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Liu S, Ding H, Li D, Lu F, Luo G, He Y, Li H, Zeng X, Li K, Gong DE, Hu X, Chen Y, Yang X. Foot screening and customized health education program for patients with diabetic peripheral neuropathy: A nurse-led, real-world observational study. INTERNATIONAL JOURNAL OF NURSING STUDIES ADVANCES 2025; 8:100291. [PMID: 39896918 PMCID: PMC11787437 DOI: 10.1016/j.ijnsa.2025.100291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 02/04/2025] Open
Abstract
Background Research has shown that DPN affects 50 % of individuals with diabetes and, in severe cases, can lead to amputation or death. Interventions led by doctors for DPN have demonstrated limited effectiveness in delaying its onset and progression. Nevertheless, there is an increasing recognition of the significance of nurse-led screening and health education in the early detection and slowing down of DPN. Method The present study conducted a retrospective analysis of medical records of 10,191 diabetic patients from 2019 to 2023, who also regularly attended outpatient clinics. Patients with incomplete medical data, transfers, critical conditions or death, existing foot ulcers or amputations, bedridden or uncooperative individuals (5,470 individuals) were excluded, and a total of 4,721 individuals were selected for analysis. The screening and intervention components of the FSCHE program were all led by nurses. A total of 2022 participants received foot screening and customized health education (FSCHE) program, while 2699 participants recevied regular care. The primary outcome is on determining the prevalence rate of DPN among all the included diabetic patients. The data was collected through experimental tests and nurse-led foot screening. Prevalence rates were reported as the number of cases per 1000 individuals. Odds Ratios were calculated to approximate Risk Ratios to determine the effectiveness of the FSCHE program. Results The prevalence of DPN in diabetic patients who received the FSCHE program decreased from 557 cases per 1000 individuals in 2019 to 199 cases per 1000 individuals in 2023. The hospitalization duration decreased from 11.2 days to 7.59 days. The risk of DPN in diabetic patients participating in the FSCHE program was 0.741 times higher than that of regular diabetes care (RR [95 % CI]: 0.741 [0.654, 0.840], p < 0.001). The DPN-related risk factors showed promising control results as well. Conclusions In this observational study conducted among Chinese patients with diabetes, it was found that the nurse-led FSCHE program effectively manages DPN and its associated risk factors. These results highlight the importance of employing objective screening tools to detect DPN at an early stage, as well as the significance of nurse-led interventions in promoting healthy behaviors and preventing the development and progression of DPN.
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Affiliation(s)
| | | | | | - Fen Lu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Gumei Luo
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Yujin He
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Hui Li
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Xiuhong Zeng
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Kaixin Li
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Dong-E Gong
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Xiling Hu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Yanming Chen
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Xubin Yang
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
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Bashir B, Pasha R, Kamath A, Malik RA, Ferdousi M, Soran H. Small nerve fibre damage and cardiac autonomic dysfunction in patients with hypertriglyceridaemia. Atherosclerosis 2025; 405:119186. [PMID: 40367727 DOI: 10.1016/j.atherosclerosis.2025.119186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND & OBJECTIVES Hypertriglyceridaemia (HTG) is an independent risk factor for small fibre neuropathy in patients with type 1, type 2 diabetes, and obesity. This study assessed for evidence of small nerve fibre damage and cardiac autonomic dysfunction in individuals with HTG, without diabetes. METHODS Participants with HTG (n=60) and age and sex-matched controls (n=31) underwent assessment of the lipid profile, neuropathic symptoms and disability, corneal confocal microscopy (CCM) and cardiac autonomic nerve function tests. RESULTS Triglyceride (TG) concentration was significantly higher [6.0 (3.6-8.7) vs 1.1 (0.7-1.4) mmol/L, p < 0.001], and HDL-C [0.9 (0.7-1.2) vs 1.5 (1.3-1.8) mmol/L, p < 0.001) was lower in the HTG group. The Neuropathy Symptom Profile score [2 (0-5) vs 0, p < 0.001], Neuropathy Disability Score [2 (0-3) vs 0, p < 0.001] and vibration perception threshold [8.9 (5.5-10.5) vs 3.0 (2.0-4.0) volts, p < 0.001] were higher, whilst corneal nerve fibre density (CNFD) [28.9 (5.9) vs 35.1 (7.2) no./mm2, p < 0.001], corneal nerve branch density (CNBD) [50.0 (30.4-66.5) vs 76.1 (56.2-112.5) no./mm2, p < 0.001], corneal nerve fibre length (CNFL) [19.8 (4.8) vs 26.0 (6.2) mm/mm2, p < 0.001], deep breathing heart rate variability (DB-HRV) [18 (13-20) vs 25 (20-30) beats/min, p < 0.001], E-I ratio [1.13 (1.09-1.20) vs 1.25 (1.18-1.31), p < 0.001], valsalva ratio [1.29 (1.18-1.49) vs. 1.47 (1.28-1.59), p = 0.01] and 30-15 ratio [1.24 (1.16-1.36) vs. 1.40 (1.27-1.49), p = 0.002] were lower in the HTG group compared to controls. Serum TG concentration correlated negatively with CCM parameters and cardiac autonomic function tests. CONCLUSION HTG, independent of diabetes, is associated with signs and symptoms of neuropathy, small nerve fibre damage and cardiac autonomic dysfunction.
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Affiliation(s)
- Bilal Bashir
- Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom; Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, United Kingdom; NIHR/WELLCOME Trust Clinical Research Facility, Manchester, United Kingdom
| | - Raabya Pasha
- Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Anoushka Kamath
- Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Rayaz A Malik
- Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom; Weill Cornell Medicine-Qatar Foundation, Education City, Doha, Qatar
| | - Maryam Ferdousi
- Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom; Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, United Kingdom; NIHR/WELLCOME Trust Clinical Research Facility, Manchester, United Kingdom.
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Li W, Yang T, Wang N, Li B, Meng C, Yu K, Zhou X, Cao R, Cui S. Maladaptive Peripheral Ketogenesis in Schwann Cells Mediated by CB 1R Contributes to Diabetic Neuropathy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2414547. [PMID: 39887953 PMCID: PMC11967812 DOI: 10.1002/advs.202414547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/08/2025] [Indexed: 02/01/2025]
Abstract
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Although studies have previously investigated metabolic disruptions in the peripheral nervous system (PNS), the exact metabolic mechanisms underlying DPN remain largely unknown. Herein, a specific form of metabolic remodeling involving aberrant ketogenesis within Schwann cells (SCs) in streptozotocin (STZ)-induced type I diabetes mellitus is identified. The PNS adapts poorly to such aberrant ketogenesis, resulting in disrupted energy metabolism, mitochondrial damage, and homeostatic decompensation, ultimately contributing to DPN. Additionally, the maladaptive peripheral ketogenesis is highly dependent on the cannabinoid type-1 receptor (CB1R)-Hmgcs2 axis. Silencing CB1R reprogrammed the metabolism of SCs by blocking maladaptive ketogenesis, resulting in rebalanced energy metabolism, reduced histopathological changes, and improved neuropathic symptoms. Moreover, this metabolic reprogramming can be induced pharmacologically using JD5037, a peripheral CB1R blocker. These findings revealed a new metabolic mechanism underlying DPN, and promoted CB1R as a promising therapeutic target for DPN.
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Affiliation(s)
- Weizhen Li
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Tuo Yang
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Ningning Wang
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Baolong Li
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Chuikai Meng
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Kaiming Yu
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Xiongyao Zhou
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Rangjuan Cao
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
| | - Shusen Cui
- Department of Hand and Foot SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchun130033China
- Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin ProvinceChangchun130033China
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Waller SE, Stockwell JB, Fung VSC, Anstey KJ, Colebatch JG, Markoulli M, Krishnan AV. Topical review: Ocular surface abnormalities in neurodegenerative disorders. Optom Vis Sci 2025; 102:68-77. [PMID: 39792646 DOI: 10.1097/opx.0000000000002215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
SIGNIFICANCE In an aging population, the number of people living with neurodegenerative disease is projected to increase. It is vital to develop reliable, noninvasive biomarkers to detect disease onset and monitor progression, and there is a growing body of research into the ocular surface as a potential source of such biomarkers. BACKGROUND This article reviews the potential of in vivo corneal confocal microscopy and tear fluid analysis as tools for biomarker development. Corneal confocal microscopy, traditionally used for studying corneal health, offers high-resolution imaging of corneal nerves and has shown promise for examining systemic diseases such as Alzheimer disease and Parkinson's disease. Complementarily, tear fluid analysis, known for its ease of collection, reflects systemic changes in neurodegenerative conditions. CONCLUSION Together, these noninvasive techniques provide insights into disease onset and progression and hold potential for advancing diagnostic and treatment strategies.
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Affiliation(s)
| | | | - Victor S C Fung
- Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, New South Wales, Australia
| | | | - James G Colebatch
- Department of Neurology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Maria Markoulli
- School of Optometry and Vision Science, UNSW Sydney, Sydney, New South Wales, Australia
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Alkotami AS, Elkholy SH, Elshamy AM, Elseidy EA, Fadel WA. Diabetic small fiber neuropathy: clinical and electrophysiological study. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2024; 60:148. [DOI: 10.1186/s41983-024-00923-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 12/04/2024] [Indexed: 01/04/2025] Open
Abstract
Abstract
Background
Diabetic neuropathy is diagnosed late due to lack of easy and readily available biomarkers; early identification can prompt proper interventions before the irreversible large fiber damage. The aim of this study is to assess small fiber dysfunction using cutaneous silent period (CSP) and sympathetic skin response (SSR) tests in patients with diabetic small fiber neuropathy (SFN) and compare results with clinical, neuropathy severity and quality of life measures. A total of 45 subjects were classified into: Group I: diabetic patients with pure SFN, group II: diabetic patients with mixed fiber neuropathy, and group III: healthy subjects. All underwent evaluation by anthropometric, clinical and quality of life measures, electrophysiological evaluation by CSP and SSR and distal leg skin biopsy.
Results
Age and gender distribution did not significantly differ between the studied groups. Both patients’ groups showed comparable poor quality of life in relation to healthy subjects. CSP onset latencies and SSR amplitudes significantly correlated with studied clinical and severity measures, but neither correlate with each other in diabetic pure SFN patients. Both CSP and SSR measures were specific in diagnosing diabetic pure SFN, but mostly with poor sensitivity. Combining sensitivities of different CSP and SSR measures improved the overall sensitivity to early screen for SFN in diabetic patients.
Conclusions
Both CSP and SSR may have the potential to early detect diabetic pure SFN. Suspected diabetic patients with SFN should be separately screened for both somatosensory and sudomotor/autonomic affection.
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Efron N. 2024 Charles F. Prentice Medal award lecture: Moments of inspiration. Optom Vis Sci 2024; 101:690-713. [PMID: 39729537 DOI: 10.1097/opx.0000000000002202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2024] Open
Abstract
In this Prentice Medal Award lecture, I shall recount my career in vision science in the context of three types of inspiration-"being inspired," "personal inspiration," and "inspiring others." My research has derived inspiration from a variety of sources, such as contemporary and historical research doyens in the ophthalmic field and beyond, artists, Greek philosophers, and abstract constructs such as principles and adages. A given moment of inspiration can range from being a profound experience to a subtle realization during a quiet moment of reflection. Here I shall recount the primary research domains of vision science that have defined my academic career in the context of the three types of inspiration defined above. These research domains are ophthalmic markers of diabetic neuropathy, ocular response to contact lens wear, contact lens-induced parainflammation, contact lens-associated microbial keratitis, grading scales for contact lens complications, contact lens prescribing surveys, material properties of contact lenses, contact lens compliance, history of contact lenses, ocular thermography, and ophthalmic bibliometrics. The notions of "being inspired" and "personal inspiration" are necessarily subjective, although I have endeavored to present them here in a scientific context. Conversely, the notion of "inspiring others" can be objectively gauged, at least in part, by counting article citations or the number of times articles are read online or downloaded from a journal website. In conclusion, my research in the vision sciences has been inspired by others, derived from personal ideas, and perhaps in turn has inspired others.
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Shen W, Hu T, Wang X, Zhang X, Lu J, Lu H, Hu Y, Liu F. Hydrogen sulfide alleviates neural degeneration probably by reducing oxidative stress and aldose reductase expression. J Cell Mol Med 2024; 28:e70192. [PMID: 39517099 PMCID: PMC11549026 DOI: 10.1111/jcmm.70192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 10/07/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
We investigated the potential role of hydrogen sulfide (H2S) as a novel therapy for diabetic peripheral neuropathy in diabetic rats. A single dose of streptozotocin (60 mg/kg) was applied to the rats for the diabetic rat models. Sodium bisulfide (50 μmol/kg/d) was injected intraperitoneally daily for 2 weeks as H2S treatment. Electromyogram, haematoxylin eosin staining, transmission electron microscopy, western blotting and enzyme-linked immunosorbent assay were then performed. H2S treatment did not affect body weights, blood glucose levels or liver function of diabetic rats, while the creatine levels of the H2S-treated diabetic rats decreased compared with the diabetic control rats. H2S treatment for 2 weeks did not affect the sciatic nerve conduction velocity of the diabetic rats. However, H2S treatment relieved neurons loss and cell atrophy of dorsal root ganglion, and axon degeneration of sciatic nerve in diabetic rats. Serum super oxide dismutase (SOD) levels and SOD2 levels in the sciatic nerve of diabetic rats were lower than the non-diabetic rats but were restored after H2S treatment. Serum and sciatic nerve homogenate malondialdehyde and aldose reductase expression were higher in diabetic rats but decreased significantly after H2S treatment. Our study revealed that H2S alleviates neural degeneration in diabetic rats probably by reducing oxidative stress and downregulating aldose reductase expression.
