Edited by: Andrew J. Zele, Queensland University of Technology, Australia
Reviewed by: Helmut Wilhelm, University Eye Hospital, Germany; Alexander Erich Hartmann, Kliniken der Stadt Köln, Germany
This article was submitted to Neuro-Ophthalmology, a section of the journal Frontiers in Neurology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The pupillary light reflex is a polysynaptic reflex that requires cranial nerves II and III, as well as central brainstem connections (
Although the pupillary light reflex is part of the routine neurological examination, its physiological background is less well-understood than most clinicians are aware of. In addition to the pathways outlined above, there is also a cortical component of pupillary innervation. For instance, emotional responses and cognitive processes such as decision making and mental arithmetic may produce pupillary dilatation (
The present study aimed at investigating cortical modulation of pupillary reflex pathways by using routinely collected data in a clinical setting. To this end, we correlated automated pupillometry with cerebral infarct locations in stroke patients after endovascular thrombectomy, which served as a paradigm for pupillary changes caused by select cerebral lesions. We hypothesized that patients with strategic infarcts localized to the prefrontal eye field (Broadman area 8) and/or the insular cortex on either side would have pupillary abnormalities compared to stroke patients without infarcts in these areas. Pupillometry data from neurologically normal patients with acute but clinically stable myocardial infarction, investigated after percutaneous coronary intervention, served as control group.
We assessed pupillometry data from stroke patients (aged ≥18 years) with an anterior circulation stroke (i.e., affecting internal carotid artery, middle cerebral artery and/or anterior cerebral artery territories) consecutively admitted for acute endovascular thrombectomy to the Department of Neurology, Rigshospitalet, Copenhagen University Hospital, during the period from March to July 2018.
Patients with a history of eye disease (e.g., following cataract operation), relevant structural pathology on CT other than ischemic stroke (e.g., tumors), and mass effects on CT exceeding a midline shift of 5 mm (measured at the level of the pineal gland) were excluded. In addition, we excluded patients with evidence of posterior circulation strokes (acute or chronic) to avoid lesions involving the brainstem and occipital cortex.
For automated pupillometry, we used the NPi®-200 Pupillometer (NeurOptics, Laguna Hills, CA 92653 USA), a portable, handheld, monocular, infrared device, which allows quantitative measurements of the pupillary response. The pupillometer releases a flash of white light (duration 0.8 s, pulse intensity 121 uW) to stimulate the pupillary light reflex. Light calibration is performed by the manufacturer and does not require any periodic re-calibration. The pupillometer digitally registers the pupillary light response as a video (sampling rate 30 Hz) and displays numeric results on a screen (Table
Variables assessed by pupillometry.
Size = Maximal Diameter (in millimeters) | Maximum pupil size before constriction |
MIN = Minimal Diameter (in millimeters) | Pupil diameter at peak constriction |
% CH = Change in diameter (%) | % of change from maximal to minimal pupil diameter |
LAT = Latency of constriction (in seconds) | Time of onset of constriction following initiation of the light stimulus |
CV = Constriction Velocity (in millimeters per second) | Average of how fast the pupil diameter is constricting measured in millimeters per second |
MCV = Maximum Constriction Velocity (in millimeters per second) | Maximum velocity of pupil constriction of the pupil diameter responding to the flash of light measured in millimeters per second |
DV = Dilation Velocity (in millimeters per second) | The average pupillary velocity when, after having reached the peak of constriction, the pupil tends to recover and to dilate back to the initial resting size, measured in millimeters per second |
NPi = Neurological Pupil Index (absolute value) | Proprietary algorithm that takes all variables above as inputs and compares to normative model to give a composite score of pupillary response from 0 to 5, with ≥3 being within physiological limits ( |
We performed a clinical practice study investigating the cortical modulation of pupillary function following strategic cerebral strokes. This figure depicts CT of the brain from 2 exemplary stroke patients 24 h following endovascular therapy for large vessel occlusive stroke. Strategic ischemic infarctions are seen in the left prefrontal eye field
Pupillometry, CT, and NIHSS data were dichotomized according to stroke location: Group 1 included stroke patients with infarcts in the prefrontal eye field and insular cortex in either hemisphere (strategic infarcts); group 2 included stroke patients without infarcts in these regions. The control group consisted of patients with acute, clinically stable myocardial infarction after percutaneous coronary intervention from the Department of Cardiology, Rigshospitalet, Copenhagen University Hospital. The latter patients underwent pupillometry as described, but neither NIHSS nor CT.
