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A man in his 30s with a history of refractory classical Hodgkin's lymphoma presented with subacute onset asymmetric sensory disturbance, and severe weakness affecting his right more than left hand. Symptom onset was 18 weeks after commencing brentuximab vedotin (BV) treatment, an anti-CD30 antibody drug-conjugate for relapsed/refractory classical Hodgkin's lymphoma. Symptoms progressed to his lower limbs with distal sensory loss, gait imbalance, bilateral foot drop and mild proximal leg weakness. He was globally areflexic. Neurophysiology revealed a mildly asymmetric, non-length dependent, motor >sensory polyradiculoneuropathy, with mixed axonal and demyelinating features. Extensive laboratory work-up, lumbar puncture and MRI of the brachial plexus, brain, spine and chest were unremarkable. Treatment with plasma exchange, followed by intravenous immunoglobulin, resulted in objective clinical improvement 4 weeks after. BV is a potent antimicrotubule agent, thus well known to cause a length-dependent sensory axonal polyneuropathy. Demyelinating polyneuropathy, with more prominent motor involvement, in association with BV is much rarer., Competing Interests: Competing interests: CO has received a speaker fee on plasma exchange from Terumo BCT. NM, HJH and RA have no conflicts of interest to declare., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acquired critical illness weakness (AWCIP) is the most frequent neuromuscular disease in intensive care medicine departments. Its importance is given by the prolongation of hospital stay and the delayed recovery it causes to patients after hospitalization. The main objective of this study was to investigate the association between neuromuscular blocking agents and the development of acquired weakness in critically ill patients., Material and Methods: We conducted a prospective study of 103 critically ill patients who were periodically monitored with electromyography., Results: The development of AWCIP was observed in 63 patients. The group of patients who developed AWCIP had a significantly higher utilization of neuromuscular blocking agents than the group who did not develop AWCIP [79.4% vs 50%, OR:3.85 (1.63-9.39), p <0.02]; likewise, this group of patients had a longer ICU stay [32 days vs 14 days, OR: 1.11 (1.06-1.17), p <0. 001] and a longer mechanical ventilation time [24 days vs 9 days, OR:1.2 (1.11-1.32), p <0.001]., Conclusion: Neuromuscular blocking agents are a factor associated with the occurrence of AWCIP., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Extracellular vesicles (EVs), exhibiting their functional activity after internalization by recipient cells, are involved in the pathogenesis of drug-induced polyneuropathy (DIPN), a common complication of antitumor therapy. In this work, the internalization of EVs obtained from colorectal cancer patients undergoing polychemotherapy and its relationship with neurotoxicity were assessed using a model system of mononuclear leukocytes. Circulating EVs were isolated from 8 colorectal cancer patients who received antitumor therapy according to the FOLFOX or XELOX regimens before the start of chemotherapy (point 1) and after 3-4 courses (point 2). Mononuclear leukocytes of a healthy donor served as a cellular model system for EV internalization in vitro. EV internalization was assessed using fluorescence microscopy. It was shown that internalization of EVs obtained from colorectal cancer patients with high neurotoxicity was higher than in the group with low neurotoxicity. The ability of CD11b-positive (CD11b⁺) and CD11b-negative (CD11b⁻) mononuclear leukocytes of a healthy donor to internalize EVs obtained from patients before and after chemotherapy did not reveal significant differences. A direct relationship was found between the relative number of CD11b⁻ cells with internalized EVs and the integral index of neurotoxicity according to the NRS scale at the peak of its manifestation (point 2) (r=0.675, p.

