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 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 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 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.

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.

scholarly journals Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy

2019 ◽  
Vol 104 (12) ◽  
pp. 6220-6228
Author(s):  
Sonja Püttgen ◽  
Gidon J Bönhof ◽  
Alexander Strom ◽  
Karsten Müssig ◽  
Julia Szendroedi ◽  
...  
Keyword(s):  
Nerve Fiber ◽  
Rating Scale ◽  
Nerve Fibers ◽  
Control Group ◽  
Fiber Density ◽  
Nerve Branch ◽  
Perception Threshold ◽  
Cross Sectional ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve

AbstractContextThe factors that determine the development of diabetic sensorimotor polyneuropathy (DSPN) as a painful or painless entity are unknown.ObjectiveWe hypothesized that corneal nerve pathology could be more pronounced in painful DSPN, indicating predominant small nerve fiber damage.Design and MethodsIn this cross-sectional study, we assessed 53 patients with painful DSPN, 63 with painless DSPN, and 46 glucose-tolerant volunteers by corneal confocal microscopy (CCM), nerve conduction (NC), and quantitative sensory testing. DSPN was diagnosed according to modified Toronto Consensus criteria. A cutoff at 4 points on the 11-point rating scale was used to differentiate between painful and painless DSPN.ResultsAfter adjustment for age, sex, body mass index, and smoking, corneal nerve fiber density, corneal nerve fiber length, and corneal nerve branch density (CNBD) were reduced in both DSPN types compared with the control group (P < 0.05). Only CNBD differed between the groups; it was greater in patients with painful DSPN compared with those with painless DSPN [55.8 (SD, 29.9) vs 43.8 (SD, 28.3) branches/mm2; P < 0.05]. Several CCM measures were associated with NC and cold perception threshold in patients with painless DSPN (P < 0.05) but not those with painful DSPN.ConclusionDespite a similarly pronounced peripheral nerve dysfunction and corneal nerve fiber loss in patients with painful and painless DSPN, corneal nerve branching was enhanced in those with painful DSPN, pointing to some susceptibility of corneal nerve fibers toward regeneration in this entity, albeit possibly not to a sufficient degree.

scholarly journals The LDIFLARE and CCM Methods Demonstrate Early Nerve Fiber Abnormalities in Untreated Hypothyroidism: A Prospective Study

2018 ◽  
Vol 103 (8) ◽  
pp. 3094-3102 ◽  
Author(s):  
Sanjeev Sharma ◽  
Victoria Tobin ◽  
Prashant R J Vas ◽  
Gerry Rayman
Keyword(s):  
Nerve Fiber ◽  
Sural Nerve ◽  
Newly Diagnosed ◽  
Fiber Density ◽  
Noninvasive Methods ◽  
Adequate Treatment ◽  
Doppler Imager ◽  
Small Fiber ◽  
Corneal Confocal Microscopy ◽  
Before And After

Abstract Context Recent studies using skin biopsy suggest presence of small-fiber neuropathy in subclinical hypothyroidism. This study uses two noninvasive methods—the laser Doppler imager flare technique (LDIFLARE) and corneal confocal microscopy (CCM)—to assess small-fiber function (SFF) and small-fiber structure (SFS), respectively, in newly diagnosed hypothyroidism (HT) before and after adequate treatment. Design and Setting Single-center, prospective, intervention-based cohort study. Patients and Participants Twenty patients with newly diagnosed HT (15 with primary HT and 5 with post-radioiodine HT) along with 20 age-matched healthy controls (HCs). Interventions Patients with HT and HCs were assessed neurologically at diagnosis and baseline, respectively. The HT group was reassessed after optimal replacement (defined as TSH level of 0.27 to 4.20 mIU/L) with levothyroxine (LT4) and HCs were reviewed after 1 year. Main Outcome Measures Neurologic assessment for small fibers was performed by using LDIFLARE for SFF and CCM for SFS; large fibers were studied by sural nerve conduction velocity (SNCV) and sural nerve amplitude (SNAP). Results At baseline, both LDIFLARE (mean ± SD) (6.74 ± 1.20 vs 8.90 ± 1.75 cm2; P = 0.0002) and CCM nerve fiber density (CNFD) (expressed as number of fibers per mm2: 50.77 ± 6.54 vs 58.32 ± 6.54; P = 0.002) were significantly reduced in the HT group compared with HCs whereas neither SNCV nor SNAP was different (P ≥ 0.05). After optimal LT4 treatment, both LDIFLARE (7.72 ± 1.12 vs 6.74 ± 1.20 cm2; P ≤ 0.0001) and CNFD (54.43 ± 5.70 vs 50.77 ± 6.54 no./mm2; P = 0.02) improved significantly but remained significantly reduced compared to HCs (P = 0.008 and P = 0.01, respectively) despite normalization of TSH. Conclusions This study demonstrates that dysfunction of small fibers precedes large neural fiber abnormalities in early HT. This can be reversed by replacement therapy to achieve a biochemically euthyroid state, but small-fiber neural outcomes continued to remain low compared with values in HCs.

