Distal Corneal Small Nerve Fibre Damage in Subjects With Obesity

Abstract Background: We have previously shown that subjects with obesity have elevated vibration and thermal perception thresholds and central corneal nerve loss and patients with diabetic neuropathy have greater corneal nerve loss at the inferior whorl compared to the central cornea. In the current study, we assessed whether there is evidence for a dying-back neuropathy in subjects with obesity with and without diabetes. Methods: 57 obese subjects, with and without diabetes (DM+, n=30; DM-, n=27 respectively) and age- and sex‑matched controls (n=21) underwent venous blood sampling and assessment of the neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration, cold and warm threshold testing, cardiac autonomic function, and corneal confocal microscopy (CCM).Results: NSP and NDS were significantly elevated in obese DM+ (p<0.0001; p=0.001) and DM- (p<0.0001; p=0.001) subjects compared to controls. Vibration perception threshold was significantly higher in DM+ (p=0.001), but not in DM- (p=0.06), compared to controls, whilst cold (p = 0.87) and warm (p = 0.52) perception thresholds did not differ between groups. Deep breathing heart rate variability was significantly lower in DM+ (p=0.01), but not DM- (p=0.9) subjects compared to controls. Corneal nerve fibre density [26.8 ±6.22 vs 26.8 ±6.01 vs 35.3 ±7.41, p<0.0001], branch density [55.4 ±28.2 vs 58.4 ±28.5 vs 88.2 ±31.1, p<0.001], fibre length (CNFL) [17.6 ±4.43 vs 19.9 ±5.43 vs 26.7 ±5.31, p <0.0001], inferior whorl length (IWL) [17.9 ±6.10 vs 18.6 ±7.42 vs 35.3 ±9.70, p<0.0001] and total nerve fibre length (TNFL) [35.5 ±9.58 vs 38.5 ±11.0 vs 62.0 ±12.3, p<0.0001] were significantly lower in obese subjects without and with diabetes compared to controls. In comparison to controls, there was a greater relative reduction in IWL compared to CNFL in DM+ (47.3% vs 25.5%) and DM- (49.3% vs 34.1%).Conclusion: We demonstrate evidence of peripheral neuropathy characterised by neuropathic symptoms, neurological deficits, elevated vibration perception and autonomic dysfunction with a dying-back neuropathy affecting the corneal nerves in obese subjects with and without type 2 diabetes.

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Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2021-319450 ◽

2021 ◽

pp. bjophthalmol-2021-319450

Author(s):

Gulfidan Bitirgen ◽

Celalettin Korkmaz ◽

Adil Zamani ◽

Ahmet Ozkagnici ◽

Nazmi Zengin ◽

...

Keyword(s):

Confocal Microscopy ◽

Nerve Fibre ◽

Fibre Length ◽

Neurological Symptoms ◽

University Hospital ◽

Nerve Branch ◽

Cross Sectional ◽

Corneal Confocal Microscopy ◽

Corneal Nerve ◽

Fibre Loss

Background/AimsLong COVID is characterised by a range of potentially debilitating symptoms which develop in at least 10% of people who have recovered from acute SARS-CoV-2 infection. This study has quantified corneal sub-basal nerve plexus morphology and dendritic cell (DC) density in patients with and without long COVID.MethodsForty subjects who had recovered from COVID-19 and 30 control participants were included in this cross-sectional comparative study undertaken at a university hospital. All patients underwent assessment with the National Institute for Health and Care Excellence (NICE) long COVID, Douleur Neuropathique 4 (DN4) and Fibromyalgia questionnaires, and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), and total, mature and immature DC density.ResultsThe mean time after the diagnosis of COVID-19 was 3.7±1.5 months. Patients with neurological symptoms 4 weeks after acute COVID-19 had a lower CNFD (p=0.032), CNBD (p=0.020), and CNFL (p=0.012), and increased DC density (p=0.046) compared with controls, while patients without neurological symptoms had comparable corneal nerve parameters, but increased DC density (p=0.003). There were significant correlations between the total score on the NICE long COVID questionnaire at 4 and 12 weeks with CNFD (ρ=−0.436; p=0.005, ρ=−0.387; p=0.038, respectively) and CNFL (ρ=−0.404; p=0.010, ρ=−0.412; p=0.026, respectively).ConclusionCorneal confocal microscopy identifies corneal small nerve fibre loss and increased DCs in patients with long COVID, especially those with neurological symptoms. CCM could be used to objectively identify patients with long COVID.

