scholarly journals Corneal confocal microscopy demonstrates axonal loss in different courses of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ioannis N. Petropoulos ◽  
Kathryn C. Fitzgerald ◽  
Jonathan Oakley ◽  
Georgios Ponirakis ◽  
Adnan Khan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Confocal Microscopy ◽  
Nerve Fiber ◽  
Clinically Isolated Syndrome ◽  
Axonal Loss ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Segmentation Methods ◽  
Relapsing Remitting ◽  
Corneal Nerve

AbstractAxonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing–remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm2, 95% CI − 18.24 to − 11.59, P < .0001), CNFL [for ACCMetrics: 19.75 ± 2.39 vs. 12.40 ± 3.30 mm/mm2, 95% CI − 8.94 to − 5.77, P < .0001; for deepNerve: 21.98 ± 2.76 vs. 14.40 ± 4.17 mm/mm2, 95% CI − 9.55 to − 5.6, P < .0001] and CNFrD [for ACCMetrics: 1.52 ± 0.02 vs. 1.45 ± 0.04, 95% CI − 0.09 to − 0.05, P < .0001; for deepNerve: 1.29 ± 0.03 vs. 1.19 ± 0.07, 95% − 0.13 to − 0.07, P < .0001]. Corneal nerve parameters were comparably reduced in different courses of MS. There was excellent reproducibility between the algorithms. Significant corneal axonal loss is detected in different courses of MS including patients with clinically isolated syndrome.

scholarly journals Corneal Confocal Microscopy to Image Small Nerve Fiber Degeneration: Ophthalmology Meets Neurology

2021 ◽  
Vol 2 ◽  
Author(s):  
Ioannis N. Petropoulos ◽  
Gulfidan Bitirgen ◽  
Maryam Ferdousi ◽  
Alise Kalteniece ◽  
Shazli Azmi ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Diabetic Neuropathy ◽  
Nerve Fiber ◽  
Clinical Intervention ◽  
Nerve Fibers ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Intraepidermal Nerve Fiber Density ◽  
Corneal Nerve ◽  
Small Nerve

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.

Corneal nerve quantification predicts the severity of symptoms in sarcoidosis patients with painful neuropathy

TECHNOLOGY ◽  
2013 ◽  
Vol 01 (01) ◽  
pp. 20-26 ◽  
Author(s):  
M. Brines ◽  
M. Swartjes ◽  
M.R. Tannemaat ◽  
A. Dunne ◽  
M. van Velzen ◽  
...  
Keyword(s):  
Nerve Fiber ◽  
Adult Population ◽  
Brief Pain Inventory ◽  
The United States ◽  
Fiber Density ◽  
Painful Neuropathy ◽  
Small Fiber ◽  
Corneal Confocal Microscopy ◽  
Fiber Number ◽  
Corneal Nerve

Small fiber neuropathy (SFN) is a debilitating condition characterized by chronic pain as well as sensory and autonomic dysfunction. SFN is an increasingly recognized component of a large number of diseases, including sarcoidosis. Although affecting an estimated 2–3% of the adult population in the United States, it often remains undiagnosed. Skin biopsy for evaluating intra-epidermal nerve fiber density (IENFD) and more recently corneal confocal microscopy (CCM) have been used to identify small fiber damage in patients with neuropathy. We demonstrate a significant reduction in IENFD, corneal nerve fiber number and length, with no change in the number of branches in patients with painful sarcoid neuropathy. Moreover, unlike IENFD, corneal nerve fiber number and length inversely correlate with the degree to which pain interferes with activities of daily living as assessed by the Brief Pain Inventory questionnaire. CCM thus constitutes an accurate, non-invasive assessment technique to aid in the diagnosis of SFN, as well as an objective marker of symptoms in patients with painful sarcoid neuropathy.

scholarly journals Combining In Vivo Corneal Confocal Microscopy with Deep Learning-based Analysis Reveals Sensory Nerve Fiber Loss in Acute SIV Infection

2020 ◽  
Author(s):  
Megan E. McCarron ◽  
Rachel L. Weinberg ◽  
Jessica M. Izzi ◽  
Suzanne E. Queen ◽  
Stuti L. Misra ◽  
...  
Keyword(s):  
Fractal Dimension ◽  
Deep Learning ◽  
Confocal Microscopy ◽  
Nerve Fiber ◽  
Fiber Length ◽  
Sensory Nerve ◽  
Corneal Confocal Microscopy ◽  
Siv Infection ◽  
Corneal Nerve

