexion and hand finger extensors weakness. • Sensorimotor axonal polyneuropathy may be an additional feature of the disease. • TIA1 p.Asn357Ser is increased in distal myopathy patients and could act as a genetic modifier. TIA1/SQSTM1 myopathy is one of the few digenic myopathies. We describe four new French adult male patients carrying the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variant and review the literature to include 20 additional cases to define the spectrum of the disease. These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG. Two of the four French patients had sensorimotor axonal polyneuropathy and an additional one had neurogenic changes in muscle biopsy. Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 p.Asn357Ser variant was present in all patients and the SQSTM1 p.Pro392Leu was the most frequent (71%) of the four reported SQSTM1 variants. We reviewed the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort finding a prevalence of 11/414=2.7% of the TIA1 p.Asn357Ser variant, with two patients having an alternative diagnosis (TTN and MYH7) with atypical phenotypes, resembling some of the features seen in TIA1/SQSTM1 myopathy. Overall, TIA1/SQSTM1 myopathy has a homogenous phenotype reinforcing the pathogenicity of its digenic variants. We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory, chronic, demyelinating, and neurodegenerative disorder of central nervous system, determined by an auto-immune dysfunction. Severe disability generally occurs in patients with progressive forms of MS that typically develop either after an earlier relapsing phase or less commonly from disease onset. Despite advances in research to slow the progression of MS, this condition remains a life-limiting disease with symptoms impacting negatively the lives of patients and caregivers. To analyze the difefrent aspects of palliative cae in patients with MS. To analyse selected literature assessing several palliative care aspects in patients with MS. People with MS have complex symptoms and different needs. These demands include how to deal with the burden of physical disability, how to organise daily life, restructuring social roles in the family and at work, keeping self-sufficiency in personal care, and preserving personal identity and community roles. An early palliative care approach aims to improve the palliative care skills and competencies of health professionals caring for the patients since the early stage of disease, including those who are actively undergoing disease-targeted therapies, rather than merely providing end-of-life care. [ABSTRACT FROM AUTHOR]

• Tangier disease results in accumulation of cholesterol esters. • It could cause neuropathy by demyelination of nerves secondary to cholesterol deposition in Schwann cells. • Miglustat is a glycosphingolipid synthesis inhibitor. • Miglustat treatment could be effective for neuropathies of Tangier disease. 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. [ABSTRACT FROM AUTHOR]

Mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene has been identified as a causative gene for autosomal dominant Parkinson's disease (PD), with the p.Y314S variant potentially associated with polyneuropathy in PD patients. The objectives of our study were to screen for UQCRC1 variants in Chinese patients with early-onset PD (EOPD) and explore the role of UQCRC1 in EOPD. We investigated the rare variants in 913 EOPD patients in our cohort using whole-exome sequencing, assessing their link to PD at both allele and gene levels. A total of 7 rare variants (minor allele frequency < 0.1%) of UQCRC1 were identified. However, no excessive burden of rare UQCRC1 variants was suggested in the EOPD patients. Further analysis with larger sample size and diverse regions is needed to determine the role of UQCRC1 in PD. [ABSTRACT FROM AUTHOR]

• Neurological testing confirmed a hypomyelinating polyneuropathy (HPN) in four dogs. • Variants in MTMR2, MPZ , and SH3TC2 were identified by whole-genome sequencing. • These variants genetically describe the first peripheral nervous system-exclusive HPNs in dogs. • Cognizance of potential genocopies is vital for genetic studies, even in one breed. Congenital hypomyelinating polyneuropathy (HPN) restricted to the peripheral nervous system was reported in 1989 in two Golden Retriever (GR) littermates. Recently, four additional cases of congenital HPN in young, unrelated GRs were diagnosed via neurological examination, electrodiagnostic evaluation, and peripheral nerve pathology. Whole-genome sequencing was performed on all four GRs, and variants from each dog were compared to variants found across >1,000 other dogs, all presumably unaffected with HPN. Likely causative variants were identified for each HPN-affected GR. Two cases shared a homozygous splice donor site variant in MTMR2 , with a stop codon introduced within six codons following the inclusion of the intron. One case had a heterozygous MPZ isoleucine to threonine substitution. The last case had a homozygous SH3TC2 nonsense variant predicted to truncate approximately one-half of the protein. Haplotype analysis using 524 GR established the novelty of the identified variants. Each variant occurs within genes that are associated with the human Charcot-Marie-Tooth (CMT) group of heterogeneous diseases, affecting the peripheral nervous system. Testing a large GR population (n = >200) did not identify any dogs with these variants. Although these variants are rare within the general GR population, breeders should be cautious to avoid propagating these alleles. [ABSTRACT FROM AUTHOR]

To evaluate the clinical features, demographic features, and treatment modalities of pediatric-onset chronic inflammatory demyelinating polyneuropathy (CIDP) in Turkey. The clinical data of patients between January 2010 and December 2021 were reviewed retrospectively. The patients were evaluated according to the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society Guideline on the management of CIDP (2021). In addition, patients with typical CIDP were divided into two groups according to the first-line treatment modalities (group 1: IVIg only, group 2: IVIg + steroid). The patients were further divided into two separate groups based on their magnetic resonance imaging (MRI) characteristics. A total of 43 patients, 22 (51.2%) males and 21 (48.8%) females, were included in the study. There was a significant difference between pretreatment and post-treatment modified Rankin scale (mRS) scores (P < 0.05) of all patients. First-line treatments include intravenous immunoglobulin (IVIg) (n = 19, 44.2%), IVIg + steroids (n = 20, 46.5%), steroids (n = 1, 2.3%), IVIg + steroids + plasmapheresis (n = 1, 2.3%), and IVIg + plasmapheresis (n = 1, 2.3%). Alternative agent therapy consisted of azathioprine (n = 5), rituximab (n = 1), and azathioprine + mycophenolate mofetil + methotrexate (n = 1). There was no difference between the pretreatment and post-treatment mRS scores of groups 1 and 2 (P > 0.05); however, a significant decrease was found in the mRS scores of both groups with treatment (P < 0.05). The patients with abnormal MRI had significantly higher pretreatment mRS scores compared with the group with normal MRI (P < 0.05). This multicenter study demonstrated that first-line immunotherapy modalities (IVIg vs IVIg + steroids) had equal efficacy for the treatment of patients with CIDP. We also determined that MRI features might be associated with profound clinical features, but did not affect treatment response. [ABSTRACT FROM AUTHOR]