Background and Purpose: The role of high-resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) in the early detection of taxane-induced polyneuropathy (TIPN) is unclear. The present prospective longitudinal controlled observational pilot study estimates the role of HRUS and CCM in the early diagnosis of TIPN in breast cancer patients., Methods: Fifteen breast cancer patients receiving paclitaxel and 15 healthy age matched controls were included. Visits before and 3 weeks, 8 weeks and 6 months after treatment included clinical examination, the total neuropathy score, nerve conduction studies (NCS), monocular CCM including corneal nerve fibre length, density and branching and HRUS of bilateral median, ulnar, radial, tibial, peroneal and sural nerves. Patients were compared between different visits and to healthy controls., Results: Total neuropathy score increased from 2.2 at baseline to 5.8 (p < 0.001) at week 8. NCS showed a decreased sensory amplitude in the sural, radial, ulnar and median nerve after 6 months (p < 0.001). HRUS revealed a significant increase of cross-sectional area in the sural nerve (p = 0.004), the median nerve (p = 0.003) at the carpal tunnel and the ulnar nerve in the forearm (p = 0.006) after 6 months. CCM showed no changes at different visits., Conclusions: Corneal confocal microscopy and HRUS do not detect early signs of TIPN during the paclitaxel treatment period. HRUS and NCS might detect congruent signs of an axonal, predominantly sensory polyneuropathy after 6 months. The clinical examination remains the most sensitive tool in the early detection of TIPN in breast cancer patients., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Nitrous oxide (N 2 O) induced neurological symptoms are increasingly encountered. Our aim is to provide clinical and diagnostic characteristics with a focus on electrodiagnostic studies., Methods: Patients with neurological sequelae due to N 2 O presenting in our hospital between November 2018 and December 2021 reporting clinical and diagnostic data were retrospectively reviewed., Results: Seventy patients (median 22 years) were included. Median N 2 O usage was 4 kg/week during 12 months. Patients' history revealed a higher rate of sensory symptoms compared to motor (97% vs. 57%) and 77% walking difficulties. Clinical diagnosis was polyneuropathy (PNP) in 44%, subacute combined degeneration (SCD) of the spine in 19%, both in 37%. Median vitamin B12 level was low (159 pmol/L), normal in 16%. The median methylmalonic acid was increased (2.66 μmol/L). Electrodiagnostic abnormalities were observed in 91%, with 72% fulfilling axonal PNP criteria, 20% showing mild to intermediate slowing. One patient fulfilled demyelinating PNP criteria not related to N 2 O abuse (Charcot-Marie-Tooth type 1a). More prominent motor nerve conduction abnormalities were found; lower limbs were more affected. In 64% with normal conduction, myography showed signs of axonal loss. Magnetic resonance imaging showed cervical myelopathy in 58% involving generally five to six segments., Conclusions: Nitrous oxide (N 2 O) leads to neurological symptoms by causing PNP and/or SCD primarily involving the legs. Distinguishing PNP and SCD clinically was shown to be insufficient. Electrodiagnostic studies showed axonal PNP. Demyelinating PNP due to N 2 O abuse was not present in our cohort. Therefore, further diagnostic work-up is warranted if demyelinating features are present., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Immune checkpoint inhibitors (ICIs) have significantly improved the clinical outcome in multiple types of advanced or metastatic malignancies and are prescribed increasingly. However, immune-related adverse events (irAEs) occur frequently. Here, we present a patient with multifocal motor neuropathy and melanoma, with worsening of muscle weakness upon ICI therapy and concomitant use of steroids for the treatment of hepatitis, which was considered an irAE. Upon treatment with highly dosed immunoglobulins and steroid tapering, the patients' muscular symptoms improved while hepatitis resolved. This case highlights the importance of careful evaluation of patients with multifocal motor neuropathy treated with ICIs, highlights the risks of treatment with steroids in multifocal motor neuropathy patients and suggests an alternative treatment of irAEs with intravenous immunoglobulins.

Competing Interests: None declared

Objective: Antibody- and complement-mediated peripheral nerve inflammation are central in the pathogenesis of MMN. Here, we studied innate immune responses to endotoxin in patients with MMN and controls to further our understanding of MMN risk factors and disease modifiers., Methods: We stimulated whole blood of 52 patients with MMN and 24 controls with endotoxin and collected plasma. With a multiplex assay, we determined levels of the immunoregulating proteins IL-1RA, IL-1β, IL-6, IL-10, IL-21, TNF-α, IL-8 and CD40L in unstimulated and LPS-stimulated plasma. We compared baseline and stimulated protein levels between patients and controls and correlated concentrations to clinical parameters., Results: Protein level changes after stimulation were comparable between groups (p > 0.05). IL-1RA, IL-1β, IL-6 and IL-21 baseline concentrations showed a positive correlation with monthly IVIg dosage (all corrected p-values < 0.016). Patients with anti-GM1 IgM antibodies showed a more pronounced IL-21 increase after stimulation (p 0.048)., Conclusions: Altered endotoxin-induced innate immune responses are unlikely to be a susceptibility factor for MMN., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Chemoinduced polyneuropathy (CIPNP) is a common side-effect of chemotherapy, significantly impairing quality of life in patients treated for cancer. Platinum preparations are the most commonly used chemotherapeutic agents used in the treatment of ovarian, testicular, breast, lung and colon cancers. Clinical examination reveals restrictions on the motor, sensory and autonomic functions of the upper and lower extremities, which occur at different stages of antitumor treatment, seriously complicating the treatment of the underlying disease. Pain and sensory disturbances may persist for months or even years after chemotherapy is completed. Thus, CIPNP is a major problem because it is impossible to predict which patients will develop neurological symptoms, to estimate their timing of manifestation, which can occur at any time during the course of chemotherapy, there is no early indication to reduce the dose of the cytotoxic drug, and there are no drugs that effectively prevent or alleviate the course of neuropathy. This review focuses on neurotoxicity with the use of platinum drugs, including the frequency of occurrence, risk factors, cumulative doses, various pathogenetic mechanisms for the development of CIPNP, clinical features and variants of the neurophysiological picture.