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Diagnosis of neuropathy and risk factors for corneal nerve loss in type 1 and type 2 diabetes: A corneal confocal microscopy study

10.2337/figshare.13020023.v1 ◽

2020 ◽

Author(s):

Maryam Ferdousi ◽

Alise Kalteniece ◽

Shazli Azmi ◽

Ioannis N Petropoulos ◽

Georgios Ponirakis ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Peripheral Neuropathy ◽

Nerve Fibre ◽

Fibre Length ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

Purpose: To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss. Methods: 490 participants including 72 healthy controls, 149 with type 1 diabetes and 269 with type 2 diabetes underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors. Results: Corneal nerve fibre density (CNFD) (P<0.0001, P<0.0001), branch density (CNBD) (P<0.0001, P<0.0001) and length (CNFL) (P<0.0001, P=0.02) were significantly lower in patients with type 1 and type 2 diabetes, compared to controls. CNFD (P<0.0001), CNBD (P<0.0001) and CNFL (P<0.0001) were lower in type 1 diabetes compared to type 2 diabetes. Receiver operating characteristics (ROC) curve analysis for the diagnosis of DPN demonstrated a good area under the curve (AUC) for CNFD=0.81, CNBD=0.74 and CNFL=0.73. Multivariable regression analysis showed a significant association between reduced corneal nerve fibre length with age (β=-0.27, P=0.007), HbA1c (β=-1.1, P=0.01) and weight (β=-0.14, P=0.03) in patients with type 2 diabetes and with duration of diabetes (β=-0.13, P=0.02), LDL cholesterol (β=1.8, P=0.04), and triglycerides (β=-2.87, P=0.009) in patients with type 1 diabetes. Conclusion: CCM identifies more severe corneal nerve loss in patients with type 1 compared to type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fibre length differ between type 1 and type 2 diabetes.

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An artificial intelligence-based deep learning algorithm for the diagnosis of diabetic neuropathy using corneal confocal microscopy: a development and validation study

Diabetologia ◽

10.1007/s00125-019-05023-4 ◽

2019 ◽

Vol 63 (2) ◽

pp. 419-430 ◽

Cited By ~ 10

Author(s):

Bryan M. Williams ◽

Davide Borroni ◽

Rongjun Liu ◽

Yitian Zhao ◽

Jiong Zhang ◽

...

Keyword(s):

Deep Learning ◽

Confocal Microscopy ◽

Diabetic Neuropathy ◽

Nerve Fibre ◽

Learning Algorithm ◽

Fibre Length ◽

Branch Points ◽

Deep Learning Algorithm ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

Abstract Aims/hypothesis Corneal confocal microscopy is a rapid non-invasive ophthalmic imaging technique that identifies peripheral and central neurodegenerative disease. Quantification of corneal sub-basal nerve plexus morphology, however, requires either time-consuming manual annotation or a less-sensitive automated image analysis approach. We aimed to develop and validate an artificial intelligence-based, deep learning algorithm for the quantification of nerve fibre properties relevant to the diagnosis of diabetic neuropathy and to compare it with a validated automated analysis program, ACCMetrics. Methods Our deep learning algorithm, which employs a convolutional neural network with data augmentation, was developed for the automated quantification of the corneal sub-basal nerve plexus for the diagnosis of diabetic neuropathy. The algorithm was trained using a high-end graphics processor unit on 1698 corneal confocal microscopy images; for external validation, it was further tested on 2137 images. The algorithm was developed to identify total nerve fibre length, branch points, tail points, number and length of nerve segments, and fractal numbers. Sensitivity analyses were undertaken to determine the AUC for ACCMetrics and our algorithm for the diagnosis of diabetic neuropathy. Results The intraclass correlation coefficients for our algorithm were superior to those for ACCMetrics for total corneal nerve fibre length (0.933 vs 0.825), mean length per segment (0.656 vs 0.325), number of branch points (0.891 vs 0.570), number of tail points (0.623 vs 0.257), number of nerve segments (0.878 vs 0.504) and fractals (0.927 vs 0.758). In addition, our proposed algorithm achieved an AUC of 0.83, specificity of 0.87 and sensitivity of 0.68 for the classification of participants without (n = 90) and with (n = 132) neuropathy (defined by the Toronto criteria). Conclusions/interpretation These results demonstrated that our deep learning algorithm provides rapid and excellent localisation performance for the quantification of corneal nerve biomarkers. This model has potential for adoption into clinical screening programmes for diabetic neuropathy. Data availability The publicly shared cornea nerve dataset (dataset 1) is available at http://bioimlab.dei.unipd.it/Corneal%20Nerve%20Tortuosity%20Data%20Set.htm and http://bioimlab.dei.unipd.it/Corneal%20Nerve%20Data%20Set.htm.