Childhood cancer survivors (CCS) are at risk of polyneuropathy due to chemotherapy, but studies in young survivors are scarce and diagnosis is challenging. We aimed to study the presence of polyneuropathy and the possible effect of cumulative doses of chemotherapeutic agents in a representative group of adolescent survivors. CCS aged nine to 18 years and age- and sex-matched controls were recruited from the cross-sectional Physical Activity and Fitness among Childhood Cancer Survivors (PACCS) study. CCS with various cancer diagnoses who had ended cancer treatment one year or more before study were included. Polyneuropathy was evaluated clinically and with nerve conduction studies (NCSs) in three motor and five sensory nerves. We used mixed-effects linear regression models to compare CCS and controls, and investigate possible associations between cumulative chemotherapy doses and NCS amplitudes. A total of 127 CCS and 87 controls were included, with 14% CCS having probable or confirmed polyneuropathy. NCS amplitudes were lower in survivors compared with controls in all nerves. The largest mean difference was 3.47 μV (95% confidence interval [CI], 2.18 to 4.75) in the tibial plantar medial sensory and 1.91 mV (95% CI, 0.78 to 3.04) in the tibial motor nerve. The cumulative dose of platinum derivatives was associated with lower tibial motor nerve amplitude (−0.20; 95% CI, −0.35 to −0.04 mV for 100 mg/m2 dose increase) but not in other nerves. We found no significant associations between vinca alkaloids cumulative dose and amplitudes. CCS without clinical signs or symptoms of polyneuropathy may have subtle nerve affection. The clinical long-term impact of this novel observation should be evaluated in larger, longitudinal studies. [ABSTRACT FROM AUTHOR]

Mutations in the neurofilament light polypeptide gene (NEFL) are an uncommon cause of Charcot-Marie-Tooth disease (CMT). The aim of this study is to elucidate the clinical characteristics and genetic spectrum of NEFL -related neuropathy in a Taiwanese CMT cohort. Mutational analysis of the coding regions of NEFL was performed by Sanger sequencing or targeted resequencing. Twenty-one patients from nine CMT pedigrees, identified from a cohort of 508 unrelated CMT patients, were found to have a NEFL mutation. Genetic, clinical and electrophysiological features were analyzed. Six NEFL mutations were identified, including two novel ones (p.P8S, p.N98Y). NEFL p.E396K was the most common mutation, accounting for 33.3% of the patients in our cohort. All patients manifested sensorimotor polyneuropathy with a mean age of disease onset of 13.5 ± 9.6 (1–40) years. Their motor nerve conduction velocities (MNCVs) of the ulnar nerve ranged from 22.1 to 48.7 m/s. Seventy percent of the patients could be classified as intermediate CMT with ulnar MNCVs between 25 and 45 m/s. Six of the 21 patients (28.6%) had additional features of central nervous system (CNS) involvement, including motor developmental delay, spasticity, cerebellar signs, neuropathic pain and scoliosis. NEFL mutations account for 1.8% (9/508) of the CMT patients in Taiwan. The present study delineates the clinical and genetic characteristics of NEFL -related neuropathy in Taiwan, and highlights that ulnar MNCV above 25 m/s and CNS involvement may serve as diagnostic clues for NEFL -related neuropathy. [ABSTRACT FROM AUTHOR]

• Upper limb nerves microstructural changes occur in people with diabetic neuropathy. • Median and ulnar nerve microstructure is altered before symptoms appear in hands. • Higher-order diffusion model may help detailing microstructure in peripheral nerves. Diffusion weighted imaging (DWI) has revealed microstructural changes in lower limb nerves in people with diabetic neuropathy. Microstructural changes in upper limb nerves using DWI in people with diabetes have not yet been explored. This cross-sectional study aimed to quantify and compare the microstructure of the median and ulnar nerve in people without diabetes (n = 10), people with diabetes without distal symmetrical polyneuropathy (DSPN; n = 10), people with DSPN in the lower limbs only (DSPN FEET ONLY ; n = 12), and people with DSPN in the upper and lower limbs (DSPN HANDS & FEET ; n = 9). DSPN diagnosis included electrodiagnosis and corneal confocal microscopy. Tensor metrics, such as fractional anisotropy, radial diffusivity and axial diffusivity, and constrained spherical deconvolution metrics, such as dispersion and complexity, were calculated. Linear mixed-models were used to quantify DWI metrics from multiple models in median and ulnar nerves across the groups, and to evaluate potential differences in metrics at the wrist and elbow based on the principle of a distal-to-proximal disease progression. Tensor metrics revealed microstructural abnormalities in the median and ulnar nerve in people with DSPN HANDS & FEET , and also already in DSPN FEET ONLY. There were significant negative correlations between electrodiagnostic parameters and tensor metrics. A distal-to-proximal pattern was more pronounced in the median nerve. Non-tensor metrics showed early microstructural changes in people with diabetes without DSPN. Compared to people without diabetes, microstructural changes in upper limb nerves can be identified in people with diabetes with and without DSPN, even before symptoms occur. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired demyelinating disease of the peripheral nervous system with unknown etiology. Alopecia universalis, an advanced form of alopecia areata (AA), is a condition characterized by complete hair loss. Here we report the first case of childhood CIDP associated with AA who was successfully treated with a combination of intravenous immunoglobulin (IVIg) and corticosteroids. This case describes a nine-year-old Japanese girl who developed alopecia, progressive muscle weakness, and eventually loss of walking ability (at ages 2, 4, and 7, respectively). She was treated with IVIg and prednisolone combination therapy, which improved muscle weakness and alopecia. She was positive for serum IgG-GM2 type anti-glycolipid antibodies, which may be associated with this rare combination of diseases. [ABSTRACT FROM AUTHOR]

1. Discuss treatment options for wide spread muscle spasms that are not related to neurotoxicity. 2. Recognize the importance of physical pain management to allow patient's a chance in addressing all of his palliative domain care needs. In managing the multifaceted challenges posed by end-stage renal disease, we employed a multidisciplinary approach to alleviate pain arising from uremic polyneuropathy, particularly muscle spasms. Our comprehensive care not only improved symptom control but also addressed the patient's existential concerns, enabling meaningful connections. This case underscores the significance of holistic care strategies in complex medical scenarios. A 76-year-old male, suffering from End-Stage Renal Disease (ESRD) and undergoing hemodialysis (HD), was admitted due to altered mental status (AMS). His medical history included Deep Vein Thrombosis (DVT), Hypertension (HTN), and Gastroesophageal Reflux Disease (GERD). It was determined that his AMS resulted from a significant drop in blood pressure during HD. The nephrologist raised concerns about the potential harm from continued HD and recommended Palliative Medicine consultation. During our interdisciplinary evaluation, the patient's AMS showed signs of improvement, although he was reluctant to discuss his care goals due to severe pain. Widespread and intense muscle spasms afflicted all his extremities, causing significant distress. With his designated medical power of attorney guiding care discussions, it was discovered that these spasms began months before admission and were unrelated to HD. To alleviate his symptoms, we initiated methocarbamol at a loading dose of 1500mg, administered four times a day for three days. Remarkably, by day two, his spasms had substantially subsided. As his pain decreased, we reduced opioid medications, allowing for improved communication and engagement in activities like watching TV. With his symptoms under control, we could address his goals of care comprehensively. He expressed spiritual distress regarding the possibility of discontinuing HD and approaching the end of his life. Our Chaplain provided support and guidance, helping him identify his present priorities. During a palliative care team meeting, his foremost goal emerged: reuniting with his sister one last time. We coordinated this meeting, and he agreed to continue HD until his sister's visit. After the loading period, we adjusted methocarbamol to a scheduled maintenance dose of 750 mg, four times daily. He was discharged to a skilled nursing facility and, a week later, enrolled in hospice care. Managing Suffering and Distress / Disease specific management [ABSTRACT FROM AUTHOR]

