Search

Introduction/aims: Multifocal motor neuropathy (MMN) is a rare disease for which epidemiological and clinical data are limited. We conducted a nationwide survey to determine disease prevalence, incidence, clinical profile, and current treatment status in Japan., Methods: A nationwide survey was conducted in 2021 using an established epidemiological method. Questionnaires were sent to all neurology and pediatric neurology departments in Japan. An initial questionnaire was administered to determine the number of patients with and incidence of MMN. A second questionnaire was administered to collect detailed clinical information. The European Federation of Neurological Societies/Peripheral Nerve Society 2010 guidelines were used as diagnostic criteria., Results: The estimated number of patients with MMN was 507. The estimated prevalence was 0.40 per 100,000 individuals. Detailed clinical profiles were available for 120 patients. The male-to-female ratio was 2.3:1 and the median onset age was 42 years. The median disease duration at diagnosis was 25 months. Most patients presented with upper limb-dominant muscle weakness. Motor nerve conduction blocks were found in 62% of patients and positive anti-GM1 IgM antibody results in 54%. A total of 117 (98%) patients received immunoglobulin therapy, and 91% of them showed improvement. At the time of the last visit (median, 82 months from treatment initiation), 89 (74%) patients were receiving maintenance immunoglobulin therapy. A slight progression of neurological deficits was observed during follow-up., Discussion: Most patients with MMN in Japan received induction and maintenance immunoglobulin therapies, which appear to suppress long-term disease progression., (© 2024 Wiley Periodicals LLC.)

Background: To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy., Methods: The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M., Results: Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], -26.5 points; 95% confidence interval: -45.5, -7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population., Conclusion: This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy., Trial Registration Information: The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015., Classification of Evidence: This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Metachromatic leukodystrophy (MLD) is a neuro-metabolic disorder due to arylsulfatase A deficiency, causing demyelination of the central and peripheral nervous system. Hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for pre-symptomatic and early symptomatic patients by stabilizing CNS disease. This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. The patients had demyelinating polyneuropathy before HCT, performed at the ages of 2 years in the first two patients and at 14 and 23 years in the other two patients. The myeloablative conditioning regimen consisted of busulfan, fludarabine and, in one case, rituximab, with anti-thymocyte globulin, cyclosporine, steroids, and/or mycophenolate mofetil for GvHD prophylaxis. Polyneuropathy after HCT progressed parallel with tapering immunosuppression and paralleled bouts of infection and graft-versus-host disease (GvHD). Differential diagnoses included MLD progression, neurological GvHD or another (auto)inflammatory cause. Laboratory, electroneurography and pathology investigations were inconclusive. In two patients, treatment with immunomodulatory drugs led to temporary improvement, but not sustained stabilization of polyneuropathy. One patient showed recovery to pre-HCT functioning, except for a Holmes-like tremor, for which a peripheral origin cannot be excluded. One patient showed marginal response to immunosuppressive treatment and died ten months after HCT due to respiratory failure. The extensive diagnostic and therapeutic attempts highlight the challenge of characterizing and treating progressive polyneuropathy in patients with MLD shortly after HCT. We advise to consider repeat electro-neurography and possibly peripheral nerve biopsy in such patients. Nerve conduction blocks, evidence of the presence of T lymphocytes and macrophages in the neuronal and surrounding nerve tissue, and beneficial effects of immunomodulatory drugs may indicate a partially (auto)immune-mediated pathology. Polyneuropathy may cause major residual disease burden after HCT. MLD patients with progressive polyneuropathy could potentially benefit from a more intensified immunomodulatory drug regime following HCT, especially at times of immune activation., (© 2024. The Author(s).)

Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)-specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US-based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium-based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene-silencing therapeutics recommended as a first-line option. Consensus is lacking on what represents "disease progression" during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy., (© 2024 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Critical illness polyneuropathy (CIP) is a very rare complication of sepsis and multi-organ failure. Herein, we report the first case of CIP reported in a patient on maintenance hemodialysis, who improved with rehabilitation. A 55-year-old male patient was emergently admitted with fever and altered consciousness and diagnosed with bacterial meningitis based on cerebral spinal fluid and cranial magnetic resonance imaging findings. Methicillin-susceptible Staphylococcus aureus was detected in blood and cerebral spinal fluid cultures. Despite treatment with appropriate antibiotics, blood cultures were positive for 9 days and serum C-reactive protein (CRP) levels were persistently elevated. Magnetic resonance imaging of hands and feet to determine infection origin revealed osteomyelitis in several fingers and toes, which required the amputation of 14 necrotic fingers and toes. Thereafter, blood cultures became negative and CRP levels declined. However, flaccid paralysis was noted in both upper and lower extremities during sepsis treatment. Nerve conduction studies showed peripheral axonal disorder in motor and sensory nerves, and CIP was determined as the cause of paralysis based on the fulfillment of all four CIP diagnostic criteria. The patient's muscle strength improved with early and appropriate medical treatment and physical therapy, and he was discharged home 147 days after admission. Prolonged high-level inflammation is a cause of CIP. Patients on hemodialysis, who are potentially immunosuppressed and vulnerable to infection, are at high risk for CIP. In patients on maintenance hemodialysis who develop flaccid paralysis during treatment for severe infection, CIP should be considered for early diagnosis and intervention., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Distal sensory polyneuropathy (DSP) is characterised by length-dependent, sensory-predominant symptoms and signs, including potentially disabling symmetric chronic pain, tingling and poor balance. Some patients also have or develop dysautonomia or motor involvement depending on whether large myelinated or small fibres are predominantly affected. Although highly prevalent, diagnosis and management can be challenging. While classic diabetes and toxic causes are well-recognised, there are increasingly diverse associations, including with dysimmune, rheumatological and neurodegenerative conditions. Approximately half of cases are initially considered idiopathic despite thorough evaluation, but often, the causes emerge later as new symptoms develop or testing advances, for instance with genetic approaches. Improving and standardising DSP metrics, as already accomplished for motor neuropathies, would permit in-clinic longitudinal tracking of natural history and treatment responses. Standardising phenotyping could advance research and facilitate trials of potential therapies, which lag so far. This review updates on recent advances and summarises current evidence for specific treatments., Competing Interests: Competing interests: MSilsby, ELF, RDD, AR, SV, ALO and NGS reports no competing interests. SH reports personal fees from Rafa Laboratories, Vertex Pharmaceuticals and GW Pharmaceuticals, and research grants from Eli Lilly, outside the scope of this work. YAR has received speaker/consultancy honoraria from LFB, Polyneuron and Argenx and has received educational sponsorships from LFB and CSL Behring and has obtained research grants from LFB and CSL Behring. MShy has no competing interests related to this publication. He serves as a consultant for Applied Therapeutics, DTx Pharma, Mitochondria in Motion, Swan Biosci and Inflectis., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Severe weakness associated with critical illness (CIW) is common. This narrative review summarizes the latest scientific insights and proposes a guide for clinicians to optimize the diagnosis and management of the CIW during the various stages of the disease from the ICU to the community stage., Main Body: CIW arises as diffuse, symmetrical weakness after ICU admission, which is an important differentiating factor from other diseases causing non-symmetrical muscle weakness or paralysis. In patients with adequate cognitive function, CIW can be easily diagnosed at the bedside using manual muscle testing, which should be routinely conducted until ICU discharge. In patients with delirium or coma or those with prolonged, severe weakness, specific neurophysiological investigations and, in selected cases, muscle biopsy are recommended. With these exams, CIW can be differentiated into critical illness polyneuropathy or myopathy, which often coexist. On the general ward, CIW is seen in patients with prolonged previous ICU treatment, or in those developing a new sepsis. Respiratory muscle weakness can cause neuromuscular respiratory failure, which needs prompt recognition and rapid treatment to avoid life-threatening situations. Active rehabilitation should be reassessed and tailored to the new patient's condition to reduce the risk of disease progression. CIW is associated with long-term physical, cognitive and mental impairments, which emphasizes the need for a multidisciplinary model of care. Follow-up clinics for patients surviving critical illness may serve this purpose by providing direct clinical support to patients, managing referrals to other specialists and general practitioners, and serving as a platform for research to describe the natural history of post-intensive care syndrome and to identify new therapeutic interventions. This surveillance should include an assessment of the activities of daily living, mood, and functional mobility. Finally, nutritional status should be longitudinally assessed in all ICU survivors and incorporated into a patient-centered nutritional approach guided by a dietician., Conclusions: Early ICU mobilization combined with the best evidence-based ICU practices can effectively reduce short-term weakness. Multi-professional collaborations are needed to guarantee a multi-dimensional evaluation and unitary community care programs for survivors of critical illnesses., (© 2023. The Author(s).)

Objective: Coexistence of polyneuropathy and gammopathy is a common but potentially challenging situation in clinical practice. This article reviews the clinical, electrophysiologic, and hematologic phenotypes of the paraproteinemic neuropathies and the diagnostic and treatment strategies for each., Latest Developments: Advances in our understanding of the underlying pathophysiology of various paraproteinemic neuropathies and their corresponding phenotypes have identified potential new therapeutic targets. Therapeutic strategies to diminish anti-myelin-associated glycoprotein (MAG) IgM antibodies have shown partial and inconsistent efficacy; however, antigen-specific immune therapy is being investigated as a novel treatment to remove the presumably pathogenic anti-MAG antibody. Advances in genetic and cell signaling studies have resulted in the approval of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia. Monoclonal antibodies are being investigated for the treatment of light chain amyloidosis., Essential Points: Early recognition and treatment of underlying plasma cell disorders improves clinical outcomes in patients with paraproteinemic neuropathy. Despite significant progress, our knowledge regarding underlying mechanisms for paraproteinemic neuropathy is still limited. Clinicians' awareness of clinical phenotypes, electrophysiologic hallmarks, and hematologic findings of the different paraproteinemic neuropathies is crucial to promptly identify and treat patients and to avert misdiagnosis. Multidisciplinary collaboration among specialists, including neurologists and hematologists, is paramount for the optimal treatment of these patients with overlapping conditions., (Copyright © 2023 American Academy of Neurology.)

Objective: This article is an overview of chronic demyelinating neuropathies and highlights the phenotypic categorization, diagnosis, and treatment of chronic immune-mediated neuropathies. The clinical and diagnostic characteristics of other chronic demyelinating neuropathies that are common mimics of immune-mediated neuropathies are also discussed., Latest Developments: The underlying pathophysiology of chronic demyelinating neuropathies is heterogeneous, and components of both humoral and cellular immune responses are thought to play a role in the immune-mediated types of chronic demyelinating neuropathy. The role of the humoral response is highlighted with a specific focus on the relatively recent discovery of antibody-mediated antinodal and paranodal demyelinating neuropathies. Additionally, new diagnostic criteria for some of the chronic demyelinating neuropathies, as well as ways to differentiate chronic inflammatory demyelinating polyradiculoneuropathy from other chronic demyelinating polyneuropathies, are discussed., Essential Points: Chronic demyelinating neuropathies can present with overlapping clinical characteristics with seemingly subtle variations. It is clinically important to differentiate these types of neuropathies because the treatment and management can vary and affect prognosis., (Copyright © 2023 American Academy of Neurology.)

