Eye Movement Deficits Are Consistent with a Staging Model of pTDP-43 Pathology in Amyotrophic Lateral Sclerosis

Abstract

Background: The neuropathological process underlying amyotrophic lateral sclerosis (ALS) can be traced as a four-stage progression scheme of sequential corticofugal axonal spread. The examination of eye movement control gains deep insights into brain network pathology and provides the opportunity to detect both disturbance of the brainstem oculomotor circuitry as well as executive deficits of oculomotor function associated with higher brain networks.

Objective: To study systematically oculomotor characteristics in ALS and its underlying network pathology in order to determine whether eye movement deterioration can be categorized within a staging system of oculomotor decline that corresponds to the neuropathological model.

Methods: Sixty-eight ALS patients and 31 controls underwent video-oculographic, clinical and neuropsychological assessments.

Results: Oculomotor examinations revealed increased anti- and delayed saccades' errors, gaze-palsy and a cerebellary type of smooth pursuit disturbance. The oculomotor disturbances occurred in a sequential manner: Stage 1, only executive control of eye movements was affected. Stage 2 indicates disturbed executive control plus 'genuine' oculomotor dysfunctions such as gaze-paly. We found high correlations (p<0.001) between the oculomotor stages and both, the clinical presentation as assessed by the ALS Functional Rating Scale (ALSFRS) score, and cognitive scores from the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).

Conclusions: Dysfunction of eye movement control in ALS can be characterized by a two-staged sequential pattern comprising executive deficits in Stage 1 and additional impaired infratentorial oculomotor control pathways in Stage 2. This pattern parallels the neuropathological staging of ALS and may serve as a technical marker of the neuropathological spreading.

Fig 1. Categories of oculomotor deficits used for the proposed staging scheme.

Results of eye movement measures used to characterize the sequential progression of oculomotor impairment in ALS patients. Scatter plots (a—h) showing the distribution of the respective eye movement parameter in healthy controls (HC) and ALS patients falling into stage 0, 1, and 2. The shading intensity in each plot indicates the increasing deficit in eye movement control raging from normal (white) to severely impaired performance (yellow). Normal outcomes are shown as blue dots, values considered as pathological are depicted as red dots. The threshold (red line) was computed from the control group and is defined as upper quartile plus 1.5 times the interquartile range (IQR) or lower quartile minus 1.5 times IQR, respectively. (a—d) Eye movement parameters reflecting executive control. (e—f) Peak eye velocities obtained from visually guided reactive saccades indicating malfunctions of the brainstem oculomotor nuclei and the underlying network. (h) Accumulated sum of saccades interrupting smooth pursuit. Negative values together with a reduced pursuit gain (not shown, for details see text) indicate the prevalence of catch-up saccades. With increasing positive values, smooth pursuit becomes disrupted due to saccadic intrusions but the ability to perform perfect pursuit remains preserved. (i) Sample recordings of smooth pursuit (blue traces) in one representative healthy control subject (HC, upper row) and one patients with ALS (lower row) during tracking of a horizontal sinusoidal (f = 0.375Hz, amplitude ±20°) target motion (black dashed traces). Whereas the control subjects performed perfectly, the patient presented a substantial gain lag that is compensated by almost periodical catch-up saccades in order to bring the eye back onto the target, considerably indicating an impaired precerebellar pontine circuit.

Fig 2. Sequential progression of impaired eye movement control in ALS.

About the half of the investigated patients with ALS were (0) without any susceptibilities in eye movement control (Stage ‘0’), the others with an exception of one patient fall into two subgroups. Given the consistency of this findings, the two subgroups can be arranged to show disease progression based on (1) deficits in executive eye movement control (Stage 1) and (2) brainstem and pontocerebellary network related oculomotor deficits comprising impaired brainstem function or disturbances in the precerebellar pontine network that paralleled gradually worsening executive oculomotor performance (Stage 2). The level of statistical significance is color coded and indicates comparison between the staged ALS patients and healthy controls. Note, that one out of 68 subject did not follow the proposed staging scheme. RAVS, rapid alternating voluntary gaze shifts.