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Background: We aimed to describe the electrophysiological progression rate of chronic idiopathic axonal polyneuropathy (CIAP) and look into the potential role of human leukocyte antigen (HLA) genetic susceptibility in its development., Methods: We recruited 57 patients with CIAP (mean age at diagnosis 67, mean follow-up 7 years). The assessments included clinical and electrophysiological data and HLA-DQ genotyping., Results: The DQA1*05 allele was found more frequently in patients than in healthy controls (odds ratio, 1.96, P = .011). In patients with length-dependent CIAP, a linear effect of time on the electrophysiological findings was found in the superficial radial (3.2% mean annual decrement, P < .001), sural (4.7% mean annual decrement, P = .002) and tibial nerve (6.1% mean annual decrement, P = .007) amplitudes, independently from age or gender., Conclusions: Patients with length-dependent CIAP, show a linear progression over time. Interesting associations of HLA-DQA1*05 allele with length-dependent CIAP and non-DQ2/DQ8 with idiopathic sensory ganglionopathy were found. These merit further investigation in larger cohorts and may suggest a role of the immune system in the pathogenesis of CIAP., (© 2021 Wiley Periodicals LLC.)

Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. The intermediate steps between the loss of these functions and the initiation of axon degeneration are unknown but the importance of these processes provides insightful clues. Prevalent demyelinating diseases of the PNS include the inherited neuropathies Charcot-Marie-Tooth Disease, Type 1 (CMT1) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and the inflammatory diseases Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Secondary axon degeneration is a common feature of demyelinating neuropathies and this process is often correlated with clinical deficits and long-lasting disability in patients. There is abundant electrophysiological and histological evidence for secondary axon degeneration in patients and rodent models of PNS demyelinating diseases. Fully understanding the involvement of secondary axon degeneration in these diseases is essential for expanding our knowledge of disease pathogenesis and prognosis, which will be essential for developing novel therapeutic strategies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose of Review: Chronic idiopathic axonal polyneuropathy (CIAP), a common neurological condition, is considered to be a benign neurological condition with a small risk of disability. However, many studies have shown a reduced quality of life and a nonnegligible affection of daily activities in patients with CIAP. Here we summarize recent data about CIAP., Recent Findings: We discuss some of the latest articles regarding risk factors, comorbidities, and possible pathogenic factors regarding CIAP. Patients with chronic polyneuropathy have impaired walking capacity, disturbed balance, and an increased risk of falls. Idiopathic polyneuropathy has a negative impact on activities of daily living. Patients with CIAP may develop plantar ulcers and neuropathic arthropathy. Small fiber involvement may occur, and two recent studies indicate that neuropathic pain is present in about two thirds of the CIAP group. Furthermore, patients with CIAP with neuropathic pain have increased fatigue and poorer emotional well being., Summary: Despite the relatively mild motor impairment seen in most patients with CIAP, the condition causes limitations in life with decreased mobility, pain, and affection of basal daily activities. Because the pathogenesis of CIAP in unclear, there is no disease modifying treatment. Further studies regarding pathogenesis, and randomized controlled clinical trials regarding possible treatment options are needed.

Neurofascin-155 (Nfasc155) is an essential glial cell adhesion molecule expressed in paranodal septate-like junctions of peripheral and central myelinated axons. The genetic deletion of Nfasc155 results in the loss of septate-like junctions and in conduction slowing. In humans, IgG4 antibodies against Nfasc155 are implicated in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies are associated with an aggressive onset, a refractoriness to intravenous immunoglobulin, and tremor of possible cerebellar origin. Here, we examined the pathogenic effects of patient-derived anti-Nfasc155 IgG4. These antibodies did not inhibit the ability of Nfasc155 to complex with its axonal partners contactin-1/CASPR1 or induce target internalization. Passive transfer experiments revealed that IgG4 antibodies target Nfasc155 on Schwann cell surface, and diminished Nfasc155 protein levels and prevented paranodal complex formation in neonatal animals. In adult animals, chronic intrathecal infusions of antibodies also induced the loss of Nfasc155 and of paranodal specialization and resulted in conduction alterations in motor nerves. These results indicate that anti-Nfasc155 IgG4 perturb conduction in absence of demyelination, validating the existence of paranodopathy. These results also shed light on the mechanisms regulating protein insertion at paranodes.

Axonal neuropathies encompass a wide range of acquired and inherited disorders with electrophysiologic characteristics that arise from the unique neurophysiology of the axon. Accurate interpretation of nerve conduction studies and electromyography requires an in-depth understanding of the pathophysiology of the axon. Here we review the unique neurophysiologic properties of the axon and how they relate to clinical electrodiagnostic features. We review the length-dependent Wallerian or "dying-back" processes as well as the emerging body of literature from acquired axonal neuropathies that highlights the importance of axonal disease at the nodes of Ranvier. Neurophysiologic features of individual inherited and acquired axonal diseases, including primary nerve disease as well as systemic immune mediated, metabolic, and toxic diseases involving the peripheral nerve, are reviewed. This comprehensive review of electrodiagnostic findings coupled with the current understanding of pathophysiology will aid the clinician in the evaluation of axonal polyneuropathies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia., Methods: Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy., Results: Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery., Discussion: We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018., (© 2017 Wiley Periodicals, Inc.)

