Severity Of Neuropathic Symptoms Research Articles

Prevalence of polyneuropathies among systemic sclerosis patients and impact on health-related quality of life.

Systemic sclerosis (SSc) is a chronic rheumatic disease that affects multiple organ systems, including the peripheral nervous system. However, studies into the involvement of polyneuropathies (PNP) have shown inconsistent results. The aim of this study was to determine the prevalence of small (SFN) and large (LFN) fibre neuropathy among SSc patients and the impact on health-related quality of life (HRQoL). The study enrolled 67 patients with diagnosed SSc. The severity of neuropathic symptoms was evaluated using shortened and revised total neuropathy scoring criteria. Nerve conduction studies were used for LFN, and quantitative sensory testing was used to evaluate SFN. Neuropathic pain was evaluated using a Douleur Neuropathique en 4 questionnaire, and the severity of anxiety symptoms was assessed using a Generalised Anxiety Disorder-7 scale. The Health Assessment Questionnaire-Disability Index was used to assess HRQoL. Previous data on antinuclear autoantibodies (ANA) test results was obtained. Statistical analysis was performed using SPSS software. LFN was diagnosed in 47.8% (n = 32/67) and SFN in 40.3% (n = 27/67) of the subjects. ANA positivity was not associated with the presence of LFN/SFN. The severity of neuropathic pain had a significant correlation with anxiety symptoms (r = 0.61, p < 0.001), the severity of neuropathy symptoms (r = 0.51, p < 0.001) and HRQoL (r = 0.45, p < 0.001). The severity of neuropathy symptoms correlated with HRQoL (r = 0.39, p = 0.001). We demonstrated that PNP are found in almost all SSc patients. Also, SFN is as common as LFN. Additionally, we found that the severity of neuropathy symptoms and neuropathic pain are both associated with a worse HRQoL.

The complex association between pain and neuropathy.

Several studies of patients with polyneuropathy failed to show differences between patients with and without pain. In the current study, we aimed to explore the association between neuropathic symptoms, mainly pain, and polyneuropathy characteristics. A prospective cross-sectional study recruiting 151 patients with non-diabetic polyneuropathy was performed between November 2016 and May 2017. A total of 38 patients with chronic inflammatory demyelinating neuropathy were excluded. Patients underwent clinical, electrophysiological and functional assessments of their polyneuropathy. Polyneuropathy characteristics were compared depending on the presence and severity of neuropathic symptoms. The presence and the severity of weakness were associated with a more severe neuropathy as measured by clinical, electrophysiological and functional assessments, while the presence of pain was associated with higher sural amplitudes, and the severity of pain showed a curvilinear association with neuropathy severity. Our study shows a novel finding of a curvilinear association between pain and polyneuropathy severity.

Hereditary Transthyretin Amyloidosis: Clinical Presentation and Management Updates.

Hereditary transthyretin amyloidosis, once a rare progressive neuropathy and/or cardiomyopathy, is now recognized with increasing worldwide frequency, various phenotypes, and over 130 gene mutations identified to date. This inherited disorder develops as a result of mutated transthyretin amyloid aggregation and systematic deposition throughout the body. With increasing knowledge about the pathophysiology of this disease, new disease-modifying therapies are being developed. In addition to slowing progression, these new agents were found to improve quality of life and reduce the severity of neuropathic symptoms. Two new gene-modifying therapies recently received Food and Drug Administration approval following the positive results from phase III trials. These include an antisense oligonucleotide, inotersen, and small interfering RNA, patisiran, which were reported to reduce the production of transthyretin and had promising safety profiles. Additional novel therapies are being explored with hopes to prolong survival. Therefore, early diagnosis of this treatable disorder has become increasingly important in clinical practice.

Corneal confocal microscopy detects small nerve fibre damage in patients with painful diabetic neuropathy

Neuropathic pain is believed to arise from damage to nociceptive C fibres in diabetic neuropathy (DN). We have utilised corneal confocal microscopy (CCM) to quantify the severity of small nerve fibre damage in relation to the severity of neuropathic pain and quality of life (QoL) in patients with and without painful DN. 30 controls and patients with painful (n = 78) and painless (n = 62) DN underwent assessment of large and small nerve fibre function, CCM, neuropathic symptoms (small fibre neuropathy symptom inventory questionnaire, neuropathic pain scale) and QoL (SF-36, pre-R-ODS and hospital anxiety and depression scale). Patients with painful compared to painless DN, had comparable neurophysiology and vibration perception, but lower corneal nerve fibre density (20.1 ± 0.87 vs. 24.13 ± 0.91, P = 0.005), branch density (44.4 ± 3.31 vs. 57.74 ± 3.98, P = 0.03), length (19.61 ± 0.81 vs. 22.77 ± 0.83, P = 0.01), inferior whorl length (18.03 ± 1.46 vs. 25.1 ± 1.95, P = 0.005) and cold sensation threshold (21.35 ± 0.99 vs. 26.08 ± 0.5, P < 0.0001) and higher warm sensation threshold (43.7 ± 0.49 vs. 41.37 ± 0.51, P = 0.004) indicative of small fibre damage. There was a significant association between all CCM parameters and the severity of painful neuropathic symptoms, depression score and QoL. CCM identifies small nerve fibre loss, which correlates with the severity of neuropathic symptoms and reduced QoL in patients with painful diabetic neuropathy.