The spectrum of immune-mediated neuropathies is broad and the different subtypes are still being researched. With the numerous subtypes of immune-mediated neuropathies, establishing the appropriate diagnosis in normal clinical practice is challenging. The treatment of these disorders is also troublesome. The authors have undertaken a literature review of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Guillain-Barre syndrome (GBS) and multifocal motor neuropathy (MMN). The molecular, electrophysiological and ultrasound features of these autoimmune polyneuropathies are analyzed, highlighting the differences in diagnosis and ultimately treatment. The immune dysfunction can lead to damage to the peripheral nervous system. In practice, it is suspected that these disorders are caused by autoimmunity to proteins located in the node of Ranvier or myelin components of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. The electrophysiological presence of conduction blocks is another important factor characterizing separate subgroups of treatment-naive motor neuropathies, including multifocal CIDP (synonyms: multifocal demyelinating neuropathy with persistent conduction block), which differs from multifocal motor neuropathy with conduction block (MMN) in both responses to treatment modalities and electrophysiological features. Ultrasound is a reliable method for diagnosing immune-mediated neuropathies, particularly when alternative diagnostic examinations yield inconclusive results. In overall terms, the management of these disorders includes immunotherapy such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the development of more disease-specific immunotherapies should expand the therapeutic possibilities for these debilitating diseases.

Purpose: Chemotherapy-related polyneuropathy (CIPN) is a very common, often dose-limiting side effect that affects the patients' quality of life. Treatment usually consists of a combination of medicinal, medical, and individualized treatment approaches, although the effectiveness of these therapies is insufficient for many patients. The aim of this article is to review and evaluate the impact of CIPN on patients' daily lives and possible effective treatment approaches., Methods: A standardized questionnaire was developed based on ten anonymous telephone interviews with CIPN patients. The content of the questionnaire was divided into 5 categories: demographics, clinical presentation, everyday symptoms, treatment of CIPN symptoms, and medical care. Mostly closed questions were used but multiple choice and individual additions by free text answers were possible., Results: CIPN limits patients' quality of life over a long period of time. In addition to diurnal and situational fluctuations, the emotional burden negatively affects patients' daily lives in many ways. From the patients' point of view, the individually implemented therapy measures were most effective in treating their complaints. But even the combination of different therapy methods insufficiently alleviates the symptoms of the patients., Conclusion: It is important and necessary to comprehensively inform patients about CIPN as a possible side effect, to point out prevention strategies, and to critically examine and evaluate different therapy approaches. In this way, misunderstandings of the doctor-patient relationship can be avoided. In addition, patient satisfaction and quality of life can be increased in the long term., (© 2023. The Author(s).)

Purpose of Review: Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV., Recent Findings: Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Competing interests: None declared.

The autoimmune peripheral neuropathies with prominent motor manifestations are a diverse collection of unusual peripheral neuropathies that are appreciated in vast clinical settings. This chapter highlights the most common immune-mediated, motor predominant neuropathies excluding acute, and chronic inflammatory demyelinating polyradiculoneuropathy (AIDP and CIDP, respectively). Other acquired demyelinating neuropathies such as distal CIDP and multifocal motor neuropathy will be covered. Additionally, the radiculoplexus neuropathies, resulting from microvasculitis-induced injury to nerve roots, plexuses, and nerves, including diabetic and nondiabetic lumbosacral radiculoplexus neuropathy and neuralgic amyotrophy (i.e., Parsonage-Turner syndrome), will be included. Finally, the motor predominant peripheral neuropathies encountered in association with rheumatological disease, particularly Sjögren's syndrome and rheumatoid arthritis, are covered. Early recognition of these distinct motor predominant autoimmune neuropathies and initiation of immunomodulatory and immunosuppressant treatment likely result in improved outcomes., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Weakness of limb and respiratory muscles that occurs in the course of critical illness has become an increasingly common and serious complication of adult and pediatric intensive care unit patients and a cause of prolonged ventilatory support, morbidity, and prolonged hospitalization. Two motor disorders that occur singly or together, namely critical illness polyneuropathy and critical illness myopathy, cause weakness of limb and of breathing muscles, making it difficult to be weaned from ventilatory support, commencing rehabilitation, and extending the length of stay in the intensive care unit, with higher rates of morbidity and mortality. Recovery can take weeks or months and in severe cases, and may be incomplete or absent. Recent findings suggest an improved prognosis of critical illness myopathy compared to polyneuropathy. Prevention and treatment are therefore very important. Its management requires an integrated team approach commencing with neurologic consultation, creatine kinase (CK) measurement, detailed electrodiagnostic, respiratory and neuroimaging studies, and potentially muscle biopsy to elucidate the etiopathogenesis of the weakness in the peripheral and/or central nervous system, for which there may be a variety of causes. These tenets of care are being applied to new cases and survivors of the coronavirus-2 disease pandemic of 2019. This chapter provides an update to the understanding and approach to critical illness motor disorders., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background/aim: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN., Materials and Methods: The databases searched were Pubmed, Cohrane, and Scopus for randomized controlled trials (RCTs) published in the last 5 years (2017-2022). Studies were considered eligible, if they assessed adult patients suffering from CIPN because of any chemotherapeutic drug for any type and any stage of cancer and if study protocols included non-pharmacological intervention with a structured protocol., Results: A total of 1,496 records were identified. Finally, 10 RCTs including 495 patients (253 in the intervention group and 242 in the control group) were included for meta-analysis. Intervention protocols included acupuncture (n=6), exercise (n=3), and yoga (n=1). NPIs significantly reduced neuropathic pain. However, the effect on QoL was not significant., Conclusion: NPIs are beneficial in the treatment of pain in patients with CIPN but their impact on QoL is not statistically supported. Larger sample sizes, more homogenous in outcome measures and interventions are needed to further explore NPIs' efficacy on CIPN symptoms., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Critical Illness Neuromyopathy (CIPNM) is a complication in sepsis patients with still enigmatic disease mechanisms. We investigated a novel electrical stimulation method to better define neuromuscular dysfunction in patients with CIPNM., Methods: We studied 18 sepsis CIPNM patients on intensive care units, 13 at an early and 5 at a later disease stage, 7 sepsis control, and 8 neuropathy control patients. We applied slow conditioning electrical pulses at motor nerves and directly at the muscle to investigate a facilitation phenomenon (FP) of small or absent compound motor action potentials (CMAPs)., Results: Serial pulses induced a 2 to 490-fold increase in CMAP amplitudes in 17/18 Intensive Care Unit (ICU)-CIPNM patients (p < 0.001). These effects were short lived and reproducible. Direct muscle stimulation in the tibialis anterior muscle resulted in up to 130-fold FP in 7/9 patients tested (p < 0.01). In 4/5 post-ICU CIPNM patients FP was up to 10-fold. None of the 7 ICU sepsis control patients without CIPNM with similar disease severity and none of 8 neuropathy patients showed FP (p < 0.001). On needle EMG only 5/16 ICU patients tested revealed spontaneous activity., Conclusions: Conditioning electrical stimulation detected a functional component of the disease process showing temporary improvement in sepsis-associated CIPNM., Significance: New test differentiates functional from degenerative pathology., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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.