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Affiliation(s)
- Wenqi Shen
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s HospitalShanghai Jiaotong UniversityShanghaiChina
| | - Tingyu Hu
- Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Xin Wang
- Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Xiaoyan Zhang
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s HospitalShanghai Jiaotong UniversityShanghaiChina
| | - Junxi Lu
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s HospitalShanghai Jiaotong UniversityShanghaiChina
| | - Huijuan Lu
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s HospitalShanghai Jiaotong UniversityShanghaiChina
| | - Yanyun Hu
- Department of Endocrinology and Metabolism, Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghaiChina
| | - Fang Liu
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s HospitalShanghai Jiaotong UniversityShanghaiChina
- Department of Endocrinology and Metabolism, Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghaiChina
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Niu X, Yin P, Shao Q, Chen L, Cui G, Xu C, Zan K. Corneal nerve fibre loss as a marker to identify the impact of diabetes on Parkinson's disease. Psychogeriatrics 2024; 24:1267-1274. [PMID: 39210676 DOI: 10.1111/psyg.13187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/13/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Patients with Parkinson's disease (PD) suffer from serious quality of life problems. Diabetes has been demonstrated as an independent risk element for PD, aggravating its severity and accelerating its progression. There are currently no suitable biomarkers to reveal the impact of diabetes on PD. The purpose of our research was to study the impact of diabetes on PD using corneal confocal microscopy (CCM), a non-invasive and objective test. METHODS Fourteen PD patients with diabetes (PD-DM), 60 PD patients without diabetes (PD-NDM), and 30 healthy controls (HC) were included in the study. The clinical symptoms of patients with PD were assessed using the Unified Parkinson's Disease Rating Scale-3 (UPDRS-3) and the Parkinson's Disease Autonomic Symptom Prognosis Scale (SCOPA-AUT). Participants underwent CCM to quantify the corneal nerve fibres. RESULTS Corneal nerve fibre density (CNFD) and corneal nerve fibre length (CNFL) in patients with PD were lower than HC. Furthermore, CNFD in PD-DM was lower than in PD-NDM (P < 0.01). We also assessed the relationship between CCM parameters and clinical scores. CNFL and Hamilton anxiety (HAMA) have a negative correlation (r = -0.261, P = 0.032), but this study did not observe a significant correlation between CCM parameters and SCOPA-AUT. Additionally, CNFD could distinguish PD-DM from PD-NDM, achieving an area under the curve of 75.06% (95% CI, 61.76%-88.36%). CONCLUSIONS The CCM could be served as an objective and sensitive biomarker to investigate the impact of diabetes in PD.
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Affiliation(s)
- Xuebin Niu
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Peixiao Yin
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Qiuyue Shao
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Lu Chen
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The First Clinical College, Xuzhou Medical University, Xuzhou, China
- Department of Ophthalmology, Xuzhou Medical University, Xuzhou, China
| | - Guiyun Cui
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Chuanying Xu
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Kun Zan
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The First Clinical College, Xuzhou Medical University, Xuzhou, China
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Chen Y, Xu Z, Liang A, Chen R, Wang Z, Chen X, Zheng K, Lu P, Liang H, Cao D, Zhang L. Comprehensive assessment of ocular parameters for identifying diagnostic indicators of diabetic peripheral neuropathy. Acta Diabetol 2024; 61:1283-1291. [PMID: 38780614 DOI: 10.1007/s00592-024-02299-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/04/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE To explore variations in systemic and ocular parameters among patients with diabetes, both with and without diabetic peripheral neuropathy (DPN) and to identify sensitive indicators for DPN diagnosis. METHODS Ninty-five patients with type 2 diabetes mellitus (T2DM) were involved in this cross-sectional study, including 49 without DPN and 46 with DPN. Ocular parameters were obtained using optical coherence tomography angiography (OCTA) and corneal confocal microscopy (CCM). RESULT Patients with DPN presented with significantly higher HbA1c (p < 0.05) and glycated albumin (GA, p < 0.01) levels, increased prevalence of diabetic retinopathy (DR, p < 0.05), and lower serum albumin (ALB, p < 0.01) and red blood cell (RBC, p < 0.05) levels. Ocular assessments revealed reduced corneal nerve fiber length (CNFL, p < 0.001) and enlarged foveal avascular zone (FAZ) area (p < 0.05) in DPN group. Logistic regression analysis indicated a significant association of presence of DR, RBC, GA, ALB, CNFL and DPN (p < 0.05, respectively). In the binary logistic regression for DPN risk, all three models including the presence of DR and CNFL exhibited the area under the curve (AUC) exceeding 0.8. CONCLUSION The study establishes a strong correlation between ocular parameters and DPN, highlighting CCM's role in early diagnosis. Combining systemic and ocular indicators improves DPN risk assessment and early management.
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Affiliation(s)
- Yesheng Chen
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, China
| | - Zhicong Xu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, China
| | - Anyi Liang
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China
| | - Ruoyu Chen
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China
| | - Zicheng Wang
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China
- School of Medicine, South China University of Technology, Guangzhou, 510000, China
| | - Xiaojun Chen
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China
| | - Kangyan Zheng
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China
- Shantou University Medical College, Shantou, 515000, China
| | - Peiyao Lu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, China
| | - Huilin Liang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, China
| | - Dan Cao
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, China.
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China.
| | - Liang Zhang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, China.
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China.
- School of Medicine, South China University of Technology, Guangzhou, 510000, China.
- Shantou University Medical College, Shantou, 515000, China.
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Nieuwenhoff MD, Nguyen HT, Niehof SP, Huygen FJPM, Verma A, Klaassen ES, Bechakra M, Geelhoed WJ, Jongen JLM, Moll AC, Vrancken AFJE, Petzold A, Groeneveld GJ. Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy. Muscle Nerve 2024; 70:782-790. [PMID: 39056231 DOI: 10.1002/mus.28213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 07/05/2024] [Accepted: 07/14/2024] [Indexed: 07/28/2024]
Abstract
INTRODUCTION/AIMS Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). METHODS Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. RESULTS Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. DISCUSSION In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.
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Affiliation(s)
- Mariska D Nieuwenhoff
- Department of Anesthesiology and Pain Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Centre for Human Drug Research, Leiden, The Netherlands
| | - Hoang-Ton Nguyen
- Department of Ophthalmology, Amsterdam UMC location VU University Medical Center, Amsterdam, The Netherlands
| | - Sjoerd P Niehof
- Department of Anesthesiology and Pain Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Frank J P M Huygen
- Department of Anesthesiology and Pain Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | | | | | - Malik Bechakra
- Department of Anesthesiology and Pain Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | | | - Joost L M Jongen
- Department of Anesthesiology and Pain Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Annette C Moll
- Department of Ophthalmology, Amsterdam UMC location VU University Medical Center, Amsterdam, The Netherlands
| | - Alexander F J E Vrancken
- Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Axel Petzold
- Department of Ophthalmology, Amsterdam UMC location VU University Medical Center, Amsterdam, The Netherlands
- Department of Neurology, Amsterdam UMC location VU University Medical Center, Amsterdam, The Netherlands
- Moorfields Eye Hospital, The National Hospital for Neurology and Neurosurgery and the Queen Square Institute of Neurology, UCL, London, UK
| | - Geert Jan Groeneveld
- Centre for Human Drug Research, Leiden, The Netherlands
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
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11
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Tummanapalli SS, Wang LL, Dhanapalaratnam R, Poynten A, Papas EB, Krishnan AV, Markoulli M. Moderate-severe peripheral neuropathy in diabetes associated with an increased risk of dry eye disease. Optom Vis Sci 2024; 101:563-570. [PMID: 39269688 DOI: 10.1097/opx.0000000000002178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2024] Open
Abstract
SIGNIFICANCE This study establishes an increased risk of developing dry eye disease (DED) in patients with diabetic peripheral neuropathy using validated diagnostic criteria for both conditions. PURPOSE The disruption of ocular surface homeostasis has been associated with diabetes. However, it remains unclear if this association is independently influenced by peripheral neuropathy secondary to diabetes. This study aimed to investigate the clinical signs and symptoms of DED and their association with the severity of peripheral neuropathy in participants with type 2 diabetes. METHODS This prospective cross-sectional study recruited 63 participants with type 2 diabetes. All participants underwent a detailed assessment of DED using dry eye questionnaires (Ocular Surface Disease Index, Dry Eye Questionnaire-5), tear osmolarity, lipid layer thickness, noninvasive keratographic tear breakup time, phenol red thread test (PRT), and ocular surface staining. Corneal nerve morphology was imaged using corneal confocal microscopy. Based on the Total Neuropathy Scale, participants were stratified into no/mild (n = 48) and moderate/severe (n = 15) neuropathy groups. RESULTS Dry eye disease was diagnosed in 31 participants (50%) of the total cohort, and the odds of developing DED in the moderate/severe neuropathy group were four times (95% confidence interval, 1.10 to 13.80; p=0.030) higher compared with the no/mild neuropathy group. The Dry Eye Questionnaire-5 scores were significantly higher (p=0.020), and PRT values (p=0.048) and corneal nerve fiber length (p<0.001) were significantly reduced in the moderate/severe neuropathy group compared with the no/mild neuropathy group. In regression analysis, neuropathy scores were independently associated with PRT measurements ( β = -0.333, p=0.023) and nerve fiber length ( β = -0.219, p=0.012) while adjusting for age, gender, hemoglobin A 1c , and duration of diabetes. CONCLUSIONS Type 2 diabetic patients with peripheral neuropathy have a risk of developing DED, which increases with the severity of neuropathy. The observation that worsening peripheral neuropathy is associated with reduced tear secretion suggests that it may contribute to aqueous insufficiency.
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Affiliation(s)
| | - Leiao Leon Wang
- School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Roshan Dhanapalaratnam
- School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Ann Poynten
- Department of Endocrinology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Eric B Papas
- School of Optometry & Vision Science, University of New South Wales, Sydney, New South Wales, Australia
| | | | - Maria Markoulli
- School of Optometry & Vision Science, University of New South Wales, Sydney, New South Wales, Australia
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12
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Nardelli D, Gambioli F, De Bartolo MI, Mancinelli R, Biagioni F, Carotti S, Falato E, Leodori G, Puglisi-Allegra S, Vivacqua G, Fornai F. Pain in Parkinson's disease: a neuroanatomy-based approach. Brain Commun 2024; 6:fcae210. [PMID: 39130512 PMCID: PMC11311710 DOI: 10.1093/braincomms/fcae210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 04/23/2024] [Accepted: 06/17/2024] [Indexed: 08/13/2024] Open
Abstract
Parkinson's disease is a progressive neurodegenerative disorder characterized by the deposition of misfolded alpha-synuclein in different regions of the central and peripheral nervous system. Motor impairment represents the signature clinical expression of Parkinson's disease. Nevertheless, non-motor symptoms are invariably present at different stages of the disease and constitute an important therapeutic challenge with a high impact for the patients' quality of life. Among non-motor symptoms, pain is frequently experienced by patients, being present in a range of 24-85% of Parkinson's disease population. Moreover, in more than 5% of patients, pain represents the first clinical manifestation, preceding by decades the exordium of motor symptoms. Pain implies a complex biopsychosocial experience with a downstream complex anatomical network involved in pain perception, modulation, and processing. Interestingly, all the anatomical areas involved in pain network can be affected by a-synuclein pathology, suggesting that pathophysiology of pain in Parkinson's disease encompasses a 'pain spectrum', involving different anatomical and neurochemical substrates. Here the various anatomical sites recruited in pain perception, modulation and processing are discussed, highlighting the consequences of their possible degeneration in course of Parkinson's disease. Starting from peripheral small fibres neuropathy and pathological alterations at the level of the posterior laminae of the spinal cord, we then describe the multifaceted role of noradrenaline and dopamine loss in driving dysregulated pain perception. Finally, we focus on the possible role of the intertwined circuits between amygdala, nucleus accumbens and habenula in determining the psycho-emotional, autonomic and cognitive experience of pain in Parkinson's disease. This narrative review provides the first anatomically driven comprehension of pain in Parkinson's disease, aiming at fostering new insights for personalized clinical diagnosis and therapeutic interventions.
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Affiliation(s)
- Domiziana Nardelli
- Laboratory of Microscopic and Ultrastructural Anatomy, Campus Biomedico University of Roma, Rome 00128, Italy
| | - Francesco Gambioli
- Laboratory of Microscopic and Ultrastructural Anatomy, Campus Biomedico University of Roma, Rome 00128, Italy
| | | | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Roma, Rome 00161, Italy
| | | | - Simone Carotti
- Laboratory of Microscopic and Ultrastructural Anatomy, Campus Biomedico University of Roma, Rome 00128, Italy
| | - Emma Falato
- Laboratory of Microscopic and Ultrastructural Anatomy, Campus Biomedico University of Roma, Rome 00128, Italy
| | - Giorgio Leodori
- IRCCS Neuromed, Pozzilli, IS 86077, Italy
- Department of Human Neuroscience, Sapienza University of Roma, Rome 00185, Italy
| | | | - Giorgio Vivacqua
- Laboratory of Microscopic and Ultrastructural Anatomy, Campus Biomedico University of Roma, Rome 00128, Italy
| | - Francesco Fornai
- IRCCS Neuromed, Pozzilli, IS 86077, Italy
- Department of Experimental Morphology and Applied Biology, University of Pisa, Pisa 56122, Italy
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13
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Kushibiki H, Mizukami H, Osonoi S, Takeuchi Y, Sasaki T, Ogasawara S, Wada K, Midorikawa S, Ryuzaki M, Wang Z, Yamada T, Yamazaki K, Tarusawa T, Tanba T, Mikami T, Matsubara A, Ishibashi Y, Hakamada K, Nakaji S. Tryptophan metabolism and small fibre neuropathy: a correlation study. Brain Commun 2024; 6:fcae103. [PMID: 38618209 PMCID: PMC11010654 DOI: 10.1093/braincomms/fcae103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 01/10/2024] [Accepted: 03/24/2024] [Indexed: 04/16/2024] Open
Abstract
Small nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20 mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group (n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-high group (n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants (P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors (β = -0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy.