Polyneuropathy (PNP) is a known complication of levodopa-carbidopa intestinal gel (LCIG) therapy of advanced Parkinson's Disease (PD). The overall prevalence of PNP in PD is estimated to be 42.1% (as shown in a review by Romagnolo et al. 2018), and the most common type is chronic axonal polyneuropathy. There is a group of acute/subacute onset demyelinating polyneuropathies, which is far less common, although it seems to be an important factor leading to the rapid discontinuation of LCIG treatment. In this systematic review, we present data on demyelinating polyneuropathy with acute/subacute onset; we identified nine papers including prospective assessments and case reports, with detailed information on 15 patients. In all patients, despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) or plasma exchange (PE), the LCIG therapy was terminated. We also present a case of subacute demyelinating polyneuropathy with effective treatment and continuation of LCIG therapy.

Reports suggested the potential occurrence of peripheral neuropathies (PN) in patients treated with BRAF (BRAFi) and/or MEK inhibitors (MEKi) for BRAF-activated tumours. We aimed to better characterize these PN. We queried the French pharmacovigilance database for all cases of PN attributed to BRAFi and/or MEKi. Fifteen patients were identified. Two main clinical PN phenotypes were seen. Six patients presented a length-dependent, axonal polyneuropathy: symptoms were mostly sensory and affecting the lower limbs; management and outcome were variable. Nine patients developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness and ataxia; cranial nerves were involved in four cases; most patients received intravenous immunoglobulins or glucocorticoids, with variable outcome; one patient was rechallenged with a different BRAFi/MEKi combination with a rapid relapse in symptoms. In conclusion, patients under BRAFi/MEKi therapy may develop treatment-induced PN. Two main phenotypes can occur: a symmetric, axonal, length-dependent polyneuropathy and a demyelinating polyradiculoneuropathy., (© 2022 British Pharmacological Society.)

We present a case of a 53-year-old male who presented with functionally limiting bilateral lower extremity neuropathic pain secondary to multiple subtypes of small fiber neuropathy. He had failed management with multiple conservative measures including oral medications, physical therapy and desensitization techniques. He ultimately underwent placement of a spinal cord stimulator and continued to experience 80% improvement of his pain, as well as improved function and quality of life at 5 month follow-up. To our knowledge, this is the first reported case of successful treatment of multiple subtypes of small fiber neuropathy with spinal cord stimulator.

Objective: The objective was to analyze the clinical characteristics and pathological characteristics of sural biopsy in nitrous oxide (N2O) -induced peripheral neuropathy., Methods: We recruited 18 patients with N2O abuse-induced neurological disorders and reported their demographic data, clinical manifestations, laboratory examinations, and nerve conduction studies. Seven patients underwent sural nerve biopsy pathologic examination., Results: All 18 patients had polyneuropathy, the nerve conduction results showed significant reductions in motor and sensory amplitudes, slowing of conduction velocities, and prolongation of latencies in most tested nerves compared to the controls. Toluidine blue staining of semi-thin sections of sural nerve biopsy showed decreased myelinated nerve fiber density, increased thin myelinated nerve fiber density, and axonal regeneration. Electron microscopy showed axonal degeneration and nerve regeneration., Conclusion: The main manifestations of peripheral nerve damage caused by the abuse of N2O are lower limb weakness and distal sensory disorder. The nerve conduction study results demonstrated that mixed axonal and demyelinating neuropathy was the most common type of neuropathy. Sural biopsy showed the main pathological change was chronic axonal degeneration., Competing Interests: The authors declare that they have no competing interests.

Rationale: Nitrous oxide (NO) is a commonly used drug in medical practice, restoration, and the automobile industry. Recreational abuse is an emerging public health problem owing to its accessibility and drug properties., Patient Concerns: A 25-year-old male was hospitalized with acute psychosis and lower-extremity sensorimotor proprioceptive ataxia due to nitrous oxide abuse., Diagnosis: Laboratory studies confirmed a vitamin B12 deficiency. Magnetic resonance imaging of the spinal cord showed normal findings. Electrophysiological testing confirmed length-dependent sensorimotor polyneuropathy, with a predominant motor component and axonal degeneration., Intervention and Outcomes: Abstinence from toxic substances was suggested, and vitamin B12 substitution was introduced. The patient was lost to follow up., Lessons: Nitrous oxide toxicity is multisystemic and is thought to result from vitamin B12 inactivation. Recent case reports postulated direct paranodal lesions resulting from nitrous oxide consumption. Neurological, neuropsychiatric, and hematological toxicities are among those explored in this case report. Correction of the functional vitamin B12 status and nitrous oxide abstinence are essential in the treatment process., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Multifocal motor neuropathy (MMN) is an immune-mediated and acquired demyelinating motor polyneuropathy. Several cases of polyneuropathy associated with severe acquired respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination have been reported. However, MMN has not been reported as a complication of SARS-CoV-2 vaccination. In this study, we report a case of MMN with progressive muscle weakness following the second dose of the Pfizer-BioNTech mRNA vaccine. It was diagnosed by clinical evaluation and electroneuromyography. SARS-CoV-2 vaccination is increasing rapidly all over the world. Some cases of polyneuropathy, especially Guillain-Barré syndrome, have been reported after vaccination. This is the first case report of MMN after SARS-CoV-2 vaccination.

