Hoda Gad, Sanjay Kalra, Rizaldy Pinzon, Rey-an Nino Gracia, Kitiyot Yotsombut, Ankia Coetzee, Jalal Nafach, Lee-Ling Lim, Pablo E. Fletcher, Vivien Lim, Rayaz A. Malik
Peripheral neuropathy (PN) often remains undiagnosed (~80%). Earlier diagnosis of PN may reduce morbidity and enable earlier risk factor reduction to limit disease progression. Diabetic peripheral neuropathy (DPN) is the most common PN and the 10 g monofilament is endorsed as an inexpensive and easily performed test for DPN. However, it only detects patients with advanced neuropathy at high risk of foot ulceration. There are many validated questionnaires to diagnose PN, but they can be time-consuming and have complex scoring systems. Primary care physicians (PCPs) have busy clinics and lack access to a readily available screening method to diagnose PN. They would prefer a short, simple, and accurate tool to screen for PN. Involving the patient in the screening process would not only reduce the time a physician requires to make a diagnosis but would also empower the patient. Following an expert meeting of diabetologists and neurologists from the Middle East, South East Asia and Latin America, a consensus was formulated to help improve the diagnosis of PN in primary care using a simple tool for patients to screen themselves for PN followed by a consultation with the physician to confirm the diagnosis.
{"title":"Earlier diagnosis of peripheral neuropathy in primary care: A call to action","authors":"Hoda Gad, Sanjay Kalra, Rizaldy Pinzon, Rey-an Nino Gracia, Kitiyot Yotsombut, Ankia Coetzee, Jalal Nafach, Lee-Ling Lim, Pablo E. Fletcher, Vivien Lim, Rayaz A. Malik","doi":"10.1111/jns.12613","DOIUrl":"10.1111/jns.12613","url":null,"abstract":"<p>Peripheral neuropathy (PN) often remains undiagnosed (~80%). Earlier diagnosis of PN may reduce morbidity and enable earlier risk factor reduction to limit disease progression. Diabetic peripheral neuropathy (DPN) is the most common PN and the 10 g monofilament is endorsed as an inexpensive and easily performed test for DPN. However, it only detects patients with advanced neuropathy at high risk of foot ulceration. There are many validated questionnaires to diagnose PN, but they can be time-consuming and have complex scoring systems. Primary care physicians (PCPs) have busy clinics and lack access to a readily available screening method to diagnose PN. They would prefer a short, simple, and accurate tool to screen for PN. Involving the patient in the screening process would not only reduce the time a physician requires to make a diagnosis but would also empower the patient. Following an expert meeting of diabetologists and neurologists from the Middle East, South East Asia and Latin America, a consensus was formulated to help improve the diagnosis of PN in primary care using a simple tool for patients to screen themselves for PN followed by a consultation with the physician to confirm the diagnosis.</p>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"28-37"},"PeriodicalIF":3.8,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12613","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Helena F. Pernice, Luke F. O'Donnell, Alexander M. Rossor, Matilde Laura, Christopher J. Record, Mariola Skorupinska, Julian Blake, Roy Poh, James Polke, Mary M. Reilly
Aim
X-linked variants in Filamin A (FLNA) are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (UCHL1) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype.
Methods
A 67-year-old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss.
Results
Neurophysiology including Somatosensory-evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene.
Conclusions
To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants.
{"title":"Digenic FLNA and UCHL1 variants resulting in a complex phenotype","authors":"Helena F. Pernice, Luke F. O'Donnell, Alexander M. Rossor, Matilde Laura, Christopher J. Record, Mariola Skorupinska, Julian Blake, Roy Poh, James Polke, Mary M. Reilly","doi":"10.1111/jns.12611","DOIUrl":"10.1111/jns.12611","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>X-linked variants in Filamin A (<i>FLNA)</i> are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (<i>UCHL1</i>) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of <i>UCHL1</i> and a heterozygous frameshift variant in the <i>FLNA</i> gene resulting in a complex phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A 67-year-old female with a confirmed pathogenic variant in the <i>FLNA</i> gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Neurophysiology including Somatosensory-evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the <i>FLNA</i> gene and a heterozygous loss of function deletion in the <i>UCHL1</i> gene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>To the best of our knowledge, this is the first case with concomitant pathogenic variants in the <i>FLNA</i> and <i>UCHL1</i> genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of <i>UCHL1</i> variants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"111-115"},"PeriodicalIF":3.8,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138830211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Roberta Bonomo, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Paola Alberti, Cecile F. Frampas, Daan R. Van der Veen, Paola Marmiroli, Debra J. Skene, Guido Cavaletti
Background and Aims
Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.
