Journal of the Peripheral Nervous System

Abstract  Considerable scientific and technological efforts have been devoted to develop neuroprostheses and hybrid bionic systems that link the human nervous system with electronic or robotic prostheses, with the main aim of restoring motor and sensory functions in disabled patients. A number of neuroprostheses use interfaces with peripheral nerves or muscles for neuromuscular stimulation and signal recording. Herein, we provide a critical overview of the peripheral interfaces available and trace their use from research to clinical application in controlling artificial and robotic prostheses. The first section reviews the different types of non‐invasive and invasive electrodes, which include surface and muscular electrodes that can record EMG signals from and stimulate the underlying or implanted muscles. Extraneural electrodes, such as cuff and epineurial electrodes, provide simultaneous interface with many axons in the nerve, whereas intrafascicular, penetrating, and regenerative electrodes may contact small groups of axons within a nerve fascicle. Biological, technological, and material science issues are also reviewed relative to the problems of electrode design and tissue injury. The last section reviews different strategies for the use of information recorded from peripheral interfaces and the current state of control neuroprostheses and hybrid bionic systems.

The Charcot‐Marie‐Tooth neuropathy score (CMTNS) is a reliable and valid composite score comprising symptoms, signs, and neurophysiological tests, which has been used in natural history studies of CMT1A and CMT1X and as an outcome measure in treatment trials of CMT1A. Following an international workshop on outcome measures in Charcot‐Marie‐Tooth disease (CMT), the CMTNS was modified to attempt to reduce floor and ceiling effects and to standardize patient assessment, aiming to improve its sensitivity for detecting change over time and the effect of an intervention. After agreeing on the modifications made to the CMTNS (CMTNS2), three examiners evaluated 16 patients to determine inter‐rater reliability; one examiner evaluated 18 patients twice within 8 weeks to determine intra‐rater reliability. Three examiners evaluated 63 patients using the CMTNS and the CMTNS2 to determine how the modifications altered scoring. For inter‐ and intra‐rater reliability, intra‐class correlation coefficients (ICCs) were ≥0.96 for the CMT symptom score and the CMT examination score. There were small but significant differences in some of the individual components of the CMTNS compared with the CMTNS2, mainly in the components that had been modified the most. A longitudinal study is in progress to determine whether the CMTNS2 is more sensitive than the CMTNS for detecting change over time.

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare, progressive, life‐threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin‐derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR‐FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR‐FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR‐FAP should be suspected if progressive peripheral sensory‐motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR‐FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large‐ and small‐fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.

Acute demyelinating inflammatory polyneuropathy (AIDP) is the most common type of Guillain‐Barré syndrome (GBS) in Europe, following several viral and bacterial infections. Data on AIDP‐patients associated with SARS‐CoV‐2 (coronavirus‐2) infection are scarce. We describe the case of a 54‐years‐old Caucasian female patient with typical clinical and electrophysiological manifestations of AIDP, who was reported positive with PCR for SARS‐CoV‐2, 3 weeks prior to onset of the neurological symptoms. She did not experience a preceding fever or respiratory symptoms, but a transient loss of smell and taste. At the admission to our neurological department, a progressive proximally pronounced paraparesis, areflexia, and sensory loss with tingling of all extremities were found, which began 10 days before. The modified Erasmus Giullain‐Barré Syndrome outcome score (mEGOS) was 3/9 at admission and 1/12 at day 7 of hospitalization. The electrophysiological assessment proved a segmental demyelinating polyneuropathy and cerebrospinal fluid examination showed an albuminocytologic dissociation. The neurological symptoms improved significantly during treatment with immunoglobulins. Our case draws attention to the occurrence of GBS also in patients with COVID‐19 (coronavirus disease 2019), who did not experience respiratory or general symptoms. It emphasizes that SARS‐CoV‐2 induces immunological processes, regardless from the lack of prodromic symptoms. However, it is likely that there is a connection between the severity of the respiratory syndrome and further neurological consequences.

Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development.

Abstract We determined the frequency of recurrent Guillain–Barré syndrome (GBS), whether vaccinations led to recurrences of GBS or an increase of disability in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and we assessed the prevalence of pain, fatigue and the impact on quality of life after GBS and CIDP. Additionally, we assessed the presence of common auto‐immune disorders. Four hundred and sixty‐one members of the Dutch society of neuromuscular disorders received a questionnaire. Two hundred and forty‐five GBS and seventy‐six CIDP patients were included (response rate 70%). Nine patients had a confirmed recurrent GBS, and two patients had experienced both GBS and CIDP. Common auto‐immune diseases were reported in 9% of GBS and 5% of CIDP patients. None of the 106 GBS patients who received a flu vaccination (range 1–37 times, total 775 vaccinations) reported a recurrence thereafter. Five out of twenty‐four CIDP patients who received a flu vaccination (range 1–17 times) reported an increase in symptoms. Pain or severe fatigue was reported in about 70% of patients after the diagnosis of GBS (median 10 years) or after onset of CIDP (median 6 years), and quality of life was significantly reduced. Flu vaccinations seem relatively safe. GBS and CIDP patients often experience pain, fatigue and a reduced quality of life for many years after the diagnosis.