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Affiliation(s)
- Hanae Kushibiki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Sho Osonoi
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yuki Takeuchi
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takanori Sasaki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Saori Ogasawara
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Kanichiro Wada
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Shin Midorikawa
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Otorhinolaryngology-Head and Neck Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Masaki Ryuzaki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Zhenchao Wang
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takahiro Yamada
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Keisuke Yamazaki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takefusa Tarusawa
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Taiyo Tanba
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tatsuya Mikami
- Innovation Center for Health Promotion, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Atsushi Matsubara
- Department of Otorhinolaryngology-Head and Neck Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yasuyuki Ishibashi
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Shigeyuki Nakaji
- Department of Social Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
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14
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Akkul Z, Erkilic K, Sener H, Polat OA, Er Arslantas E. Diabetic corneal neuropathy and its relation to the severity of retinopathy in patients with type 2 diabetes mellitus: an in vivo confocal microscopy study. Int Ophthalmol 2024; 44:108. [PMID: 38386121 DOI: 10.1007/s10792-024-03043-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 01/18/2024] [Indexed: 02/23/2024]
Abstract
PURPOSE To investigate corneal neuropathy and corneal nerve alterations in type 2 diabetes mellitus (DM) patients with different diabetic retinopathy (DR) status. METHODS A total of 87 eyes of 87 patients with DM and 28 eyes of 28 healthy control subjects were included in the study. DM patients were further classified into 3 groups: patients without DR (NDR), patients with non-proliferative DR (NPDR), and patients with proliferative DR (PDR). PDR patients were classified into 2 groups regarding having undergone retinal argon laser photocoagulation treatment (ALP). Ocular surface disease index score (OSDI), average tear break-up time (A-BUT), corneal sensitivity and cornea nerve fiber length (CNFL), cornea nerve fiber density (CNFD), and cornea nerve branch density (CNBD) of the cornea subbasal nerve plexus (SBNP) were measured using in vivo confocal microscopy (IVCM). RESULTS OSDI scores increased and A-BUT decreased in DM patients compared to the control group, but no significant difference was found between DM patient groups. Corneal sensitivity decreased in DM patients who developed DR, compared to both the controls and the NDR group. CNFD and CNFL decreased in NPDR and PDR patients compared to controls. CNFD and CNBD decreased in patients who had developed PDR, compared to all three groups. All IVCM parameters decreased with DR progression. CONCLUSION IVCM can detect early structural corneal nerve changes in diabetic patients. The presence of DM affects ocular surface parameters, especially in long-term DM patients. Corneal sensitivity loss is increased with the presence of DR. All IVCM parameters decrease with DR development and its progression.
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Affiliation(s)
- Zeynep Akkul
- Department of Ophthalmology, Erciyes University Medical Faculty, Kayseri, Turkey.
| | - Kuddusi Erkilic
- Department of Ophthalmology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Hidayet Sener
- Department of Ophthalmology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Osman Ahmet Polat
- Department of Ophthalmology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Elif Er Arslantas
- Department of Ophthalmology, Erciyes University Medical Faculty, Kayseri, Turkey
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15
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Silsby M, Feldman EL, Dortch RD, Roth A, Haroutounian S, Rajabally YA, Vucic S, Shy ME, Oaklander AL, Simon NG. Advances in diagnosis and management of distal sensory polyneuropathies. J Neurol Neurosurg Psychiatry 2023; 94:1025-1039. [PMID: 36997315 PMCID: PMC10544692 DOI: 10.1136/jnnp-2021-328489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 02/23/2023] [Indexed: 04/01/2023]
Abstract
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.
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Affiliation(s)
- Matthew Silsby
- Neurology, Westmead Hospital, Westmead, New South Wales, Australia
- Brain and Nerve Research Centre, Sydney Medical School, The University of Sydney, New South Wales, Australia
| | - Eva L Feldman
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Richard D Dortch
- Division of Neuroimaging Research, Barrow Neurological Institute, Phoenix, Arizona, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, Nashville, Tennessee, USA
- Department of Biomedical Engineering, Vanderbilt University Institute of Imaging Science, Nashville, Tennessee, USA
| | - Alison Roth
- Division of Neuroimaging Research, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Simon Haroutounian
- Department of Anesthesiology, Washington University School of Medicine in Saint Louis, St Louis, Missouri, USA
| | - Yusuf A Rajabally
- Inflammatory Neuropathy Clinic, Department of Neurology, University Hospitals Birmingham, Aston Medical School, Aston University, Birmingham, UK
| | - Steve Vucic
- Brain and Nerve Research Centre, Sydney Medical School, The University of Sydney, New South Wales, Australia
| | - Michael E Shy
- Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Anne Louise Oaklander
- Nerve Unit, Departments of Neurology and Pathology (Neuropathology), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Neil G Simon
- Northern Beaches Clinical School, Macquarie University, Frenchs Forest, New South Wales, Australia
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16
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Belkadi A, Thareja G, Khan A, Stephan N, Zaghlool S, Halama A, Ahmed AA, Mohamoud YA, Malek J, Suhre K, Malik RA. Retinal nerve fibre layer thinning and corneal nerve loss in patients with Bardet-Biedl syndrome. BMC Med Genomics 2023; 16:301. [PMID: 37996899 PMCID: PMC10666305 DOI: 10.1186/s12920-023-01739-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 11/13/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic disorder caused by variants in genes involved in the function of the primary cilium. We have harnessed genomics to identify BBS and ophthalmic technologies to describe novel features of BBS. CASE PRESENTATION A patient with an unclear diagnosis of syndromic type 2 diabetes mellitus, another affected sibling and unaffected siblings and parents were sequenced using DNA extracted from saliva samples. Corneal confocal microscopy (CCM) and retinal spectral domain optical coherence tomography (SD-OCT) were used to identify novel ophthalmic features in these patients. The two affected individuals had a homozygous variant in C8orf37 (p.Trp185*). SD-OCT and CCM demonstrated a marked and patchy reduction in the retinal nerve fiber layer thickness and loss of corneal nerve fibers, respectively. CONCLUSION This report highlights the use of ophthalmic imaging to identify novel retinal and corneal abnormalities that extend the phenotype of BBS in a patient with syndromic type 2 diabetes.
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Affiliation(s)
- Aziz Belkadi
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Gaurav Thareja
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Adnan Khan
- Faculty of Health Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Nisha Stephan
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Shaza Zaghlool
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Anna Halama
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | | | - Yasmin A Mohamoud
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Joel Malek
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Karsten Suhre
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Rayaz A Malik
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar.
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17
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Sierra-Silvestre E, Andrade RJ, Colorado LH, Edwards K, Coppieters MW. Occurrence of corneal sub-epithelial microneuromas and axonal swelling in people with diabetes with and without (painful) diabetic neuropathy. Diabetologia 2023; 66:1719-1734. [PMID: 37301795 PMCID: PMC10257488 DOI: 10.1007/s00125-023-05945-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 04/04/2023] [Indexed: 06/12/2023]
Abstract
AIMS/HYPOTHESIS Non-invasive in vivo corneal confocal microscopy is gaining ground as an alternative to skin punch biopsy to evaluate small-diameter nerve fibre characteristics. This study aimed to further explore corneal nerve fibre pathology in diabetic neuropathy. METHODS This cross-sectional study quantified and compared corneal nerve morphology and microneuromas in participants without diabetes (n=27), participants with diabetes but without distal symmetrical polyneuropathy (DSPN; n=33), participants with non-painful DSPN (n=25) and participants with painful DSPN (n=18). Clinical and electrodiagnostic criteria were used to diagnose DSPN. ANCOVA was used to compare nerve fibre morphology in the central cornea and inferior whorl, and the number of corneal sub-epithelial microneuromas between groups. Fisher's exact tests were used to compare the type and presence of corneal sub-epithelial microneuromas and axonal swelling between groups. RESULTS Various corneal nerve morphology metrics, such as corneal nerve fibre length and density, showed a progressive decline across the groups (p<0.001). In addition, axonal swelling was present more frequently (p=0.018) and in higher numbers (p=0.03) in participants with painful compared with non-painful DSPN. The frequency of axonal distension, a type of microneuroma, was increased in participants with painful and non-painful DSPN compared to participants with diabetes but without DSPN and participants without diabetes (all p≤0.042). The combined presence of all microneuromas and axonal swelling was increased in participants with painful DSPN compared with all other groups (p≤0.026). CONCLUSIONS/INTERPRETATION Microneuromas and axonal swelling in the cornea increase in prevalence from participants with diabetes to participants with non-painful DSPN and participants with painful DSPN.
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Affiliation(s)
- Eva Sierra-Silvestre
- Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia
- School of Health Sciences and Social Work, Griffith University, Brisbane, QLD, Australia
- Amsterdam Movement Sciences - Musculoskeletal Health Program, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Ricardo J Andrade
- Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia
- Movement - Interactions - Performance (MIP), Nantes University, Nantes, France
| | - Luisa H Colorado
- Centre for Vision and Eye Research, School of Optometry and Vision Science, Queensland University of Technology, Brisbane, Australia
| | - Katie Edwards
- Centre for Vision and Eye Research, School of Optometry and Vision Science, Queensland University of Technology, Brisbane, Australia
| | - Michel W Coppieters
- Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia.
- School of Health Sciences and Social Work, Griffith University, Brisbane, QLD, Australia.
- Amsterdam Movement Sciences - Musculoskeletal Health Program, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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Banerjee M, Mukhopadhyay P, Ghosh S, Basu M, Pandit A, Malik R, Ghosh S. Corneal Confocal Microscopy Abnormalities in Children and Adolescents With Type 1 Diabetes. Endocr Pract 2023; 29:692-698. [PMID: 37343765 DOI: 10.1016/j.eprac.2023.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/23/2023]
Abstract
OBJECTIVE Utility of corneal confocal microscopy (CCM) in children and adolescents with type 1 diabetes mellitus (T1DM) without neuropathic symptoms or signs and minimal abnormality in large and small nerve fiber function tests remains largely undetermined. This study aimed to evaluate the performance of CCM in comparison to thermal detection thresholds (TDT) testing and nerve conduction studies (NCS) for detecting neuropathy in children with T1DM. METHODS A cohort of children and adolescents with T1DM (n = 51) and healthy controls (n = 50) underwent evaluation for symptoms and signs of neurological deficits, including warm detection threshold, cold detection threshold, vibration perception threshold, NCS, and CCM. RESULTS Children with T1DM had no or very minimal neuropathic symptoms and deficits based on the Toronto Clinical Neuropathy Score, yet NCS abnormalities were present in 18 (35%), small fiber dysfunction defined by an abnormal TDT was found in 13 (25.5%) and CCM abnormalities were present in 25 (49%). CCM was abnormal in a majority of T1DM children with abnormal TDT (12/13, 92%) and abnormal NCS (16/18, 88%). CCM additionally was able to detect small fiber abnormalities in 13/38 (34%) in T1DM with a normal TDT and in 9/33 (27%) with normal NCS. CONCLUSION CCM was able to detect corneal nerve loss in children with and without abnormalities in TDT and NCS.
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Affiliation(s)
- Mainak Banerjee
- Department of Endocrinology, Senior Resident, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Pradip Mukhopadhyay
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Shatabdi Ghosh
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Madhurima Basu
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Alak Pandit
- Department of Neurology, Bangur Institute of Neurology, Kolkata, India
| | - Rayaz Malik
- Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar; Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Sujoy Ghosh
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India.
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19
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Badian RA, Ekman L, Pripp AH, Utheim TP, Englund E, Dahlin LB, Rolandsson O, Lagali N. Comparison of Novel Wide-Field In Vivo Corneal Confocal Microscopy With Skin Biopsy for Assessing Peripheral Neuropathy in Type 2 Diabetes. Diabetes 2023; 72:908-917. [PMID: 37058418 PMCID: PMC10281223 DOI: 10.2337/db22-0863] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 04/10/2023] [Indexed: 04/15/2023]
Abstract
Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepidermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a noninvasive diagnostic modality for DPN. Direct comparisons of skin biopsy and IVCM in controlled cohorts are lacking, as IVCM relies on subjective selection of images depicting only 0.2% of the nerve plexus. We compared these diagnostic modalities in a fixed-age cohort of 41 participants with type 2 diabetes and 36 healthy participants using machine algorithms to create wide-field image mosaics and quantify nerves in an area 37 times the size of prior studies to avoid human bias. In the same participants, and at the same time point, no correlation between IENFD and corneal nerve density was found. Corneal nerve density did not correlate with clinical measures of DPN, including neuropathy symptom and disability scores, nerve conduction studies, or quantitative sensory tests. Our findings indicate that corneal and intraepidermal nerves likely mirror different aspects of nerve degeneration, where only intraepidermal nerves appear to reflect the clinical status of DPN, suggesting that scrutiny is warranted concerning methodologies of studies using corneal nerves to assess DPN. ARTICLE HIGHLIGHTS Comparison of intraepidermal nerve fiber density with automated wide-field corneal nerve fiber density in participants with type 2 diabetes revealed no correlation between these parameters. Intraepidermal and corneal nerve fibers both detected neurodegeneration in type 2 diabetes, but only intraepidermal nerve fibers were associated with clinical measures of diabetic peripheral neuropathy. A lack of association of corneal nerves with peripheral neuropathy measures suggests that corneal nerve fibers may be a poor biomarker for diabetic peripheral neuropathy.