Introduction: Oxaliplatin is a third-generation platinum compound that used extensively for the treatment of various types of cancer especially gastrointestinal neoplasms. The main dose-limiting toxicities of oxaliplatin are hematological toxicity and peripheral sensory neuropathy., Case Report: A 42-year-old man with refractory peripheral T-cell lymphoma (PTCL) was admitted to receive GEMOX chemotherapy regimen (gemcitabine, oxaliplatin). Three days after receiving his third cycle of chemotherapy regimen, he was re-admitted to the emergency department with complaint of severe generalized weakness, and paraplegia in the lower extremities. According to clinical and para-clinical findings, chronic sensorimotor polyneuropathy with ongoing axonal loss was confirmed., Management & Outcome: Intravenous dexamethasone 8 mg three times daily was started at the time of admission for the patient. Muscle weakness and sensory impairment improved dramatically within 10 days and the patient was able to walk with assistance., Discussion: Several cases of neuropathy following oxaliplatin and only one case with gemcitabine-based chemotherapy regimen have been previously reported. However, motor symptoms are rare unless in the setting of acute neuropathy due to oxaliplatin. The most striking finding of our study was the incidence of a chronic sensorimotor axonaldemyelinating polyneuropathy in a patient who were subjected to oxaliplatin therapy. In conclusion, we report a case of severe generalized weakness and paraplegia following administration of Oxaliplatin.

Abstract: We present the case of a 37-year-old woman with alcohol use disorder, who developed leg cramping, bilateral foot drop, and hand weakness 3 months after starting disulfiram. This was accompanied by an 18-pound involuntary weight loss. Electrophysiologic findings showed a motor predominant axonal neuropathy. Neuromuscular ultrasound showed normal to small cross-sectional area of all nerves studied. This case is discussed, and the ultrasound findings are compared with another reported case., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Guselkumab is an IL-23 inhibitor that binds to the p19 subunit of IL-23 that is highly efficacious and well tolerated for the treatment of moderate-to-severe plaque psoriasis. We report a 20-year-old male who developed sensorimotor axonal polyneuropathy starting treatment with guselkumab, confirmed by neurological examination and serial neurophysiologic studies. His symptoms improved within 5 months of stopping the treatment. The neurophysiologic studies also showed improvement but with continued neuropathy and re-innervation changes on electromyography after about 10 months of stopping treatment. The time line of symptoms and a positive de-challenge are strong but not definitive evidence of guselkumab as a cause.

BACKGROUNDPaclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. Given that sensory symptoms are challenging to assess objectively in clinical practice, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as a translational surrogate marker for CIPN.METHODSNFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSNs) to paclitaxel. Patients with breast or ovarian cancer undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy, and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced (TNSr), which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single-molecule array technology.RESULTSNFL was released from iPSC-DSNs upon paclitaxel incubation in a dose- and time-dependent manner and was inversely correlated with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in patients receiving chemotherapy without CIPN or controls, resulting in an 86% sensitivity and 87% specificity. An NFLs increase of +36 pg/mL from baseline was associated with a predicted CIPN probability of more than 0.5.CONCLUSIONNFLs was correlated with CIPN development and severity, which may guide neurotoxic chemotherapy in the future.TRIAL REGISTRATIONClinicalTrials.gov NCT02753036.FUNDINGDeutsche Forschungsgemeinschaft (EXC 257 NeuroCure), BMBF (Center for Stroke Research Berlin, 01 EO 0801), Animalfree Research, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283), Charité 3R - Replace - Reduce - Refine.

Competing Interests: The authors report no conflicts of interest.

Background: During the worldwide mass vaccination campaign against SARS-CoV-2, multiple side effects have been observed. We described the case of a patient who developed pure sensitive chronic inflammatory axonal polyneuropathy (CIAP) in a close temporal relationship with the administration of the BNT162b2 (Pfizer®) vaccine., Case Report: An 82-year-old woman developed lower limb sensory loss and "pricking" associated with marked gait imbalance after she had received her second dose of Pfizer-BioNTech COVID-19 vaccine. At the electroneurographic examination, the motor nerves conduction study was normal. Median, ulnar, and sural nerves sensory compound nerve action potential (CNAP) were bilaterally absent. Somatosensory evoked potentials (SSEPs) were not recordable. Spine MRI demonstrated roots enhancement from C3 to Th2 and diffuse enhancement of cauda equina nerve roots. She was treated with IV methylprednisolone whit benefit. A follow-up visit was made 4 months after the disease onset; a diagnosis of pure sensitive CIAP has been made., Discussion: To the best of our knowledge, this is the first description of CIAP occurring in a close temporal relationship with the administration of Pfizer-BioNTech COVID-19 vaccine., (© 2021. Fondazione Società Italiana di Neurologia.)

