Disproportionate pupillary involvement in diabetic autonomic neuropathy.

OBJECTIVE: To study the degree of pupillary impairment in diabetic and non-diabetic autonomic neuropathy. METHODS: We retrospectively sampled from all patients who underwent comprehensive autonomic testing and infrared pupillometry at UT Southwestern Medical Center. Composite autonomic severity score (CASS) and pupillary indices from the average of at least three pupillary response curves were recorded. We randomly matched patients with diabetic autonomic neuropathy (DAN) and patients with autonomic impairment unrelated to diabetes (non-DAN) based on gender, age (±5 years), and CASS (±1 point). We used the paired t test to analyze differences between the groups. RESULTS: We identified 40 patients with DAN and 40 matched controls with non-DAN. M:F ratio was 1:1. Mean CASS was 4.2 and mean age was 62.4 years. Six had type I and the rest had type II diabetes mellitus. Both absolute constriction amplitude (ACA) and maximum constriction velocity (MCV) were significantly lower in DAN compared to non-DAN; mean ACA was 0.9 mm vs. 1.17 mm (p = 0.0077) and mean MCV was 2.8 vs. 3.6 mm/s (p = 0.0039). Severely diminished MCV for age was noted in 48 % of diabetic and in only 28 % of non-DAN patients. The ACA-corrected time to 75 % re-dilation was significantly delayed in DAN vs. non-DAN [mean 3.2 vs. 1.7 s/mm (p = 0.025)]. A statistically significant decline was noted for both the MCV and ACA with higher cardiovagal subscores among DAN patients. CONCLUSIONS: Parasympathetic and sympathetic pupillary dysfunction appears to be a common feature of autonomic impairment in diabetes compared to non-diabetic causes of autonomic impairment.

Dynamic pupillometry as an autonomic testing tool.

OBJECTIVE: To determine normal values for pupillometry indices in healthy control subjects and to examine these indices in patients with autonomic dysfunction and healthy controls. METHODS: Infrared video pupillometry was used to investigate the pupil response to a brief light flash in 79 healthy controls, 28 patients with normal autonomic function (composite autonomic severity score, CASS < 2), and 26 patients with moderate to severe autonomic failure (CASS > 4) seen in our autonomic laboratory from January 2008 to June 2011. In six subjects, we examined the effects of varying light stimulus intensity and light stimulus duration. Descriptive analysis, correlation, and ANCOVA adjusted for age were performed. RESULTS: We determined eight indices corresponding to parasympathetic and sympathetic pupil function. Baseline pupil diameter (BPD), maximum constriction velocity (MCV), absolute constriction amplitude (ACA), and maximum dilation velocity (MDV) negatively correlated with age (p < 0.01) among controls. MCV and ACA increased with increasing intensity of light stimulus from 3.5 to 112 µW. Indices of parasympathetic pupil innervation (MCV and ACA) were lower in the high CASS group compared to others (p < 0.0001). Indices of sympathetic pupil function, time to reach 75 % of initial resting diameter during pupillary dilation (T¾), and dilation velocity at T¾ (DV¾) did not differ significantly in the three study groups. However, T¾ corrected for the magnitude of pupillary constriction (T¾:ACA) was higher in the high CASS group suggesting sympathetic dysfunction in that group (p = 0.0003). CONCLUSIONS: Indices of pupillomotor function significantly differ between patients with moderate to severe autonomic failure and healthy controls.

A Unique Manifestation of Pupillary Fatigue in Autoimmune Autonomic Ganglionopathy.

OBJECTIVE: To demonstrate a unique abnormality of the pupillary light reflex in patients with autoimmune autonomic ganglionopathy (AAG). DESIGN: Case series. SETTING: Autonomic clinics at 2 university hospitals (University of Texas Southwestern Medical Center and Beth Israel Deaconess Medical Center). PARTICIPANTS: Seven patients with antibody-positive AAG. INTERVENTIONS: All patients with AAG underwent either monocular or binocular infrared pupillometry using a standard 2-second light stimulus at a defined intensity. Findings were compared with those from healthy control subjects and patients with other autonomic disorders. The light stimulus used in this study was selected to eliminate the normal phenomenon of pupil escape. MAIN OUTCOME MEASURES: The time to onset of redilation as well as other indices of pupillary constriction to light stimulus. RESULTS: Patients with AAG exhibited premature pupillary redilation (mean [SD], 1.02[0.20] seconds) compared with healthy control subjects (mean [SD], 2.24 [0.10] seconds) and other patients with autonomic disorders (mean [SD], 2.30 [0.12] seconds) (P.001). In healthy control subjects and patients with other autonomic disorders, pupillary redilation always followed the termination of the light stimulus; in patients with AAG, redilation consistently occurred during the light stimulus. In 1 patient, serial repetitive light stimulation further decreased the time to onset of redilation. CONCLUSIONS: Premature redilation of the pupil is a unique physiological feature seen only in patients with AAG. This phenomenon appears to be a manifestation of pupillary fatigue, a clinical correlate of defective synaptic transmission at the level of autonomic ganglia in antibody-positive AAG.

Pathways for plasmalemmal repair mediated by PKA, Epac, and cytosolic oxidation in rat B104 cells in vitro and rat sciatic axons ex vivo.

Plasmalemmal repair (sealing) is necessary for survival of damaged eukaryotic cells. Ca(2+) influx through plasmalemmal disruptions activates pathways that initiate sealing, which is commonly assessed by exclusion of extracellular dye. These sealing pathways include PKA, Epac, and cytosolic oxidation. In this article, we investigate whether PKA, Epac, and/or cytosolic oxidation, activate specific proteins required to produce a plasmalemmal seal. We report that toxin cleavage of proteins required for neurotransmitter release (SNAP-25), inhibition of Golgi trafficking (with Brefeldin A: Bref A) or inhibition of N-ethylmaleimide sensitive factor (NSF) all decrease sealing of rat B104 hippocampal cells with transected neuritis in vitro. Epac, but not PKA or cytosolic oxidation, partly overcomes the decrease in sealing produced by cleavage of SNAP-25. PKA and increased cytosolic oxidation, but not Epac, can partly overcome the decrease in sealing due to Bref A. PKA, Epac, and/or cytosolic oxidation cannot overcome NSF inhibition. Substances that affect plasmalemmal sealing of B104 neurites in vitro have similar effects on plasmalemmal sealing in rat sciatic axons ex vivo. From these and other data, we propose a model of plasmalemmal sealing having three redundant, evolutionarily conserved, parallel pathways that all converge on NSF.