Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy.

AIMS/HYPOTHESIS: Diabetic peripheral neuropathy (DPN) is a highly prevalent cause of physical disability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes and animal studies have shown that glucagon-like peptide-1 (GLP-1) receptors are present in the central and peripheral nervous systems. This study investigated whether GLP-1 RAs can improve nerve structure. METHODS: Nerve structure was assessed using peripheral nerve ultrasonography and measurement of tibial nerve cross-sectional area, in conjunction with validated neuropathy symptom scores and nerve conduction studies. A total of 22 consecutively recruited participants with type 2 diabetes were assessed before and 1 month after commencing GLP-1 RA therapy (semaglutide or dulaglutide). RESULTS: There was a pathological increase in nerve size before treatment in 81.8% of the cohort (n=22). At 1 month of follow-up, there was an improvement in nerve size in 86% of participants (p<0.05), with 32% returning to normal nerve morphology. A 3 month follow-up study (n=14) demonstrated further improvement in nerve size in 93% of participants, accompanied by reduced severity of neuropathy (p<0.05) and improved sural sensory nerve conduction amplitude (p<0.05). CONCLUSIONS/INTERPRETATION: This study demonstrates the efficacy of GLP-1 RAs in improving neuropathy outcomes, evidenced by improvements in mainly structural and morphological measures and supported by electrophysiological and clinical endpoints. Future studies, incorporating quantitative sensory testing and measurement of intraepidermal nerve fibre density, are needed to investigate the benefits for small fibre function and structure.

Moderate-severe peripheral neuropathy in diabetes associated with an increased risk of dry eye disease.

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 (ß = -0.333, p=0.023) and nerve fiber length (ß = -0.219, p=0.012) while adjusting for age, gender, hemoglobin A1c, 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.

Diagnostic accuracy of nerve ultrasonography for the detection of peripheral neuropathy in type 2 diabetes.

BACKGROUND AND PURPOSE: Nerve conduction studies (NCS) are the current objective measure for diagnosis of peripheral neuropathy in type 2 diabetes but do not assess nerve structure. This study investigated the utility of peripheral nerve ultrasound as a marker of the presence and severity of peripheral neuropathy in type 2 diabetes. METHODS: A total of 156 patients were recruited, and nerve ultrasound was undertaken on distal tibial and distal median nerves. Neuropathy severity was graded using the modified Toronto Clinical Neuropathy Scale (mTCNS) and Total Neuropathy Score (TNS). Studies were undertaken by a single ultrasonographer blinded to nerve conduction results. RESULTS: A stepwise increase in tibial nerve cross-sectional area (CSA) was noted with increasing TNS grade (p < 0.001) and each mTCNS quartile (p < 0.001). Regression analysis demonstrated a correlation between tibial nerve CSA and neuropathy severity (p < 0.001). Using receiver operator curve analysis, tibial nerve CSA of >12.88 mm yielded a sensitivity of 70.5% and specificity of 85.7% for neuropathy detection. Binary logistic regression revealed that tibial nerve CSA was a predictor of abnormal sural sensory nerve action potential amplitude (odds ratio = 1.239, 95% confidence interval [CI] = 1.142-1.345) and abnormal neuropathy score (odds ratio = 1.537, 95% confidence interval [CI] = 1.286-1.838). CONCLUSIONS: Tibial nerve ultrasound has good specificity and sensitivity for neuropathy diagnosis in type 2 diabetes. The study demonstrates that tibial nerve CSA correlates with neuropathy severity. Future serial studies using both ultrasound and NCS may be useful in determining whether changes in ultrasound occur prior to development of nerve conduction abnormalities and neuropathic symptoms.

Impact of Peripheral and Corneal Neuropathy on Markers of Ocular Surface Discomfort in Diabetic Chronic Kidney Disease.