• Common age-related cervical neuroforaminal stenoses on MRI/CT are not per se associated with nerve root enlargement on ultrasound. • Degeneration of the cervical spine is unlikely to confound the ultrasound assessment of cervical nerve roots in polyneuropathy. • Older age is associated with neuroforaminal stenosis, but is not a significant covariate of nerve root diameter in this cohort. Ultrasound can detect enlargement of cervical nerve roots, which has been described in polyneuropathies (PNP), mainly of demyelinating pathology. This study investigates whether neuroforaminal stenosis, as a common but often asymptomatic degenerative change, is associated with nerve root enlargement on ultrasound and whether neuroforaminal stenosis thus confounds cervical nerve root ultrasound findings in the diagnostic assessment of PNP. We retrospectively studied 182 patients (62 demyelinating, 71 axonal PNP; 49 without evidence of PNP) who had undergone ultrasound of the cervical nerve roots C5 and C6 and magnetic resonance or computed tomography of the cervical spine that was reviewed with respect to neuroforaminal stenoses. Patients with demyelinating PNP had larger nerve roots than those with axonal/without PNP. No significant differences in cervical nerve root diameters were found between groups with vs. without neuroforaminal stenosis. The diagnostic performance of the discrimination of PNP subtypes based on ultrasound nerve root measurements did not differ significantly when including or excluding subjects with neuroforaminal stenoses. Neuroforaminal stenosis per se does not entail relevant cervical nerve root enlargement detectable by nerve ultrasound. Ultrasound assessment of cervical nerve root size in the diagnostic evaluation of PNP is unlikely to be confounded by common degenerative changes of the cervical spine. [ABSTRACT FROM AUTHOR]

• A substantial number of patients with chronic immune mediated neuropathy are refractory to first line therapy. • The selective B-cell depleting therapy Rituximab has potential in the treatment of these patients. • Rituximab was effective in 63% of chronic inflammatory demyelinating polyradiculoneuropathy, 48% of anti-myelin-associated glycoprotein neuropathy, and 96% of autoimmune nodopathy patients included in our review. • The quality of evidence assessing the use of Rituximab in these disorders is poor. Chronic immune mediated neuropathy is a heterogenous group of peripheral nerve diseases, encompassing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), autoimmune nodopathy, multifocal motor neuropathy (MMN), and anti-myelin-associated glycoprotein (MAG) neuropathy. Rituximab (RTX) is a chimeric monoclonal antibody targeting the CD20 antigen, which has been used in the treatment of autoimmune neuropathies, although the efficacy of RTX remains unclear. A literature search was performed using Medline, Embase and Cochrane Register for studies between 2000 and 2021 using the search terms "Chronic inflammatory demyelinating polyneuropathy" OR "Multifocal motor neuropathy" OR "Myelin associated glycoprotein" OR "Distal acquired demyelinating neuropathy" OR "Multifocal acquired demyelinating sensory and motor neuropathy" OR "demyelinating neuropathy" AND "Rituximab". Twenty-three studies were included, of which two were randomised controlled trials, 6 prospective studies and 15 retrospective studies. RTX was effective in 63% of CIDP patients, 48% of anti-MAG neuropathy, and 96% of patients with autoimmune nodopathy. Neurophysiological improvement was evident in 58% of CIDP and 40% of anti-MAG neuropathy patients. Low rates of serious adverse events (2.6%) were observed. These results indicate that RTX has potential as a treatment in immune mediated polyneuropathy, although the quality of evidence supporting its use it poor. Randomized controlled trials are required to reliably establish the efficacy and safety of RTX. Trial registration number: CRD42020179666. [ABSTRACT FROM AUTHOR]

• In anti-MAG neuropathy; widenings of myelin lamellae (WML) are classically observed in the nerve biopsy (electron microscopy). • WML may be observed in polyneuropathy associated to IgM monoclonal gammopathy without anti-MAG activity. • IgM may target an unknown myelin antigen responsible for the nerve lesions similar to those observed in anti-MAG polyneuropathy. • The good response to plasma exchange and/or rituximab suggests an autoimmune origin. • Nerve biopsy may help to confirm the dysimmune process and to select an efficient treatment. We report the case of a patient with a very severe predominantly demyelinating sensorimotor polyneuropathy (with axonal loss) that had developed over several months, along with an immunoglobulin-M monoclonal gammopathy without anti-myelin associated glycoprotein antibodies (or other antibodies against myelin). Widening of myelin lamellae were frequently observed by electron microscopic examination of a nerve biopsy: immunoglobulin-M targeting an unknown myelin antigen appears to be responsible for the nerve lesions similar to those observed in anti-myelin associated glycoprotein polyneuropathy. Usually, if in anti-myelin associated glycoprotein neuropathy the response to immunotherapies is not optimal, in this case the combination of plasma exchanges and rituximab was effective, suggesting an autoimmune origin. [ABSTRACT FROM AUTHOR]

• Amyloid-A amyloidosis should be considered in differential diagnosis of amyloidosis. • Amyloid-A amyloidosis may present with peripheral nerve involvement. • Nerve biopsy is mandatory to confirm and type deposits in amyloid-A amyloidosis. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the POLG gene, encoding the mitochondrial DNA (mtDNA) gamma-polymerase, can cause early-onset mtDNA depletion syndromes, such as Alpers syndrome, or later-onset disorders characterized by the presence of multiple mtDNA deletions (MMD), which may encompass autosomal dominant or recessive progressive external ophthalmoplegia (PEO), neuropathy, ataxia, epilepsy, or parkinsonism, among others. We report on the clinical, pathological, and genetic characteristics of 27 patients with POLG-related disorders. Fourteen patients (52%) were female. 67% were adult-onset cases, with a mean age at symptom onset of 34 years (range: 0-67). The most common findings were ophthalmoplegia (80%), ptosis (77%), muscle weakness (54%), lower limb proprioceptive abnormalities (50%), and sensory ataxia (42%). Other relevant ones were tremor (26%), hearing loss (15%), and seizures (7%). SANDO was observed in 26%, pure PEO in 15%, PEO-plus in 11%, and a MNGIE-like phenotype in 4%. The mean CK level was 394 U/L (83-1500). Electrophysiological testing (21/27) revealed sensory axonal polyneuropathy in 33%, sensorimotor axonal neuropathy in 24%, and myopathic changes in 29%. Brain MRI (16 patients) showed normal results in 38%, cerebellar atrophy in 38%, brain atrophy in 31%, and leukoencephalopathy in 13%. Relevant cardiologic involvement was seen in 7%. Muscle biopsy (19 patients) showed histological mitochondrial abnormalities in 82% (i.e., ragged-red fibers and COX-negative fibers). Respiratory chain complexes activities were normal in 88%, and MMD were detected in 93% of them. Nineteen POLG pathogenic variants were identified, with the most frequent alleles being the c.[752C>T;1760C>T] and the c.1399G>A, (33% and 19% of patients, respectively). Inheritance pattern was dominant in 30% and recessive in 65% of cases. A high index of suspicion is needed for diagnosis due to clinical heterogeneity. The presence of MMD should prompt testing for POLG causative variants. [ABSTRACT FROM AUTHOR]