Clinical and biophysical characterization of 19 GJB1 mutations.

ObjectiveCharcot–Marie–Tooth disease type X1 (CMTX1), which is caused by mutations in the gap junction (GJ) protein beta‐1 gene (GJB1), is the second most common form of Charcot–Marie–Tooth disease (CMT). GJB1 encodes the GJ beta‐1 protein (GJB1), which forms GJs within the myelin sheaths of peripheral nerves. The process by which GJB1 mutants cause neuropathy has not been fully elucidated. This study evaluated the biophysical characteristics of GJB1 mutants and their correlations with the clinical features of CMTX1 patients.MethodsAll patients with a validated GJB1 mutation were assessed using the Charcot–Marie–Tooth disease neuropathy score version 2 (CMTNS). The impacts of the mutations on the biophysical functions of GJB1 were characterized by assessing intracellular localization, expression patterns, and GJ Ca2+ permeability.ResultNineteen GJB1 mutations were identified in 24 patients with a clinical diagnosis of CMT. Six are novel mutations: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P, and p.D278V. Diverse pathological effects of the mutations were demonstrated, including reduced GJB1 expression, intracellular mislocalization, and altered GJ functions. GJB1 mutations that caused a complete loss of GJ Ca2+ permeability appeared to be associated with an earlier disease onset, whereas those resulting in preservation of GJ permeability and with predominant cell membrane expression tended to have a later onset and a milder phenotype.InterpretationThis study demonstrated that the degree of loss of GJ function caused by the GJB1 mutations might contribute to the onset and severity of neuropathic symptoms in CMTX1.

Neuropathic Symptoms and Their Risk Factors in Medical Oncology Outpatients With Colorectal vs. Breast, Lung, or Prostate Cancer: Results From a Prospective Multicenter Study

ContextFew studies have examined the prevalence and severity of treatment-induced neuropathic symptoms in patients across different cancer types. ObjectivesThis study aimed to report the prevalence of numbness/tingling (N/T) and neuropathic pain in patients with colorectal cancer (CRC) vs. other cancers, describe the prevalence of moderate-to-severe N/T by specific clinical variables, and examine factors associated with the presence of these symptoms. MethodsA total of 3106 outpatients with colorectal (n = 718), breast (n = 1544), lung (n = 524), or prostate (n = 320) cancer were enrolled at any point in their treatment. Assessments were conducted at the initial visit and 28–35 days later. Patients reported pain and N/T; clinicians reported mechanism of pain and ranked the top three symptoms causing difficulties. ResultsModerate-to-severe N/T was higher in patients with CRC relative to other cancer types (25.8% vs. 17.1%, P < 0.001); 25% vs. 10.5% of clinicians rated N/T as a top three symptom for patients with CRC relative to other cancers (P < 0.001). The prevalence of neuropathic pain was comparable between patients with CRC and other cancers (P = 0.654). Patients with CRC, longer duration of cancer, prior therapy, on current therapy, older patients, and patients of black race experienced worse N/T. ConclusionPatients with CRC experience significantly higher rates of N/T but comparable neuropathic pain, relative to patients with other cancers. Awareness of the prevalence and severity of neuropathic symptoms and their associated risk factors in this patient population is critical for both clinicians and patients.

Abstract 5464: Distinct effects of eribulin on axonal microtubule composition and modifications relative to paclitaxel, vincristine and ixabepilone in preclinical models: correlations with lower levels of eribulin-induced peripheral neuropathy