Chronic immune mediated neuropathy is a heterogenous group of peripheral nerve diseases, encompassing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), autoimmune nodopathy, multifocal motor neuropathy (MMN), and anti-myelin-associated glycoprotein (MAG) neuropathy. Rituximab (RTX) is a chimeric monoclonal antibody targeting the CD20 antigen, which has been used in the treatment of autoimmune neuropathies, although the efficacy of RTX remains unclear. A literature search was performed using Medline, Embase and Cochrane Register for studies between 2000 and 2021 using the search terms "Chronic inflammatory demyelinating polyneuropathy" OR "Multifocal motor neuropathy" OR "Myelin associated glycoprotein" OR "Distal acquired demyelinating neuropathy" OR "Multifocal acquired demyelinating sensory and motor neuropathy" OR "demyelinating neuropathy" AND "Rituximab". Twenty-three studies were included, of which two were randomised controlled trials, 6 prospective studies and 15 retrospective studies. RTX was effective in 63% of CIDP patients, 48% of anti-MAG neuropathy, and 96% of patients with autoimmune nodopathy. Neurophysiological improvement was evident in 58% of CIDP and 40% of anti-MAG neuropathy patients. Low rates of serious adverse events (2.6%) were observed. These results indicate that RTX has potential as a treatment in immune mediated polyneuropathy, although the quality of evidence supporting its use it poor. Randomized controlled trials are required to reliably establish the efficacy and safety of RTX. Trial registration number: CRD42020179666., Competing Interests: Declaration of Competing Interest The authors have no financial or personal relationships to declare., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Physical exercise appeared to be effective, when implemented as an adjuvant to the pharmacotherapy option, in a variety of painful conditions. Peripheral neuropathic pain (PNP) is very prevalent and affects up to two-thirds of individuals with polyneuropathy (PN), regardless of etiology. The aim of this systematic review was to evaluate the currently available studies that assess adjuvant physical exercise for the management of PNP., Methods: A systematic literature search was conducted in the PubMed international database. For the systematic search, three medical subject headings (MeSH) were used. Term A was 'physical exercise' OR 'exercise' OR 'activity' OR 'workout' OR 'training'; term B was 'pain' OR 'painful'; term C was 'neuropathy' OR 'polyneuropathy.' Additionally, three filters were used: human subjects, English language, and full text. The reference lists of eligible papers and relevant reviews were also meticulously searched in order to include further relevant studies. Six papers eligible to be included were identified., Results: Physical exercise in various forms can be of benefit in the management of PNP when used as an adjuvant to the standard care. Overall, using the American Society of Interventional Pain Physicians (ASIPP) criteria, the current best available evidence exists for both aerobic and muscle strengthening exercise programs (level II evidence). The intensity of the exercise seems to play a significant role, with higher intensity interval training programs being more promising, though this remains to be confirmed in future studies., Conclusions: Physical exercise is a promising non-pharmacological intervention for the management of PNP. Future RCTs should be conducted to make a face-to-face comparison of the available exercise treatments with the aim to design specific exercise programs for patients with PNP.

Familial amyloidotic polyneuropathy (FAP) is caused by a mutation in the transthyretin (TTR) gene. In addition, deposition of wild-type TTR can cause senile systemic amyloidosis (SSA). To date, we have produced several transgenic mouse models for FAP and SSA by introducing TTR genes with different promoters or mutations. However, mouse TTR can associate with human TTR to produce hybrid tetramers in transgenic mice. Thus, these transgenic mice cannot be used to test the efficacy of a new therapy. In this study, we attempted to construct an optimized mouse model to verify a new therapy. The TTR gene consists of 4 exons and 3 introns. We prepared two gRNAs, one for the exon 1 and the other for exon 4, and a single donor vector carrying the whole TTR gene in which mouse exons were replaced with human exons. Using these vectors, we produced a TTR exon-humanized mouse with human exons and mouse introns using genome editing technology. These TTR exon-humanized mice showed normal TTR expression patterns in terms of serum TTR level and spatial specificity. These TTR exon-humanized mice will be useful for devising new treatment methods for FAP, including gene therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality, reduced quality of life, and increased health care costs resulting particularly from neuropathic pain and foot ulcers. Painful DSPN is encountered in 13-26% of diabetes patients, while up to 50% of patients with DSPN may be asymptomatic. Unfortunately, DSPN still remains inadequately diagnosed and treated. Herein we provide international expert consensus recommendations and algorithms for screening, diagnosis, and treatment of DSPN in clinical practice derived from a Delphi process. Typical neuropathic symptoms include pain, paresthesias, and numbness particularly in the feet and calves. Clinical diagnosis of DSPN is based on neuropathic symptoms and signs (deficits). Management of DSPN includes three cornerstones: (1) lifestyle modification, optimal diabetes treatment aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, (2) pathogenetically oriented pharmacotherapy (e.g. α-lipoic acid and benfotiamine), and (3) symptomatic treatment of neuropathic pain including analgesic pharmacotherapy (antidepressants, anticonvulsants, opioids, capsaicin 8% patch and combinations, if required) and non-pharmacological options. Considering the individual risk profile, pain management should not only aim at pain relief, but also allow for improvement in quality of sleep, functionality, and general quality of life., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Chronic inflammatory demyelinating polyneuropathy, its variants and multifocal motor neuropathy belong to a spectrum of peripheral nerve disorders with complex dysimmune disease mechanisms. Awareness of the unique clinical phenotypes but also heterogeneity between patients is vital to arrive at early suspicion and ordering appropriate tests. This includes requirements for optimal electrodiagnostic protocol, aimed to capture sufficient electrophysiologic evidence for relevant abnormalities, a case-based approach on the eventual need to further expand the diagnostic armamentarium and correct reading of their results. Considerable phenotypical variation, diverse combinations of abnormalities found on diagnostic tests and heterogeneity in disease course and treatment response, all contribute to widespread differences in success rates on timely diagnosis and optimal treatment. We aim to provide a practical overview and guidance on relevant diagnostic and management strategies, including pitfalls and present a summary of the relevant novel developments in this field.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.