Methods
Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis.
Results
At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (p < .001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (p < .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration.
Interpretation
Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile.
{"title":"Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity","authors":"Roberta Bonomo, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Paola Alberti, Cecile F. Frampas, Daan R. Van der Veen, Paola Marmiroli, Debra J. Skene, Guido Cavaletti","doi":"10.1111/jns.12609","DOIUrl":"10.1111/jns.12609","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (<i>p</i> < .05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (<i>p</i> < .05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (<i>p</i> < .001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (<i>p</i> < .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"58-71"},"PeriodicalIF":3.8,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138826110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vadim Afanasiev, Pinelopi Tsouni, Thierry Kuntzer, Anne Cairoli, Emilien Delmont, Jean-Michel Vallat, Jérôme Devaux, Marie Théaudin
Aim
Autoimmune nodopathies have specific clinicopathologic features, antibodies directed against nodal proteins (neurofascin 186) or paranodal proteins (neurofascin 155, contactin 1, contactin-associated protein 1 (Caspr1)), and usually have a poor response to first-line therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Anti-Caspr1 nodopathy treated with autologous hematopoietic stem cell transplantation (AHSCT) has not been previously reported.
Methods
We report the first case of an anti-Caspr1 antibody-positive nodopathy refractory to high-intensity immunosuppressive treatment, including rituximab, that responded dramatically to AHSCT.
Results
A 53-year-old woman presented with a rapidly progressive generalized ataxic, painful motor, and inflammatory neuropathy supported by neurophysiologic and MRI studies. Initial tests for antibodies to nodal/paranodal proteins were negative. She was treated with multiple courses of intravenous immunoglobulin and methylprednisolone, plasma exchange, rituximab, and cyclophosphamide without significant clinical benefit. Repeated testing for antibodies to nodal/paranodal proteins yielded a positive result for anti-Caspr1/IgG4 isotype antibodies. Given the poor response to multiple high intensity treatments and the relatively young age of the patient, we decided to perform AHSCT at 30 months post-onset. Immediately after AHSCT, she stopped all immunomodulatory or immunosuppressive therapy. The Overall Neuropathy Limitation Score improved from 8/12 to 4/12 at 6 months post-AHSCT. At 3 months post-AHSCT, IgG4 against Caspr1 was negative and no reactivity against paranodes could be detected.
Conclusion
We report a particularly severe anti-Caspr1 antibody autoimmune nodopathy that responded dramatically to AHSCT. Although the rarity of the disease limits the possibility of larger studies, AHSCT may be a valuable therapy in treatment-refractory cases.
{"title":"Successful autologous hematopoietic stem cell transplantation in a refractory anti-Caspr1 antibody nodopathy","authors":"Vadim Afanasiev, Pinelopi Tsouni, Thierry Kuntzer, Anne Cairoli, Emilien Delmont, Jean-Michel Vallat, Jérôme Devaux, Marie Théaudin","doi":"10.1111/jns.12610","DOIUrl":"10.1111/jns.12610","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Autoimmune nodopathies have specific clinicopathologic features, antibodies directed against nodal proteins (neurofascin 186) or paranodal proteins (neurofascin 155, contactin 1, contactin-associated protein 1 (Caspr1)), and usually have a poor response to first-line therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Anti-Caspr1 nodopathy treated with autologous hematopoietic stem cell transplantation (AHSCT) has not been previously reported.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We report the first case of an anti-Caspr1 antibody-positive nodopathy refractory to high-intensity immunosuppressive treatment, including rituximab, that responded dramatically to AHSCT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A 53-year-old woman presented with a rapidly progressive generalized ataxic, painful motor, and inflammatory neuropathy supported by neurophysiologic and MRI studies. Initial tests for antibodies to nodal/paranodal proteins were negative. She was treated with multiple courses of intravenous immunoglobulin and methylprednisolone, plasma exchange, rituximab, and cyclophosphamide without significant clinical benefit. Repeated testing for antibodies to nodal/paranodal proteins yielded a positive result for anti-Caspr1/IgG4 isotype antibodies. Given the poor response to multiple high intensity treatments and the relatively young age of the patient, we decided to perform AHSCT at 30 months post-onset. Immediately after AHSCT, she stopped all immunomodulatory or immunosuppressive therapy. The Overall Neuropathy Limitation Score improved from 8/12 to 4/12 at 6 months post-AHSCT. At 3 months post-AHSCT, IgG4 against Caspr1 was negative and no reactivity against paranodes could be detected.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We report a particularly severe anti-Caspr1 antibody autoimmune nodopathy that responded dramatically to AHSCT. Although the rarity of the disease limits the possibility of larger studies, AHSCT may be a valuable therapy in treatment-refractory cases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"116-119"},"PeriodicalIF":3.8,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138826998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Louise Sloth Kodal, Anne Møller Witt, Britt Stævnsbo Pedersen, Morten Müller Aagaard, Tina Dysgaard
Neurofilament light protein (NfL) is a part of the neuronal skeleton, primarily expressed in axons, and is released when nerves are damaged. NfL has been found to be a potential diagnostic biomarker in different types of polyneuropathies. However, whether NfL levels can be used as a predictor for the risk of disease progression is currently less understood. We searched MEDLINE (PubMed), Embase, Cochrane Library, and Web of Science Searches and included longitudinal studies with a baseline and follow-up examination of adult patients with polyneuropathy and NfL measured in blood. Twenty studies investigating NfL as a predictor of disease progression were identified, examining eight polyneuropathy subtypes. The results from studies in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) patients were divergent, with two out of five studies finding a significant association between NfL levels and clinical outcomes. Meta-analysis of the three Guillian-Barré Syndrome (GBS) studies found higher odds for the inability to run after 1 year in patients with high levels of NfL (odds ratio 2.18, 95% confidence interval 1.04–4.56). Results from studies examining other subacute or chronic polyneuropathies like Charcot–Marie–Tooth (CMT) varied in study design and results. Our findings suggest NfL can be used as a predictor of disease progression, particularly in polyneuropathies such as CIDP and GBS. However, NfL may not serve as a reliable and cost-effective biomarker for slowly progressive polyneuropathies like CMT. Future standardized studies considering NfL as a prognostic blood biomarker in patients with different types of polyneuropathies are warranted.
{"title":"Prognostic value of neurofilament light in blood in patients with polyneuropathy: A systematic review","authors":"Louise Sloth Kodal, Anne Møller Witt, Britt Stævnsbo Pedersen, Morten Müller Aagaard, Tina Dysgaard","doi":"10.1111/jns.12608","DOIUrl":"10.1111/jns.12608","url":null,"abstract":"<p>Neurofilament light protein (NfL) is a part of the neuronal skeleton, primarily expressed in axons, and is released when nerves are damaged. NfL has been found to be a potential diagnostic biomarker in different types of polyneuropathies. However, whether NfL levels can be used as a predictor for the risk of disease progression is currently less understood. We searched MEDLINE (PubMed), Embase, Cochrane Library, and Web of Science Searches and included longitudinal studies with a baseline and follow-up examination of adult patients with polyneuropathy and NfL measured in blood. Twenty studies investigating NfL as a predictor of disease progression were identified, examining eight polyneuropathy subtypes. The results from studies in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) patients were divergent, with two out of five studies finding a significant association between NfL levels and clinical outcomes. Meta-analysis of the three Guillian-Barré Syndrome (GBS) studies found higher odds for the inability to run after 1 year in patients with high levels of NfL (odds ratio 2.18, 95% confidence interval 1.04–4.56). Results from studies examining other subacute or chronic polyneuropathies like Charcot–Marie–Tooth (CMT) varied in study design and results. Our findings suggest NfL can be used as a predictor of disease progression, particularly in polyneuropathies such as CIDP and GBS. However, NfL may not serve as a reliable and cost-effective biomarker for slowly progressive polyneuropathies like CMT. Future standardized studies considering NfL as a prognostic blood biomarker in patients with different types of polyneuropathies are warranted.</p>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"17-27"},"PeriodicalIF":3.8,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138563778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage.