Introduction/aims: Previous studies have shown inconsistent data on the relationship between statin use and polyneuropathy (PN). The current systematic review and meta-analyses were conducted to comprehensively investigate the risk of incident PN among statin-users compared with non-users by identifying all available studies and summarizing their results., Methods: A systematic review was conducted from MEDLINE and EMBASE databases from inception to October 31, 2020. We included cohort and case-control studies that compared the risk of incident PN between statin-users and non-users. Point estimates and standard errors from eligible studies were pooled together using the generic inverse variance method., Results: Of 4968 retrieved articles, 6 studies in non-diabetic populations and 2 studies in diabetic populations fulfilled the inclusion criteria. Two meta-analyses were performed. The pooled analyses did not find a statistically significant association between the use of statins and risk of incident PN with the pooled odds ratio of 1.24 (95% confidence interval [CI], 0.88-1.76; I 2 74%) and 0.82 (95% CI, 0.56-1.21; I 2 80%) in non-diabetic and diabetic groups respectively., Discussion: No significant association between the use of statins and the risk of PN was observed in this systematic review and these two meta-analyses. However, there was a high degree of heterogeneity of the meta-analyses., (© 2021 Wiley Periodicals LLC.)

Peripheral neurotoxicity is the most typical non-haematological adverse effect of taxanes. Symptoms are dominated by sensory peripheral neuropathy, the incidence and degree of which depend on the cumulative dose level. The impact of neurotoxicity on the patient´s quality of life is significant, therefore it is necessary to consider the selection of therapy and the patient´s pre-existing risk factors for developing neuropathy and to get acquainted with current management options, including genetic prediction of polyneuropathy. This review article reports on a very common complication of cancer therapy that can be encountered at each internist´s outpatient dispensary.

Objectives: Levodopa-carbidopa-intestinal-gel (LCIG) infusion is an effective treatment for advanced PD with motor fluctuations. Polyneuropathy occurs as a complication in 10-15% of patients. We wanted to assess the frequency of polyneuropathy in Finnish advanced Parkinson's disease (PD) patients with continuous LCIG infusion, and the value of different clinical monitoring parameters during follow-up., Materials and Methods: Patient records of PD patients started on LCIG infusion at Helsinki University Hospital who received nerve conduction studies at baseline and 6 months after treatment initiation were reviewed for epidemiological information, mini mental state examination, baseline and 6 months' UPRDS-III, weight, body mass index, levodopa dose (LD), plasma homocysteine levels, folate, vitamin B6 and B12., Results: Out of 19 patients (n = 6 on B-vitamin substitution), two (10.5%) developed new-onset polyneuropathy after initiation of LCIG therapy (n = 0 with vitamin substitution). Neuropathy was associated with significant weight loss (BMI reduction > 1.5), but not with other monitoring parameters. Homocysteine rose significantly in patients not substituted with B-vitamin complex, but not in patients with B-vitamin substitution. Homocysteine changes correlated with LD changes in the absence of vitamin B substitution. After oral B-vitamin substitution, both patients' polyneuropathy remained electrophysiologically and clinically stable., Conclusions: Rates of polyneuropathy in Finnish PD patients with LCIG treatment are comparable to previous studies. Patients' weight should be included in regular follow up monitoring and can be used for patient self-monitoring. Vitamin B substitution appears to reduce coupling between levodopa dose and homocysteine and may be useful to prevent polyneuropathy related to LCIG., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

A 76-year-old man, who received atezolizumab for the treatment for small cell lung cancer, acutely developed limb weakness with sensory disturbance after the third course of the treatment. Nerve conduction studies were consistent with demyelinating polyneuropathy and acute demyelinating polyneuropathy caused by atezolizumab was suggested. Atezolizumab was immediately withdrawn, and intravenous immunoglobulin (IVIg) and methylprednisolone pulse therapies with subsequent oral administration of prednisolone were initiated, after which neurological deficits steadily improved. Although Guillain-Barré syndrome-like neuropathy caused by immune checkpoint inhibitor (ICI) was occasionally reported, this is the first case of acute demyelinating polyneuropathy triggered by atezolizumab, monoclonal antibody targeting programmed death-ligand 1. This case suggests that combined treatments with IVIg and corticosteroids are effective for neuropathy induced by atezolizumab as same as those by other ICI.

We describe a 65-year-old man who during his service in the military developed an acute onset of burning pain in his feet and hands shortly after an acute, severe exposure to the fumes of chemical agent resistant coating (CARC). This chemical is used in the military to paint vehicles and equipment to create metal surfaces resistant to corrosion and penetration by chemical agents. Extensive laboratory workup for peripheral neuropathies was unremarkable. Nerve conduction studies showed axonal-loss polyneuropathy. Skin biopsy confirmed a small-fibre polyneuropathy (SFP). His burning pain persisted over three decades and was partially controlled with tramadol. This is the first case of SFP caused by acute CARC exposure with long-term surveillance., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

n-Hexane gives cause to one of the most common toxic polyneuropathies seen in poorly ventilated factories. It is a sensory-motor polyneuropathy ending up with axonal degeneration. Nerve biopsy reveals paranodal axonal swelling and secondary myelin retraction in early stages. Myelin retraction imitates demyelination causing focal conduction block and failure before axonal degeneration emerges. This brings to mind the new category of nodo-paranodopathy described first for anti-ganglioside antibody-mediated neuropathies, which can be proved by electrophysiological re-evaluations. We, herein, discuss the clinical and electrophysiological follow-up of three patients with n-hexane neuropathy and remark overlaps with new concept nodo-paranodopathy.