We present two relatives, who were referred to our Neuromuscular clinic with similar phenotypes and were proven to share the same rare genetic neurodevelopmental disease. The first patient, a 16-year-old female, presented with global developmental delay, severe learning difficulties, peripheral neuropathy with fatigue, hypermobile elbows and knees and social skills difficulties. The second patient, a 10-year-old male who was the first patient's nephew, presented with global developmental delay, learning difficulties, oro-motor dysfunction, peripheral neuropathy and epilepsy, which was characterised by generalised tonic clonic seizures. There was an extensive family history of weakness without a known diagnosis. On examination, both patients had marked microcephaly, an ataxic gait, absent reflexes and distal muscle weakness. The first patient had a normal MRI brain, whereas the MRI spine showed mild thoracic scoliosis. The second patient had both normal MRI brain and spine. The nerve conduction studies showed moderate demyelinating sensory-motor polyneuropathy in both patients. Extensive blood work-up, including metabolic studies, were normal. We then proceeded with genetic testing. Microarray CGH was normal for both patients. Whole genome sequencing revealed that both patients were homozygous for pathogenic variant c.1633C>T p.(Arg545Cys) in NARS1 gene, which confirmed a diagnosis of NARS1-associated recessive neurodevelopmental disorder with microcephaly, impaired language and gait abnormalities. NARS1 is part of ancient genes, which encode a group of enzymes called aminoacyl-tRNA synthetases (ARSs) and play a crucial role in the esterification of proteinogenic amino acids to cognate RNA. Mutations in NARS1 are very rare and have been associated with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy and ataxia. Our two cases enrich the phenotypic spectrum of NARS1-associated neurodevelopmental disorders with peripheral neuropathy and highlight the fundamental role of genetics in patients with a constellation of symptoms, including neurodevelopmental difficulties and distal neuropathy. [ABSTRACT FROM AUTHOR]

TIA1/SQSTM1 myopathy is one of the few myopathies with a true digenic inheritance. Our goal was to define the phenotype presentation of the disease, genotype-phenotype correlations, and to study the prevalence of the TIA1 -N357S variant in distal myopathy. We describe four new adult male patients carrying the TIA1 -N357S and SQSTM1 -P392L variant and review the literature to include 20 additional cases. We reviewed the results of the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort for the TIA1 -N357S variant. Twenty-four patients (75% males) were included, with late-onset (52,6±10,1years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and EMG myopathic changes. Two of the four French patients also had a sensorimotor axonal polyneuropathy and an additional one had neurogenic features in tibialis anterior biopsy. Most commonly, muscle histopathology showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 -N357S variant was present in all patients and the SQSTM1-P392L was the most frequent (68%) of the four reported SQSTM1 variants. The TIA1 -N357S variant was carried by 11/414=2.7% of distal myopathy patients and two had an alternative diagnosis (TTN and MYH7) with atypical phenotypes. TIA1/SQSTM1 myopathy has a homogenous and characteristic phenotype reinforcing the pathogenicity of its digenic variants. Furthermore, sensorimotor axonal polyneuropathy may be an additional feature of the disease. Finally, we confirm an increased burden of the TIA1 -N357S variant in distal myopathy patients which could act as a genetic modifier. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines, such as interleukin (IL)-8, IL6, and IL10, have been found to be higher in patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) compared to healthy controls. When comparing immunological pathway activation in patients with hereditary polyneuropathy (Charcot-Marie-Tooth (CMT)) and CIDP, similar levels of proinflammatory cytokines have been found. Furthermore, increased levels of components of the complement pathway in mouse models and CMT patients indicate inflammatory pathway activation in CMT. This suggests that inflammatory pathway activation is a driver for disease progression in CIDP as well as CMT, but larger studies are needed. The aim with our project is to investigate potential activation of immunologic pathways in a larger cohort of patients with CMT and CIDP. We include patients diagnosed with CIDP according to EAN/PNS diagnostic criteria and patients with genetically verified CMT followed at a specialized neuromuscular center. The study is a case-control study, with CIDP patients as disease controls. Patients are examined with evaluation of disease severity and blood biomarkers. Primary disease severity score is Inflammatory Neuropathy Cause and Treatment (INCAT), a validated outcome measure for disease severity in polyneuropathies. Secondary scores are 80-points Medical Research Council (MRC)-sum score, and handgrip strength, which are all validated outcome measures for disease severity in polyneuropathies. Plasma and serum will be collected according to protocol and frozen to -80 degrees Celsius, assuring stability of biomarkers when samples are frozen. The concentration of interleukins, TNF-alfa and complement factor will be analyzed using Multiplex assay in our laboratory. To test for differences in interleukin, TNF-alfa, and complement levels in CIDP patients compared to CMT patients, we will use two-sample t-test. Correlation between levels of interleukins and disease severity will be examined using Spearman correlation. A total of 144 patients have been included, 65 patients with CIDP and 79 patients with CMT. All patients have been examined with medical examination, physiotherapeutic tests, and blood samples and data are currently being analyzed. Blood samples are ready for analysis and results are expected in September 2024. Preliminary results will be presented at the conference. There is a vast need for understanding the variability of symptoms in polyneuropathies. Immunological activation may explain the clinical variability and could potentially lead to future "biomarker-guided" treatments. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, acquired, treatable, immune-mediated disease. Autoimmune nodopathies due to antibodies against proteins of the paranode and node of Ranvier (neurofascin 186, neurofascin 155, contactin 1, and contactin-associated protein 1) represent a subgroup characterized by distinct clinical phenotype and treatment response. A 7-year-old girl with a known diagnosis of achromatopsia and mild expressive language delay presented with progressive symmetric lower extremity weakness over a period of 6 weeks. At presentation, she had bilateral upward gaze restriction, muscle strength was MRC grade 4 in lower limbs and grade 3 in bilateral ankle dorsiflexion. Tendon reflexes were absent. Electromyography (EMG) revealed motor and sensory demyelinating polyneuropathy with axonal involvement. Spinal magnetic resonance imaging showed contrast enhancement of the cauda equina roots. CSF protein concentration was 384 mg/dL (N: 15–45), with normal white blood cell count and glucose concentration. Treatment with IVIg and IV methylprednisolone (30 mg/kg/d for 5 days) was ineffective. She lost the ability of independent walking. Anti-contactin 1 and contactin-associated protein 1 (Caspr1) antibodies were positive in the serum. She was subsequently started on rituximab 750mg/m2 every week for the 1st month and then once every 6 months. The patient has received 4 doses of rituximab treatment so far. At the last visit she was able to stand independently for short periods. To our knowledge, this is the second description of a contactin 1-associated CIDP in the pediatric age group. The first patient had a Guillain-Barre syndrome like presentation, recurrent attacks, diagnosed with CIDP within a year, had a good response to rituximab and stable course, and diagnosed at age 5 years based on the analysis of archived serum and CSF samples. Shared clues were predominant motor involvement, demyelination and early axonal involvement, poor response to streoids and IVIg. Further characterization of pediatric patients may help to define clusters within the autoimmune nodopathies. Nodal/paranodal antibody testing should be considered in pediatric patients for optimizing treatment strategies. [ABSTRACT FROM AUTHOR]