AbstractPurposeTo characterize corneal subbasal nerve plexus morphologic features using in vivo corneal confocal microscopy (IVCM) in normal and SIV-infected macaques and to implement automated assessments using novel deep learning-based methods customized for macaque studies.MethodsIn vivo corneal confocal microscopy images were collected from both male and female age-matched specific-pathogen free rhesus and pigtailed macaques housed at the Johns Hopkins University breeding colony using the Heidelberg HRTIII with Rostock Corneal Module. We also obtained repeat IVCM images of 12 SIV-infected animals including pre-infection and 10 day post-SIV infection time-points. All IVCM images were analyzed using a novel deep convolutional neural network architecture developed specifically for macaque studies.ResultsDeep learning-based segmentation of subbasal nerves in IVCM images from macaques demonstrated that corneal nerve fiber length (CNFL) and fractal dimension measurements did not differ between species, but pigtailed macaques had significantly higher baseline corneal nerve fiber tortuosity than rhesus macaques (P = 0.005). Neither sex nor age of macaques was associated with differences in any of the assessed corneal subbasal nerve parameters. In the SIV/macaque model of HIV, acute SIV infection induced significant decreases in both corneal nerve fiber length and fractal dimension (P= 0.01 and P= 0.008 respectively).ConclusionsThe combination of IVCM and objective, robust, and rapid deep-learning analysis serves as a powerful noninvasive research and clinical tool to track sensory nerve damage, enabling early detection of neuropathy. Adapting the deep-learning analyses to human corneal nerve assessments will refine our ability to predict and monitor damage to small sensory nerve fibers in a number of clinical settings including HIV, multiple sclerosis, Parkinson’s disease, diabetes, and chemotherapeutic neurotoxicity.

scholarly journals Early detection of diabetic neuropathy by investigating CNFL and IENFD in thy1-YFP mice

2016 ◽  
Vol 231 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Janine Leckelt ◽  
Pedro Guimarães ◽  
Annett Kott ◽  
Alfredo Ruggeri ◽  
Oliver Stachs ◽  
...  
Keyword(s):  
Diabetic Neuropathy ◽  
Nerve Fiber ◽  
Blood Glucose Concentration ◽  
Ex Vivo ◽  
Surrogate Marker ◽  
Nerve Fibers ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Intraepidermal Nerve Fiber Density ◽  
Corneal Nerve

Small fiber neuropathy is one of the most common and painful long-term complications of diabetes mellitus. Examination of the sub-basal corneal nerve plexus is a promising surrogate marker of diabetic neuropathy. To investigate the efficacy, reliability and reproducibility of in vivo corneal confocal microscopy (IVCCM), we used thy1-YFP mice, which express yellow fluorescence protein (YFP) in nerve fibers. 4 weeks after multiple low-dose injections of streptozotocin, thy1-YFP mice showed manifest diabetes. Subsequent application of insulin-releasing pellets for 8 weeks resulted in a significant reduction of blood glucose concentration and HbA1c, a significant increase in body weight and no further increase in advanced glycation end products (AGEs). IVCCM, carried out regularly over 12 weeks and analyzed both manually and automatically, revealed a significant loss of corneal nerve fiber length (CNFL) during diabetes manifestation and significant recovery after insulin therapy. Ex vivo analyses of CNFL by YFP-based microscopy confirmed the IVCCM results (with high sensitivity between manual and automated approaches) but demonstrated that the changes were restricted to the central cornea. Peripheral areas, not accessible by IVCCM in mice, remained virtually unaffected. Because parallel assessment of intraepidermal nerve fiber density revealed no changes, we conclude that IVCCM robustly captures early signs of diabetic neuropathy.

scholarly journals Corneal Nerve Loss in Patients With TIA and Acute Ischemic Stroke in Relation To Circulating Markers of Inflammation and Vascular Integrity

2021 ◽  
Author(s):  
Adnan Khan ◽  
Aijaz Parray ◽  
Naveed Akhtar ◽  
Abdelali Agouni ◽  
Saadat Kamran ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebrovascular Disease ◽  
Acute Ischemic Stroke ◽  
Nerve Fiber ◽  
Fiber Density ◽  
Nerve Branch ◽  
Vascular Integrity ◽  
Markers Of Inflammation ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve

Abstract Background Vascular and inflammatory mechanisms are implicated in the development of cerebrovascular disease and corneal nerve loss occurs in patients with transient ischemic attack (TIA) and acute ischemic stroke (AIS). We have assessed whether serum markers of inflammation and vascular integrity are associated with the severity of corneal nerve loss in patients with TIA and AIS. Methods Corneal confocal microscopy (CCM) was performed to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) in 105 patients with TIA or AIS and age matched control subjects (n=56). Circulating levels of IL-6, MMP-2, MMP-9, E-Selectin, P-Selectin and VEGF were quantified in patients within 48 hours of presentation with a TIA or AIS. Results CNFL (P=0.000, P=0.000), CNFD (P=0.122, P=0.000) and CNBD (P=0.002, P=0.000) were reduced in patients with TIA and AIS compared to controls, respectively with no difference between patients with AIS and TIA. The NIHSS Score (P=0.000), IL-6 (P=0.011) and E-Selectin (P=0.032) were higher in patients with AIS compared to TIA with no difference in MMP-2 (P=0.636), MMP-9 (P=0.098), P-Selectin (P=0.395) and VEGF (P=0.831). CNFL (r=0.218, P=0.026) and CNFD (r=0.230, P=0.019) correlated with IL-6 and multiple regression analysis showed a positive association of CNFL and CNFD with IL-6 (P=0.041, P=0.043). Conclusions Patients with TIA and stroke have evidence of corneal nerve loss and elevated IL6 and E-selectin levels. Larger longitudinal studies are required to determine the association between inflammatory and vascular markers and corneal nerve fiber loss in patients with cerebrovascular disease.

scholarly journals Association of Cerebral Ischemia With Corneal Nerve Loss and Brain Atrophy in MCI and Dementia

2021 ◽  
Vol 15 ◽  
Author(s):  
Georgios Ponirakis ◽  
Ahmed Elsotouhy ◽  
Hanadi Al Hamad ◽  
Surjith Vattoth ◽  
Ioannis N. Petropoulos ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Nerve Fiber ◽  
Brain Atrophy ◽  
Ventricular Volume ◽  
Hippocampal Volume ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve ◽  
Cortical Ischemia

IntroductionThis study assessed the association of cerebral ischemia with neurodegeneration in mild cognitive impairment (MCI) and dementia.MethodsSubjects with MCI, dementia and controls underwent assessment of cognitive function, severity of brain ischemia, MRI brain volumetry and corneal confocal microscopy.ResultsOf 63 subjects with MCI (n = 44) and dementia (n = 19), 11 had no ischemia, 32 had subcortical ischemia and 20 had both subcortical and cortical ischemia. Brain volume and corneal nerve measures were comparable between subjects with subcortical ischemia and no ischemia. However, subjects with subcortical and cortical ischemia had a lower hippocampal volume (P &lt; 0.01), corneal nerve fiber length (P &lt; 0.05) and larger ventricular volume (P &lt; 0.05) compared to those with subcortical ischemia and lower corneal nerve fiber density (P &lt; 0.05) compared to those without ischemia.DiscussionCerebral ischemia was associated with cognitive impairment, brain atrophy and corneal nerve loss in MCI and dementia.

scholarly journals Corneal nerve loss in patients with TIA and acute ischemic stroke in relation to circulating markers of inflammation and vascular integrity

2021 ◽  
Author(s):  
Adnan Khan ◽  
Aijaz Parray ◽  
Naveed Akhtar ◽  
Abdelali Agouni ◽  
Saadat Kamran ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebrovascular Disease ◽  
Acute Ischemic Stroke ◽  
Nerve Fiber ◽  
Fiber Density ◽  
Nerve Branch ◽  
Vascular Integrity ◽  
Markers Of Inflammation ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve

Abstract Background Vascular and inflammatory mechanisms are implicated in the development of cerebrovascular disease and corneal nerve loss occurs in patients with transient ischemic attack (TIA) and acute ischemic stroke (AIS). We have assessed whether serum markers of inflammation and vascular integrity are associated with the severity of corneal nerve loss in patients with TIA and AIS. Methods Corneal confocal microscopy (CCM) was performed to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) in 105 patients with TIA or AIS and age matched control subjects (n = 56). Circulating levels of IL-6, MMP-2, MMP-9, E-Selectin, P-Selectin and VEGF were quantified in patients within 48 hours of presentation with a TIA or AIS. Results CNFL (P = 0.000, P = 0.000), CNFD (P = 0.122, P = 0.000) and CNBD (P = 0.002, P = 0.000) were reduced in patients with TIA and AIS compared to controls, respectively with no difference between patients with AIS and TIA. The NIHSS Score (P = 0.000), IL-6 (P = 0.011) and E-Selectin (P = 0.032) were higher in patients with AIS compared to TIA with no difference in MMP-2 (P = 0.636), MMP-9 (P = 0.098), P-Selectin (P = 0.395) and VEGF (P = 0.831). CNFL (r = 0.218, P = 0.026) and CNFD (r = 0.230, P = 0.019) correlated with IL-6 and multiple regression analysis showed a positive association of CNFL and CNFD with IL-6 (P = 0.041, P = 0.043). Conclusions Patients with TIA and stroke have evidence of corneal nerve loss and elevated IL6 and E-selectin levels. Larger longitudinal studies are required to determine the association between inflammatory and vascular markers and corneal nerve fiber loss in patients with cerebrovascular disease.

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