Corneal nerve loss in children with type 1 diabetes mellitus without retinopathy or microalbuminuria

Gad, Hoda; Al-Jarrah, Bara; Saraswathi, Saras; Petropoulos, Ioannis N.; Ponirakis, Georgios; Khan, Adnan; Singh, Parul; Khodor, Souhaila Al; Elawad, Mamoun; Almasri, Wesam; Abdelrahman, Husham; Elawwa, Ahmed; Khalifa, Amal; Shamekh, Ahmed; Al‐Khalaf, Fawziya; Petrovski, Goran; Zyoud, Mahmoud; Maadheed, Maryam Al; Hendaus, Mohamed A.; Hussain, Khalid; Akobeng, Anthony K; Malik, Rayaz A.

doi:10.1111/jdi.13313

Cited by 15 publications

(17 citation statements)

References 57 publications

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“…This study shows a signi cant reduction in central corneal nerve bre parameters in obese subjects with and without diabetes, in agreement with our previously published studies in subjects with obesity [13,23] and diabetes [5,24]. We now further report greater corneal nerve damage in the more distal inferior whorl compared to the central region providing support for a dying-back neuropathy, consistent with studies in adults [25,26] and children [27] with diabetes.…”

Section: Discussionsupporting

confidence: 92%

Distal Corneal Small Nerve Fibre Damage in Subjects With Obesity

Iqbal

Ferdousi

Kalteniece

et al. 2021

Preprint

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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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Section: Discussionsupporting

confidence: 92%

Distal Corneal Small Nerve Fibre Damage in Subjects With Obesity

Iqbal

Ferdousi

Kalteniece

et al. 2021

Preprint

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“…Knowing that neuropathy is a known complication associated with T1DM and CD, and that a possible bidirectional crosstalk linking the gut microbiota with the nervous system has been previously described [ 22 ], we wanted to test whether the gut microbes identified in this study were correlated with corneal neuropathy. We have shown that CCM demonstrates evidence of neuropathy in these children with T1DM [ 38 ] and to a lesser extent in those with CD [ 39 ]. We performed a linear regression to determine any possible association between the abundance of the gut microbiota and abnormal corneal nerve fiber length (CNFL) ( Supplementary Figure S8 ).…”

Section: Resultsmentioning

confidence: 99%

“…Using the Heidelberg Retina Tomograph Cornea Module (Heidelberg Engineering, Vista, CA, USA), participants underwent corneal confocal microscopy as per an established protocol [ 38 ]. Briefly, one eye was randomly selected and anaesthetized with a drop of Alcaine (proparacaine hydrochloride 0.5%; Alcon, Mississauga, ON, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…Corneal confocal microscopy (CCM) is a rapid, non-invasive and well-tolerated ophthalmic imaging technique that has been used to objectively quantify neurodegeneration in a wide range of peripheral and central neurodegenerative diseases [ 34 , 35 , 36 ]. We have also demonstrated significant corneal nerve loss in children with T1DM [ 37 , 38 ], with limited corneal nerve loss in children with CD [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

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Distinctive Microbial Signatures and Gut-Brain Crosstalk in Pediatric Patients with Coeliac Disease and Type 1 Diabetes Mellitus

Singh

Rawat

Al-Jarrah

et al. 2021

IJMS

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Coeliac disease (CD) and Type 1 diabetes mellitus (T1DM) are immune-mediated diseases. Emerging evidence suggests that dysbiosis in the gut microbiome plays a role in the pathogenesis of both diseases and may also be associated with the development of neuropathy. The primary goal in this cross-sectional pilot study was to identify whether there are distinct gut microbiota alterations in children with CD (n = 19), T1DM (n = 18) and both CD and T1DM (n = 9) compared to healthy controls (n = 12). Our second goal was to explore the relationship between neuropathy (corneal nerve fiber damage) and the gut microbiome composition. Microbiota composition was determined by 16S rRNA gene sequencing. Corneal confocal microscopy was used to determine nerve fiber damage. There was a significant difference in the overall microbial diversity between the four groups with healthy controls having a greater microbial diversity as compared to the patients. The abundance of pathogenic proteobacteria Shigella and E. coli were significantly higher in CD patients. Differential abundance analysis showed that several bacterial amplicon sequence variants (ASVs) distinguished CD from T1DM. The tissue transglutaminase antibody correlated significantly with a decrease in gut microbial diversity. Furthermore, the Bacteroidetes phylum, specifically the genus Parabacteroides was significantly correlated with corneal nerve fiber loss in the subjects with neuropathic damage belonging to the diseased groups. We conclude that disease-specific gut microbial features traceable down to the ASV level distinguish children with CD from T1DM and specific gut microbial signatures may be associated with small fiber neuropathy. Further research on the mechanisms linking altered microbial diversity with neuropathy are warranted.

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“…In previous studies, researchers reported a high sensitivity and specificity in using CCM measurements to assess type 1 diabetic peripheral neuropathy 39,40 , as well as in patients with prediabetes 41 and even children with type 1 diabetes 42 . In the present study, it is feasible to evaluate type 2 diabetes mellitus-related chronic complications by using CCM measurements, especially CNFL, but the sensitivity and specificity still need to be improved, which might be related to CCM image acquisition, automatic analysis software and slight diabetic complications in this study.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic utility of corneal confocal microscopy in type 2 diabetic peripheral neuropathy

Wang

Zhang²,

Zuo

et al. 2020

J of Diabetes Invest

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Aims/Introduction: The early pathological changes of diabetic peripheral neuropathy (DPN) are mainly small nerve fiber injuries. Corneal confocal microscopy (CCM) is an easy, rapid, non-invasive and repeatable technique to detect the damage of small nerve fibers. The purpose of this study was to explore the application of CCM in DPN and other chronic complications of type 2 diabetes mellitus. Materials and Methods: A total of 220 individuals (48 normal healthy control participants and 172 patients with type 2 diabetes mellitus) were included in the study. All participants were assessed and scored for neurological symptoms and neurological deficits, quantitative sensory test, neuroelectrophysiological test, and CCM. Results: Corneal nerve fiber density, corneal nerve fiber length and corneal nerve branch density were significantly reduced in patients with type 2 diabetes mellitus compared with normal healthy control subjects (P < 0.001, P < 0.001 and P < 0.001, respectively). In the DPN group, corneal nerve fiber density, corneal nerve branch density and corneal nerve fiber length were significantly lower than for patients without DPN (P < 0.001, P < 0.001 and P < 0.001, respectively). Receiver operating characteristic analysis showed that the optimal cutoff values were 24.68, 39 and 15.315, respectively, in which corneal nerve fiber density and corneal nerve fiber length had moderate sensitivity and specificity. Conclusion: This study provides more support for the clinical use of CCM to diagnose type 2 diabetes mellitus-related complications, especially DPN.

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Corneal nerve loss in children with type 1 diabetes mellitus without retinopathy or microalbuminuria

Cited by 15 publications

References 57 publications

Distal Corneal Small Nerve Fibre Damage in Subjects With Obesity

Distal Corneal Small Nerve Fibre Damage in Subjects With Obesity

Distinctive Microbial Signatures and Gut-Brain Crosstalk in Pediatric Patients with Coeliac Disease and Type 1 Diabetes Mellitus

Diagnostic utility of corneal confocal microscopy in type 2 diabetic peripheral neuropathy

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