The various manifestations of diabetic neuropathy, including distal symmetric sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN), are among the most prevalent chronic complications of diabetes. Major clinical complications of diabetic neuropathies, such as neuropathic pain, chronic foot ulcers, and orthostatic hypotension, are associated with considerable morbidity, increased mortality, and diminished quality of life. Despite the substantial individual and socioeconomic burden, the strategies to diagnose and treat diabetic neuropathies remain insufficient. This review provides an overview of the current clinical aspects and recent advances in exploring local and systemic biomarkers of both DSPN and CAN assessed in human studies (such as biomarkers of inflammation and oxidative stress) for better understanding of the underlying pathophysiology and for improving early detection. Current therapeutic options for DSPN are (I) causal treatment, including lifestyle modification, optimal glycemic control, and multifactorial risk intervention, (II) pharmacotherapy derived from pathogenetic concepts, and (III) analgesic treatment against neuropathic pain. Recent advances in each category are discussed, including non-pharmacological approaches, such as electrical stimulation. Finally, the current therapeutic options for cardiovascular autonomic complications are provided. These insights should contribute to a broader understanding of the various manifestations of diabetic neuropathies from both the research and clinical perspectives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is an asymmetric immune-related neuropathy with conduction block. We report 2 MADSAM cases with detailed clinical, electrophysiological, and sonography profiles., Patient Concerns and Diagnosis: Two cases presented with patchy sensorimotor impairment in both clinical and electrophysiological findings. Notably, nerve ultrasound demonstrated multifocal nerve enlargement not only at sites of conduction blockade but also at the unaffected contralateral sites. Interestingly, in our first case, focal radial nerve enlargement was observed prior to the clinical manifestations, suggesting nerve dynamic pathogenesis with variable clinical significance., Interventions and Outcomes: The first patient was initially treated with prednisolone, however, 3 months after steroid therapy, her symptoms progressed. After treatment with intravenous immunoglobulin for 3 months, the symptoms stabilized. The second patient showed improvement after 2 months of prednisolone treatment., Conclusion: These observations suggest a more widespread pathomechanism underlying MADSAM, and ultrasound may detect nerve lesions earlier than clinical electrophysiology studies, and is warranted for early detection and thorough documentation of nerve pathology., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Reliable and responsive tools for monitoring disease activity and treatment outcomes in patients with neuropathies are lacking. With the emergence of ultrasensitive blood bioassays, proteins released with nerve damage are potentially useful response biomarkers for many neurological disorders, including polyneuropathies. In this review, we provide an overview of the existing literature focusing on potential applications in polyneuropathy clinical care and trials. Whilst several promising candidates have been identified, no studies have investigated if any of these proteins can serve as response biomarkers of longitudinal disease activity, except for neurofilament light (NfL). For NfL, limited evidence exists supporting a role as a response biomarker in Guillain-Barré syndrome, vasculitic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most evidence exists for NfL as a response biomarker in hereditary transthyretin-related amyloidosis (hATTR). At the present time, the role of NfL is therefore limited to a supporting clinical tool or exploratory endpoint in trials. Future developments will need to focus on the discovery of additional biomarkers for anatomically specific and other forms of nerve damage using high-throughput technologies and highly sensitive analytical platforms in adequality powered studies of appropriate design. For NfL, a better understanding of cut-off values, the relation to clinical symptoms and long-term disability as well as dynamics in serum on and off treatment is needed to further expand and proceed towards implementation., (© 2021. The Author(s).)

