New classification of autoimmune neuropathies based on target antigens and involved domains of myelinated fibres

Autoimmune neuropathies are named by eponyms, by descriptive terminology or because of the presence of specific antibodies and are traditionally classified, on the basis of pathology and electrophysiology, as primary demyelinating or axonal. However, autoimmune disorders targeting specific molecules of the nodal region, although not showing pathological evidence of demyelination, can exhibit all the electrophysiological changes considered characteristic of a demyelinating neuropathy and acute neuropathies with antiganglioside antibodies, classified as axonal and due to nodal dysfunction, can present with reversible conduction failure and prompt recovery that appear contradictory with the common view of an axonal neuropathy. These observations bring into question the concepts of demyelinating and axonal nerve conduction changes and the groundwork of the classical dichotomous classification.We propose a classification of autoimmune neuropathies based on the involved domains of the myelinated fibre and, when known, on the antigen. This classification, in our opinion, helps to better systematise autoimmune neuropathies because points to the site and molecular target of the autoimmune attack, reconciles some contrasting pathological and electrophysiological findings, circumvents the apparent paradox that neuropathies labelled as axonal may be promptly reversible and finally avoids taxonomic confusion and possible misdiagnosis.

Slowly-conducting pyramidal tract neurons in macaque and rat

SummaryAnatomical studies report a large proportion of fine myelinated fibres in the primate pyramidal tract (PT), while very few pyramidal tract neurons (PTNs) with slow conduction velocities (CV) (< ∼10 m/s) are reported electrophysiologically. This discrepancy might reflect recording bias towards fast PTNs or prevention of antidromic invasion by recurrent inhibition of slow PTNs from faster axons. We investigated these factors in recordings made with a polyprobe (32 closely-spaced contacts) from motor cortex of anaesthetised rats (n=2) and macaques (n=3), concentrating our search on PTNs with long antidromic latencies. We identified 21 rat PTNs with antidromic latencies > 2.6 ms and estimated CV 3-8 m/s, and 67 macaque PTNs (> 3.9ms, CV 6-12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that recurrent inhibition prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs.

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article. Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres.

Clinicopathological correlations of sural nerve biopsies in TTR Val30Met familial amyloid polyneuropathy

Familial amyloid polyneuropathy with the substitution of methionine for valine at position 30 in the TTR gene is the most common type of hereditary transthyretin amyloidosis. Although several authors have previously reported a size-dependent fibre loss, predominantly involving unmyelinated and small-diameter myelinated fibres, the mechanisms of nerve fibre loss have not been fully understood. In this study, we establish the morphometric pattern of peripheral neuropathy in patients with familial amyloid polyneuropathy and asymptomatic mutation carriers in the biopsies from our archive and correlated the pathological findings with clinical features. A total of 98 patients with familial amyloid polyneuropathy and 37 asymptomatic mutation carriers (TTR Val30Met mutation), aged between 17 and 84 years, who underwent sural nerve biopsy between 1981 and 2017 at Centro Hospitalar Universitário do Porto were studied. Thirty-one controls were included for comparison. The median age at nerve biopsy was 26.0 [interquartile range = 23.5–39.5] years for asymptomatic mutation carriers, 45.0 [35.0–60.0] years for patients with familial amyloid polyneuropathy and 44.0 [30.0–63.0] years for controls. The median duration between nerve biopsy and symptoms’ onset was 7.0 [3.3–11.8] years (range: 1–27 years) in the asymptomatic carriers. Most patients were in an earlier disease stage (93% with a polyneuropathy disability scale ≤2). Patients had loss of small and myelinated fibres compared with both asymptomatic carriers and controls (P &lt; 0.001), whereas asymptomatic carriers showed loss of small myelinated fibres when compared with controls (P &lt; 0.05). The loss of myelinated fibres increased with disease progression (P &lt; 0.001), and patients in more advanced clinical stage showed more frequent amyloid deposition in the nerve (P = 0.001). There was a positive correlation between large myelinated fibre density and time to symptoms’ onset in the asymptomatic carriers that developed early-onset form of the disease (r = 0.52, P &lt; 0.01). In addition, asymptomatic carriers with amyloid deposition already present in sural nerve biopsies developed symptoms earlier than those with no amyloid (P &lt; 0.01). In conclusion, this study confirms that the loss of small fibre size is an initial event in familial amyloid polyneuropathy, already present in asymptomatic gene carriers, starting several years before the onset of symptoms. We show for the first time that large myelinated fibres’ loss and amyloid deposition are pathological features that correlate independently with short period to the onset of symptoms for asymptomatic carriers that developed early-onset form of the disease. These findings are therapeutically relevant, as it would allow for a better interpretation of the role of disease-modifying agents in transthyretin familial amyloid polyneuropathy.