Guillain-Barré Syndrome (GBS) can lead to significant functional impairments, yet little is understood about the recovery phase and long-term consequences for patients in low- and medium-income countries. To evaluate the functional status and identify factors influencing outcomes among patients with GBS in Colombia. Telephone interviews were conducted with GBS patients enrolled in the Neuroviruses Emerging in the Americas Study between 2016 and 2020. The investigation encompassed access to health services and functional status assessments, utilizing the modified Rankin Scale (mRS), GBS Disability Score (GDS), Barthel Index (BI), and International Classification of Functioning (ICF). Univariate analysis, principal component analysis, linear discriminant analysis, and linear regression were employed to explore factors influencing functional status. Forty-five patients (mean age = 50[±22] years) with a median time from diagnosis of 28 months (IQR = 9–34) were included. Notably, 22% and 16% of patients did not receive rehabilitation services during the acute episode and post-discharge, respectively. Most patients demonstrated independence in basic daily activities (median BI = 100, IQR = 77.5–100), improvement in disability as the median mRS at follow-up was lower than at onset (1 [IQR = 0–3] vs. 4.5 [IQR = 4–5], p < 0.001), and most were able to walk without assistance (median GDS = 2, IQR = 0–2). A shorter period from disease onset to interview was associated with worse mRS (p = 0.015) and ICF (p = 0.019). Negative outcomes on GDS and ICF were linked to low socioeconomic status, ICF to the severity of weakness at onset, and BI to an older age. This study underscores that the functional recovery of GBS patients in Colombia is influenced not only by the natural course of the disease but also by socioeconomic factors, emphasizing the crucial role of social determinants of health. • The functional recovery of Colombian GBS patients is influenced by the disease's natural history and by social factors. • Socioeconomic status is associated with functional outcomes, highlighting the impact of social determinants of health. • GBS patients in resource-limited settings face difficulties in accessing rehabilitation during the recovery phase. [ABSTRACT FROM AUTHOR]

• Inflammation serves as an important factor in the development of diabetes and diabetic peripheral polyneuropathy. • The activation of advanced glycation end products (AGEs)/receptor for AGE plays a key part in the activation of the intracellular signaling cascade leading to cytokine release. • Increased release of inflammatory cytokines is related to diabetes, diabetic neuropathy and neuropathic pain. • Anti-inflammatory therapy shows promise for the treatment of diabetic symmetrical polyneuropathy. Diabetic distal symmetric polyneuropathy is the most common type of peripheral neuropathy complication of diabetes mellitus. Neuroinflammation is emerging as an important contributor to diabetes-induced neuropathy. Long-term hyperglycemia results in increased production of advanced glycation end products (AGEs). AGEs interact with their receptors to activate intracellular signaling, leading to the release of various inflammatory cytokines. Increased release of inflammatory cytokines is associated with diabetes, diabetic neuropathy, and neuropathic pain. Thus, anti-inflammatory intervention is a potential therapy for diabetic distal symmetric polyneuropathy. Further characterization of inflammatory mechanisms might identify novel therapeutic targets to mitigate diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegia (HSP) encompasses several rare genetic disorders characterized by progressive lower extremity spasticity and weakness caused by corticospinal tract degeneration. Published literature on genetically confirmed pediatric HSP cases is limited.Methods: We conducted a retrospective review of childhood-onset HSP cases followed in the neuromuscular clinics at Children's and Emory Healthcare in Atlanta. Clinical presentation, family history, examination, electrodiagnostic data, neuroimaging, genetic test results, comorbidities, and treatment were recorded.Results: Sixteen patients with HSP (eight males, eight females) with a mean age 19 years ± 15.7 years were included. Ten patients (66%) presented with gait difficulty. Seven (44%) were ambulatory at the last clinic follow-up visit with an average disease duration of 7.4 years. Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1), SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1). Symptom onset to genetic confirmation on an average was 8.2 years. Sensory motor axonal polyneuropathy was found in seven patients, and two exhibited cerebellar atrophy on magnetic resonance imaging (MRI) of the brain. Neurological comorbidities included developmental delay (n = 9), autism (n = 5), epilepsy (n = 3), and attention-deficit/hyperactivity disorder (n = 2).Conclusions: In our study, a significant proportion (70%) of subjects with childhood-onset HSP had comorbid neurocognitive deficits, polyneuropathy with or without neuroimaging abnormalities, and rare genetic etiology. Genetic diagnosis was established either through inherited genetic neuropathy panel or whole-exome sequencing, which supports the utility of whole-exome sequencing in aiding in HSP diagnosis. [ABSTRACT FROM AUTHOR]

• A novel mutation in the CYP27A1 gene has been identified. • Brain and spinal lesion were present. • A suspicion index proposed by Mignarri et al. (2014) facilitated the diagnosis. • Treatment improved biochemical and electrophysiological abnormalities. Cerebrotendinous xanthomatosis (CTX) is a rare inherited disorder of the alternative pathway of bile acid biosynthesis, due to mutation(s) of the gene CYP27A1, leading to sterol 27-hydroxylase deficiency. The latter results in a systematic deposition of cholestanol and cholesterol to the central nervous system and tendons, premature cataract, as well as the manifestation of systematic symptoms, such as chronic diarrhea, osteoporosis, and premature atherosclerosis. Due to its marked clinical heterogeneity, prompt diagnosis of this disorder is challenging. We present a case of a 38-year-old male with gait difficulty, a progressive deterioration in ambulation, several episodes of vertigo and episodic diarrhea. Clinical history revealed neonatal jaundice, juvenile bilateral cataracts, borderline intellectual capacity, hypothyroidism, testicular cancer. Magnetic resonance imaging demonstrated increased T2-weighted signal in internal capsules, midbrain, cerebellum, and spinal cord. Electrodiagnostic study showed mixed polyneuropathy. Genetic analysis revealed a novel, biallelic, most likely pathogenic mutation, in gene CYP2A1 (c.1410_1411del). Plasma sterol profiling confirmed the diagnosis of CTX. Our patient was treated with chenodeoxycholic acid and one year later, he shows a progressive improvement of gait, normalization of plasma sterol biochemistry and electrophysiological parameters. This case highlights the importance of maintaining a high index of suspicion as the key to an early diagnosis of CTX, taking into consideration its clinical variability and, if promptly identified, the good response to treatment. [ABSTRACT FROM AUTHOR]