Outcome measures included the pupillary diameter before and after light exposure, percentage change of pupillary diameters, and pupillary constriction and dilatation velocities, as well as the neurological pupil index (NPi), which is a proprietary pupillometry sum score (i.e., a composite of quantitative pupillary parameters and a measure of the briskness of the pupil light reflex) from 0 to 5, with ≥3 indicating physiological limits (including a maximal difference between the 2 eyes of < 0.7) (
Statistical tests were performed using Prism 7 software (GraphPad Software; La Jolla, CA, USA). Baseline characteristics, dichotomized ASPECT (
All measurements were performed as part of routine clinical assessment. Data were anonymized and handled according to the European Union's Data Protection Law. The Ethics Committee of the Capital Region of Denmark approved the study concept and waived the need for written consent because risks were deemed negligible.
Seventy-four patients were admitted for acute endovascular thrombectomy from March 1 to July 11, 2018. Twenty-four patients fulfilled exclusion criteria and their data were omitted. Fifty patients with an anterior circulation stroke were included for analysis [26 (52%) females; mean age 71.8 years,
Clinical baseline characteristics.
Age (years; mean ± standard deviation) | 72.6 ± 11.8 | 71.9 ± 8 | 67.8 ± 13.6 | NS | NS |
Females | 12 (48%) | 14 (56%) | 11 (44%) | NS | NS |
Hypertension | 23 (92%) | 20 (80%) | 15 (60%) | NS | 0.009 |
Cholesterol | 19 (76%) | 21 (84%) | 23 (92%) | NS | NS |
Diabetes | 5 (20%) | 4 (16%) | 2 (8%) | NS | NS |
Smoking | 7 (28%) | 8 (32%) | 5 (20%) | NS | NS |
Alcohol Abuse | 4 (16%) | 3 (12%) | 0 | NS | NS |
Platelet Inhibition | 18 (72%) | 20 (80%) | 24 (96%) | NS | NS |
Anticoagulation | 7 (28%) | 5 (20%) | 3 (12%) | NS | NS |
Antihypertensives | 20 (80%) | 16 (64%) | 14 (56%) | NS | NS |
Sedative medication (i.e. antiepileptic and psychotropic drugs) | 1 (4%) | 6 (24%) | 1 (4%) | NS | NS |
Of 25 patients with strategic infarctions (group 1), 17 had an involvement of the insular cortex alone, 2 of the prefrontal eye field, and 5 of both areas (Figure
As expected, infarct volumes (estimated with the ASPECT score) were correlated with the presence of a strategic stroke. Patients with an ASPECT score ≤ 7 (
The clinical severity, as revealed by the NIHSS score, was also associated with stroke location. NIHSS scores >10 (
General pupillary function was normal in the 3 groups: The NPi index was >3 in all 75 patients (i.e., 150 eyes examined). Likewise, NPi differences between left and right eyes were always within physiological limits (< 0.7). Maximal and minimal pupillary diameters, percentage changes in pupillary sizes, latency of pupillary constrictions, as well as constriction and dilation velocities were also similar between group 1 (strategic infarcts) and group 2 (other infarcts) (Table
Pupillometry data from stroke patients with and without strategic infarctions, and controls.