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Affiliation(s)
- Reza A. Badian
- Department of Medical Biochemistry, Unit of Regenerative Medicine, Oslo University Hospital, Oslo, Norway
| | - Linnéa Ekman
- Department of Translational Medicine, Hand Surgery, Lund University, Malmö, Sweden
| | - Are Hugo Pripp
- Oslo Centre of Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway
| | - Tor Paaske Utheim
- Department of Ophthalmology, Oslo University Hospital, Oslo, Norway
- Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway
| | - Elisabet Englund
- Department of Clinical Sciences, Pathology, Lund University, Lund, Sweden
| | - Lars B. Dahlin
- Department of Translational Medicine, Hand Surgery, Lund University, Malmö, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Hand Surgery, Skåne University Hospital, Malmö, Sweden
| | - Olov Rolandsson
- Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
| | - Neil Lagali
- Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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20
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Gylfadottir SS, Itani M, Kristensen AG, Nyengaard JR, Sindrup SH, Jensen TS, Finnerup NB, Karlsson P. Assessing Corneal Confocal Microscopy and Other Small Fiber Measures in Diabetic Polyneuropathy. Neurology 2023; 100:e1680-e1690. [PMID: 36750383 PMCID: PMC10115507 DOI: 10.1212/wnl.0000000000206902] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 12/23/2022] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Damage to small nerve fibers is common in diabetic polyneuropathy (DPN), and the diagnosis of DPN relies on subjective symptoms and signs in a combination with objective confirmatory tests, typically electrophysiology or intraepidermal nerve fiber density (IENFD) from skin biopsy. Corneal confocal microscopy (CCM) has been introduced as a tool to detect DPN. However, it is unclear if CCM can reliably be used to diagnose DPN and how the technique compares with other commonly used measures of small fiber damage, such as IENFD, cold detection threshold (CDT), and warm detection threshold (WDT). Therefore, we assessed and compared the use of CCM, IENFD, CDT, and WDT in the diagnosis of DPN in patients with type 2 diabetes. METHODS In this cohort study, the participants underwent detailed neurologic examination, electrophysiology, quantification of IENFD, CCM, and quantitative sensory testing. Definition of DPN was made in accordance with the Toronto criteria for diabetic neuropathy (without relying on IENFD and thermal thresholds). RESULTS A total of 214 patients with at least probable DPN, 63 patients without DPN, and 97 controls without diabetes were included. Patients with DPN had lower CCM measures (corneal nerve fiber length [CNFL], nerve fiber density, and branch density), IENFD, CDT, and WDT compared with patients without DPN (p ≤ 0.001, <0.001, 0.002, p < 0.001, p = 0.003, and <0.005, respectively), whereas there was no difference between controls and patients with diabetes without DPN. All 3 CCM measures showed a very low diagnostic sensitivity with CNFL showing the highest (14.4% [95% CI 9.8-18.4]) and a specificity of 95.7% (88.0-99.1). In comparison, the sensitivity of abnormal CDT and/or WDT was 30.5% (24.4-37.0) with a specificity of 84.9% (74.6-92.2). The sensitivity of abnormal IENFD was highest among all measures with a value of 51.1% (43.7-58.5) and a specificity of 90% (79.5-96.2). CCM measures did not correlate with IENFD, CDT/WDT, or neuropathy severity in the group of patients with DPN. DISCUSSION CCM measures showed the lowest sensitivity compared with other small fiber measures in the diagnosis of DPN. This indicates that CCM is not a sensitive method to detect DPN in recently diagnosed type 2 diabetes. CLASSIFICATION OF EVIDENCE This study provides Class III evidence that CCM measures aid in the detection of DPN in recently diagnosed type 2 diabetics but with a low sensitivity when compared with other small fiber measures.
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Affiliation(s)
- Sandra S Gylfadottir
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark
| | - Mustapha Itani
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark
| | - Alexander G Kristensen
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark
| | - Jens R Nyengaard
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark
| | - Søren Hein Sindrup
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark
| | - Troels S Jensen
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark
| | - Nanna B Finnerup
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark
| | - Pall Karlsson
- From the Department of Clinical Medicine (S.S.G., T.S.J., N.B.F., P.K.), Danish Pain Research Centre, and Core Centre for Molecular Morphology (J.R.N., P.K.), Aarhus University; Departments of Neurology (S.S.G, T.S.J., N.B.F.), Clinical Neurophysiology (A.G.K.), and Pathology (J.R.N.), Aarhus University Hospital; and Department of Neurology (M.I., S.H.S.), Odense University Hospital, Denmark.
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21
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Thimm A, Carpinteiro A, Oubari S, Papathanasiou M, Kessler L, Rischpler C, Malik RA, Herrmann K, Reinhardt HC, Rassaf T, Kleinschnitz C, Hagenacker T, Stettner M. Corneal confocal microscopy identifies corneal nerve loss and increased Langerhans cells in presymptomatic carriers and patients with hereditary transthyretin amyloidosis. J Neurol 2023:10.1007/s00415-023-11689-z. [PMID: 37014422 DOI: 10.1007/s00415-023-11689-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/21/2023] [Accepted: 03/25/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, but life-threatening protein misfolding disorder due to TTR gene mutations. Cardiomyopathy (ATTRv-CM) and polyneuropathy (ATTRv-PN) with early small nerve fibre involvement are the most common manifestations. Timely diagnosis and treatment initiation are key to limiting progression of disease. Corneal confocal microscopy (CCM) is a non-invasive method to quantify corneal small nerve fibres and immune cell infiltrates in vivo. METHODS This cross-sectional study investigated the utility of CCM in 20 patients with ATTRv amyloidosis (ATTRv-CM, n = 6; ATTRv-PN, n = 14) and presymptomatic carriers (n = 5) compared to 20 age- and sex-matched healthy controls. Corneal nerve fibre density, corneal nerve fibre length, corneal nerve branch density, and cell infiltrates were assessed. RESULTS Corneal nerve fibre density and nerve fibre length were significantly lower in patients with ATTRv amyloidosis compared to healthy controls regardless of the clinical phenotype (ATTRv-CM, ATTRv-PN) and corneal nerve fibre density was significantly lower in presymptomatic carriers. Immune cell infiltrates were only evident in patients with ATTRv amyloidosis, which correlated with reduced corneal nerve fibre density. CONCLUSIONS CCM identifies small nerve fibre damage in presymptomatic carriers and symptomatic patients with ATTRv amyloidosis and may serve as a predictive surrogate marker to identify individuals at risk of developing symptomatic amyloidosis. Furthermore, increased corneal cell infiltration suggests an immune-mediated mechanism in the pathogenesis of amyloid neuropathy.
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Affiliation(s)
- Andreas Thimm
- Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
- Center for Translational Neuro- and Behavioral Scienes (C-TNBS), University Hospital Essen, Essen, Germany.
| | - Alexander Carpinteiro
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany
- Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Sara Oubari
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Maria Papathanasiou
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany
| | - Lukas Kessler
- Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
| | | | - Rayaz Ahmed Malik
- Institute of Cardiovascular Science, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
- Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Ken Herrmann
- Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
| | - Hans Christian Reinhardt
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany
| | - Christoph Kleinschnitz
- Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
- Center for Translational Neuro- and Behavioral Scienes (C-TNBS), University Hospital Essen, Essen, Germany
| | - Tim Hagenacker
- Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
- Center for Translational Neuro- and Behavioral Scienes (C-TNBS), University Hospital Essen, Essen, Germany
| | - Mark Stettner
- Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
- Center for Translational Neuro- and Behavioral Scienes (C-TNBS), University Hospital Essen, Essen, Germany
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22
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Machet J, Park M, Richardson A, Carnell M, Mouat MA, Smith NJ, Turner N, Cochran BJ, Rye KA, Di Girolamo N. Type 2 diabetes influences intraepithelial corneal nerve parameters and corneal stromal-epithelial nerve penetration sites. J Diabetes Investig 2023; 14:591-601. [PMID: 36727569 PMCID: PMC10034950 DOI: 10.1111/jdi.13974] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/16/2022] [Accepted: 01/01/2023] [Indexed: 02/03/2023] Open
Abstract
INTRODUCTION The quantification of intraepithelial corneal basal nerve parameters by in vivo confocal microscopy represents a promising modality to identify the earliest manifestations of diabetic peripheral neuropathy. However, its diagnostic accuracy is hampered by its dependence on neuron length, with minimal consideration for other parameters, including the origin of these nerves, the corneal stromal-epithelial nerve penetration sites. This study sought to utilize high-resolution images of murine corneal nerves to analyze comprehensively the morphological changes associated with type 2 diabetes progression. MATERIALS AND METHODS βIII-Tubulin immunostained corneas from prediabetic and type 2 diabetic mice and their respective controls were imaged by scanning confocal microscopy and analyzed automatically for nerve parameters. Additionally, the number and distribution of penetration sites was manually ascertained and the average length of the axons exiting them was computed. RESULTS The earliest detectable changes included a significant increase in nerve density (6.06 ± 0.41% vs 8.98 ± 1.99%, P = 0.03) and branching (2867.8 ± 271.3/mm2 vs 4912.1 ± 1475.3/mm2 , P = 0.03), and in the number of penetration sites (258.80 ± 20.87 vs 422.60 ± 63.76, P = 0.0002) at 8 weeks of age. At 16 weeks, corneal innervation decreased, most notably in the periphery. The number of penetration sites remained significantly elevated relative to controls throughout the monitoring period. Similarly, prediabetic mice exhibited an increased number of penetration sites (242.2 ± 13.55 vs 305.6 ± 30.96, P = 0.003) without significant changes to the nerves. CONCLUSIONS Our data suggest that diabetic peripheral neuropathy may be preceded by a phase of neuron growth rather than regression, and that the peripheral cornea is more sensitive than the center for detecting changes in innervation.
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Affiliation(s)
- Joshua Machet
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Mijeong Park
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Alexander Richardson
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Michael Carnell
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW, Australia
| | - Margaret A Mouat
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Nicola J Smith
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Nigel Turner
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
- Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
| | - Blake J Cochran
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Kerry-Anne Rye
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Nick Di Girolamo
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
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Edwards RR, Schreiber KL, Dworkin RH, Turk DC, Baron R, Freeman R, Jensen TS, Latremoliere A, Markman JD, Rice ASC, Rowbotham M, Staud R, Tate S, Woolf CJ, Andrews NA, Carr DB, Colloca L, Cosma-Roman D, Cowan P, Diatchenko L, Farrar J, Gewandter JS, Gilron I, Kerns RD, Marchand S, Niebler G, Patel KV, Simon LS, Tockarshewsky T, Vanhove GF, Vardeh D, Walco GA, Wasan AD, Wesselmann U. Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations. THE JOURNAL OF PAIN 2023; 24:204-225. [PMID: 36198371 PMCID: PMC10868532 DOI: 10.1016/j.jpain.2022.08.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/01/2022] [Accepted: 08/17/2022] [Indexed: 11/06/2022]
Abstract
Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.
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Affiliation(s)
| | | | | | - Dennis C Turk
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
| | - Ralf Baron
- Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, House D, 24105 Kiel, Germany
| | - Roy Freeman
- Harvard Medical School, Boston, Massachusetts
| | | | | | | | | | | | | | | | | | - Nick A Andrews
- Salk Institute for Biological Studies, San Diego, California
| | | | | | | | - Penney Cowan
- American Chronic Pain Association, Rocklin, California
| | - Luda Diatchenko
- Department of Anesthesia and Faculty of Dentistry, McGill University, Montreal, California
| | - John Farrar
- University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | - Robert D Kerns
- Yale University, Departments of Psychiatry, Neurology, and Psychology, New Haven, Connecticut
| | | | | | - Kushang V Patel
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
| | | | | | | | | | - Gary A Walco
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
| | - Ajay D Wasan
- University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ursula Wesselmann
- Department of Anesthesiology/Division of Pain Medicine, Neurology and Psychology, The University of Alabama at Birmingham, Birmingham, Alabama
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24
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Diabetic Retinopathy: Soluble and Imaging Ocular Biomarkers. J Clin Med 2023; 12:jcm12030912. [PMID: 36769560 PMCID: PMC9917666 DOI: 10.3390/jcm12030912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/18/2023] [Accepted: 01/22/2023] [Indexed: 01/26/2023] Open
Abstract
Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus, represents the leading cause of acquired blindness in the working-age population. Due to the potential absence of symptoms in the early stages of the disease, the identification of clinical biomarkers can have a crucial role in the early diagnosis of DR as well as for the detection of prognostic factors. In particular, imaging techniques are fundamental tools for screening, diagnosis, classification, monitoring, treatment planning and prognostic assessment in DR. In this context, the identification of ocular and systemic biomarkers is crucial to facilitate the risk stratification of diabetic patients; moreover, reliable biomarkers could provide prognostic information on disease progression as well as assist in predicting a patient's response to therapy. In this context, this review aimed to provide an updated and comprehensive overview of the soluble and anatomical biomarkers associated with DR.
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25
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Pacaud D, Romanchuk KG, Virtanen H, Ferdousi M, Nettel-Aguirre A, Mah JK, Tavakoli M, Zochodne DW, Malik RA. Corneal nerve and nerve conduction abnormalities in children with type 1 diabetes. Pediatr Diabetes 2022; 23:1665-1673. [PMID: 36131228 DOI: 10.1111/pedi.13419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 09/08/2022] [Accepted: 09/17/2022] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE In vivo corneal confocal microscopy (CCM) is a novel, rapid, and non-invasive technique that identifies early small fiber damage and can predict the progression and development of clinical neuropathy in adults with type 1 diabetes. However, its usefulness in children is not well established. This study compared corneal confocal microscopy with neuropathic symptoms, signs, and objective measures of neuropathy for the diagnosis of diabetic neuropathy in children with type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 83 children with type 1 diabetes and 83 healthy participants of similar age underwent assessment of neuropathy symptoms, signs, nerve conduction studies, quantitative sensory and autonomic function testing, and in vivo CCM. RESULTS Only of 3/83 (4%) children with type 1 diabetes had subclinical neuropathy. However, corneal nerve fiber density (p = 0.001), branch density (p = 0.006), fiber length (p = 0.002), tibial motor nerve amplitude and conduction velocity, and sural sensory nerve amplitude and conduction velocity (all p < 0.004) were lower in participants with type 1 diabetes than in the controls. Vibration, cooling, and warm perception thresholds and deep breathing heart rate variability were not found to be different (all p > 0.05) between children with type 1 diabetes and healthy controls. Multivariate regression analysis identified a possible association between body mass index and decreased corneal nerves. CONCLUSIONS Decreased corneal nerves and abnormal nerve conduction were found in children with type 1 diabetes. CCM may allow rapid objective detection of subclinical diabetic neuropathy in children and adolescents with type 1 diabetes.