SIGNIFICANCE: There is a reduction in corneal nerve fiber density and length in type 2 diabetes mellitus with chronic kidney disease compared with type 2 diabetes mellitus alone; however, this difference does not result in worse ocular surface discomfort or dry eye disease. PURPOSE: This study aimed to determine the clinical impact of corneal nerve loss on ocular surface discomfort and markers of ocular surface homeostasis in people with type 2 diabetes mellitus without chronic kidney disease (T2DM-no CKD) and those with type 2 diabetes mellitus with concurrent chronic kidney disease (T2DM-CKD). METHODS: Participants were classified based on estimated glomerular filtration rates into two groups: T2DM-CKD (n = 27) and T2DM-no CKD (n = 28). RESULTS: There was a significant difference between the T2DM-CKD and T2DM-no CKD groups in corneal nerve fiber density (14.9 ± 8.6 and 21.1 ± 7.1 no./mm 2 , respectively; P = .005) and corneal nerve fiber length (10.0 ± 4.6 and 12.3 ± 3.7 mm/mm 2 , respectively; P = .04). Fluorescein tear breakup time was significantly reduced in T2DM-CKD compared with T2DM-no CKD (8.1 ± 4.4 and 10.7 ± 3.8 seconds, respectively; P = .01), whereas ocular surface staining was not significantly different (3.5 ± 1.7 and 2.7 ± 2.3 scores, respectively; P = .12). In terms of ocular surface discomfort, there were no significant differences in the ocular discomfort score scores (12.5 ± 11.1 and 13.6 ± 12.1, respectively; P = .81) and Ocular Pain Assessment Survey scores (3.3 ± 5.4 and 4.3 ± 6.1, respectively; P = .37) between the T2DM-CKD and T2DM-no CKD. CONCLUSIONS: The current study demonstrated that corneal nerve loss is greater in T2DM-CKD than in T2DM-no CKD. However, these changes do not impact ocular surface discomfort or markers of ocular surface homeostasis.

Progression of axonal excitability abnormalities with increasing clinical severity of diabetic peripheral neuropathy.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is a frequent complication for persons with type 2 diabetes. Previous studies have failed to demonstrate any significant impact of treatment for DPN. The present study assessed the role of axonal ion channel dysfunction in DPN and explored the hypothesis that there may be a progressive change in ion channel abnormalities that varied with disease stage. METHODS: Neurophysiological studies were conducted using axonal excitability techniques, a clinical method of assessing ion channel dysfunction. Studies were conducted in 178 persons with type 2 diabetes, with participants allocated into four groups according to clinical severity of neuropathy, assessed using the Total Neuropathy Grade. RESULTS: Analysis of excitability data demonstrated a progressive and stepwise reduction in two parameters that are related to the activity of Kv1.1 channels, namely superexcitability and depolarizing threshold electrotonus at 10-20 ms (p < 0.001), and mathematical modelling of axonal excitability findings supported progressive upregulation of Kv1.1 conductances with increasing greater disease severity. CONCLUSION: The findings are consistent with a progressive upregulation of juxtaparanodal Kv1.1 conductances with increasing clinical severity of diabetic peripheral neuropathy. SIGNIFICANCE: From a translational perspective, the study suggests that blockade of Kv1.1 channels using 4-aminopyridine derivatives such as fampridine may be a potential treatment for DPN.

Impact of SGLT2 Inhibitors on Corneal Nerve Morphology and Dendritic Cell Density in Type 2 Diabetes.

PURPOSE: This study aims to determine the effects of SGLT2 inhibitors on corneal dendritic cell density and corneal nerve measures in type 2 diabetes. METHODS: Corneal dendritic cell densities and nerve parameters were measured in people with type 2 diabetes treated with SGLT2 inhibitors (T2DM-SGLT2i) [n = 23] and those not treated with SGLT2 inhibitors (T2DM-no SGLT2i) [n = 23], along with 24 age and sex-matched healthy controls. RESULTS: There was a reduction in all corneal nerve parameters in type 2 diabetes groups compared to healthy controls (All parameters: p < 0.05). No significant differences in corneal nerve parameters were observed between T2DM-SGLT2i and T2DM-no SGLT2i groups (All parameters: p > 0.05). Central corneal dendritic cells were significantly reduced [mature (p = 0.03), immature (p = 0.06) and total (p = 0.002)] in the T2DM-SGLT2i group compared to the T2DM-no SGLT2i group. Significantly, higher mature (p = 0.04), immature (p = 0.004), total (p = 0.002) dendritic cell densities in the T2DM-no SGLT2i group were observed compared to the healthy controls. In the inferior whorl, no significant difference in immature (p = 0.27) and total dendritic cell densities (p = 0.16) between T2DM-SGLT2i and T2DM-no SGLT2i were observed except mature dendritic cell density (p = 0.018). No differences in total dendritic cell density were observed in the central (p > 0.09) and inferior whorl (p = 0.88) between T2DM-SGLT2i and healthy controls. CONCLUSION: The present study showed a reduced dendritic cell density in people with type 2 diabetes taking SGLT2 inhibitors compared to those not taking these medications.

