Diagnosing and quantifying a common deficit in multiple sclerosis: Internuclear ophthalmoplegia

Abstract

Objective: We present an objective and quantitative approach for diagnosing internuclear ophthalmoplegia (INO) in multiple sclerosis (MS).

Methods: A validated standardized infrared oculography protocol (DEMoNS [Demonstrate Eye Movement Networks with Saccades]) was used for quantifying prosaccades in patients with MS and healthy controls (HCs). The versional dysconjugacy index (VDI) was calculated, which describes the ratio between the abducting and adducting eye. The VDI was determined for peak velocity, peak acceleration, peak velocity divided by amplitude, and area under the curve (AUC) of the saccadic trajectory. We calculated the diagnostic accuracy for the several VDI parameters by a receiver operating characteristic analysis comparing HCs and patients with MS. The National Eye Institute Visual Function Questionnaire-25 was used to investigate vision-related quality of life of MS patients with INO.

Results: Two hundred ten patients with MS and 58 HCs were included. The highest diagnostic accuracy was achieved by the VDI AUC of 15° horizontal prosaccades. Based on a combined VDI AUC and peak velocity divided by amplitude detection, the prevalence of an INO in MS calculated to 34%. In the INO group, 35.2% of the patients with MS reported any complaints of double vision, compared to 18.4% in the non-INO group (p = 0.010). MS patients with an INO had a lower overall vision-related quality of life (median 89.9, interquartile range 12.8) compared to patients without an INO (median 91.8, interquartile range 9.3, p = 0.011).

Conclusions: This study provides an accurate quantitative and clinically relevant definition of an INO in MS. This infrared oculography-based INO standard will require prospective validation. The high prevalence of INO in MS provides an anatomically well described and accurately quantifiable model for treatment trials in MS.

Figure 1. Measurement with infrared oculography

(A) Setup of the measurement. Participants were seated in front of a display monitor with their head stabilized with a chin and forehead rest. The camera was located in front of the chin rest, just below the line of sight. (B) Target used in the measurements: circle with a black cross in the center. (C) Schematic representation of the AUC. The AUC is assessed from the first starting saccade (left eye in red, right eye in blue) until the last ending saccade (left or right eye). In this period, the area is calculated for both eyes separately by summing the horizontal eye position at every time point minus the horizontal start position of the saccade. (D–G) Horizontal eye position (y-axis) against the time (x-axis) of a leftward saccade of 4 different patients with multiple sclerosis, captured by infrared oculography. The blue line represents the right eye; the red line represents the left eye. (D) Leftward saccade without adduction delay, VDI AUC 1.07 and VDI Pv/Am 1.00. (E) Leftward saccade with clear adduction delay, VDI AUC 1.60 and VDI Pv/Am 2.32. (F) Leftward saccade with mild adduction delay, VDI AUC 1.37 and VDI Pv/Am of 1.15. (G) Leftward saccade with mild adduction delay, VDI AUC 1.12 and VDI Pv/Am of 1.25. AUC = area under the curve of the saccadic trajectory; Pv/Am = peak velocity divided by amplitude; VDI = versional dysconjugacy index.

Figure 2. VDI distribution

Distribution of the VDI AUC and Pv/Am of 15° saccades of healthy controls and patients with MS. Both leftward and rightward VDIs are included. The INO detection thresholds are indicated by the dashed lines. Patients with MS who had VDIs above one of these thresholds (red-shaded areas) are classified as INO. (A) VDI AUC, detection threshold 1.174. (B) VDI Pv/Am, detection threshold 1.180. AUC = area under the curve; INO = internuclear ophthalmoplegia; MS = multiple sclerosis; Pv/Am = peak velocity divided by amplitude; VDI = versional dysconjugacy index.

Figure 3. VDI parameter comparisons

Venn diagram showing the (overlap between) the detection of internuclear ophthalmoplegias with different VDI parameters. For every parameter, the number and percentage of VDIs in the multiple sclerosis group that exceeded the VDI cutoffs at a specificity level of 98% (table 2) are presented. Both leftward and rightward VDIs are included. (A) VDIs of 15° saccades. Total number of VDIs above the thresholds: 100. The bold black line indicates the combined detection of the VDI AUC and VDI Pv/Am of 15° saccades, which resulted in the highest accuracy. With this detection, 97% of the number of VDIs above the threshold is included, which corresponds to 23% of all VDIs of patients with multiple sclerosis included in the analysis. The corresponding specificity (percentage of VDIs of healthy controls that do not exceed the threshold) is 97%. (B) VDIs of 8° saccades. Total number of VDs above the thresholds is 85. AUC = area under the curve of saccadic trajectory; Pv/Am = peak velocity divided by amplitude; VDI = versional dysconjugacy index.

Figure 4. Eye movement complaints and vision-related QoL

(A) Frequency of complaints (of any severity) on the eye movement questionnaire of patients with and without INO. (B) Vision-related QoL scores of patients with and without INO. The overall score and the scores of a few subdomains are shown. INO = internuclear ophthalmoplegia; QoL = quality of life.