• 8% of our CIDP cohort were autoimmune nodopathies. • In IgG4 anti-NF155 and anti-CNTN1 nodopathies, there were poor responses to IVIG. • One patient with IgG1 anti-NF155 had multifocal CIDP and a good prognosis with IVIG. • Detecting nodo-paranodal antibodies is crucial in diagnosis and disease prognosis. We report on our cohort of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who fulfilled the 2010 diagnostic criteria of CIDP. Patients were consecutively recruited and their demographics, clinical features and serological analysis of autoantibodies against neurofascin (NF)-155, NF-186, contactin-1 (CNTN1) and contactin-associated protein 1 were obtained. A total of 26 patients for which there was serologic testing were included: 22 typical CIDP, 3 distal CIDP and 1 multifocal CIDP. Of these, 2 patients had previously reported paranodal antibodies; one with autoantibodies IgG4 against NF155 and one with IgG4 against CNTN1. The patient with IgG4 anti-NF155 had young-onset, predominantly distal phenotype with associated tremor and sensory ataxia and poor response to intravenous immunoglobulin (IVIG). The patient with IgG4 anti-CNTN1 antibodies had a subacute onset, sensory ataxia, membranous nephropathy but responded poorly to IVIG. Autoimmune nodopathies represented 8% of our CIDP cohort. The clinical features and treatment response of patients with IgG4 anti-NF155 and anti-CNTN1 were similar to previous reports. Detecting the presence of autoimmune nodopathies was crucial in refining the diagnosis and determining the prognosis. [ABSTRACT FROM AUTHOR]

• Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for refractory CIDP. • AHSCT offers long-term remission with an overall acceptable risk profile. • Severe disability caused by CIDP can be ameliorated with AHSCT. Autologous haematopoietic stem cell transplantation is an emerging treatment option in refractory chronic inflammatory demyelinating polyradiculoneuropathy. We describe a case of a 46-year-old male, with history of IgG/lambda monoclonal gammopathy, who was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy at 27 years of age. After an initial 10-year period of corticotherapy response, the patient experienced severe relapses and disease progression, evolving to a refractory state. First-line and escalating treatment could not achieve clinical stabilization, leading to severe disability. Pre-treatment with ibrutinib was initiated and autologous haematopoietic stem cell transplantation was performed without significant complications. Marked clinical improvement was observed in the following months, both subjective and objective. A significant proportion of the patients who respond to the first-line immunosuppressive therapy eventually become treatment-refractory. Autologous haematopoietic stem cell transplantation may be a treatment option, offering long-term remission with an overall acceptable side effect and risk profile. [ABSTRACT FROM AUTHOR]

Comprehensive data on variant transthyretin amyloidosis polyneuropathy (ATTRv-PN) in Greece are lacking. We presently provide an overview of ATTRv-PN in Greece, focusing on unexplored non-endemic regions of the country. In total, we identified 57 cases of ATTRv-PN diagnosed over the past 25 years, including 30 from the island of Crete, an apparent endemic region. Patients carried 10 different TTR mutations (C10R; P24S; V30M; R34G; R34T; I68L; A81T; E89Q; E89K and V94A). Carriers of the common V30M mutation constituted 54.3 % of the cohort. A known founder effect for the V30M mutation was present on the island of Crete. Non-endemic cases identified outside the island of Crete are presently reported in more detail. The age of onset ranged from 25 to 77 years, with a mean of 51.1 years. A mean diagnostic delay of 3.2 years was observed. V30M patients had earlier onset and less cardiac involvement than patients carrying other mutations. Genotype-phenotype correlations were largely consistent with published data. We conclude that, with the exception of the Cretan cluster, ATTRv-PN is not endemic in the Greek population. This makes timely diagnosis more challenging, yet absolutely essential given the availability of therapies that can alter the long-term course of the disease. • Data on ATTRv-polyneuropathy in Greece are lacking • In total, 57 cases of ATTRv-polyneuropathy were identified over the last 25 years • Patients carried 10 different mutations, of which V30M constituted 54% • With the exception of the island of Crete, ATTRv-polyneuropathy is not endemic in Greece [ABSTRACT FROM AUTHOR]

Explanted livers from patients with familial amyloid polyneuropathy have often been used for domino liver transplantation (DLT). This has expanded the organ pool for liver transplantation. We evaluated the effects of a single-center DLT program on waiting list duration and patient survival. Liver transplants conducted from 2007 to 2017 were analyzed. Selected patients, all liver transplant candidates above the age of 60 years and patients with hepatocellular carcinoma, were offered DLT. Survival, time on waiting list, and operative factors were evaluated. The study group included 485 patients transplanted with grafts from deceased donors (conventional liver transplantation) and 149 patients who were offered and accepted a potential DLT, of whom 34 underwent DLT and 115 did not; these patients received a deceased donor graft (non-DLT). Five-year and overall estimated survival rates respectively were 79% and 54.4% for DLT and 67.6% and 46.7% for non-DLT (P =.67, log rank test). No differences were noted in survival (P =.816) or waiting times (P = 1.0) between DLT and non-DLT groups. As expected, survival time in the conventional liver transplantation group was longer (84.7% and 60.6%, P <.001). Donor age and ischemia time were significantly different between DLT and non-DLT (P <.001). DLT has enabled 6% additional transplantations without affecting waiting time or survival (34/600). [ABSTRACT FROM AUTHOR]

Reliable and responsive tools for monitoring disease activity and treatment outcomes in patients with neuropathies are lacking. With the emergence of ultrasensitive blood bioassays, proteins released with nerve damage are potentially useful response biomarkers for many neurological disorders, including polyneuropathies. In this review, we provide an overview of the existing literature focusing on potential applications in polyneuropathy clinical care and trials. Whilst several promising candidates have been identified, no studies have investigated if any of these proteins can serve as response biomarkers of longitudinal disease activity, except for neurofilament light (NfL). For NfL, limited evidence exists supporting a role as a response biomarker in Guillain-Barré syndrome, vasculitic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most evidence exists for NfL as a response biomarker in hereditary transthyretin-related amyloidosis (hATTR). At the present time, the role of NfL is therefore limited to a supporting clinical tool or exploratory endpoint in trials. Future developments will need to focus on the discovery of additional biomarkers for anatomically specific and other forms of nerve damage using high-throughput technologies and highly sensitive analytical platforms in adequality powered studies of appropriate design. For NfL, a better understanding of cut-off values, the relation to clinical symptoms and long-term disability as well as dynamics in serum on and off treatment is needed to further expand and proceed towards implementation. [ABSTRACT FROM AUTHOR]

• Deficiency of adenosine deaminase 2 (DADA2) is a treatable genetic cause of systemic vasculitis. • Peripheral nerve involvement may include vasculitic neuropathy. • Think of DADA2 if peripheral neuropathy appears in context of a systemic syndrome. • ADA2 activity level can be measured in plasma to guide genetic testing. • TNF inhibitors are an effective treatment for the vasculitic phenotype of DADA2. Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2. [ABSTRACT FROM AUTHOR]