Purpose of Review: This article describes clinical features of axonal sensorimotor polyneuropathies based on selected etiologies., Recent Findings: Axonal sensorimotor polyneuropathies have been well described for some time. Recent advances include the assessment of the incidence of peripheral neuropathy in the elderly, the recognition of the limited influence of electrodiagnostic testing on the clinical management of uncomplicated axonal sensorimotor polyneuropathy, the development of guidelines for treatment of painful neuropathy, the identification of risk factors predisposing patients for chemotherapy-induced neuropathy, a report on the association of metabolic syndrome and idiopathic axonal sensorimotor neuropathy, and the availability of more cost-effective genetic testing for identifying inherited polyneuropathies., Summary: Axonal sensorimotor polyneuropathies carry an extensive list of differential diagnoses. Diagnosis is based on detailed history, physical examination, recognition of associated neurologic and non-neurologic features, and appropriate testing. Disease-modifying treatments are lacking in many cases. Management focuses on modification of predisposing lifestyle and medical factors, rehabilitation, and pain relief.

α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau. The identified neuropathological features closely resembled those in brains of p.A53T patients. Small molecules targeting αSyn reverted the degenerative phenotype under both basal and induced stress conditions, indicating a treatment strategy for PD and other synucleinopathies. Furthermore, mutant neurons showed disrupted synaptic connectivity and widespread transcriptional alterations in genes involved in synaptic signaling, a number of which have been previously linked to mental disorders, raising intriguing implications for potentially converging disease mechanisms., Competing Interests: The authors declare no conflict of interest.

Chronic idiopathic axonal polyneuropathy (CIAP) is a term describing neuropathies with both sensory and motor involvement in a length dependant distribution where neurophysiology reveals axonal damage, neuropathy onset is insidious and shows slow or no progression of the disease over at least 6 months with no aetiology being identified despite appropriate investigations. This entity merits further consideration given how common it is, the absence of clarity regarding aetiopathogenesis, natural history and therapies. A systematic computer-based literature search was conducted on PubMed database. We used two Medical Subject Headings terms in title. Term A was "axonal", "cryptogenic", "idiopathic" or "unknown" and Term B was "neuropathy" or "polyneuropathy". This search strategy resulted in the identification of 658 articles. After eligibility assessment, 48 papers were used for this review. CIAP is usually diagnosed in the sixth decade of life and it is more prevalent in males (ratio 3:2). It is usually slowly progressive. Some data support a potential role of autoimmunity in CIAP and further larger prospective studies are required to address such potential link and any treatment implications. CIAP is a common type of polyneuropathy but the least studied. Increasing awareness and research into this entity may result in better understanding and in the development of treatment strategies.

Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade β-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Gougerot-Sjögren syndrome (GSS) is an autoimmune disease characterized by a lymphocytic infiltration and destruction of saliva and lachrymal glands. About 20% of patients develop a neurological involvement., Case Report: A 29-year-old woman was admitted with a dysautonomic and sensorial neuropathy. Clinical manifestations (dry syndrome and positive Schirmer's test), blood (anti-SSA and anti-SSB antibodies) and histological (chronic sialadenitis) tests linked this neuropathy to a primary GSS. The characteristics of this case were acute onset (within a few days), severe clinical presentation (continued confinement to bed and malnutrition) and non-responsiveness to all treatments (intravenous immunoglobulins, corticosteroids, plasmapheresis, rituximab)., Conclusion: This case illustrates various clinical signs and inconstant responsiveness to treatment of neuropathy associated with primary GSS., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Sjögren syndrome (SS) has been known to manifest with neurological complications, most frequently of the peripheral nervous system, and often in advance of xerostomia and xerophthalmia. There has been one case report of a patient with SS presenting with acute motor neuropathy similar to Guillain-Barré syndrome (GBS). We report the case of a patient who developed rapidly fulminant acute motor axonal neuropathy (AMAN) with positive anti-GM1 antibody at high titers in association with serological and pathological evidence of SS without xerostomia or xerophthalmia.

