Corneal microstructure in diabetes mellitus and its association with peripheral neuropathy and cardiac autonomic neuropathy

Abstract

The overall focus of this research project was the ocular and systemic neurological complications of diabetes mellitus (DM) in man, and how they interrelate, with a view to being better able to understand and predict their development for earlier therapeutic intervention and prognostic accuracy. Therefore, a series of inter-related studies in this thesis investigated complications of DM involving the cornea and ocular surface, and their association with peripheral neuropathy and cardiac autonomic neuropathy. Established nerve biopsy techniques with electron microscopy, and ex vivo confocal microscopy of skin punch biopsies allow direct examination of long nerve fibre damage and repair in DM. However, both are invasive procedures and may induce persistent pain at the biopsy site, cold intolerance and sensory deficits. However, laser-scanning in vivo corneal confocal microscopy (IVCM), as demonstrated in this thesis, enables non-invasive imaging of living human corneal nerves, potentially providing an alternative means of grading and monitoring nerve damage in DM. The human corneal sub-basal nerve plexus architecture in normal and in those with DM was evaluated. The normal and diabetic corneal sub-basal nerve plexus exhibits a clockwise ‘whorl’ orientation that may have implications for post-surgical nerve regeneration. Other ocular parameters including corneal sensitivity, hysteresis, central thickness and topography along with the pre-ocular tear film metrics were compared between eyes of normal participants and participants with DM. Significant changes in the corneal sub-basal nerve density, corneal sensitivity threshold, and pre-ocular tear film in those with DM indicates a compromised ocular surface that may result in diabetic keratopathy. Having established differences in the sub-basal nerve plexus between DM and normal corneas, the effect of the most common treatment for diabetic retinopathy, pan retinal photocoagulation (PRP), on corneal nerves was explored. The corneal nerve changes after PRP were established to be related primarily to DM and appeared independent of the laser treatment. The relationship between ocular parameters including corneal sub-basal nerve plexus density, corneal sensitivity, diabetic retinopathy, peripheral neuropathy and cardiac autonomic neuropathy were evaluated. The correlation of corneal sub-basal nerve density with corneal sensitivity and total neuropathy score, a measure of peripheral neuropathy, confirms that reduced sub-basal nerve density reflects peripheral neuropathy in DM. This enables assessment of nerve damage without the need for painful and invasive skin biopsies and suggests a potential surrogate role for corneal IVCM in the diagnosis and assessment of peripheral diabetic neuropathy and potentially the monitoring of novel treatments. The nexus of studies that constitute this research thesis investigated the crucial importance of early assessment of the cornea to determine the neuropathic effect of DM on the eye and, by association, upon the extremities of the body. The integration of IVCM corneal evaluation in screening programs, in addition to retinal screening, could aid in monitoring disease progression in DM at an early stage thus enabling better prognosis and more timely interventions.