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Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001420 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001420 ◽

Cited By ~ 2

Author(s):

Georgios Ponirakis ◽

Muhammad A Abdul-Ghani ◽

Amin Jayyousi ◽

Hamad Almuhannadi ◽

Ioannis N Petropoulos ◽

...

Keyword(s):

Body Weight ◽

Nerve Branch ◽

Sudomotor Function ◽

Corneal Confocal Microscopy ◽

Corneal Nerves ◽

Corneal Nerve ◽

Branch Density ◽

Bolus Insulin ◽

Basal Bolus ◽

Vibration Perception

IntroductionTo assess the effect of exenatide and pioglitazone or basal-bolus insulin on diabetic peripheral neuropathy (DPN) in patients with poorly controlled type 2 diabetes (T2D).Research design and methodsThis is a substudy of the Qatar Study, an open-label, randomized controlled trial. 38 subjects with poorly controlled T2D were studied at baseline and 1-year follow-up and 18 control subjects were assessed at baseline only. A combination of exenatide (2 mg/week) and pioglitazone (30 mg/day) or glargine with aspart insulin were randomly assigned to patients to achieve an HbA1c <53 mmol/mol (<7%). DPN was assessed with corneal confocal microscopy (CCM), DN4, vibration perception and sudomotor function.ResultsSubjects with T2D had reduced corneal nerves, but other DPN measures were comparable with the control group. In the combination treatment arm (n=21), HbA1c decreased by 35.2 mmol/mol (3.8 %) (p<0.0001), body weight increased by 5.6 kg (p<0.0001), corneal nerve branch density increased (p<0.05), vibration perception worsened (p<0.05), and DN4 and sudomotor function showed no change. In the insulin treatment arm, HbA1c decreased by 28.7 mmol/mol (2.7 %) (p<0.0001), body weight increased by 4.6 kg (p<0.01), corneal nerve branch density and fiber length increased (p≤0.01), vibration perception improved (p<0.01), and DN4 and sudomotor function showed no change. There was no association between the change in CCM measures with change in HbA1c, weight or lipids.ConclusionsTreatment with exenatide and pioglitazone or basal-bolus insulin results in corneal nerve regeneration, but no change in neuropathic symptoms or sudomotor function over 1 year.

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Diagnosis of neuropathy and risk factors for corneal nerve loss in type 1 and type 2 diabetes: A corneal confocal microscopy study

10.2337/figshare.13020023 ◽

2020 ◽

Author(s):

Maryam Ferdousi ◽

Alise Kalteniece ◽

Shazli Azmi ◽

Ioannis N Petropoulos ◽

Georgios Ponirakis ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Peripheral Neuropathy ◽

Nerve Fibre ◽

Fibre Length ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

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Corneal confocal microscopy identifies small fibre damage and progression of diabetic neuropathy

Scientific Reports ◽

10.1038/s41598-021-81302-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shaishav Dhage ◽

Maryam Ferdousi ◽

Safwaan Adam ◽

Jan Hoong Ho ◽

Alise Kalteniece ◽

...