PyPNS: Multiscale Simulation of a Peripheral Nerve in Python

Bioelectronic Medicines that modulate the activity patterns on peripheral nerves have promise as a new way of treating diverse medical conditions from epilepsy to rheumatism. Progress in the field builds upon time consuming and expensive experiments in living organisms. To reduce experimentation load and allow for a faster, more detailed analysis of peripheral nerve stimulation and recording, computational models incorporating experimental insights will be of great help. We present a peripheral nerve simulator that combines biophysical axon models and numerically solved and idealised extracellular space models in one environment. We modelled the extracellular space as a three-dimensional resistive continuum governed by the electro-quasistatic approximation of the Maxwell equations. Potential distributions were precomputed in finite element models for different media (homogeneous, nerve in saline, nerve in cuff) and imported into our simulator. Axons, on the other hand, were modelled more abstractly as one-dimensional chains of compartments. Unmyelinated fibres were based on the Hodgkin-Huxley model; for myelinated fibres, we adapted the model proposed by McIntyre et al. in 2002 to smaller diameters. To obtain realistic axon shapes, an iterative algorithm positioned fibres along the nerve with a variable tortuosity fit to imaged trajectories. We validated our model with data from the stimulated rat vagus nerve. Simulation results predicted that tortuosity alters recorded signal shapes and increases stimulation thresholds. The model we developed can easily be adapted to different nerves, and may be of use for Bioelectronic Medicine research in the future.

Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc

Intercellular adhesion and electrical excitability are considered separate cellular properties. Studies of myelinated fibres, however, show that voltage-gated sodium channels (VGSCs) aggregate with cell adhesion molecules at discrete subcellular locations, such as the nodes of Ranvier. Demonstration of similar macromolecular organization in cardiac muscle is missing. Here we combine nanoscale-imaging (single-molecule localization microscopy; electron microscopy; and ‘angle view’ scanning patch clamp) with mathematical simulations to demonstrate distinct hubs at the cardiac intercalated disc, populated by clusters of the adhesion molecule N-cadherin and the VGSC NaV1.5. We show that the N-cadherin-NaV1.5 association is not random, that NaV1.5 molecules in these clusters are major contributors to cardiac sodium current, and that loss of NaV1.5 expression reduces intercellular adhesion strength. We speculate that adhesion/excitability nodes are key sites for crosstalk of the contractile and electrical molecular apparatus and may represent the structural substrate of cardiomyopathies in patients with mutations in molecules of the VGSC complex.

Analysis of Fascicular Structure and Connective Tissue Sheaths in Sural Nerve during Aging

Summary The aim of our study was to analyze the changes of connective tissue sheaths of epi-, peri- and endoneurium of sural nerve during aging. The study was conducted on sural nerve samples of 10 cases aged 9-80 years. The specimens were embedded in paraffin using standard procedures, after which 5-μm-thick cross-sections of nerve trunks were made and stained using Masson’s trichrome staining. After morphological analysis of fascicular structure and connective sheaths of the nerve, morphometric analysis was conducted using the software for digital image analysis “ImageJ”. Each investigated case was analyzed for total neural, epineurial and fascicular cross-section area, mean values of perineurial index, volume density of myelinated axons and of endoneurial content. To test the difference in mean values for statistical significance we used the Student’s T-test for small independent sample. The number of fascicles was 5-13, while the majority of the nerves had less than 10 fascicles. Fascicular structure, which included the number of fascicles and epifascicular/fascicular area ratio, did not show significant changes during aging. Perineurial thickness /fascicle size ratio statistically significantly increased in the older investigated group (p<0.05). Myelinated fibres were of smaller diameter, with more irregular form and markedly less frequent in older cases. Quantitative analysis showed statistically significant decrease in volume density of myelinated fibres in the older group. As results of applied investigation methods we found thickening of perineurial sheath of sural nerve during aging, as well as endoneurial fibrosis. Future investigations of age-related changes should focus on analysis of the components of extracellular matrix within perineurium and endoneurium.