The integrity of peripheral nerves relies on communication between axons and Schwann cells. The axonal signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown. Here we show that ablation of the prion protein PrP(C) triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. Ablation of the neighboring Prnd locus, or inbreeding to four distinct mouse strains, did not modulate the CDP. CDP was triggered by depletion of PrP(C) specifically in neurons, but not in Schwann cells, and was suppressed by PrP(C) expression restricted to neurons but not to Schwann cells. CDP was prevented by PrP(C) variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrP(C) lacking its glycolipid membrane anchor. These results indicate that neuronal expression and regulated proteolysis of PrP(C) are essential for myelin maintenance.

Routine motor nerve conduction studies measure latencies, conduction velocities and amplitudes of compound action potentials. These measurements can be very useful in defining the pathology, while they provide little insight into the underlying disease mechanisms. Increasingly, the technique of 'threshold tracking' is being used in research and clinical studies on large myelinated axons. Nerve excitability testing is a non-invasive approach in investigating the pathophysiology of peripheral nerve disorders, which determines the electrical properties of the nerve membrane at the site of stimulation. We have found evidence that in patients with critical illness polyneuropathy peripheral nerves are depolarized. The correlations with serum factors suggest that this membrane depolarization is related to endoneurial hyperkalemia and/or hypoxia. While other mechanisms of depolarization may well be involved, the degree to which potential-sensitive nerve excitability indices are related to serum potassium and bicarbonate suggests that other factors, independent of potassium and acid-base balance, are likely to be of relatively minor significance.

Chronic inflammatory demyelinating polyradiculoneuropathy is an autoimmune disease that target myelin sheats of peripheral nerves. Its diagnosis is often difficult to make, and a number of cases are probably not identified because of the clinical and electrophysiological heterogeneity. Typical cases associate progressive or relapsing-remitting motor and sensory deficit with increased CSF protein content and electrophysiological features of demyelination. In some cases electrophysiological studies fail to show evidence of demyelination, conventional electrophysiological diagnostic criteria are not filled yet the patient may respond to immunomodulatory treatments. In such cases, presence of clinical characteristics suggestive of CIDP (that means not compatible with a length-dependent axonal process) are critical justifying fully investigations including sural nerve biopsy. The main clinical characteristic are: a symmetric proximal and distal motor weakness predominantly affecting the lower limbs, a diffuse areflexia, a sensory deficit characterized by a preferential involvement of large fibers, an evolution which may be either chronic progressive or recurrent. Usual therapeutic agents (corticosteroids, intravenous immunoglobulins, plasma exchanges) seem to have the same efficacy whatever the electrophysiologic profile.

We investigated the associations of baseline epidermal nerve fiber (ENF) densities and morphology (percent ENF swellings) and quantitative sensory testing (QST) with clinically defined human immunodeficiency virus (HIV)-associated distal polyneuropathy (DSP) and whether these measures are predictive of development of symptomatic DSP over time. Fifty-seven HIV-infected subjects with and without DSP and 19 controls participated. Mean ENF densities were lower at the distal leg and proximal thigh in asymptomatic or symptomatic DSP than in controls. Mean ENF densities did not differ significantly among the HIV groups. Percent ENF swellings was higher in patients with symptomatic DSP than controls at the distal leg, and was also greater at the proximal thigh in patients with asymptomatic or symptomatic DSP than in controls. The percent ENF swellings at the distal leg correlated with the thresholds for both minimal (HP 0.5) and intermediate (HP 5.0) heat pain (HP) intensity. A higher percent ENF swellings in the distal leg [hazard ratio (HR) 1.16, 95% CI 1.02-1.31] and HP 0.5 thresholds (HR 1.03, 95% CI 1.01-1.05) were the only two measures associated with a shorter time to development of symptomatic DSP. Quantitation of ENF swellings and heat pain thresholds deserve further study as predictors of symptomatic neuropathy.

The peripheral nerve is supplied by the vasa nervorum. The epi- and perineurial vessels are innervated by an autonomic plexus, which plays a role in regulation of the endoneurial blood flow. This innervation is decreased in diabetes and alcohol polyneuropathy and seems to precede the development of diabetic polyneuropathy. A decreased innervation may therefore play a role in the development of polyneuropathy. In peripheral arterial disease (PAD) clinical and morphological features are present, related to severity of ischemia. To investigate the innervation of the vasa nervorum in severe ischemia, we performed immunofluorescence staining with the general neural marker protein gene product (PGP) 9.5 in whole mount preparations of epineurial vessels of nine sural nerves taken from patients with legs amputated because of severe PAD (59+/-15 years, mean +/- SD) and ten age-matched controls (61+/-24 years). In patients with PAD the nerve density of the perivascular plexus was decreased in comparison with controls (mean intercept density/mm +/- SD) 26.0+/-6.9 in PAD and 39.9+/-10.7 in controls, area% 6.0+/-1.6 in PAD and 9.9+/-2.6 in controls, both P<0.01, t-test). A decreased perivascular plexus may result in a diminished regulation of the endoneurial blood flow in patients with severe PAD.