Diabetes is the main cause of peripheral neuropathy where older patients are at increased risk of diabetic distal symmetrical polyneuropathy (DSPN) due to age-related nerve degeneration and vascular changes. The aim of the study was to investigate the effect of resistance training on nerve conduction, measures of neuropathy and arterial stiffness in older patients with DSPN. In a randomized controlled trial, thirty-four older adults with type-2 diabetes and peripheral neuropathy were enrolled and randomly assigned to experimental and control groups. The experimental group carried out circuit resistance training (1-3 rounds, 11 exercises, 10-15 reps, 50%-60% of 1RM, 3 times per week) for 12 weeks. Measurements were performed at baseline and 48 h after the intervention. Measures of DSPN including Michigan neuropathy screening instrument (MNSI), Michigan diabetic neuropathy score (MDNS), motor nerve action potential amplitude (APA), sensory and motor nerve conduction velocity (NCV) improved following intervention (p < 0.001, p = 0.001, p = 0.034, p = 0.001, and p = 0.001, respectively). Sensory APA did not change after the intervention (p = 0.139). Cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) improved in the experimental group compared with the control group (p = 0.014 and p = 0.033, respectively). In addition, HbA1C decreased following the 12-week resistance training program (p = 0.002). Older adults with DSPN respond positively to resistance training by improved neuropathy symptoms, nerve conduction, arterial stiffness and glucose regulation. Resistance training offers a positive intervention that can abate the progression of DSPN in older adults., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The Neurological involvement is the most common extra-renal complication of Shiga toxin-producing E. coli-hemolytic uremic syndrome (HUS) or typical HUS. On brain magnetic resonance examination, main neurological signs encompass acute lesions of the basal ganglia and the white matter, which could usually regress after Eculizumab infusion. In contrast, peripheral nervous system (PNS) manifestations in typical HUS are very rare and, when occurring, they require a careful management of neurological sequelae and an intensive multidisciplinary neuro-rehabilitation program., Case Presentation: Here, we present two pediatric cases of severe and complicated typical HUS with PNS manifestations who required therapeutic treatment and an intensive multidisciplinary neuro-rehabilitation program. In both cases, PNS manifestations were followed by the recovery from typical HUS-related severe central neurological damage and manifested mainly with marked bilateral motor deficit and hyporeflexia/areflexia in the lower limbs. The peripheral polyneuropathy was treated with immunosuppressive therapy (methylprednisolone boluses, i.v. immunoglobulins, plasma exchange), followed by a prolonged intensive neuro-rehabilitation program. After 8 months of rehabilitation, both patients gained complete functional recovery., Conclusions: PNS manifestations during typical HUS are a rare event and potentially leading to severe disability. A timely clinical assessment is mandatory to set up a prompt therapeutic and rehabilitation program and to obtain a complete clinical and functional recovery., (© 2021. The Author(s).)

Objectives: Dorsal root ganglion stimulation (DRGS) is a promising neurostimulation modality in the treatment of painful polyneuropathy. The aim of this prospective pilot study was to investigate the effect of DRGS on pain intensity in patients with intractable painful polyneuropathy., Materials and Methods: Nine patients with chronic, intractable painful polyneuropathy in the lower limbs were recruited. In each subject, between two and four DRGS leads were placed at the level of the L5 and S1 dorsal root ganglion. If trial stimulation was successful, a definitive implantable pulse generator (IPG) was implanted. Pain intensity was scored using an 11-point numeric rating scale (NRS) and reported as median and interquartile range (IQR), and compared to baseline values using the Wilcoxon signed-rank test. Additionally, patients' global impression of change (PGIC), pain extent, presence of neuropathic pain, physical functioning, quality of life, and mood were assessed., Results: Eight out of nine patients had a successful trial phase, of which seven received an IPG. Daytime pain decreased from a median (IQR) NRS score of 7.0 (5.9-8.3) to 2.0 (1.0-3.5) and 3.0 (1.6-4.9) in the first week and at six months after implantation, respectively. Similar effects were observed for night time and peak pain scores., Conclusions: The results of this study suggest that DRGS significantly reduces both pain intensity and PGIC in patients with intractable painful polyneuropathy in the lower extremities. Large-scale clinical trials are needed to prove the efficacy of DRGS in intractable painful polyneuropathy., (© 2020 International Neuromodulation Society.)

Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.

This article discusses the chronic immune-mediated polyneuropathies, a broad category of acquired polyneuropathies that encompasses chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the most common immune-mediated neuropathy, the CIDP variants, and the vasculitic neuropathies. Polyneuropathies associated with rheumatological diseases and systemic inflammatory diseases, such as sarcoidosis, will also be briefly covered. These patients' history, examination, serum studies, and electrodiagnostic studies, as well as histopathological findings in the case of vasculitis, confirm the diagnosis and differentiate them from the more common length-dependent polyneuropathies. Prompt identification and initiation of treatment is imperative for these chronic immune-mediated polyneuropathies to prevent disability and even death., Competing Interests: Disclosure Dr S. Cox has nothing to disclose. Dr K.G. Gwathmey has received speaking and consulting honoraria from Alexion pharmaceuticals., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Critical illness-associated weakness (CIAW) is an umbrella term used to describe a group of neuromuscular disorders caused by severe illness. It can be subdivided into three major classifications based on the component of the neuromuscular system (i.e. peripheral nerves or skeletal muscle or both) that are affected. This includes critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and an overlap syndrome, critical illness polyneuromyopathy (CIPNM). It is a common complication observed in people with critical illness requiring intensive care unit (ICU) admission. Given CIAW is found in individuals experiencing grave illness, it can be challenging to study from a practical standpoint. However, over the past 2 decades, many insights into the pathophysiology of this condition have been made. Results from studies in both humans and animal models have found that a profound systemic inflammatory response and factors related to bioenergetic failure as well as microvascular, metabolic, and electrophysiological alterations underlie the development of CIAW. Current management strategies focus on early mobilization, achieving euglycemia, and nutritional optimization. Other interventions lack sufficient evidence, mainly due to a dearth of large trials. The goal of this Physiology in Medicine article is to highlight important aspects of the pathophysiology of these enigmatic conditions. It is hoped that improved understanding of the mechanisms underlying these disorders will lead to further study and new investigations for novel pharmacologic, nutritional, and exercise-based interventions to optimize patient outcomes.