Chronic Kidney Disease Has No Impact on Tear Film Substance P Concentration in Type 2 Diabetes.

PURPOSE: The study aimed to ascertain the potential effects of chronic kidney disease (CKD) on substance P concentration in the tear film of people with type 2 diabetes. METHODS: Participants were classified into two groups: type 2 diabetes with concurrent chronic kidney disease (T2DM-CKD (n = 25)) and type 2 diabetes without chronic kidney disease (T2DM-no CKD (n = 25)). Ocular surface discomfort assessment, flush tear collection, in-vivo corneal confocal microscopy, and peripheral neuropathy assessment were conducted. Enzyme-linked immunosorbent assays were utilized to ascertain the levels of tear film substance P in collected flush tears. Correlation analysis, hierarchical multiple linear regression analysis, and t-tests or Mann-Whitney U tests were used in the analysis of data for two-group comparisons. RESULTS: There was no substantial difference between the T2DM-CKD and T2DM-no CKD groups for tear film substance P concentration (4.4 (0.2-50.4) and 5.9 (0.2-47.2) ng/mL, respectively; p = 0.54). No difference was observed in tear film substance P concentration between the low-severity peripheral neuropathy and high-severity peripheral neuropathy groups (4.4 (0.2-50.4) and 3.3 (0.3-40.7) ng/mL, respectively; p = 0.80). Corneal nerve fiber length (9.8 ± 4.6 and 12.4 ± 3.8 mm/mm2, respectively; p = 0.04) and corneal nerve fiber density (14.7 ± 8.5 and 21.1 ± 7.0 no/mm2, respectively; p < 0.01) were reduced significantly in the T2DM-CKD group compared to the T2DM-no CKD group. There were significant differences in corneal nerve fiber density (21.0 ± 8.1 and 15.8 ± 7.7 no/mm2, respectively; p = 0.04) and corneal nerve fiber length (12.9 ± 4.2 and 9.7 ± 3.8 mm/mm2, respectively; p = 0.03) between the low- and high-severity peripheral neuropathy groups. CONCLUSION: In conclusion, no significant difference in tear film substance P concentration was observed between type 2 diabetes with and without CKD. Corneal nerve loss, however, was more significant in type 2 diabetes with chronic kidney disease compared to type 2 diabetes alone, indicating that corneal nerve morphological measures could serve greater utility as a tool to detect neuropathy and nephropathy-related corneal nerve changes.

Disorders of vision in multiple sclerosis.

Multiple sclerosis (MS) is a neurological inflammatory disorder known to attack the heavily myelinated regions of the nervous system including the optic nerves, cerebellum, brainstem and spinal cord. This review will discuss the clinical manifestations and investigations for MS and other similar neurological inflammatory disorders affecting vision, as well as the effects of MS treatments on vision. Assessment of visual pathways is critical, considering MS can involve multiple components of the visual pathway, including optic nerves, uvea, retina and occipital cortex. Optical coherence tomography is increasingly being recognised as a highly sensitive tool in detecting subclinical optic nerve changes. Magnetic resonance imaging (MRI) is critical in MS diagnosis and in predicting long-term disability. Optic neuritis in MS involves unilateral vision loss, with characteristic pain on eye movement. The visual loss in neuromyelitis optica spectrum disorder tends to be more severe with preferential altitudinal field loss, chiasmal and tract lesions are also more common. Other differential diagnoses include chronic relapsing inflammatory optic neuropathy and giant cell arteritis. Leber's hereditary optic neuropathy affects young males and visual loss tends to be painless and subacute, typically involving both optic nerves. MS lesions in the vestibulocerebellum, brainstem, thalamus and basal ganglia may lead to abnormalities of gaze, saccades, pursuit and nystagmus which can be identified on eye examination. Medial longitudinal fasciculus lesions can cause another frequent presentation of MS, internuclear ophthalmoplegia, with failure of ipsilateral eye adduction and contralateral eye abduction nystagmus. Treatments for MS include high-dose corticosteroids for acute relapses and disease-modifying medications for relapse prevention. These therapies may also have adverse effects on vision, including central serous retinopathy with corticosteroid therapy and macular oedema with fingolimod.