Methods
We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density.
Results
NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement.
Interpretation
NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.
{"title":"Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing","authors":"Alessia Chiorazzi, Annalisa Canta, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez-Menendez, Paola Marmiroli, Guido Cavaletti, Paola Alberti","doi":"10.1111/jns.12607","DOIUrl":"10.1111/jns.12607","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test <i>in vivo</i> axonal properties and can be used to monitor early changes leading to axonal damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"47-57"},"PeriodicalIF":3.8,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12607","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138445147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Perry T. C. van Doormaal, Simone Thomas, Senda Ajroud-Driss, Robert N. Cole, Lauren R. DeVine, Mazen M. Dimachkie, Stefanie Geisler, Roy Freeman, David M. Simpson, J. Robinson Singleton, A. Gordon Smith, Amro Stino, PNRR Study Group, Ahmet Höke
Background and Aims
Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain.
Methods
We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping.
Results
In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified.
Interpretation
This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.
{"title":"Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients","authors":"Perry T. C. van Doormaal, Simone Thomas, Senda Ajroud-Driss, Robert N. Cole, Lauren R. DeVine, Mazen M. Dimachkie, Stefanie Geisler, Roy Freeman, David M. Simpson, J. Robinson Singleton, A. Gordon Smith, Amro Stino, PNRR Study Group, Ahmet Höke","doi":"10.1111/jns.12606","DOIUrl":"10.1111/jns.12606","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the univariate analysis, 73 proteins showed a <i>p</i>-value <.05 and 12 proteins showed a <i>p</i>-value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted <i>p</i>-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"88-96"},"PeriodicalIF":3.8,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12606","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138291270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a “double-edged sword” as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain–Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.
{"title":"Synergistic effects of immune checkpoints and checkpoint inhibitors in inflammatory neuropathies: Implications and mechanisms","authors":"Aritrani Sarkar, Madhu Nagappa, Saikat Dey, Sandipan Mondal, Gopika Suresh Babu, Saptamita Pal Choudhury, Pokala Akhil, Monojit Debnath","doi":"10.1111/jns.12605","DOIUrl":"10.1111/jns.12605","url":null,"abstract":"<p>Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a “double-edged sword” as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain–Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.</p>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"6-16"},"PeriodicalIF":3.8,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138291271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessandro Geroldi, Stefano Tozza, Chiara Fiorillo, Maria Nolano, Paola Fossa, Floriana Vitale, Regi Domi, Andrea Gaudio, Alessia Mammi, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Federico Zara, Matteo Cataldi, Vincenzo Salpietro, Consuelo Barbara Venturi, Sara Massucco, Angelo Schenone, Fiore Manganelli, Paola Mandich, Emilia Bellone, Fabio Gotta
Background and Aims
POLR3B gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in POLR3B are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in POLR3B with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.
Methods
Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.
Results
Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in POLR3B, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.
Interpretation
Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in POLR3B-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.
{"title":"A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers","authors":"Alessandro Geroldi, Stefano Tozza, Chiara Fiorillo, Maria Nolano, Paola Fossa, Floriana Vitale, Regi Domi, Andrea Gaudio, Alessia Mammi, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Federico Zara, Matteo Cataldi, Vincenzo Salpietro, Consuelo Barbara Venturi, Sara Massucco, Angelo Schenone, Fiore Manganelli, Paola Mandich, Emilia Bellone, Fabio Gotta","doi":"10.1111/jns.12602","DOIUrl":"10.1111/jns.12602","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p><i>POLR3B</i> gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in <i>POLR3B</i> are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in <i>POLR3B</i> with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in <i>POLR3B</i>, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in <i>POLR3B</i>-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"620-628"},"PeriodicalIF":3.8,"publicationDate":"2023-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12602","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66783962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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