• Relapse and axonal damage were analyzed in the PATH study of subcutaneous immunoglobulin (IgPro20) in CIDP. • On placebo, non-axonal damage patients relapsed more than axonal damage patients. • IgPro20 was less effective in patients with axonal damage than those without. To assess axonal function prior to subcutaneous immunoglobulin (SCIG) therapy or placebo in relation to relapse in chronic inflammatory demyelinating polyneuropathy (CIDP) to determine whether axonal damage can predict therapy response. Relapse rates in patients from the Polyneuropathy and Treatment with Hizentra (PATH) study, where patients were treated with placebo or SCIG (IgPro20), were analyzed by baseline (post-intravenous immunoglobulin stabilization) axonal damage (≤1 mV peroneal compound muscle action potential) status. In patients with non-axonal damage, relapses were significantly higher with placebo (73.0%) than IgPro20 (0.2 g/kg: 39.1%, 0.4 g/kg: 19.2%). In patients with axonal damage, IgPro20 had no effect on relapse (placebo: 25.0%, IgPro20: 0.2 g/kg: 30.0%, 0.4 g/kg: 19.4%). Patients with axonal damage relapsed significantly less on placebo versus non-axonal damage, but they also demonstrated higher baseline disability. Axonal damage may correspond to relapse upon treatment withdrawal; patients with axonal damage relapse less, possibly reflecting poor response to immunoglobulin therapy, while non-axonal damage patients may experience more relapse, perhaps indicating better treatment response. In CIDP patients with axonal loss, immunoglobulin therapy may not be as effective. Assessing axonal damage could help guide therapy, with immunoglobulins ideally used before substantial axonal damage arises. [ABSTRACT FROM AUTHOR]

• We made reference values for nerve conduction studies with mixture model clustering. • Precise, individual reference values were based on age, sex, height and temperature. • Z-scores can be calculated to quantify the (ab)normality of a test result. Objective: to obtain locally valid reference values (RVs) from existing nerve conduction study (NCS) data. Methods: we used age, sex, height and limb temperature-based mixture model clustering (MMC) to identify normal and abnormal measurements on NCS data from two university hospitals. We compared MMC-derived RVs to published data; examined the effect of using different variables; validated MMC-derived RVs using independent data from 26 healthy control subjects and investigated their clinical applicability for the diagnosis of polyneuropathy. Results: MMC-derived RVs were similar to published RVs. Clustering can be achieved using only sex and age as variables. MMC is likely to yield reliable results with fewer abnormal than normal measurements and when the total number of measurements is at least 300. Measurements from healthy controls fell within the 95% MMC-derived prediction interval in 97.4% of cases. Conclusions: MMC can be used to obtain RVs from existing data, providing a locally valid, accurate reflection of the (ab)normality of an NCS result. Significance: MMC can be used to generate locally valid RVs for any test for which sufficient data are available. 1 All code and a test dataset have been placed online (gitlab.com/lumc/clinicalneurophysiology/ReferenceValues). 1 [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated neuropathy for which there is no clearly identified risk factor. The present study identified rare variants in the FBXO38 gene in three familial cases of CIDP with response to corticosteroids in three generations with incomplete penetrance, and in an unrelated fourth case with diffuse nerve hypertrophy. FBXO38 may be involved in the regulation of the immunity mediated by CD8 T cells, which have an important role in CIDP pathophysiology, through PD1 degradation. Considering these findings, FBXO38 should be investigated as a potential genetic factor in larger cohorts of patients with CIDP. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disorder of the peripheral nerves with an incompletely understood underlying pathophysiology. This investigation focused on defining B and T cell frequencies, T cell functional capacity and innate immune system analysis in patients with CIDP. By using multi-parameter flow cytometry, we examined the phenotype and function of PBMCs in 25 CIDP patients who were relatively clinically stable on treatment who met EFNS/PNS criteria, 21 patients with genetically confirmed hereditary neuropathy and 25 healthy controls. We also evaluated the regulatory T cell (Treg) inhibitory capacity by co-culturing Treg and effector T cells. Proinflammatory CD4 T cells, especially type 1 helper T cell (Th1) and CD8 T cells in patients with CIDP were found to have an enhanced capacity to produce inflammatory cytokines. There was no difference in frequency of Th17 regulatory cells in CIDP patients versus healthy controls, however, Treg function was impaired in CIDP patients. There was no remarkable difference in innate immune system measures. Within B cell subsets, transitional cell frequency was decreased in CIDP patients. Patients with CIDP clinically stable on treatment continued to show evidence of a proinflammatory state with impaired Treg function. This potentially implies an inadequate suppression of ongoing inflammation not addressed by standard of care therapies as well as persistent activity of disease while on treatment. Targeting T cells, especially inhibiting Th1 and polyfunctional CD8 T cells or improving Treg cell function could be potential targets for future therapeutic research. • T reg dysfunction is a part of the underlying immunologic dysregulation in chronic inflammatory demyelinating neuropathy. • Treated patients with CIDP show persistent underlying immunologic dysfunction compared with controls. • A proinflammatory state with impaired T reg function is present in relatively clinically stable treated patients with CIDP. [ABSTRACT FROM AUTHOR]

We previously reported that nerve enlargement assessment by nerve ultrasonography of the intermediate upper limb is applicable for distinguishing demyelinating Charcot-Marie-Tooth disease (CMT) from chronic inflammatory demyelinating polyneuropathy (CIDP). However, differences in the severity and distribution patterns of lower extremity nerve enlargement have not been established for either disease. Therefore, we examined the utility of lower extremity nerve ultrasonography for differentiating between CMT and CIDP. Twelve patients with demyelinating CMT and 17 patients with CIDP were evaluated. The median, ulnar, tibial, and fibular nerves were evaluated in three regions: the distal upper extremity, intermediate upper extremity, and lower extremity. Of the 14 selected screening sites, the number of sites that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined. The screening ESNs in the intermediate region and lower extremities were greater in patients with demyelinating CMT than in patients with CIDP and greater than the ESN in the distal region (p = 0.010, p = 0.001, and p = 0.101, respectively). The ESNs in the intermediate region and lower extremities significantly differed among patients with typical CIDP, CIDP variants, and demyelinating CMT (p = 0.084 and p < 0.001). Among the 14 selected screening sites, the combined upper and lower extremity ESNs exhibited the highest AUC (0.92; p < 0.001). Combining the upper and lower extremities for ultrasonographic nerve measurement more accurately distinguishes CIDP from demyelinating CMT. • The distribution patterns of nerve enlargement differ between CIDP and demyelinating CMT. • We examined the utility of lower extremity NUS for differentiating between these two diseases. • Diffuse nerve enlargement of the lower limbs was observed in demyelinating CMT patients compared to CIDP patients. • The addition of lower limb NUS at screening accurately discriminates between both conditions. [ABSTRACT FROM AUTHOR]

• Hereditary transthyretin amyloidosis was seen in all major malaysian ethnic groups. • Ala97Ser was the commonest mutation and found exclusively in Chinese Malaysians. • Patients present with late-onset polyneuropathy and variable autonomic dysfunction. • Cardiac involvement was common but often asymptomatic. We report the clinical and genetic characteristics of hereditary transthyretin amyloidosis in the multi-ethnic Malaysian population. Subjects with genetically confirmed transthyretin amyloidosis seen between 2001 till August 2020 were included. There were 30 patients and 14 asymptomatic carriers, of which 26 (59.1%) were men. The majority (86.7%) were ethnic Chinese while two (6.7%) each were Malay and Sri Lankan Tamil ethnicity respectively. Among patients, mean age of symptom-onset was 55.9 ± 9.8 years with mean duration from symptom-onset to diagnosis of 3.2 ± 2.5 years. Common presenting symptoms were sensory symptoms of upper limbs (43.3%), symmetric sensory symptoms of both lower limbs (16.7%) and autonomic symptoms (16.7%). Nerve conduction studies showed sensorimotor polyneuropathy in 25 (83.3%) patients (22, axonal). Abnormal echocardiograms were seen in 24 (80%) patients, although 15 were asymptomatic. Of six different TTR mutations found, Ala97Ser was the commonest, and found exclusively in 84.6% of Chinese patients. Other mutations among Chinese patients were Val30Met, Ala25Thr and Asp39Val. Our Malay and Tamil patients had Glu54Lys and Gly47Val mutations respectively. In conclusion, TTR Ala97Ser is the commonest mutation among ethnic Chinese Malaysians which presented with late-onset progressive sensorimotor polyneuropathy, autonomic dysfunction and subclinical cardiac involvement. [ABSTRACT FROM AUTHOR]