Current and Emerging Pharmacotherapeutic Interventions for the Treatment of Peripheral Nerve Disorders.

Peripheral nerve disorders are caused by a range of different aetiologies. The range of causes include metabolic conditions such as diabetes, obesity and chronic kidney disease. Diabetic neuropathy may be associated with severe weakness and the loss of sensation, leading to gangrene and amputation in advanced cases. Recent studies have indicated a high prevalence of neuropathy in patients with chronic kidney disease, also known as uraemic neuropathy. Immune-mediated neuropathies including Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy may cause significant physical disability. As survival rates continue to improve in cancer, the prevalence of treatment complications, such as chemotherapy-induced peripheral neuropathy, has also increased in treated patients and survivors. Notably, peripheral neuropathy associated with these conditions may be chronic and long-lasting, drastically affecting the quality of life of affected individuals, and leading to a large socioeconomic burden. This review article explores some of the major emerging clinical and experimental therapeutic agents that have been investigated for the treatment of peripheral neuropathy due to metabolic, toxic and immune aetiologies.

Impact of Chronic Kidney Disease on Corneal Neuroimmune Features in Type 2 Diabetes.

Aim: To determine the impact of chronic kidney disease on corneal nerve measures and dendritic cell counts in type 2 diabetes. Methods: In vivo corneal confocal microscopy images were used to estimate corneal nerve parameters and compared in people with type 2 diabetes with chronic kidney disease (T2DM-CKD) (n = 29) and those with type 2 diabetes without chronic kidney disease (T2DM-no CKD) (n = 29), along with 30 healthy controls. Corneal dendritic cell densities were compared between people with T2DM-CKD and those with T2DM-no CKD. The groups were matched for neuropathy status. Results: There was a significant difference in corneal nerve fiber density (p < 0.01) and corneal nerve fiber length (p = 0.04) between T2DM-CKD and T2DM-no CKD groups. The two diabetes groups had reduced corneal nerve parameters compared to healthy controls (all parameters: p < 0.01). Immature central dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group ((7.0 (3.8−12.8) and 3.5 (1.4−13.4) cells/mm2, respectively, p < 0.05). Likewise, central mature dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group (0.8 (0.4−2.2) and 0.4 (0.6−1.1) cells/mm2, respectively, p = 0.02). Additionally, total central dendritic cell density was increased in the T2DM-CKD group compared to T2DM-no CKD group (10.4 (4.3−16.1) and 3.9 (2.1−21.0) cells/mm2, respectively, p = 0.03). Conclusion: The study showed that central corneal dendritic cell density is increased in T2DM-CKD compared to T2DM-no CKD, with groups matched for peripheral neuropathy severity. This is accompanied by a loss of central corneal nerve fibers. The findings raise the possibility of additional local factors exacerbating central corneal nerve injury in people with diabetic chronic kidney disease.

Lifestyle intervention - a study on maintenance in general practice.

AIM: This article aims to explore the factors contributing to sustained or nonsustained behaviour change following a lifestyle intervention in general practice. METHODS: Twenty patients who had participated in a general practice health check and group lifestyle support program were interviewed by telephone after 12 months. The interviews were transcribed and analysed thematically. RESULTS: Patients reported positive effects of the intervention on their behaviour change, especially the group peer support. However, their maintenance of these changes varied. Factors that contributed to sustained behaviour change included social support and self efficacy. Factors contributing to relapse included competing demands on time, comorbidity and stress. DISCUSSION: Greater attention needs to be given to maintenance of behaviour change in lifestyle management programs. Following completion of the program, there needs to be greater support for relapse prevention and management and effective integration back into general practice.