The Retinal Nerve Fiber Layer Thickness Is Associated with Systemic Neurodegeneration in Long-Term Type 1 Diabetes.

Purpose: To determine whether the retinal nerve fiber layer thickness can be used as an indicator for systemic neurodegeneration in diabetes. Methods: We used existing data from 38 adults with type 1 diabetes and established polyneuropathy. Retinal nerve fiber layer thickness values of four scanned quadrants (superior, inferior, temporal, and nasal) and the central foveal thickness were extracted directly from optical coherence tomography. Nerve conduction velocities were recorded using standardized neurophysiologic testing of the tibial and peroneal motor nerves and the radial and median sensory nerves, 24-hour electrocardiographic recordings were used to retrieve time- and frequency-derived measures of heart rate variability, and a pain catastrophizing scale was used to assess cognitive distortion. Results: When adjusted for hemoglobin A1c, the regional thickness of the retinal nerve fiber layers was (1) positively associated with peripheral nerve conduction velocities of the sensory and motor nerves (all P < 0.036), (2) negatively associated with time and frequency domains of heart rate variability (all P < 0.033), and (3) negatively associated to catastrophic thinking (all P < 0.038). Conclusions: Thickness of the retinal nerve fiber layer was a robust indicator for clinically meaningful measures of peripheral and autonomic neuropathy and even for cognitive comorbidity. Translational Relevance: The findings indicate that the thickness of the retinal nerve fiber layer should be studied in adolescents and people with prediabetes to determine whether it is useful to predict the presence and severity of systemic neurodegeneration.

Palpebral Fissure Response to Phenylephrine Indicates Autonomic Dysfunction in Patients With Type 1 Diabetes and Polyneuropathy.

Purpose: The superior and inferior tarsal muscles are sympathetically innervated smooth muscles. Long-term diabetes often leads to microvascular complications, such as, retinopathy and autonomic neuropathy. We hypothesized that diabetes induces (1) sympathetic paresis in the superior and inferior tarsal muscles and that this measure is associated with (2) the severity of diabetic retinopathy, (3) the duration of diabetes, and (4) autonomic function. In addition, association between the severity of retinopathy and autonomic function was investigated. Methods: Forty-eight participants with long-term type 1 diabetes and confirmed distal symmetrical polyneuropathy were included. Palpebral fissure heights were measured bilaterally in response to topically applied 10% phenylephrine to the right eye. The presence of proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy and disease duration were denoted. Time and frequency derived heart rate variability parameters obtained from 24-hour continuous electrocardiography were recorded. Results: The difference in palpebral fissure heights between phenylephrine treated and untreated eyes (∆PFH) was 1.02 mm ± 0.29 (P = 0.001). The ∆PFH was significantly lower in the PDR group (0.41 mm ± 0.43 vs. 1.27 mm ± 1.0), F(1,35) = 5.26, P = 0.011. The ∆PFH was lower with increasing diabetes duration, r(37) = -0.612, P = 0.000. Further, the ∆PFH was lower with diminished autonomic function assessed as total frequency power in electrocardiogram (r = 0.417, P = 0.014), and sympathetic measures of very low (r = 0.437, P = 0.010) and low frequency power (r = 0.384, P = 0.025). Conclusions: The ∆PFH is a simple ambulatory sympathetic measure, which was associated with the presence of PDR, disease duration, and autonomic function. Consequently, ∆PFH could potentially be an inexpensive and sensitive clinical indicator of autonomic dysfunction.

Psychophysical and vasomotor evidence for interdependency of TRPA1 and TRPV1-evoked nociceptive responses in human skin: an experimental study.

The TRPA1 and TRPV1 receptors are important pharmaceutical targets for antipruritic and analgesic therapy. Obtaining further knowledge on their roles and interrelationship in humans is therefore crucial. Preclinical results are contradictory concerning coexpression and functional interdependency of TRPV1 and TRPA1, but no human evidence exists. This human experimental study investigated whether functional responses from the subpopulation of TRPA1 nociceptors could be evoked after defunctionalization of TRPV1 nociceptors by cutaneous application of high-concentration capsaicin. Two quadratic areas on each forearm were randomized to pretreatment with an 8% topical capsaicin patch or vehicle for 24 hours. Subsequently, areas were provoked by transdermal 1% topical capsaicin (TRPV1 agonist) or 10% topical allyl isothiocyanate ("AITC," a TRPA1 agonist), delivered by 12 mm Finn chambers. Evoked pain intensities were recorded during pretreatments and chemical provocations. Quantitative sensory tests were performed before and after provocations to assess changes of heat pain sensitivity. Imaging of vasomotor responses was used to assess neurogenic inflammation after the chemical provocations. In the capsaicin-pretreated areas, both the subsequent 1% capsaicin- and 10% AITC-provoked pain was inhibited by 92.9 ± 2.5% and 86.9 ± 5.0% (both: P < 0.001), respectively. The capsaicin-ablated skin areas showed significant heat hypoalgesia at baseline (P < 0.001) as well as heat antihyperalgesia, and inhibition of neurogenic inflammation evoked by both 1% capsaicin and 10% AITC provocations (both: P < 0.001). Ablation of cutaneous capsaicin-sensitive afferents caused consistent and equal inhibition of both TRPV1- and TRPA1-provoked responses assessed psychophysically and by imaging of vasomotor responses. This study suggests that TRPA1 nociceptive responses in human skin strongly depend on intact capsaicin-sensitive, TRPV1 fibers.

Translational pain biomarkers in the early development of new neurotherapeutics for pain management.

Translation of the analgesic efficacy of investigational neurotherapeutics from pre-clinical pain models into clinical trial phases is associated with a high risk of failure. Application of human pain biomarkers in early stages of clinical trials can potentially enhance the rate of successful translation, which would eventually reduce both length and costs of drug development after the pre-clinical stage. Human pain biomarkers are based on the standardized activation of pain pathways followed by the assessment of ongoing and paroxysmal pain, plus evoked responses which can be applied to healthy individuals and patients prior to and after pharmacological interventions. This review discusses the rationality and feasibility of advanced human pain biomarkers in early phases of drug development for pain management which is still an unmet medical need.