Journal of the Peripheral Nervous System

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.

Dietary‐associated diseases have increased tremendously in our current population, yet key molecular changes associated with high‐fat diets that cause clinical pre‐diabetes, obesity, hyperglycemia, and peripheral neuropathy remain unclear. This study examines molecular and metabolic aspects altered by voluntary exercise and a high‐fat diet in the mouse dorsal root ganglion. Mice were examined for changes in mRNA and proteins encoding anti‐inflammatory mediators, metabolic‐associated molecules, and pain‐associated ion channels. Proteins involved in the synaptosomal complex and pain‐associated TRP ion channels decrease in the dorsal root ganglion of high‐fat exercise animals relative to their sedentary controls. Exercise reversed high‐fat diet induced mechanical allodynia without affecting weight gain, elevated blood glucose, and utilization of fat as a fuel source. Independent of weight or fat mass changes, high‐fat exercised mice display reduced inflammation‐associated mRNAs. The benefits of exercise on abnormal peripheral nerve function appear to occur independent of systemic metabolic changes, suggesting that the utilization of fats and inflammation in the peripheral nervous system may be key for diet‐induced peripheral nerve dysfunction and the response to exercise.

Abstract  We have recently developed a model of sciatic inflammatory neuritis (SIN) to assess how immune activation near peripheral nerves influences somatosensory processing. Administration of zymosan (yeast cell walls) around a single sciatic nerve produces dose‐dependent low‐threshold mechanical allodynia without thermal hyperalgesia. Low (4 μg) doses produce both territorial and extraterritorial allodynia restricted to the injected hindleg. In contrast, higher (40 μg) doses produce territorial and extraterritorial allodynias of both hindlegs, an effect not accounted for by systemic spread of the zymosan. The aim of these experiments was to determine whether these behavioral allodynias were correlated with immunological and/or anatomical changes in or around the sciatic nerve. These experiments reveal that zymosan‐induced bilateral allodynia was associated with the following: (a) increased release of both interleukin‐1β and tumor necrosis factor‐α from peri‐sciatic immune cells; (b) increased release of reactive oxygen species from peri‐sciatic immune cells; (c) no change in circulating levels of proinflammatory cytokine; (d) no apparent zymosan‐induced influx of immune cells into the sciatic nerve from the endoneurial blood vessels; (e) mild edema of the sciatic, which was predominantly restricted to superficial regions closest to the peri‐sciatic immune cells; and (f) no anatomic evidence of changes in either the ipsilateral saphenous nerve or contralateral sciatic nerve that could account for the appearance of extraterritorial or contralateral (“mirror”) allodynia, respectively. No reliable differences were found when the low‐dose zymosan was compared with vehicle controls. Taken together, these data suggest that substances released by peri‐sciatic immune cells may induce changes in the sciatic nerve, leading to the appearance of bilateral allodynia.

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.

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.

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.

Increasing literature has linked COVID‐19 to peripheral nervous system (PNS) diseases. In addition, as we move from the pandemic to the vaccination era, literature interest is shifting towards the potential association between COVID‐19 vaccines and PNS manifestations. We reviewed published literature on COVID‐19, COVID‐19 vaccines and PNS manifestations between 1 January 2020 and 1 December 2021. For Guillain‐Barré syndrome (GBS), isolated cranial neuropathy (ICN) and myositis associated with COVID‐19, the demographic, clinical, laboratory, electrophysiological and imaging features were included in a narrative synthesis. We identified 169 studies on COVID‐19‐associated complications, including 63 papers (92 patients) on GBS, 29 papers (37 patients) on ICN and 11 papers (18 patients) on myositis. Additional clinical phenotypes included chronic inflammatory demyelinating polyneuropathy, vasculitic neuropathies, neuralgic amyotrophy, critical care‐related complications, and myasthenia gravis. PNS complications secondary to COVID‐19 vaccines have been reported during randomized clinical trials, in real‐world case reports, and during large‐scale surveillance programs. These mainly include cases of GBS, Bell's palsy, and cases of neuralgic amyotrophy. Based on our extensive review of the literature, any conclusion about a pathophysiological correlation between COVID‐19 and PNS disorders remains premature, and solely supported by their temporal association, while epidemiological and pathological data are insufficient. The occurrence of PNS complications after COVID‐19 vaccines seems limited to a possible higher risk of facial nerve palsy and GBS, to a degree that widespread access to the ongoing vaccination campaign should not be discouraged, while awaiting for more definitive data from large‐scale surveillance studies.

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.

Abstract  Peripheral neurological disorders like neuropathies may cause impairments (such as weakness and sensory deficits), which may lead to problems in daily life and social functioning with a possible decrement in quality of life expectations. Choosing the proper outcome measure to evaluate the therapeutic efficacy of an intervention at one of these levels of outcome should therefore be considered as fundamental to the design of randomized trials in peripheral neurological disorders. However, these choices are dependent not only on the proposed research purposes but also, and perhaps more importantly, on the fulfillment of the scientific needs of these measures. With an increasing demand for accuracy, a thorough and comprehensive evaluation of an outcome measure is needed to determine its simplicity, communicability, validity, reliability, and responsiveness before being clinically applicable, techniques that are being captured by the science of clinimetrics. Most neurologists are still unfamiliar with these rigorous methodological essentials or overlook some of them in their trial preparations because these are considered time consuming and mind numbing. This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain‐Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy‐related neuropathies. The need for comparison responsiveness studies between equally valid and reliable measures and to standardize their use is emphasized in these conditions. Finally, specific recommendations are given to move from classic to modern clinimetric approach when constructing, evaluating, and selecting outcome measures using new methods like Rasch analysis, accentuating the need of shifting toward a more modern era.

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.