Pupillary Reflex Differences Distinguish Autism From Typical Development

Daniel M. Keller, PhD

May 28, 2010

May 28, 2010 (Philadelphia, Pennsylvania) — In an effort to find discrete phenotypic features that are consistently present in autistic populations, researchers at the University of Missouri Thompson Center for Autism in Columbia have shown that children and young adults with autism have prolonged latency and less constriction of their pupils in reaction to light.

Using the latency component of the pupillary light reflex, they were able to distinguish subjects with or without autism with 89.6% success. When constriction amplitude was figured in, the success rate increased to 92.5%, researcher Judith Miles, MD, PhD, professor of pediatrics and medical genetics and pathology, told attendees of the 9th Annual International Meeting for Autism Research.

Dr. Miles and colleagues originally looked at autism subgroups defined by physical dysmorphologies and family histories. But she said the pupillary light reflex (PLR), which is the pupil's response to short flashes of light, "is a promising model system, and the components seem to be promising biomarkers" of autism. It consists of a latency period, a constriction time leading to constriction of some maximum amplitude, and a redilation time.

"The latency and constriction amplitude are the 2 components that we found best separate autistic groups from controls," Dr. Miles reported.

She explained that 2 groups of antagonistic muscles control the size of the pupil. The sphincter is under parasympathetic control, and dilators are controlled by the sympathetic system. Coauthor and biomedical engineer Dr. Gary Yao designed and built equipment to provide the light stimulus and measure and record the PLR.

The study involved 29 people with autism (27 boys) with an mean ± SD age of 12.4 ± 4.4 years (range, 6-20 years). None of the participants was taking medication. The 44 typically developing controls (21 boys) were aged 10.4 ± 2.7 years (range, 6-16 years).

The researchers have collected extensive medical, autism and family history, physical and neurologic, laboratory, autism spectrum, cognitive, and functional data on each family participating in their Autism Research Program, from which the study participants were recruited.

Prolonged Latency of Pupillary Constriction in Autism

In the light-adapted state, the autistic group showed a latency to the beginning of pupillary constriction of about 240 milliseconds vs about 210 milliseconds for the controls (P < .0001), as estimated from bar graphs shown in the presentation. In the dark adapted state, latencies were slightly shorter but showed the same relationship (P < .0001). Using latency alone, the researchers could reliably classify subjects as autistic or not with 89.6% accuracy.

They also looked to see whether the latency measure could distinguish autistic children and young adults according to their clinical presentations. They found that subjects with persistent toe-walking (n = 7) had prolonged latency compared with non–toe-walkers (n = 9; P = .01).

Dr. Miles presented 2 possible explanations for these findings. First, evidence suggests that PLR is modulated by the cerebellum. And although little is known about the neurologic basis of prolonged idiopathic toe-walking in autism, she said a study on this gait disturbance that occurs in about 20% of people with autism suggests cerebellar involvement. Second, the long latency may be a marker for some general impairment of cell-to-cell connections or synaptic function.

Amplitude of Pupillary Constriction Blunted in Autism

Pupillary constriction amplitude in autism is also different from controls. In the dark-adapted state, there was a significant difference (P = .039). "Constriction amplitude differences between autism and controls is less robust than what we found for latency," Dr. Miles said. "However, when we combine...constriction amplitude and latency, the children with autism were discriminated from typically developing controls with 92.5% success."

She noted that parents report that about 35% of children with autism show significant improvements in language and social interactions when they have a fever. From her data on more than 500 children, she noticed that of the children who improved with fever, some of the clinical characteristics that improved were related to autonomic dysfunction, suggesting that "the fever improvers are a discrete, neurologically based subgroup," she said.

On testing, the researchers found that subjects who improved when they had fevers (all tested without fevers) had larger constriction amplitudes, very similar to normal controls, whereas those not improved with fever had amplitudes less than the autism group as a whole (P = .006 for improvers vs nonimprovers).

"Increased constriction amplitude is consistent with increased parasympathetic tone. Thus, fever responders are likely to have increased parasympathetic tone," Dr. Miles suggested.

In summary, she said the study shows that pupillary constriction latency and amplitude differ in people with autism. Furthermore, PLR changes correlate with 2 clinical phenotypes, toe-walking and fever improvement. Dr. Miles concluded that PLR may be a good model system for studying the neurologic basis of autism because PLR is relatively simple and well understood and is clinically accessible.

Session moderator John Welsh, PhD, a professor at Seattle Children's Hospital Research Institute and professor in the Department of Pediatrics at the University of Washington in Seattle, said the study moves in the direction of creating an easy-to-implement diagnostic measure of autism "that could be employed very early in children before they're diagnosed with autism based on their social and language inabilities." He said the PLR could potentially work in such an age group.

With the PLR, "we're looking at...the most simple cranial nerve system, which is simply the pupillary light reflex, and now we have learned that that's disturbed in autism," he said. "So that creates further evidence that we're dealing with very broad spectrum pathophysiology associated with autism."

He noted 1 limitation of the study is the possibility of false-positive results "because there are many other ways that might lead to changes in pupillary light reflex...[so] it might be like a first aid screening [test] to sort of raise awareness," with more sophisticated tests of language and social functioning later.

Dr. Miles and Dr. Welsh have disclosed no relevant financial relationships.

9th Annual International Meeting for Autism Research (IMFAR): Abstract 109.004. Presented May 20, 2010.

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