**5.3. Neurodegeneration outside the retina**

of diabetes. Neurofunctional impairment becomes apparent as a dysfunction in dark adaption [119], abnormal contrast sensitivity [120], and altered microperimetry [105], as well as electroretinogram (ERG) results. The electroretinogram (ERG) is one of the most effective diagnostic tools in this context, with the oscillatory potential implicit time being the most consistent and widely reported aspect of the ERG that changes early in DR [121]. A delay in implicit time in multifocal ERG (mfERG) has been shown to be highly predictive (86% sensitivity and 84% specificity) of new retinopathy development at specific locations over 3 years in patients with early stages of DR at baseline [122, 123]. The European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) trial currently tests mfERG for its use and potential in DR prediction. However, while ERG is a very sensitive technique to detect neurofunctional deficits, it is also a quite burdensome and time-consuming

Anatomical evaluation of retinal neurodegeneration has become possible with the implementation of SD-OCT. In OCT, the most useful measure for identifying diabetes-induced neurodegeneration is the thickness-reduction of the retinal nerve fiber layer (RNFL) and the ganglion cell complex, consisting of the ganglion cell layer (GCL) and the inner plexiform layer (IPL). Retinal ganglion cells (RGCs) are the retinal neurons in which the apoptotic process related to diabetes is first detected [124]. An impaired integrity of these cells compromises information processing and the transmission of visual signals to the brain. The damage primarily affects the RGC's nuclei and dendrites, as shown by a diffuse thinning of the combined retinal ganglion cell-inner plexiform layer (GCIPL). Secondarily, their axons are affected too, as indicated by a reduction of the retinal nerve fiber layer (RNFL) thickness [125]. A significant thinning of the GCIPL complex alone [126] or in combination with thinning of the RNFL has already been shown in patients with type 1 diabetes even without any fundoscopically manifest signs of DR [127, 128]. A longitudinal analysis in patients with type 1 diabetes depicted an average progressive thickness loss of 0.25 μm/year and 0.29 μm/ year in the RNFL and the GCL + IPL, respectively, over a 4-year follow-up period in patients with no or minimal DR, independent of age, sex and even Hb1Ac. Intriguingly, the extent of thickness loss was similar to that of patients with severe glaucoma [129]. Research results are also consistent in finding reduced RNFL and GCIPL thicknesses in patients with type 2

Further, relation between structural signs of diabetic retinal neurodegeneration and functional deficits has been investigated thoroughly. Reduced GCIPL complex thickness has been shown to significantly correlate with impaired visual function assessed by contrast sensitivity and pattern ERG amplitudes in patients with diabetes without DR [131]. In patients with type 1 diabetes and no or minimal DR, GCL thickness was an important predictor of loss of

Research has also started to focus on the temporal and causal relationship of neurogenic and vascular changes in DR. Preliminary results of the EUROCONDOR study suggest that in patients with no or mild DR, retinal vessel caliber is independently associated with structural changes of the neuroretina. Specifically, CRAE was statistically significantly associated with macular GCL thickness and CRVE with RNFL thickness at the optic disc [134]. An

macular visual function measured by the Rarebit perimetry [133].

examination.

22 Early Events in Diabetic Retinopathy and Intervention Strategies

diabetes [130–132].

Neurodegenerative changes occur outside the retina too. The cornea is one of the most densely innervated structures of the human body. A rich network of sensory nerves, known as the subbasal nerve plexus (SNP), derives from the ophthalmic division of the trigeminal nerve and lies between the corneal epithelium and Bowman's membrane [139]. This layer can be visualized with corneal confocal microscopy (CCM), a highly reproducible [140] in vivo imaging technique that provides diagnostic efficiency comparable to that of intra-epidermal nerve fiber density (IENFD) assessment [141, 142]. IENFD is the current gold standard for evaluating small nerve fiber damage, but is invasive, time-consuming and requires significant laboratory expertise. Evaluation of small fiber neuropathy is essential, as they constitute 70–90% of peripheral nerves and are preferentially involved in the development of diabetic peripheral neuropathy (DPN). DPN affects at least 50% of patients with diabetes mellitus and is the main initiating factor for foot ulceration and subsequent lower extremity amputation [143]. Unfortunately, to date, the guidelines for DPN mainly advocate electrophysiology besides clinical symptom testing, which is sensitive only for the detection of large fiber damage [144]. CCM could potentially serve as a non-invasive, objective biomarker for identifying small fiber damage and making an early diagnosis of DPN. The main changes in SNP morphology detected in patients with diabetes include a decrease in corneal nerve fiber density (CNFD), defined as the total number of major nerves per mm2 ; corneal nerve fiber length (CNFL), defined as the total length of all nerve fibers and branches (mm/mm2 ); and corneal nerve branch density (CNBD), defined as the number of branches emanating from major nerves per mm2 [145]. Previous studies have evaluated the relationship between SNP morphology and the development and progression of DR. SNP impairment appears to progress in parallel with DR and could even be demonstrated in patients with diabetes without DR [146–149]. This finding would support the concept that besides neuronal loss in the retina, corneal neurodegeneration might precede the development of visible microangiopathy in DR too.

**Author details**

Austria

**References**

750-759

837-853

Julia Hafner\*, Sonja Karst and Ursula Schmidt-Erfurth

International Publishing; 2017. pp. 1-5

Ophthalmology. 2017;**135**:306-312

England Journal of Medicine. 2000;**342**:381-389

Trial. Ophthalmology. 1995;**102**:647-661

\*Address all correspondence to: julia.hafner@meduniwien.ac.at

pathy in diabetes. Diabetes Care. 2004;**27**(Suppl 1):S84-S87

Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna,

Potential Imaging Biomarkers in the Development and Progression of Diabetic Retinopathy

http://dx.doi.org/10.5772/intechopen.71747

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[1] Herman WH. The global burden of diabetes: An overview. In: Dagogo-Jack S, editor. Diabetes Mellitus in Developing Countries and Underserved Communities. Cham: Springer

[2] Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retino-

[3] Steyerberg EW, Pencina MJ, Lingsma HF, Kattan MW, Vickers AJ, Van Calster B. Assessing the incremental value of diagnostic and prognostic markers: A review and

[4] Ikram MK, Cheung CY, Lorenzi M, Klein R, Jones TLZ, Wong TY. Retinal vascular caliber as a biomarker for diabetes microvascular complications. Diabetes Care. 2013;**36**:

[5] Ting DSW, Tan GSW, Agrawal R, Yanagi Y, Sie NM, Wong CW, et al. Optical coherence tomographic angiography in type 2 diabetes and diabetic retinopathy. JAMA

[6] Lachin JM, Genuth S, Cleary P, Davis MD, Nathan DM. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The New

[7] Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications

[8] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet (London, England). 1998;**352**:

[9] Sun JK, Keenan HA, Cavallerano JD, Asztalos BF, Schaefer EJ, Sell DR, et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme

duration: The joslin 50-year medalist study. Diabetes Care. 2011;**34**(4):968-974

illustration. European Journal of Clinical Investigation. 2012;**42**:216-228

Even though recent studies indicate that inner retinal layer thinning representing retinal neurodegeneration is associated with DPN, the direct relation between SNP morphology and variables of retinal neurodegeneration has not yet been clarified. Eventually, CCM has the potential to be a surrogate for an early diagnosis of and an early biomarker for DR and DPN that could identify those at risk.