Background: Human immunodeficiency virus (HIV)-associated distal symmetric peripheral neuropathy (DSPN) is one of the most frequent neurological complications of HIV infection, and causes pain and dysaesthesias in millions globally. Many individuals with this infection report using acupuncture to manage their symptoms, but evidence supporting the use of acupuncture is limited. This systematic review will assess the effectiveness and safety of acupuncture for patients with HIV-associated DSPN., Methods: Databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Scopus, Web of science, AMED (Allied and Complementary Medicine), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, Wanfang Database, VIP Database and clinical trials registers (the WHO International Clinical Trials Registry Platform portal and www.ClinicalTrials.gov) will be electronically searched from inception to December 1, 2020. All randomized controlled trials in English or Chinese without restriction on publication status will be included. Selection of studies, extraction of data, and assessment of studies quality will be independently performed by 2 reviewers. The primary outcome measure will be the change in pain intensity assessed by validated scales. Secondary outcomes include change in neurologic summary scores, quality of life, physical function evaluated by admitted tools, and adverse events related to acupuncture reported in the included trials. If possible, a meta-analysis will be conducted to provide an estimate of the pooled treatment effect using Review Manager 5.3 statistical software. Otherwise, qualitative descriptive analysis will be given. The results will be presented as the risk ratio for binary data and the mean difference (MD) or standardized MD for continuous data., Results: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference., Conclusion: This review will be the first review entirely focused on assessing the effectiveness and safety of acupuncture for HIV-associated DSPN., Prospero Registration Number: CRD42020210994., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The transthyretin (TTR) amyloidoses (ATTR) are progressive, degenerative diseases resulting from dissociation of the TTR tetramer to monomers, which subsequently misfold and aggregate, forming a spectrum of aggregate structures including oligomers and amyloid fibrils. To determine whether circulating nonnative TTR (NNTTR) levels correlate with the clinical status of patients with V30M TTR familial amyloid polyneuropathy (FAP), we quantified plasma NNTTR using a newly developed sandwich enzyme-linked immunosorbent assay. The assay detected significant plasma levels of NNTTR in most presymptomatic V30M TTR carriers and in all FAP patients. NNTTR was not detected in age-matched control plasmas or in subjects with other peripheral neuropathies, suggesting NNTTR can be useful in diagnosing FAP. NNTTR levels were substantially reduced in patients receiving approved FAP disease-modifying therapies (e.g., the TTR stabilizer tafamidis, 20 mg once daily). This NNTTR decrease was seen in both the responders (average reduction 56.4 ± 4.2%; n = 49) and nonresponders (average reduction of 63.3 ± 4.8%; n = 32) at 12 mo posttreatment. Notably, high pretreatment NNTTR levels were associated with a significantly lower likelihood of clinical response to tafamidis. Our data suggest that NNTTR is a disease driver whose reduction is sufficient to ameliorate FAP so long as pretreatment NNTTR levels are below a critical clinical threshold.

It has been hypothesized that low levels of C1 esterase inhibitor (C1-INH), a key inhibitor of the complement pathway, may play a role in the occurrence of adverse events (AEs) associated with intravenous immunoglobulin (IVIG) therapy. This open-label pilot study evaluated C1-INH replacement, with recombinant human C1-INH (rhC1-INH), as a potential therapy for adults requiring IVIG and experiencing AEs. Patients received two rounds of IVIG infusion [pre-treatment phase (no rhC1-INH), 4-8 weeks] and then three rounds of one dose of intravenous rhC1-INH 50 U/kg (maximum, 4,200 U) with subsequent IVIG infusion (treatment phase, 6-12 weeks). Nineteen adults completed the study; all had an autoimmune condition linked to common variable immunodeficiency (CVID) or polyneuropathy, and 57.9% had low baseline C1-INH levels. Mean ± SD total scores improved significantly with the Headache Impact Test (from 62.8 ± 6.2 at pre-treatment to 57.7 ± 9.1 after treatment; mean Δ, -5.0; p = 0.02) and Modified Fatigue Impact Scale (from 59.3 ± 13.1 to 51.2 ± 15.4; mean Δ, -8.1; p = 0.006). Significant improvements in the Migraine Disability Assessment were observed for three of five items ( p ≤ 0.002). Mean ± SD C1-INH level increased from 26.8 ± 5.9 mg/dl after the second round of IVIG (pre-treatment) to 32.1 ± 7.8 mg/dl after the third rhC1-INH treatment; functional C1-INH levels increased from 115.8 ± 34.7% to 158.3 ± 46.8%. Future research is warranted to explore the benefit of C1-INH therapy for reduction of IVIG-related AEs, as well as the role of C1-INH in patients with CVID and autoimmune disease., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03576469., Competing Interests: IRM reports serving as a speaker and an advisory board member for Pharming Group NV. JRH is an employee of Pharming Healthcare Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Pharming Healthcare Inc. The funder had the following involvement in the study: interpretation of data and medical accuracy review of the article content., (Copyright © 2021 Melamed, Miranda, Heffron and Harper.)

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.

Leukoencephalomyelopathy (LEM) is suggested to be an age-related degenerative condition in geriatric Eastern quolls ( Dasyurus viverrinus ), manifesting in animals greater than 3.5 yr of age. This case series describes four LEM cases from two zoologic collections; three in nongeriatric animals, with one only 1 yr of age, and details advanced diagnostic investigation, including magnetic resonance imaging, cerebrospinal fluid analysis, and electrodiagnostic studies, not previously reported in Eastern quolls. Animals presented clinically with forelimb proprioceptive deficits and hindlimb and lumbar muscle hypotrophy, which were not noted in previous reports, in addition to hindlimb ataxia. Blindness and emaciation, which have been reported previously, were not seen. Disease progression was variable, and time from first clinical signs to euthanasia ranged from 46 days to over 2 yr. Histopathologic findings in the central nervous system were typical of those in previous LEM cases; concomitant polyneuropathy was observed in two quolls. Our findings suggest that age-related degeneration may not be the only cause of LEM in Eastern quolls. Because all quolls were related, a familial component cannot be excluded. LEM should be further investigated for its potential impact on future captive breeding programs, and our findings suggest that daily quality-of-life assessment should guide euthanasia of affected animals.