Npi L | 4.52 ± 0.08 | 4.38 ± 0.08 | 4.42 ± 0.07 | 0.2 | 0.36 |
Size L (mm) | 3.44 ± 0.16 | 3.31 ± 0.15 | 3.17 ± 0.17 | 0.55 | 0.24 |
Min L (mm) | 2.33 ± 0.01 | 2.41 ± 0.09 | 2.30 ± 0.09 | 0.53 | 0.32 |
%Ch L | 31.6 ± 1.71 | 26.1 ± 1.63 | 25.4 ± 2.07 | 0.03 |
0.02 |
CV L (mm/s) | 2.09 ± 0.17 | 1.87 ± 0.16 | 1.71 ± 0.17 | 0.36 | 0.13 |
MCV L (mm/s) | 3.39 ± 0.28 | 2.75 ± 0.25 | 2.59 ± 0.26 | 0.1 | 0.05 |
DV L (mm/s) | 0.88 ± 0.06 | 0.84 ± 0.08 | 0.80 ± 0.07 | 0.68 | 0.43 |
Lat L (s) | 0.24 ± 0.01 | 0.24 ± 0.01 | 0.24 ± 0.01 | 0.54 | 0.84 |
Npi R | 4.45 ± 0.08 | 4.44 ± 0.08 | 4.44 ± 0.07 | 0.99 | 0.94 |
Size R (mm) | 3.34 ± 0.14 | 3.29 ± 0.17 | 3.17 ± 0.18 | 0.81 | 0.45 |
Min R (mm) | 2.33 ± 0.09 | 2.35 ± 0.11 | 2.3 ± 0.09 | 0.84 | 0.84 |
%Ch R | 29.4 ± 2.14 | 27.7 ± 1.42 | 25.4 ± 2.03 | 0.53 | 0.18 |
CV R (mm/s) | 2.03 ± 0.15 | 2.09 ± 0.14 | 1.66 ± 0.17 | 0.74 | 0.12 |
MCV R (mm/s) | 3.19 ± 0.27 | 3.06 ± 0.23 | 2.53 ± 0.24 | 0.88 | 0.11 |
DV R (mm/s) | 0.83 ± 0.08 | 0.83 ± 0.06 | 0.84 ± 0.09 | 0.94 | 0.89 |
Lat R (s) | 0.24 ± 0.01 | 0.23 ± 0.01 | 0.24 ± 0.01 | 0.33 | 0.97 |
A positive correlation between maximum size and constriction velocity was found for both right and left eyes. The Pearson coefficient for left eyes was
Pupillometry data from patients with strategic cerebral infarcts and controls: Maximal pupillary diameters and constriction velocities. Solid lines denote the best fit from linear regression analysis.
A weak correlation was also found for minimum size and dilation velocity in controls but not in patients with strategic infarctions. Thus, the coefficient for left eyes in group 1 was r = 0.25 (
Pupillometry data from patients with strategic cerebral infarcts and controls: Minimal pupillary diameters and dilatation velocities. Solid lines denote the best fit from linear regression analysis.
Linear regression analysis of constriction velocities, plotted against maximum pupillary diameters, was unaffected by hemispheric stroke lateralization (Figures
Pupillometry data from patients with left, respectively, right hemisphere cerebral infarcts (plotted against pupillometry data from controls without hemispheric strokes): Maximal pupillary diameters and constriction velocities. Solid lines denote the best fit from linear regression analysis.
Pupillometry data from patients with left, respectively, right hemisphere cerebral infarcts (plotted against pupillometry data from controls without hemispheric strokes): Minimal pupillary diameters and dilatation velocities. Solid lines denote the best fit from linear regression analysis, showing the relationship between minimum diameter and dilation velocity.
The human pupillary light reflex, as assessed by the speed of pupillary constriction and diameters before and after constriction, does not seem to be affected by strategic infarcts of the prefrontal eye field or insular cortex. This finding does not support the hypothesis of strategic strokes altering pupillary function, probably because the present model is a model of cortical lesioning as opposed to cortical activation. Hence, cortical activation may lead to pupillary dilation (
Subtle changes in pupillary function, however, may still be possible immediately after the light reflex, i.e., when the light stimulus is over, and the pupils dilate back to baseline. Thus, while we observed a robust correlation between pupillary size and constriction velocity [confirming previous studies (
Limitations to our study, besides the modest sample size, include the use of CT instead of Magnetic Resonance Imaging to estimate stroke location and the use of the ASPECT score which is a crude measure of stroke volume (
On the positive side, all pupillometry data besides the NPi are based on objective and well-known indices (Table
Of note, we also introduced a new cortical lesion model in humans (which are very rare for obvious reasons), using strategic infarctions in patients after endovascular thrombectomy for acute ischemic stroke. Given the rapidly increasing use of endovascular stroke therapy (
Overall pupillary function is unaffected by prefrontal eye field or insular cortex strokes in humans. Subtle changes, perhaps related to autonomic dysfunction, may still occur immediately after the light reflex when the pupils dilate back to baseline. Replication using a larger sample size is needed to further explore the possible influence of hemispheric lateralization. We suggest that endovascular therapy for acute ischemic stroke due to occlusive large vessel disease may serve as a pragmatic and realistic clinical research model for the study of acquired cortical lesions in humans.
CP: acquisition of data, analysis and interpretation, writing of the manuscript, critical revision for important intellectual content, approval of final manuscript; PM, JG: acquisition of data, critical revision for important intellectual content, approval of final manuscript; TT, GK: analysis and interpretation, critical revision for important intellectual content, approval of final manuscript; JK: study concept, analysis and interpretation, critical revision for important intellectual content, approval of final manuscript; DK: study concept, acquisition of data, analysis and interpretation, writing of the manuscript, critical revision for important intellectual content, approval of final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at: