Panagiotis A. Kallinikos

Central Manchester University Hospitals NHS Foundation Trust, Manchester, England, United Kingdom

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Publications (20)53.31 Total impact

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    ABSTRACT: PURPOSE/AIM: To employ corneal confocal microscopy to assess differences in the extent of corneal nerve fiber alterations between diabetic patients classed according to retinopathy status and nondiabetic patients. Two hundred seventy-eight corneas of 139 patients with type 2 diabetes mellitus and 94 corneas of 47 age-matched control participants were scanned using corneal confocal microscopy. Images of the subbasal nerve plexus were collected and analyzed for nerve fiber density (NFD), nerve branch density (NBD), nerve fiber length (NFL), and nerve fiber tortuosity (NFT). Diabetic patients were categorized into three groups according to the classification of diabetic retinopathy (DR) proposed in the Early Treatment of Diabetic Retinopathy Study, based on indirect fundoscopy, fundus photography, and fluorescein angiography findings. A separate classification into four groups according to the severity of peripheral diabetic neuropathy (DN) was also used, based on the results of clinical and electrodiagnostic examinations. Average NFD, NBD, and NFL differed significantly according to DR status and were found to be lower, whereas NFT was found to be higher in diabetic patients than control participants. A positive correlation between diabetic corneal neuropathy and peripheral DN was also found. Nerve fiber alterations of the subbasal nerve plexus of diabetic corneas appear to progress in parallel with DR and peripheral DN. Corneal confocal microscopy could possibly represent a promising adjuvant technique for the early diagnosis and assessment of human DN.
    Current eye research 05/2012; 37(10):898-906. · 1.51 Impact Factor
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    ABSTRACT: We have assessed whether corneal confocal microscopy can be used to detect alterations in nerve morphology following an improvement in risk factors associated with diabetic neuropathy. Twenty-five patients with diabetes with mild to moderate neuropathy and 18 control subjects underwent corneal confocal microscopy to quantify corneal nerve fibre (density, branch density, length and tortuosity) at baseline and after 24 months from first visit. This was not planned as an intervention trial and was simply an observational follow-up. At baseline, nerve fibre density (18.8 ± 2.1 vs. 46.0 ± 3.8 number/mm(2), P = 0.001), nerve branch density (6.9 ± 1.5 vs. 35.6 ± 6.7 number/mm(2), P < 0.0001), nerve fibre length (8.3 ± 0.9 vs. 13.5 ± 0.8 mm/mm(2), P < 0.0001) and nerve fibre tortuosity (19.8 ± 1.6 vs. 22.7 ± 2.2, P < 0.05) were significantly lower in patients with diabetes than in control subjects. At follow-up, glycaemic control (HbA(1c) 64 ± 3 to 58 ± 2 mmol/mol, P = 0.08), total cholesterol (4.9 ± 0.2 to 4.2 ± 0.2 mmol/l, P = 0.01), systolic blood pressure (145.8 ± 4.9 to 135.9 ± 3.7 mmHg, P = 0.09) and diastolic blood pressure (77.8 ± 2.7 to 70.8 ± 2.5, P = 0.03) improved. Nerve fibre density (24.1 ± 2.0, P = 0.05), nerve branch density (11.1 ± 1.3, P < 0.01) and nerve fibre tortuosity (22.6 ± 1.5, P = 0.05) increased significantly, with no change in nerve fibre length (8.4 ± 0.5). Improvement in nerve fibre density correlated significantly with the improvement in HbA(1c) (r = -0.51, P = 0.008). Via four multifactorial regressions, this confirms the negative association between HbA(1c) and nerve fibre density (P = 0.02). This study shows that corneal confocal microscopy may be employed in longitudinal studies to assess progression of human diabetic neuropathy and also supports the hypothesis that improvements in risk factors for diabetic neuropathy, in particular HbA(1c) , may lead to morphological repair of nerve fibres.