Abstract  The changes in the expression of brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (NT‐3), and neurotrophin‐4 (NT‐4) in the rat neuromuscular system as a result of three different types of sciatic nerve injuries have been evaluated. The changes in mRNA and protein levels for BDNF, NT‐3, and NT‐4 in the soleus muscle and sciatic nerve were assessed 4–28 days after sciatic nerve transection (neurotmesis), sciatic nerve crush (axonotmesis), and mild acute compression (neurapraxia). BDNF mRNA levels increased dramatically with nerve transection in the soleus muscle and the sciatic nerve 7–14 days after injury, whereas the changes were low in other types of injury. The changes of protein levels for BDNF were also similar. The mRNA and the protein levels of NT‐3 in the soleus muscle did not show any significant difference. The mRNA for NT‐4 in the soleus muscle decreased from 4 to 14 days after sciatic nerve transection, and the protein level was also minimum 14 days after sciatic nerve transection. Our results indicate that the neurotrophic factors in the neuromuscular system could play a role in differentiating peripheral nerve injury.

Abstract  The objectives of this study were to evaluate the clinical and electrophysiological findings in peroneal mononeuropathies following a weight‐reduction diet. Thirty patients with acute peroneal palsy and weight loss were studied. Complete nerve conduction studies (NCS) were performed in upper and lower limbs. NCS showed conduction block (CB) of the peroneal nerve at the fibular head that recovered in 29 patients within 3 weeks to 3 months. Severity of CB was correlated with clinical weakness. Three patients had abnormalities consistent with polyneuropathy (PNP). NCS in asymptomatic relatives confirmed familial neuropathy. Nerve biopsy and molecular study were consistent with hereditary neuropathy with liability to pressure palsies (HNPP). One of these peroneal palsies (6 months) recovered after neurolysis. Weight loss might be a risk factor in peroneal mononeuropathies. NCS is a tool in the diagnosis of the site and severity of the nerve injury. Testing should be considered for relatives of patients with PNP because peroneal mononeuropathies may be the first expression of HNPP.

Abstract  Mutations of the neurofilament‐light (NEFL/NF‐L) gene were examined in 124 unrelated Japanese patients with Charcot‐Marie‐Tooth disease (CMT) without known gene mutations, and 248 normal Japanese individuals. A new method, which can detect basepair mismatches with RNase cleavage on agarose gel electrophoresis, coupled with DNA sequencing, identified 8 novel sequence variations in the NF‐L gene. In these sequence variants, 5 variants were polymorphisms, including 3 single nucleotide polymorphisms (SNPs), and 3 other missense mutations (Pro22Thr, Asn97Ser and Ala148Val) were found in the patients with CMT phenotype. The variant alleles in the NF‐L gene could influence the developing process of CMT phenotype and also might cause CMT phenotype.

The outcome of Guillain‐Barré syndrome (GBS) remains unchanged since plasma exchange and intravenous immunoglobulin (IVIg) were introduced over 20 years ago. Pathogenesis studies on GBS have identified the terminal component of complement cascade as a key disease mediator and therapeutic target. We report the first use of terminal complement pathway inhibition with eculizumab in humans with GBS. In a randomised, double‐blind, placebo‐controlled trial, 28 subjects eligible on the basis of GBS disability grade of at least 3 were screened, of whom 8 (29%) were randomised. Five received eculizumab for 4 weeks, alongside standard IVIg treatment. The safety outcomes, monitored via adverse events capture, showed eculizumab to be well‐tolerated and safe when administered in conjunction with IVIg. Primary and secondary efficacy outcomes in the form of GBS disability scores (GBS DS), MRC sum scores, Rasch overall disability scores, and overall neuropathy limitation scores are reported descriptively. For the primary efficacy outcome at 4 weeks after recruitment, two of two placebo‐ and two of five eculizumab‐treated subjects had improved by one or more grades on the GBS DS. Although the small sample size precludes a statistically meaningful analysis, these pilot data indicate further studies on complement inhibition in GBS are warranted.