• Excitability testing with threshold tracking was performed in 111 type 2 diabetics with and without diabetic polyneuropathy and 60 controls. • Changes in sensory and motor excitability in diabetic polyneuropathy were subtle, perhaps because of the relatively short disease duration. • There were only weak correlations between the excitability parameters and clinical scores. The aim of the present study was to gain insight into the pathophysiology of diabetic polyneuropathy (DPN) and examine the diagnostic value of sensory and motor axonal excitability testing. One hundred and eleven type 2 diabetics with and without DPN (disease duration: 6.36 ± 0.25 years) and 60 controls were included. All participants received a thorough clinical examination including Michigan Neuropathy Screening Instrument (MNSI) score, nerve conduction studies (NCS), and sensory and motor excitability tests. Patients were compared by the likelihood of neuropathy presence, ranging from no DPN (17), possible/probable DPN (46) to NCS-confirmed DPN (48). Motor excitability tests showed differences in rheobase and depolarizing threshold electrotonus measures between NCS-confirmed DPN group and controls but no changes in hyperpolarising threshold electrotonus or recovery cycle parameters. Sensory excitability showed even less changes despite pronounced sensory NCS abnormalities. There were only weak correlations between the above motor excitability parameters and clinical scores. Changes in excitability in the examined patient group were subtle, perhaps because of the relatively short disease duration. Less pronounced excitability changes than NCS suggest that axonal excitability testing is not of diagnostic value for early DPN and does not provide information on the mechanisms. [ABSTRACT FROM AUTHOR]

• Critically illness polyneuropathy/myopathy (CIN/CIM) was more prevalent in COVID-19 ICU patients with severe illness. • Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp) levels were higher in the CIN/CIM group and GFAp correlated with motor nerve amplitudes. • COVID-19 patients who later developed CIN/CIM had significantly higher NfL and GFAp in the early phase of ICU care. The aim was to characterize the electrophysiological features and plasma biomarkers of critical illness polyneuropathy (CIN) and myopathy (CIM) in coronavirus disease 2019 (COVID-19) patients with intensive care unit acquired weakness (ICUAW). An observational ICU cohort study including adult patients admitted to the ICU at Uppsala University Hospital, Uppsala, Sweden, from March 13th to June 8th 2020. We compared the clinical, electrophysiological and plasma biomarker data between COVID-19 patients who developed CIN/CIM and those who did not. Electrophysiological characteristics were also compared between COVID-19 and non-COVID-19 ICU patients. 111 COVID-19 patients were included, 11 of whom developed CIN/CIM. Patients with CIN/CIM had more severe illness; longer ICU stay, more thromboembolic events and were more frequently treated with invasive ventilation for longer than 2 weeks. In particular CIN was more frequent among COVID-19 patients with ICUAW (50%) compared with a non-COVID-19 cohort (0%, p = 0.008). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp) levels were higher in the CIN/CIM group compared with those that did not develop CIN/CIM (both p = 0.001) and correlated with nerve amplitudes. CIN/CIM was more prevalent among COVID-19 ICU patients with severe illness. COVID-19 patients who later developed CIN/CIM had significantly higher NfL and GFAp in the early phase of ICU care, suggesting their potential as predictive biomarkers for CIN/CIM. [ABSTRACT FROM AUTHOR]

The cornea's intense innervation is responsible for corneal trophism and ocular surface hemostasis maintenance. Corneal diabetic neuropathy affects subbasal nerve plexus, with progressive alteration of nerves' morphology and density. The quantitative analysis of nerve fibers can be performed with in vivo corneal confocal microscopy considering the main parameters such as corneal nerve fibers length, corneal nerve fibers density, corneal nerve branching density, tortuosity coefficient, and beadings frequency. As the nerve examination permits the detection of early changes occurring in diabetes, the in vivo corneal confocal microscopy becomes, over time, an important tool for diabetic polyneuropathy assessment and follow-up. In this review, we summarize the actual evidence about corneal nerve changes in diabetes and the relationship between the grade of alterations and the duration and severity of the disease. We aim at understanding how diabetes impacts corneal nerves and how it correlates with sensorimotor peripheral polyneuropathy and retinal complications. We also attempt to analyze the safety of the most common surgical procedures such as cataract and refractive surgery in diabetic patients and to highlight the specific risk factors. We believe that information about the corneal nerve fibers' condition obtained from the in vivo subbasal nerve plexus investigation may be crucial in monitoring peripheral small fiber polyneuropathy and that it will help with decision-making in ophthalmic surgery in diabetic patients. [ABSTRACT FROM AUTHOR]

We report a case of a 36 year old gentleman presenting with polyneuropathy and Korsakkoff Syndrome complicating Sleeve Gastrectomy. [ABSTRACT FROM AUTHOR]

• Several cases of Guillain-Barré syndrome associated with COVID-19 vaccine have been reported, including rare variants such as bilateral facial palsy with paraesthesias. • We report 9 cases of bilateral facial palsy with a history of COVID-19 vaccination within the previous month. • Nerve conduction studies revealed demyelinating polyneuropathy in 4 patients, and 5 presented bilateral focal facial nerve involvement, exclusively. • Ganglioside antibody panel was positive in 4 patients (anti-GM1=2, anti-GD1a=1 and anti-sulfatide=1). • Epidemiological studies are essential to determine whether any causal relationship may exist with this rare GBS variant and COVID-19 vaccine administration. Several cases of Guillain-Barré Syndrome (GBS) associated with COVID-19 vaccination have been reported, including the rare subtype known as Bilateral Facial Palsy with paresthesias (BFP). To date, it is not known whether a causal relationship may exist between the two. We report 9 cases of BFP in patients vaccinated against COVID-19 in the previous month. Nerve conduction studies revealed demyelinating polyneuropathy in 4 patients, and 5 presented bilateral, focal facial nerve involvement, exclusively. Ganglioside antibody panel was positive in 4 patients (anti-GM1=2, anti-GD1a=1 and anti-sulfatide=1). Seven patients received intravenous immunoglobulin treatment, one plasma exchange, and one patient died from sudden cardiac arrest following arrhythmia before treatment could be administered. Rates of BFP following COVID-19 vaccination, did not differ from those reported in previous series. Epidemiological studies are essential to determine whether a causal relationship may exist between this rare form of GBS and COVID-19 vaccination. [ABSTRACT FROM AUTHOR]