Neurologic adverse effects of triazole antifungal compounds used for the treatment of systemic and deep mycoses are relatively rare. The most common presentation is the involvement of peripheral nervous system, usually presenting with subjective symptoms such as paresthesia, dysesthesia, or numbness. Among these compounds, fluconazole has relatively more frequent neurological adverse reactions.A 54-year-old man was admitted with numbness and weakness in his both feet, which gradually worsened and resulted in difficulty in ambulation over time. He had no morbidity other than hypertension. He developed polyneuropathy (PNP), lower gastrointestinal system bleeding, acute renal insufficiency, thrombotic thrombocytopenic purpura, and confusional state. Severely disabling axonal and demyelinating sensorimotor PNP which led to immobilization of the patient for a few weeks but was recovered. When a more detailed past medical history was taken, he admitted to ingestion of 200 mg/day fluconazole for 1 month for onychomycosis without any prescription. This unusual combination of these rare adverse reactions of fluconazole may be explained by activation of an immune mechanism triggered by the drugs and genetic factors, or some other unknown individual factors.This case is reported due to the presence of rare systemic and neurologic adverse events of fluconazole, leading to this unusual clinical picture. We would like to emphasize fluconazole-related systemic and neurologic adverse reactions with life-threatening potential should be kept in mind.

The aim of this study was to evaluate the presence and characterization of chemotherapy-induced neuropathy (CIPN) and neuropathic pain 5 years after adjuvant chemotherapy with docetaxel or oxaliplatin. Patients from an ongoing prospective study, who had received adjuvant chemotherapy with docetaxel or oxaliplatin in 2011 to 2012 were invited to participate. The patients underwent a thorough examination with interview, neurological examination, questionnaires, assessment tools, nerve conduction studies (NCS), quantitative sensory testing, MScan motor unit number estimation (MUNE), and corneal confocal microscopy (CCM). Patients were divided into no, possible, probable, and confirmed CIPN. Out of the 132 eligible patients, 63 agreed to participate: 28 had received docetaxel and 35 had received oxaliplatin. Forty-one percent had confirmed CIPN, 34% possible or probable CIPN, and 22% did not have CIPN. The CIPN was characterized mainly by sensory nerve fiber loss, with a more pronounced large fiber than small fiber loss but also some motor fiber loss identified on NCS and MUNE. In general, patients had mild neuropathy with relatively low scores on assessment tools and no association with mood and quality of life. CCM was not useful as a diagnostic tool. Of the patients with probable or confirmed CIPN, 30% experienced pain, which was most often mild, but still interfered moderately with daily life in 20% to 25% and was associated with lower quality of life. In conclusion CIPN was confirmed in 41% 5 years after chemotherapy. The neuropathy was generally mild, but in patients with neuropathic pain it was associated with lower quality of life., (© 2020 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background: Polyneuropathy caused by n-hexane in its occupational settings is diagnosed with bilaterally symmetrical sensory and motor abnormalities. However, no effective treatments are available., Methods: We use the detailed physical, neurological examinations, rehabilitation assessment scale, and electrophysiological examinations at hospital admission and six months' follow up to assess the effect of a rehabilitation program on peripheral nerve injury caused by n-hexane nine patients., Results: We found that all patients complained about sensory issues of numbness in the distal extremities and decreasing strength with a decreased locomotion speed and gait abnormalities on admission, which is following the result of electrophysiological examinations. After they underwent a hospitalized rehabilitation program for 6 months, all of them showed a significant improvement in muscle strength, balance, deep tendon reflex, walking speed, and Barthel index, which showed a significant improvement in their athletic ability, although some patients still had gait abnormalities. According to the electrophysiological test results, nine patients had increased motor conduction velocities and amplitudes and shortened distal latencies in the four limbs compared with the results upon admission or one month later. However, only some indexes of sensory nerve conduction showed significant differences. With the recovery of movement and sensory function, they could live entirely independently and even return to work., Conclusions: We suggest that early general physical evaluation with electrophysiological examinations and comprehensive rehabilitation, including different modalities, therapeutic exercise, nerve mobilization, gait training, occupational therapy, traditional Chinese medicine treatment, and patient education, are essential so that patients can perform activities of daily living independently and return to work early.