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Affiliation(s)
- Danièle Pacaud
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Pediatric Diabetes, Pediatric Neurology and Pediatric Ophthalmology divisions, Alberta Children's Hospital, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
| | - Kenneth G Romanchuk
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Pediatric Diabetes, Pediatric Neurology and Pediatric Ophthalmology divisions, Alberta Children's Hospital, Calgary, Alberta, Canada
| | - Heidi Virtanen
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Pediatric Diabetes, Pediatric Neurology and Pediatric Ophthalmology divisions, Alberta Children's Hospital, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
| | - Maryam Ferdousi
- Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.,NIHR/Wellcome Trust Clinical Research Facility, Manchester, UK
| | - Alberto Nettel-Aguirre
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Centre for Health and Social Analytics, NIASRA, University of Wollongong, Wollongong, New South Wales, Australia
| | - Jean K Mah
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Pediatric Diabetes, Pediatric Neurology and Pediatric Ophthalmology divisions, Alberta Children's Hospital, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
| | - Mitra Tavakoli
- Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, UK.,Exeter Centre of Excellence for Diabetes Research, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK
| | - Douglas W Zochodne
- Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Rayaz A Malik
- Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.,NIHR/Wellcome Trust Clinical Research Facility, Manchester, UK.,Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
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Matuszewska-Iwanicka A, Stratmann B, Stachs O, Allgeier S, Bartschat A, Winter K, Guthoff R, Tschoepe D, Hettlich HJ. Mosaic vs. Single Image Analysis with Confocal Microscopy of the Corneal Nerve Plexus for Diagnosis of Early Diabetic Peripheral Neuropathy. Ophthalmol Ther 2022; 11:2211-2223. [PMID: 36184730 DOI: 10.1007/s40123-022-00574-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION The assessment of the corneal nerve fibre plexus with corneal confocal microscopy (CCM) is an upcoming but still experimental method in the diagnosis of early stage diabetic peripheral neuropathy (DPN). Using an innovative imaging technique-Heidelberg Retina Tomograph equipped with the Rostock Cornea Module (HRT-RCM) and EyeGuidance module (EG)-we were able to look at greater areas of subbasal nerve plexus (SNP) in order to increase the diagnostic accuracy. The aim of our study was to evaluate the usefulness of EG instead of single image analysis in diagnosis of early stage DPN. METHODS This prospective study was performed on 60 patients with type 2 diabetes mellitus, classified equally into two subgroups based on neuropathy deficient score (NDS): patients without DPN (group 1) or with mild DPN (group 2). The following parameters were analysed in the two subgroups: corneal nerve fibre length (CNFL; mm/mm2), corneal nerve fibre density (CNFD; no./mm2), corneal nerve branch density (CNBD; no./mm2). Furthermore, we compared the data calculated with the novel mosaic, EG-based method with those received from single image analysis using different quantification tools. RESULTS Using EG we did not find a significant difference between group 1 and group 2: CNFL (16.81 ± 5.87 mm/mm2 vs. 17.19 ± 7.19 mm/mm2, p = 0.895), CNFD (254.05 ± 115.36 no./mm2 vs. 265.91 ± 161.63 no./mm2, p = 0.732) and CNBD (102.68 ± 62.28 no./mm2 vs. 115.38 ± 96.91 no./mm2, p = 0.541). No significant difference between the EG method of analysing the SNP and the single image analysis of 10 images per patient was detected. CONCLUSION On the basis of our results it was not possible to differentiate between early stages of large nerve fibre DPN in patients with type 2 diabetes mellitus via SNP analysis. To improve sensitivity and specificity of this method newer technologies are under current evaluation. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT05326958.
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Affiliation(s)
- Aleksandra Matuszewska-Iwanicka
- Eye Clinic Johannes Wesling Hospital, Ruhr Universität Bochum, Augen-Praxisklinik Minden, Königstraße 120, 32427, Minden, Germany.
| | - Bernd Stratmann
- Herz- und Diabeteszentrum NRW, Diabeteszentrum, Ruhr Universität Bochum, Bad Oeynhausen, Germany
| | - Oliver Stachs
- Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany
| | - Stephan Allgeier
- Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Andreas Bartschat
- Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Karsten Winter
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Rudolf Guthoff
- Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany
| | - Diethelm Tschoepe
- Herz- und Diabeteszentrum NRW, Diabeteszentrum, Ruhr Universität Bochum, Bad Oeynhausen, Germany
- Stiftung DHD (Der herzkranke Diabetiker) Stiftung in der Deutschen Diabetes-Stiftung, Bad Oeynhausen, Germany
| | - Hans-Joachim Hettlich
- Eye Clinic Johannes Wesling Hospital, Ruhr Universität Bochum, Augen-Praxisklinik Minden, Königstraße 120, 32427, Minden, Germany
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So WZ, Qi Wong NS, Tan HC, Yu Lin MT, Yu Lee IX, Mehta JS, Liu YC. Diabetic corneal neuropathy as a surrogate marker for diabetic peripheral neuropathy. Neural Regen Res 2022; 17:2172-2178. [PMID: 35259825 PMCID: PMC9083173 DOI: 10.4103/1673-5374.327364] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Diabetic neuropathy is a prevalent microvascular complication of diabetes mellitus, affecting nerves in all parts of the body including corneal nerves and peripheral nervous system, leading to diabetic corneal neuropathy and diabetic peripheral neuropathy, respectively. Diabetic peripheral neuropathy is diagnosed in clinical practice using electrophysiological nerve conduction studies, clinical scoring, and skin biopsies. However, these diagnostic methods have limited sensitivity in detecting small-fiber disease, hence they do not accurately reflect the status of diabetic neuropathy. More recently, analysis of alterations in the corneal nerves has emerged as a promising surrogate marker for diabetic peripheral neuropathy. In this review, we will discuss the relationship between diabetic corneal neuropathy and diabetic peripheral neuropathy, elaborating on the foundational aspects of each: pathogenesis, clinical presentation, evaluation, and management. We will further discuss the relevance of diabetic corneal neuropathy in detecting the presence of diabetic peripheral neuropathy, particularly early diabetic peripheral neuropathy; the correlation between the severity of diabetic corneal neuropathy and that of diabetic peripheral neuropathy; and the role of diabetic corneal neuropathy in the stratification of complications of diabetic peripheral neuropathy.
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Affiliation(s)
- Wei Zheng So
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Singapore Eye Research Institute, Singapore, Singapore
| | - Natalie Shi Qi Wong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Singapore Eye Research Institute, Singapore, Singapore
| | - Hong Chang Tan
- Department of Endocrinology, Singapore General Hospital, Singapore, Singapore
| | | | | | - Jodhbir S Mehta
- Singapore Eye Research Institute; Department of Cornea and External Eye Disease, Singapore National Eye Centre; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
| | - Yu-Chi Liu
- Singapore Eye Research Institute; Department of Cornea and External Eye Disease, Singapore National Eye Centre; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
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Britten-Jones AC, Craig JP, Anderson AJ, Downie LE. Association between systemic omega-3 polyunsaturated fatty acid levels, and corneal nerve structure and function. Eye (Lond) 2022:10.1038/s41433-022-02259-0. [PMID: 36163491 DOI: 10.1038/s41433-022-02259-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 08/23/2022] [Accepted: 09/09/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have anti-inflammatory and neuroprotective properties. This study sought to determine the relationship between corneal parameters and systemic omega-3 fatty acid levels. METHODS Forty-seven participants with no/mild peripheral neuropathy (26 with diabetes and 21 without) underwent comprehensive ocular surface and systemic PUFA assessments. Corneal anatomical parameters were assessed using in vivo confocal microscopy. Corneal sensitivity was measured using non-contact esthesiometry. Relationships between systemic PUFA levels and corneal parameters were evaluated with multiple linear regression, adjusted for age, sex, neuropathy symptom score, and presence of diabetes and dry eye disease. The relationship between corneal nerve fibre length (CNFL) and corneal sensitivity threshold was evaluated. RESULTS The median Omega-3 Index, a measure of erythrocyte EPA and DHA, was 5.21% (interquartile range: 4.44-5.94%) in the study population. Mean ( ± SD) CNFL was 13.53 ± 3.37 mm/mm2. Multiple linear regression showed that Omega-3 Index (β = 0.33; p = 0.02), age (β = -0.46; p = 0.001) and diabetes (β = -0.30; p = 0.03) were independently associated with CNFL (R2 = 0.39, p = 0.002). In a separate model, DHA (β = 0.32; p = 0.027) and age (β = -0.41; p = 0.003) were associated with CNFL (R2 = 0.37, p = 0.003). Neither systemic EPA nor omega-6 fatty acid levels correlated with CNFL. There was no association between PUFA levels and corneal sensitivity or corneal immune cell density. A negative correlation was found between CNFL and corneal sensation thresholds to a cooled stimulus in diabetes participants, in the central (ρ = -0.50; p = 0.009) and peripheral (ρ = -0.50; p = 0.01) cornea. CONCLUSIONS A positive relationship between the systemic Omega-3 Index and corneal nerve parameters suggests omega-3 PUFA intake may influence corneal nerve architecture.
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Affiliation(s)
| | - Jennifer P Craig
- Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, Auckland, New Zealand
| | - Andrew J Anderson
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Australia
| | - Laura E Downie
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Australia.
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29
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Tong KP, Intine R, Wu S. Vitamin C and the management of diabetic foot ulcers: a literature review. J Wound Care 2022; 31:S33-S44. [PMID: 36113854 DOI: 10.12968/jowc.2022.31.sup9.s33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The lifetime risk of developing a diabetic foot ulcer (DFU) in people with diabetes is as high as 25%. A trio of factors constitute the diabetic foot syndrome that characterises DFUs, including neuropathy, vascular disease and infections. Vitamin C has important functions in the nervous, cardiovascular, and immune systems that are implicated in DFU development. Furthermore, vitamin C deficiency has been observed in individuals with DFUs, suggesting an important function of vitamin C in DFU management and treatment. Therefore, this literature review evaluates the role of vitamin C in the nervous, cardiovascular and immune systems in relation to wound healing and DFUs, as well as discussing vitamin C's lesser known role in depression, a condition that affects many individuals with a DFU. METHOD A literature search was done using PubMed, Cochrane Library, Embase, Ovid, Computer Retrieval of Information on Scientific Projects, and NIH Clinical Center. Search terms included 'diabetic foot ulcer,' 'diabetic foot,' 'vitamin C,' and 'ascorbic acid.' RESULTS Of the 71 studies initially identified, seven studies met the inclusion criteria, and only three were human clinical trials. Overall, the literature on this subject is limited, with mainly observational and animal studies, and few human clinical trials. CONCLUSION There is a need for additional human clinical trials on vitamin C supplementation in individuals with a DFU to fill the knowledge gap and guide clinical practice.
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Affiliation(s)
- Khanh Phuong Tong
- Dr William M Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, Illinois, US
| | - Robert Intine
- School of Graduate and Postdoctoral Studies, College of Health Professions, Rosalind Franklin University of Medicine and Science, Illinois, US
| | - Stephanie Wu
- Dr William M Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, Illinois, US
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30
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Eftekharpour E, Fernyhough P. Oxidative Stress and Mitochondrial Dysfunction Associated with Peripheral Neuropathy in Type 1 Diabetes. Antioxid Redox Signal 2022; 37:578-596. [PMID: 34416846 DOI: 10.1089/ars.2021.0152] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Significance: This review highlights the many intracellular processes generating reactive oxygen species (ROS) in the peripheral nervous system in the context of type 1 diabetes. The major sources of superoxide and hydrogen peroxide (H2O2) are described, and scavenging systems are explained. Important roles of ROS in regulating normal redox signaling and in a disease setting, such as diabetes, contributing to oxidative stress and cellular damage are outlined. The primary focus is the role of hyperglycemia in driving elevated ROS production and oxidative stress contributing to neurodegeneration in diabetic neuropathy (within the dorsal root ganglia [DRG] and peripheral nerve). Recent Advances: Contributors to ROS production under high intracellular glucose concentration such as mitochondria and the polyol pathway are discussed. The primarily damaging impact of ROS on multiple pathways including mitochondrial function, endoplasmic reticulum (ER) stress, autophagy, and epigenetic signaling is covered. Critical Issues: There is a strong focus on mechanisms of diabetes-induced mitochondrial dysfunction and how this may drive ROS production (in particular superoxide). The mitochondrial sites of superoxide/H2O2 production via mitochondrial metabolism and aerobic respiration are reviewed. Future Directions: Areas for future development are highlighted, including the need to clarify diabetes-induced changes in autophagy and ER function in neurons and Schwann cells. In addition, more clarity is needed regarding the sources of ROS production at mitochondrial sites under high glucose concentration (and lack of insulin signaling). New areas of study should be introduced to investigate the role of ROS, nuclear lamina function, and epigenetic signaling under diabetic conditions in peripheral nerve.
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Affiliation(s)
- Eftekhar Eftekharpour
- Department of Physiology and Pathophysiology and Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Paul Fernyhough
- Department of Pharmacology & Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.,Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Canada
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31
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Cosmo E, Midena G, Frizziero L, Bruno M, Cecere M, Midena E. Corneal Confocal Microscopy as a Quantitative Imaging Biomarker of Diabetic Peripheral Neuropathy: A Review. J Clin Med 2022; 11:5130. [PMID: 36079060 PMCID: PMC9457345 DOI: 10.3390/jcm11175130] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Distal symmetric polyneuropathy (DPN), particularly chronic sensorimotor DPN, represents one of the most frequent complications of diabetes, affecting 50% of diabetic patients and causing an enormous financial burden. Whilst diagnostic methods exist to detect and monitor this condition, they have significant limitations, mainly due to their high subjectivity, invasiveness, and non-repeatability. Corneal confocal microscopy (CCM) is an in vivo, non-invasive, and reproducible diagnostic technique for the study of all corneal layers including the sub-basal nerve plexus, which represents part of the peripheral nervous system. We reviewed the current literature on the use of CCM as an instrument in the assessment of diabetic patients, particularly focusing on its role in the study of sub-basal nerve plexus alterations as a marker of DPN. CCM has been demonstrated to be a valid in vivo tool to detect early sub-basal nerve plexus damage in adult and pediatric diabetic patients, correlating with the severity of DPN. Despite its great potential, CCM has still limited application in daily clinical practice, and more efforts still need to be made to allow the dissemination of this technique among doctors taking care of diabetic patients.