    Diabetic Medicine 06/2011; 28(10):1261-7. · 3.24 Impact Factor
  • Acta Ophthalmologica 09/2010; 88(s246):0-0. · 2.35 Impact Factor
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    ABSTRACT: The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies. A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM). Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = -0.475, P < 0.0001; NBD r = -0.511, P < 0.0001; and NFL r = -0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm(2) with a sensitivity of 0.82 (95% CI 0.68-0.92) and specificity of 0.52 (0.40-0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm(2) with a sensitivity of 0.71 (0.42-0.92) and specificity of 0.64 (0.54-0.74). CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity.
    Diabetes care 08/2010; 33(8):1792-7. · 7.74 Impact Factor
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    ABSTRACT: Corneal confocal microscopy (CCM) is a rapid, noninvasive, clinical examination technique that quantifies small nerve fiber pathology. We have used it to assess the neurological benefits of pancreas transplantation in type 1 diabetic patients. In 20 patients with type 1 diabetes undergoing simultaneous pancreas and kidney transplantation (SPK) and 15 control subjects, corneal sensitivity was evaluated using noncontact corneal esthesiometry, and small nerve fiber morphology was assessed using CCM. Corneal sensitivity (1.54 +/- 0.28 vs. 0.77 +/- 0.02, P < 0.0001), nerve fiber density (NFD) (13.8 +/- 2.1 vs. 42 +/- 3.2, P < 0.0001), nerve branch density (NBD) (4.04 +/- 1.5 vs. 26.7 +/- 2.5, P < 0.0001), and nerve fiber length (NFL) (2.23 +/- 0.2 vs. 9.69 +/- 0.7, P < 0.0001) were significantly reduced, and nerve fiber tortuosity (NFT) (15.7 +/- 1.02 vs. 19.56 +/- 1.34, P = 0.04) was increased in diabetic patients before pancreas transplantation. Six months after SPK, 15 patients underwent a second assessment and showed a significant improvement in NFD (18.04 +/- 10.48 vs. 9.25 +/- 1.87, P = 0.001) and NFL (3.60 +/- 0.33 vs. 1.84 +/- 0.33, P = 0.002) with no change in NBD (1.38 +/- 0.74 vs. 1.38 +/- 1.00, P = 1.0), NFT (15.58 +/- 1.20 vs. 16.30 +/- 1.19, P = 0.67), or corneal sensitivity (1.23 +/- 0.39 vs. 1.54 +/- 00.42, P = 0.59). Despite marked nerve fiber damage in type 1 diabetic patients undergoing pancreas transplantation, small fiber repair can be detected within 6 months of pancreas transplantation using CCM. CCM is a novel noninvasive clinical technique to assess the benefits of therapeutic intervention in human diabetic neuropathy.
    Diabetes care 11/2007; 30(10):2608-12. · 7.74 Impact Factor
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    ABSTRACT: Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fifty-four diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy.
    Diabetes 09/2007; 56(8):2148-54. · 7.90 Impact Factor
  • Diabetes care 08/2007; 30(7):1895-7. · 7.74 Impact Factor
  • Diabetes Care. 01/2007; 30(12).
  • Panagiotis Kallinikos, Philip Morgan, Nathan Efron
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    ABSTRACT: To monitor quantitative changes in stromal keratocyte density and the level of tear film inflammatory mediators following extended contact lens wear. Twenty-two subjects aged 32 +/- 11 years participated in this cross-sectional study. Eleven subjects had worn silicone hydrogel (Si-H) lenses on a 30-day continuous wear basis for 12 months. Eleven subjects had worn rigid gas permeable lenses on the same basis for 12 months. Eleven age-matched control subjects were also recruited. Ultrasound pachometry, confocal microscopy, and tear fluid sample collection were performed on all subjects. Tear samples were assayed for epidermal growth factor (EGF), hepatocyte growth factor (HGF) and interleukin (IL)-8. Corneal thickness was similar for all subject groups. Total keratocyte density was not different between the 3 groups; however, keratocyte density was lower for rigid lens wearers in the anterior to mid stroma and lower for Si-H lens wearers in the posterior stroma compared with control subjects. Rigid lens wearers exhibited an irregular keratocyte distribution across the corneal stroma. EGF concentration and rate of release was greater in the tears collected from the rigid lens wearers and Si-H lens wearers, and IL-8 concentration was higher in the samples collected from the rigid lens wearers compared with the samples collected from the control subjects. Mechanical stimulation of the corneal surface due to the physical presence of a contact lens and the consequent release of inflammatory mediators may account for a loss or redistribution of keratocytes.