Brain-derived neurotrophic factor (BDNF) is a protein with a potent influence on several aspects of neuronal and blood vessel functions. However, its prognostic potential and functional role in multiple myeloma (MM) remain largely unknown. In this study, we investigated the influence of BDNF on the risk of chemotherapy-induced peripheral neuropathy (CIPN) and clinical outcome. Study group consisted of 91 newly-diagnosed MM patients treated with bortezomib and/or thalidomide-based chemotherapy. Detection of BDNF in serum was performed using ELISA. Polyneuropathy was assessed according to the CTCAE Criteria v5. We observed that BDNF concentration correlated with the severity of polyneuropathy (P = 0·0463). Higher BDNF values were noted in patients who responded to treatment (P = 0·0326), and BDNF proved to be a useful marker to predict lack of response after eight cycles of treatment (sensitivity - 100%, specificity - 61·5%, P = 0·0142). Moreover this marker showed significant diagnostic usefulness in diagnosis of CIPN (sensitivity - 76%, specificity - 71·43%; area under the curve (AUC)= 0·77, 95%, confidence interval (CI): 0·64-0·88; P < 0·0001). Low BDNF was an independent, unfavourable prognostic factor associated with reduced overall survival (OS) (hazard ratio (HR) = 2·79, P = 0·0470). In conclusion, BDNF level may play a prognostic role and constitute a useful biomarker in predicting CIPN in MM patients., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Ibrutinib is an oral irreversible inhibitor of Bruton's tyrosine kinase signaling. It is a well-tolerated agent with some side-effects, the most common of which are atrial fibrillation, diarrhea, upper respiratory tract infection, fatigue, nausea, rash and cytopenias. Most of these toxicities are mild, although some have a severe clinical course., Case Report: The case is here reported of a chronic lymphocytic leukemia patient with ibrutinib-induced polyneuropathy. A 63-year-old male patient with chronic lymphocytic leukemia was given ibrutinib as a third line treatment regimen. After the 10th month of therapy he had progressive complaints of numbness and tingling in his legs. The patient was diagnosed as grade 3 sensorineural polyneuropathy with electromyography. Management and outcome: Considering that ibrutinib treatment may cause neuropathy, the ibrutinib was discontinued, after which the neuropathic complaints improved. However, the neck and axillary lymph nodes were enlarged and treatment had to be re-started therefore ibrutinib was started at a low dose and gradually increased. The patient is currently in the 14th month of treatment and still using ibrutinib without any severe side-effects., Discussion: To the best of our knowledge, polyneuropathy as a unique side-effect of ibrutinib has not been previously reported. In addition to the well-known side effects of ibrutinib treatment, it should be kept in mind that polyneuropathy may also develop.

Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot-Marie-Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes ( ARHGEF10 , SBF2 , FGD4 , FZD3  and NXN ) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results: FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.

Rationale: Lithium is the first-line medication for bipolar disorder, given a narrow therapeutic window of 0.8 to 1.2 mEq/L. Change of lithium pharmacokinetics following bariatric surgery may lead to lithium toxicity, which is particularly concerned., Patient Concerns: We presented a 39-year-old man with morbid obesity and bipolar affective disorder for 20 years, who was treated with lithium. He developed serious lithium toxicity following sleeve gastrectomy and prolonged neurologic sequelae., Diagnoses: He suffered from persistent watery diarrhea, general weakness, and then drowsy consciousness. Lithium level was checked immediately to be 3.42 mEq/L and lithium toxicity was diagnosed., Interventions: After 3 courses of hemodialysis, his serum lithium level subsequently declined to 0.63 mEq/L, while his consciousness returned normal. Lithium was replaced by lamotrigine., Outcomes: The patient was discharged thirty-five days after admission, while his serum lithium declined to 0.06 mEq/L. Neurologic sequelae were noted by muscle weakness and pain sensation in both feet. The nerve conduction test revealed sensorimotor polyneuropathy with conduction block. He was advised to keep a passive range of motion exercise., Lessons: Although the consensus guideline remains lacking, our report reviewed cases of relevance in the literature and highlighted the awareness of the potential risk of lithium toxicity following bariatric surgery. We suggest close monitoring of the lithium levels and perhaps a dosage adjustment for the postoperative period.

Objective: This pilot study aims to evaluate the effectiveness and safety of acupuncture in the treatment of chemotherapy-induced peripheral neuropathy (CIPN)., Methods: This study was a pilot randomized controlled trial, which was conducted with cooperation between Beijing University of Chinese Medicine (BUCM), China, and Tehran University of Medical Science (TUMS), Iran. Forty participants with CIPN were randomly assigned (1 : 1) to receive twelve sessions of acupuncture (20 minutes each session over 4 weeks) or take one 300 mg tablet of vitamin B1 and three 300 mg capsules of gabapentin per day for 4 weeks, after which both groups were followed up for 4 weeks. The primary endpoint was CIPN symptom severity measured by the Numerical Rating Scale (NRS). The secondary endpoints included sensory neuropathy grade evaluated by the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), neurophysiological assessment of CIPN by the nerve conduction study (NCS), and the patient overall satisfaction with treatment. Safety was assessed at each visit., Results: The NRS and NCI-CTCAE sensory neuropathy grading scales decreased significantly over time in both groups (both P < 0.001), with a significantly higher reduction in the acupuncture group ( P < 0.001 and P = 0.03, respectively). In addition, the acupuncture group showed a higher overall satisfaction with the treatment at the end of treatment and after 4 weeks follow-up, in comparison with the vit B1 and gabapentin group ( P = 0.01 and P = 0.001, respectively). The NCS (except for the latency of the sural nerve) in the acupuncture group improved significantly ( P < 0.05), while improvement in the vit B1 and gabapentin group was not observed ( P > 0.05)., Conclusion: Our study revealed that acupuncture, as a kind of traditional Chinese therapeutic method, is significantly effective and safe in the treatment of CIPN. Moreover, acupuncture is more effective than using vitamin B1 and gabapentin as the conventional treatment. Trial registration. This trial is registered with the Iranian Registry of Clinical Trials (IRCT20190615043900N1)., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Somayeh Iravani et al.)