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Affiliation(s)
| | | | - Luisa Frizziero
- Department of Neuroscience-Ophthalmology, University of Padova, 35128 Padova, Italy
| | | | | | - Edoardo Midena
- IRCCS—Fondazione Bietti, 00198 Rome, Italy
- Department of Neuroscience-Ophthalmology, University of Padova, 35128 Padova, Italy
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32
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Tyler EF, McGhee CNJ, Lawrence B, Braatvedt GD, Mankowski JL, Oakley JD, Sethi S, Misra SL. Corneal Nerve Changes Observed by In Vivo Confocal Microscopy in Patients Receiving Oxaliplatin for Colorectal Cancer: The COCO Study. J Clin Med 2022; 11:jcm11164770. [PMID: 36013010 PMCID: PMC9409896 DOI: 10.3390/jcm11164770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/08/2022] [Accepted: 08/08/2022] [Indexed: 11/24/2022] Open
Abstract
An objective method of early identification of people at risk of chemotherapy-induced peripheral neuropathy is needed to minimize long-term toxicity and maximize dose intensity. The aims of the study were to observe corneal nerve microstructure and corneal sensitivity changes and peripheral neuropathy in patients receiving oxaliplatin, and to determine its association with corneal parameters at different stages of treatment and assess utility as non-invasive markers to detect and monitor peripheral neuropathy. Twenty-three patients scheduled to receive oxaliplatin chemotherapy with intravenous 5-FU for gastro-intestinal cancer were recruited and followed up with for 12 months. Ocular examinations including corneal and retinal evaluations, alongside peripheral neuropathy assessment, were performed. The corneal nerve density did not show significant change after chemotherapy when measured with a widely used semi-automated program or an automated analysis technique. Macula and optic nerve function did not change during or after oxaliplatin chemotherapy. However, the corneal nerve density modestly correlated with clinical peripheral neuropathy after 20 weeks of chemotherapy (r = 0.61, p = 0.01) when peripheral neuropathy is typical most profound, and corneal nerve sensitivity correlated with neuropathy at 12 (r = 0.55, p = 0.01) and 20 weeks (r = 0.64, p = 0.006). In conclusion, corneal changes detected on confocal microscopy show moderate association with peripheral neuropathy, indicating their potential to identify the development of oxaliplatin-induced peripheral neuropathy. However, further studies are required to confirm these findings.
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Affiliation(s)
- Ellen F. Tyler
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
| | - Charles N. J. McGhee
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
| | - Benjamin Lawrence
- Department of Oncology, The University of Auckland, Auckland 1142, New Zealand
| | - Geoffrey D. Braatvedt
- Department of Endocrinology, Greenlane Clinical Centre, Auckland District Health Board, Auckland 1051, New Zealand
| | - Joseph L. Mankowski
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD 21205, USA
| | | | - Sargun Sethi
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
| | - Stuti L. Misra
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
- Correspondence:
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Picconi F, Ryan CP, Russo B, Ciotti S, Pepe A, Menduni M, Lacquaniti F, Frontoni S, Moscatelli A. The evaluation of tactile dysfunction in the hand in type 1 diabetes: a novel method based on haptics. Acta Diabetol 2022; 59:1073-1082. [PMID: 35641837 PMCID: PMC9242965 DOI: 10.1007/s00592-022-01903-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/05/2022] [Indexed: 11/30/2022]
Abstract
AIMS We present an innovative method based on haptics for the evaluation of the sense of touch in the hand, in people affected by type 1 diabetes. METHODS Forty individuals affected by diabetes and 20 healthy controls took part in the study; the diabetes group was further divided into two subgroups based on vibration sensitivity in the lower limb. By means of a novel haptic device, tactile sensitivity in the fingertip was measured as the ability of the participants to discriminate slip motion speed. RESULTS Tactile sensitivity was significantly lower in individuals affected by diabetes as compared to controls. Depending on the subgroup, the difference from the controls was equal to 0.11 (95% CI from 0.029 to 0.186) and to 0.267 (95% CI from 0.198 to 0.336). Within the diabetes group, tactile sensitivity correlated with vibration sensitivity in the upper (p = 0.001) and lower limb (p = 0.003). A significant relationship between nerve conduction parameters and tactile sensitivity was found (p = 0.03). Finally, we combined the different predictors (clinical, vibratory and electroneurography data) by using cluster analysis; tactile sensitivity was found to be significantly different between different clusters (p = 0.004). CONCLUSIONS Early signs of tactile dysfunction in the hand were found in individuals affected by diabetes, even in absence of diabetic neuropathy. The protocol presented in this study is a promising tool for the assessment of tactile dysfunction in the hand in people affected by type 1 diabetes.
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Affiliation(s)
- F Picconi
- Unit of Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita, Fatebenefratelli Hospital, Rome, Italy
| | - C P Ryan
- Department of Systems Medicine and Centre of Space Biomedicine, University of Rome Tor Vergata, Rome, Italy
- Laboratory of Neuromotor Physiology, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - B Russo
- Unit of Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita, Fatebenefratelli Hospital, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - S Ciotti
- Department of Systems Medicine and Centre of Space Biomedicine, University of Rome Tor Vergata, Rome, Italy
- Laboratory of Neuromotor Physiology, IRCCS Fondazione Santa Lucia, Rome, Italy
- Research Centre "E. Piaggio" and Department of Information Engineering, University of Pisa, Pisa, Italy
| | - A Pepe
- Unit of Neurology, S. Giovanni Calibita Fatebenefratelli Hospital, Rome, Italy
| | - M Menduni
- Unit of Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita, Fatebenefratelli Hospital, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - F Lacquaniti
- Department of Systems Medicine and Centre of Space Biomedicine, University of Rome Tor Vergata, Rome, Italy
- Laboratory of Neuromotor Physiology, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - S Frontoni
- Unit of Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita, Fatebenefratelli Hospital, Rome, Italy.
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - A Moscatelli
- Department of Systems Medicine and Centre of Space Biomedicine, University of Rome Tor Vergata, Rome, Italy
- Laboratory of Neuromotor Physiology, IRCCS Fondazione Santa Lucia, Rome, Italy
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Raicher I, Ravagnani LHC, Correa SG, Dobo C, Mangueira CLP, Macarenco RSES. Investigation of nerve fibers in the skin by biopsy: technical aspects, indications, and contribution to diagnosis of small-fiber neuropathy. EINSTEIN-SAO PAULO 2022; 20:eMD8044. [PMID: 35830153 PMCID: PMC9262281 DOI: 10.31744/einstein_journal/2022md8044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/06/2022] [Indexed: 11/05/2022] Open
Abstract
Skin biopsy with investigation of small-diameter nerve fibers in human epidermis and dermis has been proven to be a useful method for confirming small-fiber neuropathy. In medical practice, small-fiber neuropathy is increasingly recognized as a leading cause of neuropathic pain. It is a prevalent complaint in medical offices, brought by patients often as a “painful burning sensation”. The prevalence of neuropathic pain is high in small-fiber neuropathies of different etiologies, especially in the elderly; 7% of population in this age group present peripheral neuropathy. Pain and paresthesia are symptoms which might cause disability and impair quality of life of patients. The early detection of small-fiber neuropathy can contribute to reducing unhealthy lifestyles, associated to higher incidence of the disease.
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Tronstad C, Pabst O, Amini M, Kleggetveit IP, Elvebakk O, Martinsen OG, Jenssen TG, Hisdal J, Berg TJ, Qvigstad E. Development of a prototype toe sensor for detection of diabetic peripheral small fiber neuropathy. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2022; 2022:99-104. [PMID: 36086669 DOI: 10.1109/embc48229.2022.9871101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Diabetic peripheral neuropathy (DPN) affects a large proportion of people with diabetes, and early detection is essential to prevent further progression. Widespread clinical testing relies on simplicity and cost-effectiveness of examination. Early signs of DPN may be detected by assessing the sudomotor nerves, and sudomotor activity can be measured by bioimpedance. We present a prototype toe probe for DPN detection including sensors for measuring skin AC conductance, skin temperature and humidity. The prototype was tested on five participants with DPN and five healthy age-matched controls in a pilot study. Sudomotor sensor responses to a simple deep breathing test were very weak or absent in the DPN group, with all controls having larger responses than the DPN group. Evaporation was lower for the DPN group, and skin temperature was higher on average. For the same foot, the results for sudomotor responses were in agreement with sensory neurography amplitudes from the sural nerve whereas the monofilament test gave normal results for two of the DPN participants. If sufficient detection accuracy is confirmed in larger studies, the method may provide a simple and cost-effective tool to support clinical examination. Clinical Relevance- We present the early realization and testing of a simple device to support early detection of diabetic peripheral neuropathy.
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Abicca I, Giannini D, Gilardi M, Roszkowska AM, Parravano M, Picconi F, Frontoni S, Schiano-Lomoriello D. A Novel Algorithm for the Evaluation of Corneal Nerve Beadings by in vivo Confocal Microscopy in Patients With Type 1 Diabetes Mellitus. Front Med (Lausanne) 2022; 9:897259. [PMID: 35646958 PMCID: PMC9133533 DOI: 10.3389/fmed.2022.897259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/13/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Peripheral neuropathy could complicate diabetes mellitus (DM). In vivo confocal microscopy (IVCM) is an ocular examination for the diagnosis of small fiber neuropathies and the detection of the earliest corneal sub-basal nerve plexus (SBP) alterations. Corneal SBP characteristics include focal enlargement along with the nerve fiber, called corneal beadings. These dilatations represent a mitochondrial accumulation induced by the reactive oxygen stress, as a consequence of hyperglycemia. For this reason, corneal beadings are considered indicative of metabolic activity. This study aimed to describe the corneal characteristics of a population of type 1 diabetes mellitus (T1DM) well metabolically controlled, using a new algorithm for the analysis of corneal beading size (BS). Methods Patients aged ≥18 years affected by T1DM were compared with healthy subjects who underwent IVCM (Confoscan 4; Nidek Technologies Padova, Italy). Starting from the coordinates of the beadings detected by the IVCM, we implemented a new algorithm for automatically measuring BS in corneal SBP images. Results We compared 20 eyes of T1DM patients with 26 healthy controls. The corneal nerves' fiber length (p = 0.008), corneal nerves' fiber length density (p = 0.008), and the number of fibers (p = 0.017) were significantly lower in the diabetic group compared with controls. There was no difference between diabetic and healthy eyes in the mean number of corneal beadings both in the frame of analysis (p = 0.606) and for 0.1 mm of SBP nerve (p = 0.145). Regarding the BS, patients with T1DM had corneal beadings larger than controls (p = 0.036). Conclusions We found that the corneal beadings parameters are similar in healthy and T1DM individuals. Nevertheless, measuring the BS with our algorithm, we showed that corneal beadings are enlarged in patients affected by T1DM when compared with healthy controls. Identifying beading expansion in corneal nerve fiber using IVCM should become a useful tool to predict peripheral neuropathy at an early stage.
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Affiliation(s)
- Irene Abicca
- IRCCS–Fondazione Bietti, Rome, Italy
- *Correspondence: Irene Abicca
| | | | | | - Anna Maria Roszkowska
- Ophthalmology Clinic, Department of Biomedical Sciences, University of Messina, Messina, Italy
| | | | - Fabiana Picconi
- Unit of Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita, Fatebenefratelli Hospital, Rome, Italy
| | - Simona Frontoni
- Unit of Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita, Fatebenefratelli Hospital, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
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Thimm A, Carpinteiro A, Oubari S, Papathanasiou M, Kessler L, Rischpler C, Malik RA, Reinhardt HC, Rassaf T, Herrmann K, Kleinschnitz C, Stettner M, Hagenacker T. Corneal confocal microscopy to detect early immune-mediated small nerve fibre loss in AL amyloidosis. Ann Clin Transl Neurol 2022; 9:853-863. [PMID: 35488792 PMCID: PMC9186132 DOI: 10.1002/acn3.51565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/11/2022] [Accepted: 04/11/2022] [Indexed: 12/02/2022] Open
Abstract
Objective Light chain (AL) amyloidosis is a life‐threatening disorder characterised by extracellular deposition of amyloid leading to dysfunction of multiple organs. Peripheral nerve involvement, particularly small fibre neuropathy, may be associated with poorer survival. Corneal confocal microscopy (CCM) is a rapid and non‐invasive imaging technique to quantify corneal small nerve fibres and immune cells in vivo. We aimed to evaluate CCM as a tool for early diagnosis of peripheral nerve involvement in AL amyloidosis. Methods CCM and nerve conduction studies (NCS) were undertaken in 21 newly diagnosed, treatment‐naïve AL amyloidosis patients and 21 age‐ and sex‐matched healthy controls. Corneal nerve fibre density (CNFD), corneal nerve branch density and fibre length, and cell infiltrates were quantified in the sub‐basal layer of the cornea. Results There was a significant reduction in CNFD and nerve fibre length, even without large fibre affection and an increase in cell density, particularly around corneal nerve fibres in patients with AL amyloidosis compared to controls. Additionally, cell infiltration correlated with reduced nerve fibre density in patients with AL amyloidosis, but reduced CNFD did not correlate with laboratory parameters of organ dysfunction. Interpretation Our study is the first to show that CCM allows rapid non‐invasive identification of early small nerve fibre damage associated with immune cell infiltration in patients with AL amyloidosis. CCM detects peripheral nerve involvement more sensitively than NCS.
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Affiliation(s)
- Andreas Thimm
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Essen, Germany
| | - Alexander Carpinteiro
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany.,Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Sara Oubari
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
| | - Maria Papathanasiou
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany
| | - Lukas Kessler
- Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
| | | | - Rayaz Ahmed Malik
- Institute of Cardiovascular Science, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.,Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Hans Christian Reinhardt
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
| | - Christoph Kleinschnitz
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Essen, Germany
| | - Mark Stettner
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Essen, Germany
| | - Tim Hagenacker
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Essen, Germany
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Zhu BT. Biochemical mechanism underlying the pathogenesis of diabetic retinopathy and other diabetic complications in humans: the methanol-formaldehyde-formic acid hypothesis. Acta Biochim Biophys Sin (Shanghai) 2022; 54:415-451. [PMID: 35607958 PMCID: PMC9828688 DOI: 10.3724/abbs.2022012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/18/2021] [Indexed: 11/25/2022] Open
Abstract
Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions. Mechanistically, while formaldehyde is a cross-linking agent capable of causing extensive cytotoxicity, formic acid is an inhibitor of mitochondrial cytochrome oxidase, capable of inducing histotoxic hypoxia, ATP deficiency and cytotoxicity. Chronic increase in the production and accumulation of these toxic one-carbon metabolites in diabetic patients can drive the pathogenesis of ocular as well as other diabetic complications. This hypothesis is supported by a large body of experimental and clinical observations scattered in the literature. For instance, methanol is known to have organ- and species-selective toxicities, including the characteristic ocular lesions commonly seen in humans and non-human primates, but not in rodents. Similarly, some of the diabetic complications (such as ocular lesions) also have a characteristic species-selective pattern, closely resembling methanol intoxication. Moreover, while alcohol consumption or combined use of folic acid plus vitamin B is beneficial for mitigating acute methanol toxicity in humans, their use also improves the outcomes of diabetic complications. In addition, there is also a large body of evidence from biochemical and cellular studies. Together, there is considerable experimental support for the proposed hypothesis that increased metabolic formation of toxic one-carbon metabolites in diabetic patients contributes importantly to the development of various clinical complications.