    Cornea 02/2006; 25(1):1-10. · 1.75 Impact Factor
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    01/2005;
  • Panagiotis Kallinikos, Nathan Efron
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    ABSTRACT: To employ confocal microscopy to investigate the etiology of keratocyte loss after short-term contact lens wear by monitoring quantitative changes in keratocyte density. Twenty neophyte subjects aged 26 +/- 3 years participated in the study, which was conducted over the course of three experimental sessions. In the first session, one eye of each subject was fitted with a silicone hydrogel contact lens, and the other eye served as the control. Both corneas were exposed to an anoxic environment for 2 hours. Ultrasound pachometry and confocal microscopy were performed on both eyes at baseline, immediately after the experiment and 2 hours post experiment. This procedure was repeated after 72 hours, but in this case one eye of each subject was fitted with a hyper-Dk rigid contact lens, and the fellow eye served again as the control. In the third experimental session, each subject was asked to periodically rub one eye only. Tear samples collected from the rubbed and control eyes were assayed for epidermal growth factor (EGF), hepatocyte growth factor (HGF), and interleukin (IL)-8. The increase in corneal thickness was similar in the experimental and control eyes. Both anterior and posterior keratocyte densities decreased in the experimental eyes compared with the control eyes, in all sessions. EGF and IL-8 concentrations were increased in the rubbed eyes compared with the control eyes. It is hypothesized that the mechanical stimulation of the corneal surface, due to the physical presence of a contact lens, induces the release of inflammatory mediators that cause keratocyte dysgenesis or apoptosis.
    Investigative Ophthalmology &amp Visual Science 10/2004; 45(9):3011-20. · 3.44 Impact Factor
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    ABSTRACT: Corneal confocal microscopy is a reiterative, rapid, noninvasive in vivo clinical examination technique capable of imaging corneal nerve fibers. Nerve fiber tortuosity may indicate a degenerative and attempted regenerative response of nerve fibers to diabetes. The purpose of this study was to define alterations in the tortuosity of corneal nerve fibers in relation to age, duration of diabetes, glycemic control, and neuropathic severity. The cornea and collected images of the subbasal nerve plexus of 18 diabetic patients (stratified into mild, moderate, and severe neuropathic groups using conventional clinical measures of neuropathy) and 18 age-matched nondiabetic control subjects were scanned, and a novel mathematical paradigm was applied to quantify the extent of nerve tortuosity, which was termed the tortuosity coefficient (TC). TC was significantly different between the four clinical groups (F(3) = 12.2, P < 0.001). It was significantly greater in the severe neuropathic group than in control subjects (P < 0.003) and in the mild (P < 0.004) and moderate (P < 0.01) neuropathic groups. TC did not correlate significantly with the age (r = -0.003, P > 0.05), duration of diabetes (r = -0.219, P > 0.05), or hemoglobin A1c (HbA1c; r = 0.155, P > 0.05) of diabetic patients. Corneal confocal microscopy allows rapid, noninvasive in vivo evaluation of corneal nerve tortuosity. This morphologic abnormality relates to the severity of somatic neuropathy and may reflect an alteration in the degree of degeneration and regeneration in diabetes.