Keyword(s):

Confocal Microscopy ◽

Diabetic Neuropathy ◽

Nerve Fibre ◽

Fibre Length ◽

Autonomic Nerve ◽

Perception Threshold ◽

Fibre Density ◽

Symptom Profile ◽

Corneal Confocal Microscopy ◽

Patients With Diabetes

AbstractAccurately quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials. We have undertaken detailed neuropathy phenotyping to assess the longitudinal utility of different measures of neuropathy in patients with diabetes. Nineteen patients with diabetes (age 52.5 ± 14.7 years, duration of diabetes 26.0 ± 13.8 years) and 19 healthy controls underwent assessment of symptoms and signs of neuropathy, quantitative sensory testing, autonomic nerve function, neurophysiology, intra-epidermal nerve fibre density (IENFD) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL). Mean follow-up was 6.5 years. Glycated haemoglobin (p = 0.04), low-density lipoprotein-cholesterol (LDL-C) (p = 0.0009) and urinary albumin creatinine ratio (p < 0.0001) improved. Neuropathy symptom profile (p = 0.03), neuropathy disability score (p = 0.04), vibration perception threshold (p = 0.02), cold perception threshold (p = 0.006), CNFD (p = 0.03), CNBD (p < 0.0001), CNFL (p < 0.0001), IENFD (p = 0.04), sural (p = 0.02) and peroneal motor nerve conduction velocity (p = 0.03) deteriorated significantly. Change (∆) in CNFL correlated with ∆CPT (p = 0.006) and ∆Expiration/Inspiration ratio (p = 0.002) and ∆IENFD correlated with ∆CNFD (p = 0.005), ∆CNBD (p = 0.02) and ∆CNFL (p = 0.01). This study shows worsening of diabetic neuropathy across a range of neuropathy measures, especially CCM, despite an improvement in HbA1c and LDL-C. It further supports the utility of CCM as a rapid, non-invasive surrogate measure of diabetic neuropathy.

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Corneal confocal microscopy detects small fibre neurodegeneration in Parkinson's disease using automated analysis

Scientific Reports ◽

10.1038/s41598-020-76768-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sze Hway Lim ◽

Maryam Ferdousi ◽

Alise Kalteniece ◽

Lewis Kass-Iliyya ◽

Ioannis N. Petropoulos ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Confocal Microscopy ◽

Nerve Fibre ◽

Fibre Length ◽

Mean Difference ◽

Nerve Branch ◽

Corneal Confocal Microscopy ◽

Corneal Nerve ◽

Branch Density

AbstractWe studied the utility of corneal confocal microscopy (CCM) in detecting a reduction in corneal nerve parameters in a large cohort of patients with Parkinson’s disease (PD) compared to controls using a fully automated potentially scalable method of analysis. We also assessed if CCM parameters are related to the severity and sub-type of PD. 98 participants with PD and 26 healthy controls underwent CCM with automated corneal nerve quantification, MDS-UPDRS III, Hoehn and Yahr scale, Montreal Cognitive Assessment, Parkinson’s Disease Questionnaire-39 and PD subtype assessment. Corneal nerve fibre density (mean difference: − 5.00 no/mm2, 95% confidence interval (CI) [− 7.89, − 2.12], p = 0.001), corneal nerve branch density (mean difference: − 10.71 no/mm2, 95% CI [− 16.93, − 4.48], p = 0.003), corneal total branch density (mean difference: − 14.75 no/mm2, 95% CI [− 23.58, − 5.92], p = 0.002), and corneal nerve fibre length (mean difference: − 2.57 mm/mm2, 95% CI [− 4.02, − 1.12], p = 0.001) were significantly lower in PD participants compared to controls. There was no correlation between corneal nerve parameters and duration, severity or subtype of PD, cognitive function or quality of life. CCM with automated corneal nerve analysis identifies nerve fibre damage and may act as a biomarker for neurodegeneration in PD.

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Corneal nerve loss as a surrogate marker for poor pial collaterals in patients with acute ischemic stroke

Scientific Reports ◽

10.1038/s41598-021-99131-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Adnan Khan ◽

Ajay Menon ◽

Naveed Akhtar ◽

Saadat Kamran ◽

Ahmad Muhammad ◽

...