A 37-year-old man who had been on bromvalerylurea (BU) medication for 11 years at a maximum dose of 2,400 mg per day for headache therapy was admitted to our hospital due to gait disturbance. He had weight loss and exanthema all over his body. Cognitive dysfunction, intellectual deterioration, attention disturbance, decreased muscle strength, and decreased vibratory sense in the lower limbs were observed. Brain MRI showed diffuse brain atrophy, and a peripheral nerve conduction examination revealed decreased nerve conduction velocity and action potential amplitude in the extremities. We diagnosed him with chronic BU intoxication based on pseudohyperchloremia, BU detected in the blood, and bromide elevation. By discontinuing BU and performing intravenous infusion, neurological symptoms and exanthema were improved, and peripheral nerve conduction examination findings also improved. There are few reports of peripheral neuropathy cases of chronic BU intoxication; herein we report one such case along with previously reported cases.

Burn-related neuropathy is common and often involves pain, paresthesia, or muscle weakness. Irisin, an exercise-induced myokine after cleavage from its membrane precursor fibronectin type III domain-containing 5 (FNDC5), exhibits neuroprotective and anti-inflammatory activities. A rat model of third-degree burn on the right hind paw was used to investigate the therapeutic role of irisin/FNDC5. Rats received burn injury and were treated with intrathecal recombinant adenovirus containing the irisin sequence (Ad-irisin) at 3 weeks postburn. One week later, mechanical allodynia was examined. The expression of irisin in cerebrospinal fluid (CSF) was detected. Ipsilateral gastrocnemius muscle and lumbar spinal cord were also obtained for further investigation. Furthermore, the anti-apoptotic effect of recombinant irisin in SH-SY5Y cells was evaluated through tumor necrosis factor alpha (TNFα) stimulus to mimic burn injury. We noted intrathecal Ad-irisin attenuated pain sensitization and gastrocnemius muscle atrophy by modulating the level of irisin in CSF, and the expression of neuronal FNDC5/irisin and TNFα in the spinal cord. Ad-irisin also ameliorated neuronal apoptosis in both dorsal and ventral horns. Furthermore, recombinant irisin attenuated TNFα-induced SH-SY5Y cell apoptosis. In summary, irisin attenuated allodynia and muscle wasting by ameliorating neuroinflammation-induced neuronal apoptosis.

We report a case of severe sensory-motor axonal neuropathy on the lower extremities associated with diabetic ketoacidosis (DKA). A sixteen-year-old boy developed coma and admitted to our hospital. We diagnosed him with DKA based on remarkable hyperglycemia, severe acidosis with hyperketonemia. Intensive glycemic control with insulin was immediately started. He had complications of heart failure, rhabdomyolysis, and renal failure, which required intensive care including mechanical ventilation and hemodialysis. When recovered from the critical condition, he noticed severe weakness, numbness, and pain on the lower limbs, and urinary retention. On nerve conduction studies, both motor and sensory action potentials were absent. Serum anti-ganglioside antibodies were negative. Albuminocytologic dissociation was evident in the cerebrospinal fluid. MRI study revealed marked gadolinium enhancement of the cauda equina. After high-dose intravenous immunoglobulin treatment, he was relieved from leg pain, but the leg weakness and bladder bowel dysfunction did not show immediate improvement. It took approximately six months until he became able to stand and walk using ankle orthosis. Acute neuropathy is a rare complication of diabetes mellitus. Painful neuropathy is known to emerge in association with diabetic treatment, but it seldom causes severe motor disturbance. On the other hand, motor-dominant polyneuropathy has been reported to occur acutely along the treatment of DKA and hyperosmolar hyperglycemia syndrome (HHS). Present case and previous cases with DKA and HHS suggest that rapid correction of glucose level is one of the underlying factors of acute neuropathy related with diabetic treatment.

Aims/introduction: Despite its major clinical impact, distal symmetric polyneuropathy remains frequently undiagnosed and undertreated in clinical practice. We previously reported in the PROTECT Study that 70% of type 2 diabetes patients with distal symmetric polyneuropathy were unaware of having the latter condition., Materials and Methods: In the present follow up after 2.5 ± 0.7 years, 122 and 85 participants with and without type 2 diabetes, respectively, completed questionnaires to obtain information about the further course of disease and its management., Results: At follow up, 49 and 48% of the respondents with type 2 diabetes and without diabetes, respectively, reported that the intensity of paresthesia or numbness in the feet increased, whereas for burning and pain in the feet the corresponding percentages were 56 and 61%. However, 33 and 40% of the respondents with type 2 diabetes and without diabetes, respectively, reporting neuropathic symptoms at follow up did not receive any pharmacotherapy. Pharmacotherapy of neuropathic symptoms at follow up among participants with type 2 diabetes and without diabetes included mainly World Health Organization Step 1 analgesics (17% each; excluding acetylsalicylic acid), pregabalin/gabapentin (20 and 12%), vitamin B complex (13 and 22%), benfotiamine (13 and 2%), opioids (7 and 12%), antidepressants (4 and 5%) and α-lipoic acid (4 and 2%)., Conclusions: These findings point to insufficient care, inadequate treatment adherence or limited efficacy of treatments in patients with polyneuropathy, suggesting that effective measures should be implemented to correct these healthcare deficits., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

The immune-mediated neuropathies are a broad category of diseases differentiated by time course, affected nerve fibers, and disease associations. This article spans the common, well-defined inflammatory demyelinating polyradiculoneuropathies (Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy) to the rarer, acquired demyelinating neuropathy variants (Miller-Fisher syndrome and multifocal motor neuropathy), vasculitic neuropathies, and sensory neuronopathies (dorsal root ganglionopathies). These case studies illustrate the characteristic clinical patterns of the immune-mediated neuropathies encountered in neurologic practice. Recommendations for diagnostic evaluation and treatment approach accompany each case. Prompt recognition of these disorders is imperative; delays in treatment may result in prolonged morbidity and permanent disability., Competing Interests: Disclosure Dr K.G. Gwathmey serves as a consultant to Alexion pharmaceuticals. Dr A.G. Smith serves as a consultant to Alexion, Argenx, Disarm, and Regenesis, and receives research funding from NINDS and NIDDK., (Copyright © 2020 Elsevier Inc. All rights reserved.)