scholarly journals Assessment and comparison of the morphology and function of the corneal sub-basal nerve plexus in type-1 diabetes mellitus patients and in healthy subjects

2016 ◽  
Vol 1 (1) ◽  
pp. 51-63
Author(s):  
Irmante Derkac ◽  
Ingrida Januleviciene ◽  
Kirwan Asselineau ◽  
Dzilda Velickiene
Keyword(s):  
Nerve Fiber ◽  
Healthy Subjects ◽  
Nerve Fibers ◽  
Corneal Sensitivity ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve ◽  
Type 1 Dm ◽  
Nerve Fiber Density

Aim/purpose: It is believed that small nerve bundles are damaged in the earliest stages of neuropathy caused by diabetes mellitus (DM). Our goal was to evaluate and compare anatomical characteristics of corneal nerve fibers and corneal sensitivity in type-1 DM patients and in healthy control subjects.Design: A prospective, masked, controlled cross-sectional clinical study.Method: Thirty patients with type-1 DM and ten non-diabetic healthy subjects underwent a corneal confocal microscopy to evaluate the corneal sub-basal nerve fibers (density, number of nerves and branches, total nerve length) and contact corneal esthesiometry.Results: Diabetic patients had significantly lower corneal nerve fiber density density (14.32 ± 5.87 vs. 19.71 ± 5.59 mm/mm2; p = 0.023 ) nerve branches number (4.57 ± 3,91 vs. 9.90 ± 5.8 n°/image; p = 0.006) , nerve fiber length (2.28 ± 0.94 vs. 3.13 ± 0.89 mm; p = 0.032) and corneal sensitivity (1.13 ± 0.29 vs. 0.98 ± 0.058 gr/mm2 p = 0.02), as compared with controls. A negative correlation was found between corneal nerve fiber length, corneal nerve number, corneal nerve fiber density and disease duration (p < 0.05).Conclusion: Corneal confocal microscopy and corneal sensitivity evaluation are noninvasive techniques helping to detect early changes in the sub-basal nerve plexus characteristic for diabetic neuropathy (DN) in patients with type-1 DM. Further studies are required to investigate the role of corneal neuropathy assessment using these novel techniques as a toll to detect early DN. 

scholarly journals Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study

2021 ◽  
Vol 14 ◽  
pp. 175628642110043
Author(s):  
Nadine Egenolf ◽  
Caren Meyer zu Altenschildesche ◽  
Luisa Kreß ◽  
Katja Eggermann ◽  
Barbara Namer ◽  
...  
Keyword(s):  
Neurological Examination ◽  
Punch Biopsy ◽  
Small Fiber Neuropathy ◽  
Fiber Density ◽  
Axon Reflex ◽  
Small Fiber ◽  
Corneal Confocal Microscopy ◽  
Intraepidermal Nerve Fiber Density ◽  
Number Of Patients ◽  
Skin Punch Biopsy

Background and aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard. Methods: In this case–control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART). Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact. Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.

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