Keyword(s):

Ischemic Stroke ◽

Endothelial Cell ◽

Acute Ischemic Stroke ◽

Nerve Fibre ◽

Fibre Length ◽

Surrogate Marker ◽

Nerve Branch ◽

Cell Parameters ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

AbstractIn patients with acute ischemic stroke, pial collaterals play a key role in limiting neurological disability by maintaining blood flow to ischemic penumbra. We hypothesized that patient with poor pial collaterals will have greater corneal nerve and endothelial cell abnormalities. In a cross-sectional study, 35 patients with acute ischemic stroke secondary to middle cerebral artery (MCA) occlusion with poor (n = 12) and moderate-good (n = 23) pial collaterals and 35 healthy controls underwent corneal confocal microscopy and quantification of corneal nerve and endothelial cell morphology. In patients with MCA stroke, corneal nerve fibre length (CNFL) (P < 0.001), corneal nerve fibre density (CNFD) (P = 0.025) and corneal nerve branch density (CNBD) (P = 0.002) were lower compared to controls. Age, BMI, cholesterol, triglycerides, HDL, LDL, systolic blood pressure, NIHSS and endothelial cell parameters did not differ but mRS was higher (p = 0.023) and CNFL (p = 0.026) and CNBD (p = 0.044) were lower in patients with poor compared to moderate-good collaterals. CNFL and CNBD distinguished subjects with poor from moderate-good pial collaterals with an AUC of 72% (95% CI 53–92%) and 71% (95% CI 53–90%), respectively. Corneal nerve loss is greater in patients with poor compared to moderate-good pial collaterals and may act as a surrogate marker for pial collateral status in patients with ischemic stroke.

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The Reference Distribution of Annual Change in Corneal Nerve Fibre Length in Diabetes

Canadian Journal of Diabetes ◽

10.1016/j.jcjd.2018.08.029 ◽

2018 ◽

Vol 42 (5) ◽

pp. S10

Author(s):

Evan Jh Lewis ◽

Mitra Tavakoli ◽

Leif E. Lovblom ◽

Elise M. Halpern ◽

Maria Jeziorska ◽

...

Keyword(s):

Nerve Fibre ◽

Fibre Length ◽

Annual Change ◽

Reference Distribution ◽

Corneal Nerve

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Bilateral morphometric analysis of corneal sub-basal nerve plexus in patients undergoing unilateral cataract surgery: a preliminary in vivo confocal microscopy study

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-315449 ◽

2020 ◽

pp. bjophthalmol-2019-315449 ◽

Cited By ~ 3

Author(s):

Giuseppe Giannaccare ◽

Federico Bernabei ◽

Marco Pellegrini ◽

Fabio Guaraldi ◽

Federica Turchi ◽

...

Keyword(s):

Confocal Microscopy ◽

Cataract Surgery ◽

Nerve Fibre ◽

Fibre Length ◽

Nerve Plexus ◽

In Vivo Confocal Microscopy ◽

Corneal Nerve ◽

Branch Density ◽

Unilateral Cataract

AimsTo evaluate bilateral morphometric changes of corneal sub-basal nerve plexus (CSNP) occurring after unilateral cataract surgery by in vivo confocal microscopy (IVCM) images analysed with automated software.MethodsIVCM was performed before (V0) and 1 month after surgery (V1) in both operated eyes (OEs) and unoperated eyes (UEs) of 30 patients. Thirty age and sex-matched subjects acted as controls. Corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), corneal nerve total branch density (CTBD), corneal nerve fibre area (CNFA), corneal nerve fibre width, corneal nerve fractal dimension (CNFrD) and dendritic cells density were calculated.ResultsMean CNFD, CNBD, CNFL, CTBD, CNFA and CNFrD significantly decreased at V1 versus V0 in both eyes (respectively, 15.35±7.00 vs 21.21±6.56 n/mm2 in OEs and 20.11±6.69 vs 23.20±7.26 in UEs; 13.57±12.16 vs 26.79±16.91 n/mm2 in OEs and 24.28±14.88 vs 29.76±15.25 in UEs; 9.67±3.44 mm/mm2 vs 13.49±3.42 in OEs and 12.53±3.60 vs 14.02±3.82 in UEs; 22.81±18.77 vs 42.25±24.64 n/mm2 in OEs and 38.06±20.52 vs 43.93±22.27 in UEs; 0.0040±0.0021 vs 0.0058±0.0020 mm2/mm2 in OEs and 0.0049±0.0016 vs 0.0057±0.0019 in UEs; 1.418±0.058 vs 1.470±0.037 in OEs and 1.466±0.040 vs 1.477±0.036 in UEs; always p<0.049).ConclusionPatients undergoing cataract surgery exhibit bilateral alterations of CSNP. This finding could have broad implications in the setting of sequential cataract surgery.

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