title: Spatial analysis improves the detection of early corneal nerve fiber loss in patients with recently diagnosed type 2 diabetes.
abstract: Corneal confocal microscopy (CCM) has revealed reduced corneal nerve fiber (CNF) length and density (CNFL, CNFD) in patients with diabetes, but the spatial pattern of CNF loss has not been studied. We aimed to determine whether spatial analysis of the distribution of corneal nerve branching points (CNBPs) may contribute to improving the detection of early CNF loss. We hypothesized that early CNF decline follows a clustered rather than random distribution pattern of CNBPs. CCM, nerve conduction studies (NCS), and quantitative sensory testing (QST) were performed in a cross-sectional study including 86 patients recently diagnosed with type 2 diabetes and 47 control subjects. In addition to CNFL, CNFD, and branch density (CNBD), CNBPs were analyzed using spatial point pattern analysis (SPPA) including 10 indices and functional statistics. Compared to controls, patients with diabetes showed lower CNBP density and higher nearest neighbor distances, and all SPPA parameters indicated increased clustering of CNBPs (all P<0.05). SPPA parameters were abnormally increased >97.5th percentile of controls in up to 23.5% of patients. When combining an individual SPPA parameter with CNFL, ≥1 of 2 indices were >99th or <1st percentile of controls in 28.6% of patients compared to 2.1% of controls, while for the conventional CNFL/CNFD/CNBD combination the corresponding rates were 16.3% vs 2.1%. SPPA parameters correlated with CNFL and several NCS and QST indices in the controls (all P<0.001), whereas in patients with diabetes these correlations were markedly weaker or lost. In conclusion, SPPA reveals increased clustering of early CNF loss and substantially improves its detection when combined with a conventional CCM measure in patients with recently diagnosed type 2 diabetes.
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.|Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Dan
authors.identifier: http://orcid.org/0000-0001-8956-3552
authors.initials: D
authors.lastname: Ziegler
authors.affiliation: Institute of Anatomy, University of Leipzig, Leipzig, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Winter
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strom
authors.affiliation: Department of Ophthalmology, University of Rostock, Rostock, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Zhivov
authors.affiliation: Institute for Applied Computer Science, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Allgeier
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papanas
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Ziegler
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Brüggemann
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Ringel
authors.affiliation: Department of Ophthalmology, University of Rostock, Rostock, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Peschel
authors.affiliation: Institute for Applied Computer Science, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Köhler
authors.affiliation: Department of Ophthalmology, University of Rostock, Rostock, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stachs
authors.affiliation: Department of Ophthalmology, University of Rostock, Rostock, Germany.
authors.forename: Rudolf F
authors.initials: RF
authors.lastname: Guthoff
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.|Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
mesh_terms: D000328:Adult; D000368:Aged; D003315:Cornea / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000502:physiology*