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a worldwide concern in patients receiving neurotoxic agents for cancer therapy. High tone external muscle stimulation is a promising therapeutic approach to alleviate symptoms of CIPN., Methods: This pilot study aims to investigate whether the application of home-based high-tone external muscle stimulation therapy (HTEMS) improves symptoms of CIPN. The trial is planned as a therapist- and assessor-blinded, 1:1 randomized controlled study. A total of 50 patients with chemotherapy-induced peripheral polyneuropathy will be included. All patients will perform therapy at home. Study participants will be allocated randomly to the HTEMS therapy (intervention group) or to the transcutaneous electrical nerve stimulation (TENS, control group), respectively, following a standardized therapy schedule. Compliance of participants can be verified by reading out the tool box. Outcomes will be evaluated at baseline and after 8 weeks of home-based therapy. The primary outcome includes improvement of CIPN according to the patient-reported EORTC QLQ-CIPN 20 questionnaire. Secondary outcomes are the patient-reported change in health-related quality of life and clinician-reported changes of vibration sensibility, tendon reflexes, temperature sensibility, perception of touch, and strength of the lower leg muscles. Further a safety- and process evaluation will be performed., Discussion: This pilot RCT aims to evaluate the impact of home-based HTEMS as compared to TENS in CIPN. There is a need for an effective treatment for CIPN and the results of this study are expected to possibly identify a novel and effective treatment strategy in the future.

Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age-matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CIAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between IENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pembrolizumab is a humanized monoclonal antibody that targets the programmed cell death 1 protein (PD-1) receptor and blocks the inhibitory checkpoint interaction between PD-1 and its ligands. This interaction leads to the upregulation of effector T-cells and downregulating regulatory T-cell production. Although this mechanism is essential for the management of cancer, it may lead to decreased self-tolerance with an autoimmune reaction toward healthy functioning tissue. One of the less commonly reported and less understood immune-related adverse events includes neuromuscular complications. We present a rare case of autoimmune demyelinating polyneuropathy and hydrocephalus secondary to pembrolizumab use for cutaneous squamous cell carcinoma of the cheek.

Background and Purpose: Assessment of the severity of chronic peripheral neuropathy during oxaliplatin treatment is based on symptoms. Efforts to adjust the total dose of oxaliplatin to prevent severe neuropathy can be complicated by the worsening of neuropathy symptoms following treatment. Objective measures of the structure and function of peripheral nerves during early phases of treatment may aid in determining the optimal oxaliplatin dose in individual patients. Intraepidermal nerve fibre density (IENFD) has been suggested as an early marker of peripheral neuropathy., Methods: Sixty patients were examined before treatment and following 25% and 50% of the total planned oxaliplatin dose. Fifty-five of them were also examined at completion of chemotherapy and 6 months later. IENFD in skin biopsies from the distal leg, nerve conduction studies and quantitative sensory testing at the dorsum of the foot were performed. Forty-six healthy subjects were examined at baseline and after 6 and 52 weeks for comparison., Results: Intraepidermal nerve fibre density was not reduced during treatment. Sural nerve amplitude and conduction velocity, vibration detection thresholds, mechanical detection threshold and cold detection threshold were significantly reduced during treatment. Compared to reference values and spontaneous changes in healthy subjects, the largest proportions of patients with deterioration were found for vibration detection thresholds followed by nerve conduction studies, mechanical detection threshold, cold detection threshold and IENFD., Conclusions: Significant changes were most pronounced for measures of large nerve fibre function, especially vibration sensation. Skin biopsies do not seem to provide a clinically relevant objective measure of peripheral nerve deterioration during oxaliplatin treatment., (© European Academy of Neurology 2019.)

Background: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity., Materials and Methods: This was a randomized, open-label study testing 4-week cycles of 80 mg/m 2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m 2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m 2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m 2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated., Results: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w ( n = 7, 50%) and NAB150/2w ( n = 10, 62.5%) groups than in the NAB100/w ( n = 13, 81.3%) or NAB150/w ( n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5 -rs7349683, EPHA6 -rs301927, and EPHA8 -rs209709 were associated with an increased risk of paclitaxel-induced neuropathy., Conclusion: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m 2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)