Watching the eyes of a person with ALS might help clinicians assess their brain function, according to a paper in the November 11 PLoS One. Researchers from the University of Ulm, Germany, used gaze-tracking technology to classify two stages of ocular deficit in people with the disease. First, conscious control over the line of sight weakens, suggesting problems with executive function that likely reflect pathology in the cortex. By the second stage, involuntary eye movements become erratic, indicating neurodegeneration in the brainstem. “Eye movement may serve as a window into the brain and its pathological alterations in ALS,” said senior author Elmar Pinkhardt. It could even serve as a biomarker for progression, the authors posit.

ALS causes paralysis, but the nerves controlling the eyes traditionally have been thought to be spared. However, scientists have observed that in people who survive for a long time with the disease, eye control is affected (reviewed in Sharma et al., 2011). Eye movements are affected in other diseases too, including Alzheimer’s (Molitor et al., 2015). Pinkhardt and co-author Albert Ludolph wondered if defects in eye movement might correlate with the spread of pathology across the brain. Specifically, they probed how eye-tracking lined up with a staging scheme for TDP-43 proteinopathy proposed in 2013. In this four-step staging, aggregates are thought to appear first in the motor cortex, brainstem, and spinal cord, and then spread to the prefrontal neocortex, precerebellar nuclei, and midbrain by stage 2. Next they creep into the postcentral neocortex and striatum, and finally affect the temporal lobe by stage 4 (see Nov 2013 conference news). However, those stages are only apparent upon autopsy. Eye-tracking, Pinkhardt and Ludolph reasoned, might give them an opportunity to observe the effects of TDP-43 proteinopathy in living patients.

Trailing gaze.

Compared to controls, people with ALS poorly tracked a moving target. [Courtesy of Gorges et al.]

First author Martin Gorges and colleagues recruited 68 people with ALS (none of them with frontotemporal dementia, which can co-occur with ALS), and 31 healthy controls for eye-tracking tests. Subjects faced a curved screen lined with tiny red and green lights. In diverse tests, the researchers asked participants to look at a newly lit dot, delay looking at the new light, or look away from it. The scientists could also project a smoothly traveling red dot onto the screen for subjects to follow (see image at right). In addition, they asked subjects to look back and forth between two lights as quickly as they could for 30 seconds. A camera tracked the movement of each eye, although, since they tended to move together, the authors averaged their movements as if the subjects were monocular.

The subjects fell into three categories. Thirty people with ALS reacted just like healthy controls. Of the other 38, the authors characterized 25 as oculomotor stage 1, meaning they made more mistakes than controls when asked to delay glancing at a light or look away from it, and reversed gaze fewer times in the 30-second back-and-forth test. These characteristicjos indicate problems with executive control of eye motion, which is managed by brain regions affected in TDP-43 proteinopathy stage 1.

Twelve ALS participants had more severe executive defects, plus other problems. Their eyes moved slowly, and when tracking the moving dot, their gaze tended to lag initially, and then jerk, or saccade, to catch up. That happens when the brainstem or precerebellar networks malfunction. The authors attributed this to TDP-43 proteinopathy stage 2 and labeled it oculomotor stage 2 in ALS.

One subject manifested the brainstem symptoms of oculomotor stage 2 without the executive-function indicators of oculomotor stage 1. Pinkhardt speculated that a comorbidity other than ALS pathology affected eye movement in this person, noting that many conditions can influence eye tracking.

This study marks the first time that researchers have correlated eye movements with brain pathology staging, Pinkhardt said. In addition, Gorges found that that oculomotor stages correlated with worsening performance on the standard ALS functional rating scale, which rates abilities such as speech, swallowing, and walking. The authors wrote that this supports their assertion that eye-movement defects could serve as a marker of disease progression.

However, the link between eye-movement problems and TDP-43 pathological staging is somewhat speculative and inexact, noted co-author Johannes Brettschneider of Herford Hospital in Germany, who came up with the four TDP-43 stages. “The PlosOne paper is valuable because it collects thorough data on oculomotor changes in a large number of ALS cases, but it cannot prove that all these findings are caused by TDP-43 pathology, or that indeed the staging we published in 2013 is correct,” he wrote to Alzforum (see full comment below).

“I think it is a really solid study with a good number of participants,” agreed Malcolm Proudfoot of Oxford University in the United Kingdom, who did not participate in the project. However, he was not entirely sold on the ocular staging scheme. “For the time being, this is still being inferred as the Ulm group didn’t include any longitudinal data, unlike the pathological staging criteria which are based on brains from people who died of ALS ,” he said (see full comment below). The fact that stage 2 oculomotor defects almost always coexist with the stage 1 deficits suggests that stage 2 follows stage 1, he said, but it is not conclusive. In contrast, Proudfoot’s own analyses indicates that eye movements in people with ALS remain stable for up to two years, suggesting they do not progress from one stage to another (Proudfoot et al., 2015). Pinkhardt said longitudinal studies are now in progress.

What do these kinds of eye measurements offer clinicians? Pinkhardt and Proudfoot agreed that eye movements might serve as a biomarker, but Proudfoot suspected they would not make a difference at the diagnosis stage. Nearly half of Pinkhardt’s ALS subjects tracked lights as well as healthy controls did, and those people presumably were in the earliest stages of disease, when a diagnostic test would be most useful. Eye movements also falter in conditions that might be confused with ALS, such as progressive supranuclear palsy, meaning they might not help with differential diagnoses either.

However, Proudfoot thought eye movements could provide a secondary endpoint in ALS clinical trials. The reason is that as patients become paralyzed and lose the ability to speak or write, some rely on their eyes to communicate. Assistive technology can even follow a person’s gaze, allowing them to pick out letters on a screen to compose messages or have an artificial voice articulate on their behalf. Communication is so important to quality of life, Proudfoot noted, that retaining the ability to control eye movements properly might be a good indicator of a drug’s efficacy in late stages. Plus, he noted that developers of eye-tracking communicators may need to consider the gaze defects.

For now, most clinicians cannot track eye movements with any more sophistication than asking a patient to follow their finger, but that could change thanks to smartphones and tablets, predicted Sebastian Crutch of University College London, who did not participate in the study. “It is not unreasonable to anticipate a day when a brief, automated, quantitative assessment of oculomotor functions could become part of standard clinical neurology assessments,” he said (see full comment below).—Amber Dance