For chronic idiopathic axonal polyneuropathy (CIAP), even after extensive evaluation, no cause has yet been found. Considering the age and sex distribution of patients with this disease, it is possible that vascular disease plays a role in the development of this polyneuropathy. As endoneurial vessel abnormalities can be related to ischemia, we investigated endoneurial vessels in sural nerve biopsies of 18 patients with CIAP. As controls we used sural nerves of 4 patients with diabetes mellitus, 6 patients with hereditary motor and sensory neuropathy type II (HMSN type III) and 10 autopsy cases. Basal lamina area thickness, endothelial cell area, lumen area, and the number of basal laminae, endothelial cells and periendothelial cell nuclei were investigated. Basal lamina area thickness, endoneurial cell area and number of endothelial cell nuclei in CIAP were increased in comparison with HMSN type III, whereas the basal lamina area thickness of patients with CIAP and diabetes mellitus were in the same range. The structure of the basal lamina area in CIAP differed from diabetes mellitus; in diabetes mellitus there was a larger number of lamellae, whereas in CIAP there was an increase in collagen. There was no correlation between basal lamina area thickness and age. In CIAP patients with peripheral vascular disease of the legs, basal lamina area thickness was increased. The relation between basal lamina area thickening and peripheral vascular disease of the legs in CIAP may indicate a role for ischemia in the development of this polyneuropathy.

Exposure to a variety of agricultural, industrial, and pharmaceutical chemicals produces nerve damage classified as a central-peripheral distal axonopathy. Morphologically, this axonopathy is characterized by distal axon swellings and secondary degeneration. Over the past 25 years substantial research efforts have been devoted toward deciphering the molecular mechanisms of these presumed hallmark neuropathic features. However, recent studies suggest that axon swelling and degeneration are related to subchronic low-dose neurotoxicant exposure rates (i.e., mg toxicant/kg/day) and not to the development of neurophysiological deficits or behavioral toxicity. This suggests these phenomena are nonspecific and of uncertain pathophysiologic relevance. This possibility has significant implications for research investigating mechanisms of neurotoxicity, development of exposure biomarkers, design of risk assessment models, neurotoxicant classification schemes, and clinical diagnosis and treatment of toxic neuropathies. In this commentary we will review the evidence for the dose-related dependency of distal axonopathies and discuss how this concept might influence our current understanding of chemical-induced neurotoxicities., (Copyright 2000 Academic Press.)

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterised clinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal abnormalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the GAN locus in 16q24.1 to a 5-cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three consanguineous Tunisian families. We have now established a contig-based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombinants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase-known recombinations. Taken together, these results allow us to establish a transcription map of the region, and to narrow down the GAN position to a < 590 kb critical interval, an important step toward the identification of the defective gene.

"Quality of life" (QOL) measurement reflects the impact of a disease on the daily life of a patient, and this can be used as an outcome measure in clinical trials. QOL measurements are rarely used in patients with neuromuscular disease. The aim of this study was to determine whether QOL is reduced in chronic polyneuropathy, whether there is a relationship between QOL and objective measures of disease severity, and whether measuring QOL is a useful addition to the assessment of severity of polyneuropathy. We measured QOL in 90 patients with chronic axonal polyneuropathy (33 with hereditary motor and sensory neuropathy type II and 57 with chronic idiopathic axonal polyneuropathy) using the RAND 36-item Health Survey questionnaire (RAND-36). We compared the results with the QOL of a reference population, with summed motor and sensory scores, and with the Rankin scale for handicap. Patients had worse scores than the reference population on seven of eight areas of the RAND-36. Patients with both low motor and low sensory scores rated lower in physical and emotional areas than less impaired patients. A low Rankin score was related only to physical domains. We conclude that in patients with chronic axonal polyneuropathy the severity of disease can be assessed with a general QOL instrument, and that this provides additional information, particularly on areas related to emotional and social functioning.

We report the case of a woman with axonal sensory and autonomic neuropathy lasting several months who improved in association with steroid administration. During the course of her disease and in the follow-up, the patient underwent repeated cerebrospinal fluid (CSF) examinations, neurophysiological somatic, autonomic nervous system studies and sural nerve biopsy. Clinical and laboratory assessments demonstrated the occurrence of a monophasic, chronic sensory and autonomic neuropathy. A sural nerve biopsy suggested an axonopathy. After a progressive worsening of symptoms lasting about 6 months, steroid treatment was started and within 6 months a complete recovery, with normalization of the CSF findings, was observed. Although the 'chronic inflammatory neuropathies' are still debated entities, the features of this chronic, exclusively sensory and autonomic neuropathy are new, and the occurrence of a high protein level in the CSF, together with the favorable outcome associated with steroid treatment, suggests that our case might be another variant in this debated area., (Copyright 1999 Lippincott Williams & Wilkins.)