Abstract Microtubule targeting agents (MTAs) are widely used anti-cancer drugs. They suppress microtubule dynamics, prevent complete spindle formation and induce cell cycle arrest and cell death in rapidly dividing tumor cells. Unfortunately, systemic administration of different MTAs can also lead to significant side effects including debilitating, dose-limiting peripheral neuropathy. Interestingly, different MTAs vary with respect to the frequency and severity of neuropathic symptoms. MTAs are hypothesized to induce neuropathy by disrupting the normal functions of microtubules, including maintenance of elongated axonal structures and mediating axonal transport of cellular components between the cell body and nerve endings. Consistent with this notion, different MTAs vary in their mechanisms of microtubule binding and regulation of microtubule dynamics. To begin testing the hypothesis that differing molecular mechanisms underlie the variable nature of peripheral neuropathy, we examined biochemical changes in microtubule composition, modification and the levels of selected microtubule associated proteins, all of which affect microtubule dynamics and microtubule action. We compared sciatic nerves from mice treated with a Q2Dx3 schedule for 2 weeks at the maximum tolerated doses of paclitaxel, ixabepilone, vincristine or eribulin. Sciatic nerves were fixed, sectioned and immunostained with antibodies directed against α-tubulin, acetylated-tubulin and tyrosinated tubulin as well as the microtubule (+) end binding proteins EB1 and EB3. Images, acquired by confocal microscopy, were analyzed with Imaris software to quantitate drug-induced changes. The most marked effects were observed with eribulin treatment. Sciatic nerves from eribulin treated mice exhibited ∼2.5 fold increase in α-tubulin signal, ∼12 fold increase in acetylated tubulin signal, ∼1.5 fold increase in tyrosinated tubulin signal and ∼2 fold increase in EB1 signal. No significant change was observed for EB3. In contrast, with the exception of a ∼5 fold increase in the acetylated tubulin signal in paclitaxel treated mice, no other statistically significant effects were observed with paclitaxel, ixabepilone or vincristine treatment. The data suggest that the mechanisms of eribulin action alter normal axonal cell biology, leading to increased abundance of tubulin and EB1. Increased levels of acetylated tubulin observed with paclitaxel and eribulin treatment suggests increased microtubule stabilization. Taken together, the data suggest that eribulin affects neuronal microtubules differently than paclitaxel, ixabepilone or vincristine, correlating with its relatively low level of induced peripheral neuropathy. We gratefully thank Eisai Inc. for support of this research. Citation Format: Sarah J. Benbow, Brett M. Cook, Krystyna M. Wozniak, Barbara S. Slusher, Bruce A. Littlefield, Leslie Wilson, Stuart C. Feinstein, Mary A. Jordan. Distinct effects of eribulin on axonal microtubule composition and modifications relative to paclitaxel, vincristine and ixabepilone in preclinical models: correlations with lower levels of eribulin-induced peripheral neuropathy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5464. doi:10.1158/1538-7445.AM2014-5464

Corneal confocal microscopy: A novel noninvasive means to diagnose neuropathy in patients with fabry disease

Neuropathy is a cause of significant disability in patients with Fabry disease, yet its diagnosis is difficult. In this study we compared the novel noninvasive techniques of corneal confocal microscopy (CCM) to quantify small-fiber pathology, and non-contact corneal aesthesiometry (NCCA) to quantify loss of corneal sensation, with established tests of neuropathy in patients with Fabry disease. Ten heterozygous females with Fabry disease not on enzyme replacement therapy (ERT), 6 heterozygous females, 6 hemizygous males on ERT, and 14 age-matched, healthy volunteers underwent detailed quantification of neuropathic symptoms, neurological deficits, neurophysiology, quantitative sensory testing (QST), NCCA, and CCM. All patients with Fabry disease had significant neuropathic symptoms and an elevated Mainz score. Peroneal nerve amplitude was reduced in all patients and vibration perception threshold was elevated in both male and female patients on ERT. Cold sensation (CS) threshold was significantly reduced in both male and female patients on ERT (P < 0.02), but warm sensation (WS) and heat-induced pain (HIP) were only significantly increased in males on ERT (P < 0.01). However, corneal sensation assessed with NCCA was significantly reduced in female (P < 0.02) and male (P < 0.04) patients on ERT compared with control subjects. According to CCM, corneal nerve fiber and branch density was significantly reduced in female (P < 0.03) and male (P < 0.02) patients on ERT compared with control subjects. Furthermore, the severity of neuropathic symptoms and the neurological component of the Mainz Severity Score Index correlated significantly with QST and CCM. This study shows that CCM and NCCA provide a novel means to detect early nerve fiber damage and dysfunction, respectively, in patients with Fabry disease.

Meaningful Degrees of Prevention or Improvement of Nerve Conduction in Controlled Clinical Trials of Diabetic Neuropathy

Use of nerve conduction in assessing therapy in preventing or ameliorating neuropathy is desirable because abnormalities of nerve conduction are associated with severity of neuropathic symptoms and deficits. Assuming that a therapy is associated with a statistically significant improvement of nerve conduction, what degree of nerve conduction change is clinically meaningful? We suggest that in controlled clinical trials, a mean change of 2 points on the neurologic disability score is clinically detectable and meaningful. Based on our previously published cross-sectional epidemiological data, this corresponds to a change of motor nerve conduction velocity of the average ulnar median and peroneal nerves of 2.9 m/s and peroneal nerve of 2.2 m/s. The corresponding changes of amplitude were 1.2 and 0.7 mV, respectively. Smaller degrees of nerve conduction change were found when only insulin-dependent patients were evaluated.