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Affiliation(s)
- Bao Ting Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and DevelopmentSchool of MedicineThe Chinese University of Hong KongShenzhen518172China
- Department of PharmacologyToxicology and TherapeuticsSchool of MedicineUniversity of Kansas Medical CenterKansas CityKS66160USA
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Petropoulos IN, Bitirgen G, Ferdousi M, Kalteniece A, Azmi S, D'Onofrio L, Lim SH, Ponirakis G, Khan A, Gad H, Mohammed I, Mohammadi YE, Malik A, Gosal D, Kobylecki C, Silverdale M, Soran H, Alam U, Malik RA. Corneal Confocal Microscopy to Image Small Nerve Fiber Degeneration: Ophthalmology Meets Neurology. FRONTIERS IN PAIN RESEARCH 2022; 2:725363. [PMID: 35295436 PMCID: PMC8915697 DOI: 10.3389/fpain.2021.725363] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/26/2021] [Indexed: 12/13/2022] Open
Abstract
Neuropathic pain has multiple etiologies, but a major feature is small fiber dysfunction or damage. Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that can image small nerve fibers in the cornea and has been utilized to show small nerve fiber loss in patients with diabetic and other neuropathies. CCM has comparable diagnostic utility to intraepidermal nerve fiber density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fiber loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease and dementia. We conclude that corneal confocal microscopy has good diagnostic and prognostic capability and fulfills the FDA criteria as a surrogate end point for clinical trials in peripheral and central neurodegenerative diseases.
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Affiliation(s)
| | - Gulfidan Bitirgen
- Department of Ophthalmology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Maryam Ferdousi
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Alise Kalteniece
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Shazli Azmi
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom.,Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Luca D'Onofrio
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Sze Hway Lim
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | | | - Adnan Khan
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Hoda Gad
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Ibrahim Mohammed
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | - Ayesha Malik
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - David Gosal
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | - Christopher Kobylecki
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | - Monty Silverdale
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine, Clinical Sciences Centre, Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool University Hospital National Health System (NHS) Foundation Trust, Liverpool, United Kingdom
| | - Rayaz A Malik
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.,Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
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40
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Shillo P, Yiangou Y, Donatien P, Greig M, Selvarajah D, Wilkinson ID, Anand P, Tesfaye S. Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes. FRONTIERS IN PAIN RESEARCH 2022; 2:731658. [PMID: 35295465 PMCID: PMC8915761 DOI: 10.3389/fpain.2021.731658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/13/2021] [Indexed: 01/19/2023] Open
Abstract
Painful diabetic peripheral neuropathy can be intractable with a major impact, yet the underlying pain mechanisms remain uncertain. A range of neuronal and vascular biomarkers was investigated in painful diabetic peripheral neuropathy (painful-DPN) and painless-DPN and used to differentiate painful-DPN from painless-DPN. Skin biopsies were collected from 61 patients with type 2 diabetes (T2D), and 19 healthy volunteers (HV). All subjects underwent detailed clinical and neurophysiological assessments. Based on the neuropathy composite score of the lower limbs [NIS(LL)] plus seven tests, the T2D subjects were subsequently divided into three groups: painful-DPN (n = 23), painless-DPN (n = 19), and No-DPN (n = 19). All subjects underwent punch skin biopsy, and immunohistochemistry used to quantify total intraepidermal nerve fibers (IENF) with protein gene product 9.5 (PGP9.5), regenerating nerve fibers with growth-associated protein 43 (GAP43), peptidergic nerve fibers with calcitonin gene-related peptide (CGRP), and blood vessels with von Willebrand Factor (vWF). The results showed that IENF density was severely decreased (p < 0.001) in both DPN groups, with no differences for PGP9.5, GAP43, CGRP, or GAP43/PGP9.5 ratios. There was a significant increase in blood vessel (vWF) density in painless-DPN and No-DPN groups compared to the HV group, but this was markedly greater in the painful-DPN group, and significantly higher than in the painless-DPN group (p < 0.0001). The ratio of sub-epidermal nerve fiber (SENF) density of CGRP:vWF showed a significant decrease in painful-DPN vs. painless-DPN (p = 0.014). In patients with T2D with advanced DPN, increased dermal vasculature and its ratio to nociceptors may differentiate painful-DPN from painless-DPN. We hypothesized that hypoxia-induced increase of blood vessels, which secrete algogenic substances including nerve growth factor (NGF), may expose their associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN.
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Affiliation(s)
- Pallai Shillo
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Yiangos Yiangou
- Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Philippe Donatien
- Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Marni Greig
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Dinesh Selvarajah
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Iain D Wilkinson
- Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom
| | - Praveen Anand
- Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
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41
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Al-Bazz DY, Nelson AJ, Burgess J, Petropoulos IN, Nizza J, Marshall A, Brown E, Cuthbertson DJ, Marshall AG, Malik RA, Alam U. Is Nerve Electrophysiology a Robust Primary Endpoint in Clinical Trials of Treatments for Diabetic Peripheral Neuropathy? Diagnostics (Basel) 2022; 12:731. [PMID: 35328284 PMCID: PMC8947384 DOI: 10.3390/diagnostics12030731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/10/2022] Open
Abstract
There is currently no FDA-approved disease-modifying therapy for diabetic peripheral neuropathy (DPN). Nerve conduction velocity (NCV) is an established primary endpoint of disease-modifying therapies in DPN and clinical trials have been powered with an assumed decline of 0.5 m/s/year. This paper sought to establish the time-dependent change in NCV associated with a placebo, compared to that observed in the active intervention group. A literature search identified twenty-one double-blind, randomised controlled trials in DPN of ≥1 year duration conducted between 1971 and 2021. We evaluated changes in neurophysiology, with a focus on peroneal motor and sural sensory NCV and amplitude in the placebo and treatment groups. There was significant variability in the change and direction of change (reduction/increase) in NCV in the placebo arm, as well as variability influenced by the anatomical site of neurophysiological measurement within a given clinical trial. A critical re-evaluation of efficacy trials should consider placebo-adjusted effects and present the placebo-subtracted change in NCV rather than assume a universal annual decline of 0.5 m/s/year. Importantly, endpoints such as corneal confocal microscopy (CCM) have demonstrated early nerve repair, whilst symptoms and NCV have not changed, and should thus be considered as a viable alternative.
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Affiliation(s)
- Dalal Y. Al-Bazz
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Andrew J. Nelson
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Jamie Burgess
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Ioannis N. Petropoulos
- Research Division, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha 24144, Qatar; (I.N.P.); (R.A.M.)
| | - Jael Nizza
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Anne Marshall
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Emily Brown
- Obesity and Endocrinology Research Group, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (E.B.); (D.J.C.)
| | - Daniel J. Cuthbertson
- Obesity and Endocrinology Research Group, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (E.B.); (D.J.C.)
| | - Andrew G. Marshall
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
- Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester M13 9WL, UK
| | - Rayaz A. Malik
- Research Division, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha 24144, Qatar; (I.N.P.); (R.A.M.)
- Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester M13 9WL, UK
| | - Uazman Alam
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester M13 9PL, UK
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42
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Khan A, Pasquier J, Ramachandran V, Ponirakis G, Petropoulos IN, Chidiac O, Thomas B, Robay A, Jayyousi A, Al Suwaidi J, Rafii A, Menzies RA, Talal TK, Najafi-Shoushtari SH, Abi Khalil C, Malik RA. Altered Circulating microRNAs in Patients with Diabetic Neuropathy and Corneal Nerve Loss: A Pilot Study. J Clin Med 2022; 11:jcm11061632. [PMID: 35329958 PMCID: PMC8956033 DOI: 10.3390/jcm11061632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/27/2022] [Indexed: 02/05/2023] Open
Abstract
An alteration in circulating miRNAs may have important diagnostic and therapeutic relevance in diabetic neuropathy. Patients with type 2 diabetes mellitus (T2DM) underwent an assessment of neuropathic symptoms using Douleur Neuropathique 4 (DN4), the vibration perception threshold (VPT) using a Neurothesiometer, sudomotor function using the Sudoscan, corneal nerve morphology using corneal confocal microscopy (CCM) and circulating miRNAs using high-throughput miRNA expression profiling. Patients with T2DM, with (n = 9) and without (n = 7) significant corneal nerve loss were comparable in age, gender, diabetes duration, BMI, HbA1c, eGFR, blood pressure, and lipid profile. The VPT was significantly higher (p < 0.05), and electrochemical skin conductance (p < 0.05), corneal nerve fiber density (p = 0.001), corneal nerve branch density (p = 0.013), and corneal nerve fiber length (p < 0.001) were significantly lower in T2DM patients with corneal nerve loss compared to those without corneal nerve loss. Following a q-PCR-based analysis of total plasma microRNAs, we found that miR-92b-3p (p = 0.008) was significantly downregulated, while miR-22-3p (p = 0.0001) was significantly upregulated in T2DM patients with corneal nerve loss. A network analysis revealed that these miRNAs regulate axonal guidance and neuroinflammation genes. These data support the need for more extensive studies to better understand the role of dysregulated miRNAs’ in diabetic neuropathy.
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Affiliation(s)
- Adnan Khan
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (A.K.); (G.P.); (I.N.P.)
- Faculty of Health Sciences, Khyber Medical University, Peshawar P.O. Box 25100, Pakistan
| | - Jennifer Pasquier
- Epigenetics Cardiovascular Laboratory, Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (J.P.); (O.C.); (B.T.); (A.R.); (A.R.)
| | - Vimal Ramachandran
- MicroRNA Core Laboratory, Research Division, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (V.R.); (S.H.N.-S.)
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Georgios Ponirakis
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (A.K.); (G.P.); (I.N.P.)
| | - Ioannis N. Petropoulos
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (A.K.); (G.P.); (I.N.P.)
| | - Omar Chidiac
- Epigenetics Cardiovascular Laboratory, Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (J.P.); (O.C.); (B.T.); (A.R.); (A.R.)
| | - Binitha Thomas
- Epigenetics Cardiovascular Laboratory, Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (J.P.); (O.C.); (B.T.); (A.R.); (A.R.)
| | - Amal Robay
- Epigenetics Cardiovascular Laboratory, Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (J.P.); (O.C.); (B.T.); (A.R.); (A.R.)
| | - Amin Jayyousi
- Hamad Medical Corporation, Doha P.O. Box 24144, Qatar; (A.J.); (J.A.S.); (R.A.M.); (T.K.T.)
| | - Jassim Al Suwaidi
- Hamad Medical Corporation, Doha P.O. Box 24144, Qatar; (A.J.); (J.A.S.); (R.A.M.); (T.K.T.)
| | - Arash Rafii
- Epigenetics Cardiovascular Laboratory, Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (J.P.); (O.C.); (B.T.); (A.R.); (A.R.)
| | - Robert A. Menzies
- Hamad Medical Corporation, Doha P.O. Box 24144, Qatar; (A.J.); (J.A.S.); (R.A.M.); (T.K.T.)
| | - Talal K. Talal
- Hamad Medical Corporation, Doha P.O. Box 24144, Qatar; (A.J.); (J.A.S.); (R.A.M.); (T.K.T.)
| | - Seyed Hani Najafi-Shoushtari
- MicroRNA Core Laboratory, Research Division, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (V.R.); (S.H.N.-S.)
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Charbel Abi Khalil
- Epigenetics Cardiovascular Laboratory, Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (J.P.); (O.C.); (B.T.); (A.R.); (A.R.)
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Correspondence: (C.A.K.); (R.A.M.); Tel.: +974-4492-8484 (C.A.K.); +974-4492-8256 (R.A.M.)
| | - Rayaz A. Malik
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar; (A.K.); (G.P.); (I.N.P.)
- Correspondence: (C.A.K.); (R.A.M.); Tel.: +974-4492-8484 (C.A.K.); +974-4492-8256 (R.A.M.)
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Hossain MJ, Kendig MD, Letton ME, Morris MJ, Arnold R. Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions. Diabetes Metab J 2022; 46:198-221. [PMID: 35385634 PMCID: PMC8987683 DOI: 10.4093/dmj.2021.0347] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/25/2022] [Indexed: 11/08/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the 'Neurodiab' criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.
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Affiliation(s)
- Md Jakir Hossain
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Michael D. Kendig
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Meg E. Letton
- Department of Exercise Physiology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Margaret J. Morris
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Ria Arnold
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
- Department of Exercise Physiology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
- Department of Exercise and Rehabilitation, School of Medical, Indigenous and Health Science, University of Wollongong, Wollongong, Australia
- Corresponding author: Ria Arnold https://orcid.org/0000-0002-7469-6587 Department of Exercise Physiology, School of Health Sciences, UNSW Sydney, Sydney, NSW 2052, Australia E-mail:
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Newlin Lew K, Arnold T, Cantelmo C, Jacque F, Posada-Quintero H, Luthra P, Chon KH. Diabetes Distal Peripheral Neuropathy: Subtypes and Diagnostic and Screening Technologies. J Diabetes Sci Technol 2022; 16:295-320. [PMID: 34994241 PMCID: PMC8861801 DOI: 10.1177/19322968211035375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Diabetes distal symmetrical peripheral neuropathy (DSPN) is the most prevalent form of neuropathy in industrialized countries, substantially increasing risk for morbidity and pre-mature mortality. DSPN may manifest with small-fiber disease, large-fiber disease, or a combination of both. This review summarizes: (1) DSPN subtypes (small- and large-fiber disease) with attention to clinical signs and patient symptoms; and (2) technological diagnosis and screening for large- and small-fiber disease with inclusion of a comprehensive literature review of published studies from 2015-present (N = 66). Review findings, informed by the most up-to-date research, advance critical understanding of DSPN large- and small-fiber screening technologies, including those designed for point-of-care use in primary care and endocrinology practices.