    Investigative Ophthalmology &amp Visual Science 02/2004; 45(2):418-22. · 3.44 Impact Factor
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    ABSTRACT: The accurate detection, characterization and quantification of human diabetic neuropathy are important to define at risk patients, anticipate deterioration, and assess new therapies. Corneal confocal microscopy is a reiterative, rapid, non-invasive in vivo clinical examination technique capable of imaging corneal nerve fibres. The aim of this study was to define the ability of this technique to quantify the extent of degeneration and regeneration of corneal nerve fibres in diabetic patients with increasing neuropathic severity. We scanned the cornea and collected images of Bowman's layer (containing a rich nerve plexus) from 18 diabetic patients and 18 age-matched control subjects. Corneal nerve fibre density (F(3)=9.6, p<0.0001), length (F(3)=23.8, p<0.0001), and branch density (F(3)=13.9, p<0.0001) were reduced in diabetic patients compared with control subjects, with a tendency for greater reduction in these measures with increasing severity of neuropathy. Corneal confocal microscopy is a rapid, non-invasive in vivo clinical examination technique which accurately defines the extent of corneal nerve damage and repair and acts as a surrogate measure of somatic neuropathy in diabetic patients. It could represent an advance to define the severity of neuropathy and expedite assessment of therapeutic efficacy in clinical trials of human diabetic neuropathy.
    Diabetologia 05/2003; 46(5):683-8. · 6.49 Impact Factor
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    ABSTRACT: Purpose: The accurate detection and quantification of human diabetic neuropathy are important to define at risk patients, anticipate deterioration, and assess new therapies. Current methods either lack sensitivity, require expert assessment (neurophysiology) or are highly invasive (skin/nerve biopsy). Corneal confocal microscopy is a rapid (2 min) non-invasive in vivo clinical examination technique capable of quantifying corneal small nerve fibre morphology. We stratified 102 diabetic patients aged (58 12 years), duration of diabetes (15 11yrs) in accordance with severity of somatic neuropathy using the Neuropathy Deficit Score (NDS) (none (1.3 0.9, n = 33), mild (3.9 0.6, n = 37), moderate (6.8 0.9, n = 22) and severe (9.8 0.5, n = 12)) and compared to 18 age-matched control subjects (55.4 8.2 years). Corneal sensitivity using non-contact (NCCA) ( p = 0.0001) and contact (Cochet- Bonnett) (CCA) aesthesiometry ( p = 0.007) decreased significantly with increasing neuropathic severity and correlated with each other ( p = 0.007). NDS correlated with reduction in corneal sensitivity (NCCA ( p = 0.0001), CCA ( p = 0.008)). Corneal nerve fibre density (NFD, p < 0.0001), nerve fibre length (NFL, p = 0.01), nerve fibre branch density (NBD) ( p < 0.0001) decreased and nerve fibre tortuosity (NFT) ( p = 0.008) increased in diabetic patients compared with control subjects. Furthermore, there was a significant correlation between NDS and NFD ( p = 0.0001), NBD ( p = 0.004) and NFL ( p = 0.011). Corneal sensitivity may be used as a simple clinical means to assess severity of somatic neuropathy. Furthermore, corneal confocal microscopy is a rapid, non-invasive in vivo clinical examination technique which accurately defines corneal nerve damage and repair and acts as a surrogate measure of somatic neuropathy. It represents a significant advance to simply and reiteratively quantify severity of neuropathy and may help expedite assessment of therapeutic efficacy in clinical trials of human diabetic neuropathy.
    01/2003;
  • Panagiotis A. Kallinikos, Nathan Efron
    01/2003;
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    ABSTRACT: Published abstract of the 27th BCLA Annual Clinical Conference
    01/2003;
  • Panagiotis A. Kallinikos, Nathan Efron
    01/2003;
  • 01/2002;
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Publication Stats

571 Citations
53.31 Total Impact Points

Institutions

  • 2010
    • Central Manchester University Hospitals NHS Foundation Trust
      Manchester, England, United Kingdom
  • 2004–2007
    • The University of Manchester
      • Faculty of Life Sciences
      Manchester, England, United Kingdom