Dysfunction of the pupillary light reflex in experimental autoimmune autonomic ganglionopathy

Abstract

Autoimmune autonomic ganglionopathy (AAG) is an antibody-mediated form of severe autonomic failure. AAG is associated with serum antibodies against ganglionic acetycholine receptors (AChR) and appears to result from impaired synaptic transmission in autonomic ganglia. The rabbit model of experimental AAG (EAAG), induced by immunization, reproduces the cardinal features of the human disease. Pupillary dysfunction is a prominent and defining feature in both AAG and EAAG. We adapted infrared computer-assisted video pupillometry to record direct pupil light responses in control and EAAG rabbits. Offline analysis algorithms were used to determine latency, velocity and amplitude of the constriction and redilation phases of the light reflex. Following immunization, pupillary abnormalities were the earliest sign of evolving autonomic failure. EAAG rabbits showed significant reduction in velocity and amplitude of pupil constriction while redilation parameters were only mildly affected. Fatigue in pupillary constriction, evidenced by premature redilation of the pupil prior to termination of the light stimulus, was observed only in seropositive rabbits. The severity of pupillary abnormalities was significantly correlated with ganglionic AChR antibody level. In chronic EAAG, treatment with pyridostigmine produced a partial recovery of pupil function. We conclude that pupillometry is a robust and sensitive diagnostic tool to assess autonomic dysfunction, distinguish AAG from other disorders, and assess responses to therapy. In EAAG, pupillary dysfunction is partially reversible, parasympathetic pupil function is more severely compromised than sympathetic function, and fatigue of pupillary constriction may be seen. These characteristic abnormalities of the pupillary light reflex may prove to have diagnostic value.

A Unique Manifestation of Pupillary Fatigue in Autoimmune Autonomic Ganglionopathy

“…Our study demonstrates that 1) Premature pupil redilation is seen in patients with AAG similar to the phenomenon described in the experimental AAG rabbit model 5 ; 2) Using this light stimulation protocol we did not see premature redilation, indicating fatigue of pupillary constriction, in healthy controls or in patients with other autonomic diseases such as diabetes; and 3) Pupillary fatigue is demonstrable with either monocular or binocular pupillometry.…”

“…Since myasthenia gravis is characterized by muscle fatigue, we hypothesized that AAG might be associated with fatigue in autonomic function. In an experimental model of AAG (EAAG) in rabbits, a unique pupillary abnormality suggestive of pupillary fatigue was seen 5 . The current study was performed to determine if pupillary fatigue may be detected in antibody positive AAG patients using dynamic pupillometry.…”

Direct and consensual murine pupillary reflex metrics: Establishing normative values

“…The animals were fully acclimated to the research environment, had unrestricted access to food and water and were maintained in a 12hour light-dark cycle. For testing, mice were lightly sedated with intraperitoneal injection of ketamine (40 mg/ml), xylazine (3 mg/ml), and acepromazine (1.5 mg/ml) (Mukherjee and Vernino 2007). Alternate forms of sedation (isoflurane or pentobarbital) had been noted to cause impairment of pupillary responses.…”

“…1A and B). The system uses infrared cameras to capture (30 times per second) digital images of the pupils in darkness (Mukherjee and Vernino 2007). Pupil diameter is determined by threshold detection of the dark pupil and correction for distance of the pupil from the camera.…”

Pupillary Light Reflexes are Associated with Autonomic Dysfunction in Bolivian Diabetics But Not Chagas Disease Patients

“…Constriction ratio was calculated as minimum pupil radius divided by baseline pupil radius. 23 Statistical analysis. Data were entered using Microsoft Access 2007 (Microsoft Corp.), then cleaned and analyzed using STATA Version 11.0 (StataCorp LP, College Station, TX).…”