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Affiliation(s)
- Kelley Newlin Lew
- School of Nursing, University of
Connecticut (UConn), Storrs, CT, USA
- Kelley Newlin Lew, School of Nursing,
University of Connecticut (UConn), 231 Glenbrook Road, Storrs, CT 06269, USA.
| | - Tracey Arnold
- School of Nursing, University of
Connecticut (UConn), Storrs, CT, USA
| | | | - Francky Jacque
- Hispanic Alliance of Southeastern
Connecticut, New London, CT, USA
| | - Hugo Posada-Quintero
- Biomedical Engineering Department,
University of Connecticut (UConn), Storrs, CT, USA
| | - Pooja Luthra
- Division of Endocrinology and
Metabolism, UConn Health, Farmington, CT, USA
| | - Ki H. Chon
- Biomedical Engineering Department,
University of Connecticut (UConn), Storrs, CT, USA
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Jolivalt CG, Aghanoori MR, Navarro-Diaz MC, Han MM, Sanchez G, Guernsey L, Quach D, Johe K, Fernyhough P, Calcutt NA. Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes. J Diabetes Res 2022; 2022:8566970. [PMID: 35967127 PMCID: PMC9372526 DOI: 10.1155/2022/8566970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/17/2022] [Indexed: 12/03/2022] Open
Abstract
AIMS Mitochondrial dysfunction contributes to many forms of peripheral and central nervous system degeneration. Therapies that protect mitochondrial number and function have the potential to impact the progression of conditions such as diabetic neuropathy. We therefore assessed indices of mitochondrial function in dorsal root ganglia (DRG) and brain cortex of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes and tested the therapeutic impact of a neurogenic compound, NSI-189, on both mitochondrial function and indices of peripheral and central neurological dysfunction. MATERIALS AND METHODS ZDF rats were maintained for 16 weeks of untreated diabetes before the start of oral treatment with NSI-189 for an additional 16 weeks. Nerve conduction velocity, sensitivity to tactile and thermal stimuli, and behavioral assays of cognitive function were assessed monthly. AMP-activated protein kinase (AMPK) phosphorylation, mitochondrial protein levels, and respiratory complex activities were assessed in the DRG and brain cortex after 16 weeks of treatment with NSI-189. RESULTS Treatment with NSI-189 selectively elevated the expression of protein subunits of complexes III and V and activities of respiratory complexes I and IV in the brain cortex, and this was accompanied by amelioration of impaired memory function and plasticity. In the sensory ganglia of ZDF rats, loss of AMPK activity was ameliorated by NSI-189, and this was accompanied by reversal of multiple indices of peripheral neuropathy. CONCLUSIONS Efficacy of NSI-189 against dysfunction of the CNS and PNS function in type 2 diabetic rats was accompanied by improvement of mitochondrial function. NSI-189 exhibited actions at different levels of mitochondrial regulation in central and peripheral tissues.
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Affiliation(s)
- C. G. Jolivalt
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - M. R. Aghanoori
- Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - M. C. Navarro-Diaz
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - M. M. Han
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - G. Sanchez
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - L. Guernsey
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - D. Quach
- Neuralstem Inc., Germantown, MD, USA
| | - K. Johe
- Neuralstem Inc., Germantown, MD, USA
| | - P. Fernyhough
- Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - N. A. Calcutt
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
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Gad H, Petropoulos IN, Khan A, Ponirakis G, MacDonald R, Alam U, Malik RA. Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: A systematic review and meta-analysis. J Diabetes Investig 2022; 13:134-147. [PMID: 34351711 PMCID: PMC8756328 DOI: 10.1111/jdi.13643] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that identifies corneal nerve fiber damage. Small studies suggest that CCM could be used to assess patients with diabetic peripheral neuropathy (DPN). AIM To undertake a systematic review and meta-analysis assessing the diagnostic utility of CCM for sub-clinical DPN (DPN- ) and established DPN (DPN+ ). DATA SOURCES Databases (PubMed, Embase, Central, ProQuest) were searched for studies using CCM in patients with diabetes up to April 2020. STUDY SELECTION Studies were included if they reported on at least one CCM parameter in patients with diabetes. DATA EXTRACTION Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and inferior whorl length (IWL) were compared between patients with diabetes with and without DPN and controls. Meta-analysis was undertaken using RevMan V.5.3. DATA SYNTHESIS Thirty-eight studies including ~4,000 participants were included in this meta-analysis. There were significant reductions in CNFD, CNBD, CNFL, and IWL in DPN- vs controls (P < 0.00001), DPN+ vs controls (P < 0.00001), and DPN+ vs DPN- (P < 0.00001). CONCLUSION This systematic review and meta-analysis shows that CCM detects small nerve fiber loss in subclinical and clinical DPN and concludes that CCM has good diagnostic utility in DPN.
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Affiliation(s)
- Hoda Gad
- Department of MedicineWeill Cornell Medicine‐QatarDohaQatar
| | | | - Adnan Khan
- Department of MedicineWeill Cornell Medicine‐QatarDohaQatar
| | | | | | - Uazman Alam
- Diabetes and Neuropathy ResearchDepartment of Eye and Vision Sciences and Pain Research InstituteInstitute of Ageing and Chronic DiseaseUniversity of Liverpool and Aintree University Hospital NHS Foundation TrustLiverpoolUK
- Department of Diabetes and EndocrinologyRoyal Liverpool and Broadgreen University NHS Hospital TrustLiverpoolUK
- Division of Endocrinology, Diabetes and GastroenterologyUniversity of ManchesterManchesterUK
| | - Rayaz A Malik
- Department of MedicineWeill Cornell Medicine‐QatarDohaQatar
- Institute of Cardiovascular MedicineUniversity of ManchesterManchesterUK
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Sloan G, Alam U, Selvarajah D, Tesfaye S. The Treatment of Painful Diabetic Neuropathy. Curr Diabetes Rev 2022; 18:e070721194556. [PMID: 34238163 DOI: 10.2174/1573399817666210707112413] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/18/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, and Liverpool University Hospital, NHS Foundation Trust, Liverpool, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
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Carmichael J, Fadavi H, Ishibashi F, Howard S, Boulton AJM, Shore AC, Tavakoli M. Implementation of corneal confocal microscopy for screening and early detection of diabetic neuropathy in primary care alongside retinopathy screening: Results from a feasibility study. Front Endocrinol (Lausanne) 2022; 13:891575. [PMID: 36313738 PMCID: PMC9597366 DOI: 10.3389/fendo.2022.891575] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 09/12/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Screening for diabetic peripheral neuropathy (DPN) is essential for early detection and timely intervention. Quantitative assessment of small nerve fiber damage is key to the early diagnosis and assessment of its progression. Corneal confocal microscopy (CCM) is a non-invasive, in-vivo diagnostic technique that provides an accurate surrogate biomarker for small-fiber neuropathy. In this novel study for the first time, we introduced CCM to primary care as a screening tool for DPN alongside retinopathy screening to assess the level of neuropathy in this novel cohort. RESEARCH DESIGN AND METHODS 450 consecutive subjects with type 1 or type 2 diabetes attending for annual eye screening in primary care optometry settings underwent assessment with CCM to establish the prevalence of sub-clinical diabetic peripheral neuropathy. Subjects underwent assessment for neurological and ocular symptoms of diabetes and a history of diabetic foot disease, neuropathy and diabetic retinopathy (DR). RESULTS CCM examination was completed successfully in 427 (94.9%) subjects, 22% of whom had neuropathy according to Diabetic Neuropathy Symptom (DNS) score. The prevalence of sub-clinical neuropathy as defined by abnormal corneal nerve fiber length (CNFL) was 12.9%. In the subjects with a short duration of type 2 diabetes, 9.2% had abnormal CNFL. CCM showed significant abnormalities in corneal nerve parameters in this cohort of subjects with reduction of corneal nerve fiber density (CNFD, p<0.001), CNFL (p<0.001) and corneal nerve branch density (CNBD, p<0.001) compared to healthy subjects. In subjects who had no evidence of DR (67% of all subjects), 12.0% had abnormal CNFL. CONCLUSIONS CCM may be a sensitive biomarker for early detection and screening of DPN in primary care alongside retinopathy screening.
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Affiliation(s)
- Josie Carmichael
- Exeter Centre of Excellence for Diabetes Research, National Institute for Health and Care Research (NIHR) Exeter Clinical Research Facility, and Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
| | - Hassan Fadavi
- Peripheral Neuropathy Group, Imperial College, London, United Kingdom
- University of Manchester, Division of Diabetes, Endocrinology & Gastroenterology, University of Manchester, Manchester, United Kingdom
| | - Fukashi Ishibashi
- Internal Medicine, Ishibashi Medical and Diabetes Centre, Hiroshima, Japan
| | - Susan Howard
- National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care (NIHR CLAHRC), Manchester, United Kingdom
| | - Andrew J. M. Boulton
- University of Manchester, Division of Diabetes, Endocrinology & Gastroenterology, University of Manchester, Manchester, United Kingdom
| | - Angela C. Shore
- Exeter Centre of Excellence for Diabetes Research, National Institute for Health and Care Research (NIHR) Exeter Clinical Research Facility, and Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
| | - Mitra Tavakoli
- Exeter Centre of Excellence for Diabetes Research, National Institute for Health and Care Research (NIHR) Exeter Clinical Research Facility, and Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
- University of Manchester, Division of Diabetes, Endocrinology & Gastroenterology, University of Manchester, Manchester, United Kingdom
- *Correspondence: Mitra Tavakoli,
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Verdugo RJ, Matamala JM, Inui K, Kakigi R, Valls-Solé J, Hansson P, Bernhard Nilsen K, Lombardi R, Lauria G, Petropoulos IN, Malik RA, Treede RD, Baumgärtner U, Jara PA, Campero M. Review of techniques useful for the assessment of sensory small fiber neuropathies: Report from an IFCN expert group. Clin Neurophysiol 2022; 136:13-38. [DOI: 10.1016/j.clinph.2022.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 02/09/2023]
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Burgess J, Ferdousi M, Gosal D, Boon C, Matsumoto K, Marshall A, Mak T, Marshall A, Frank B, Malik RA, Alam U. Chemotherapy-Induced Peripheral Neuropathy: Epidemiology, Pathomechanisms and Treatment. Oncol Ther 2021; 9:385-450. [PMID: 34655433 PMCID: PMC8593126 DOI: 10.1007/s40487-021-00168-y] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/12/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSE This review provides an update on the current clinical, epidemiological and pathophysiological evidence alongside the diagnostic, prevention and treatment approach to chemotherapy-induced peripheral neuropathy (CIPN). FINDINGS The incidence of cancer and long-term survival after treatment is increasing. CIPN affects sensory, motor and autonomic nerves and is one of the most common adverse events caused by chemotherapeutic agents, which in severe cases leads to dose reduction or treatment cessation, with increased mortality. The primary classes of chemotherapeutic agents associated with CIPN are platinum-based drugs, taxanes, vinca alkaloids, bortezomib and thalidomide. Platinum agents are the most neurotoxic, with oxaliplatin causing the highest prevalence of CIPN. CIPN can progress from acute to chronic, may deteriorate even after treatment cessation (a phenomenon known as coasting) or only partially attenuate. Different chemotherapeutic agents share both similarities and key differences in pathophysiology and clinical presentation. The diagnosis of CIPN relies heavily on identifying symptoms, with limited objective diagnostic approaches targeting the class of affected nerve fibres. Studies have consistently failed to identify at-risk cohorts, and there are no proven strategies or interventions to prevent or limit the development of CIPN. Furthermore, multiple treatments developed to relieve symptoms and to modify the underlying disease in CIPN have failed. IMPLICATIONS The increasing prevalence of CIPN demands an objective approach to identify at-risk patients in order to prevent or limit progression and effectively alleviate the symptoms associated with CIPN. An evidence base for novel targets and both pharmacological and non-pharmacological treatments is beginning to emerge and has been recognised recently in publications by the American Society of Clinical Oncology and analgesic trial design expert groups such as ACTTION.
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Affiliation(s)
- Jamie Burgess
- Department of Cardiovascular and Metabolic Medicine, The Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool University Hospital NHS Trust, Liverpool, UK.
- Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool, L9 7AL, UK.
| | - Maryam Ferdousi
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, NIHR/Wellcome Trust Clinical Research Facility, Manchester, UK
| | - David Gosal
- Department of Neurology, Salford Royal NHS Foundation Trust, Salford, UK
| | - Cheng Boon
- Department of Clinical Oncology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Kohei Matsumoto
- Department of Cardiovascular and Metabolic Medicine, The Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool University Hospital NHS Trust, Liverpool, UK
| | - Anne Marshall
- Department of Cardiovascular and Metabolic Medicine, The Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool University Hospital NHS Trust, Liverpool, UK
| | - Tony Mak
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Andrew Marshall
- Faculty of Health and Life Sciences, Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, UK
- Faculty of Health and Life Sciences, The Pain Research Institute, University of Liverpool, Liverpool, L9 7AL, UK
- Department of Pain Medicine, The Walton Centre, Liverpool, L9 7LJ, UK
| | - Bernhard Frank
- Department of Pain Medicine, The Walton Centre, Liverpool, L9 7LJ, UK
| | - Rayaz A Malik
- Research Division, Qatar Foundation, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
- Institute of Cardiovascular Sciences, University of Manchester, Manchester, M13 9PL, UK
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine, The Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool University Hospital NHS Trust, Liverpool, UK.
- Division of Endocrinology, Diabetes and Gastroenterology, University of Manchester, Manchester, M13 9PT, UK.
- Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool, L9 7AL, UK.
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