Gorges M, Müller HP, Lulé D, Del Tredici K, Brettschneider J, Keller J, Pfandl K, Ludolph AC, Kassubek J, Pinkhardt EH. Eye Movement Deficits Are Consistent with a Staging Model of pTDP-43 Pathology in Amyotrophic Lateral Sclerosis. PLoS One. 2015;10(11):e0142546. Epub 2015 Nov 11 PubMed.
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The authors of this study analyzed changes in oculomotor function in ALS cases and—based on what we know about the underlying anatomical structures—tried to relate these changes to the distribution of TDP-43 pathology. This relation is, of course, somewhat speculative, but many studies in the field try to establish a connection between clinical phenotypes and findings in neuropathology. The relation between the oculomotor changes reported here and the distribution of TDP-43 as described in our Annals paper is rather loose and not very exact.
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.
View all comments by Johannes BrettschneiderUCL Institute of Neurology
Although relatively early days (as the authors note, they await confirmation in larger samples and with longitudinal follow-up), this study valuably attempts to go beyond merely detecting a clinical deficit or correlating a clinical deficit with a particular neuroimaging finding or other biomarker, and instead tries to stage the level of dysfunction currently being exhibited by an individual.
Eye-tracking is not yet a routinely available clinical tool, but with the proliferation of such technologies in smartphones and tablets, 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.
More generally, computational, mathematical and engineering techniques are now routinely used to evaluate complex magnetic resonance imaging (MRI) datasets describing the structure of the brain in people with dementia. By contrast, we have barely examined whether similar techniques and technology can be harnessed to address highly complex clinical and cognitive datasets, such as those elicited by quantitative assessment of oculomotor function.
View all comments by Sebastian CrutchUniversity of Oxford
I think this is a really solid study by the Ulm group with a good number of participants. There are lots of overlapping findings with our study, which is great because it indicates the results are reproducible. For example, we also found that anti-saccade error rates correlated with falling ALSFRSr (Proudfoot et al., 2015). Here, Gorges and colleagues used a more sensitive measure of cognitive disturbance (the ECAS, as opposed to the ACE), which was very sensible, allowing them to find correlations between cognition and eye-tracking measures that were much less robust in our data.
A lot of the discussion in their paper focuses on the utility of eye-tracking measures as a staging tool. They hope this can provide some clinical translation of their previous pathological staging criteria. The trouble is that our longitudinal data showed stability of eye-tracking measures rather than progressive decline. Having said that, they looked at a different range of measures, and it’s possible that some more basic eye movements (smooth pursuit and max peak velocity) may get worse as the disease progresses. 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 (by definition, “end-stage”).
I think this work is really important considering the ongoing development of eye-tracking devices for communication, which may need to take account of oculomotor deficits as the disease progresses. I don’t think we have enough data yet on what proportion of people with advanced ALS can actually make good use of these devices—it’s a try-it-and-see approach on an individual basis, which is of course perfectly reasonable.
A future consideration is of course what the diagnostic value of these measures are (given that many other conditions also affect eye movements) and what their prognostic value turns out to be. We don’t yet have the data to assess its diagnostic potential fully, but my hunch is that it won’t be super-useful. You can see in the Ulm paper that a big portion of people with ALS do just fine on the tests, and you can expect that they represent the patients with the lowest overall burden of disease—just the people in whom there might be some diagnostic doubt. The other group with diagnostic doubt might be those patients in whom you know something is definitely wrong, but can’t exactly classify the neurological problem. Given that eye-movement dysfunction is a very prominent feature of, say, PSP, again I’m not sure it will help. It might be that functional neuroimaging using an eye-tracking task could distinguish the anatomical (and hence pathological) cause of an individual’s oculomotor dysfunction to provide diagnostic support. For example, there was a recent great paper by the Munoz group that evidenced dysfunction in the DLPFC—an expected culprit (Witiuk et al., 2014).
But yes, relative to “follow my finger,” I’m sure these assessments are more sensitive, and with much less inter-user variability that permits repeated longitudinal study. I don’t think it is novel “bedside” information, but it is way more quantitative. My hope is that early signs of dysfunction will be predictive of subsequent deterioration in the oculomotor domain, whereas patients with normal eye movements at diagnosis will remain normal. As communication is so important, you could easily envisage this being a secondary end point in a clinical trial. We came to a pragmatic conclusion, based on our data, that these tools could also support cognitive assessments in very disabled ALS patients, but you would first need to establish reliable normative ranges.
The main findings of the paper are also the most contentious, that of classification. I think the evidence that executive impairments always coexist with catch-up saccades is suggestive, but that longitudinal evidence would be definitive. Further investigation of smooth pursuit in ALS looks to be worthwhile.
References:
Proudfoot M, Menke RA, Sharma R, Berna CM, Hicks SL, Kennard C, Talbot K, Turner MR. Eye-tracking in amyotrophic lateral sclerosis: A longitudinal study of saccadic and cognitive tasks. Amyotroph Lateral Scler Frontotemporal Degener. 2015 Jan-Feb;17(1-2):101-11. Epub 2015 Aug 27 PubMed.
Witiuk K, Fernandez-Ruiz J, McKee R, Alahyane N, Coe BC, Melanson M, Munoz DP. Cognitive deterioration and functional compensation in ALS measured with fMRI using an inhibitory task. J Neurosci. 2014 Oct 22;34(43):14260-71. PubMed.
View all comments by Malcolm ProudfootMake a Comment
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