The pupillary dark reflex in acute disorders of consciousness

doi:10.21203/rs.3.rs-4679946/v1

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Research Article

The pupillary dark reflex in acute disorders of consciousness

https://doi.org/10.21203/rs.3.rs-4679946/v1

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Background. In intensive care patients with disorders of consciousness (DoC), the pupillary light reflex is a measure of pupillary parasympathetic function. By contrast, the pupillary dark reflex leads to pupil dilation in response to darkness and primarily reflects the sympathetic function of the pupil. To our knowledge, this reflex has not been systematically investigated in DoC patients. We hypothesized that the pupillary dark reflex correlates with consciousness levels after acute brain injury, and that this correlation is not necessarily the same as that of the pupillary light reflex.

Methods. From November 2022 to March 2023, we enrolled 100 study participants: 25 clinically unresponsive (coma or unresponsive wakefulness syndrome) and 25 clinically low-responsive (minimally conscious state or better) patients from the intensive care units of a tertiary referral center, and 50 age- and sex-matched healthy controls. Exclusion criteria were active or chronic eye disease. We used automated pupillometry to assess the pupillary dark reflex and the pupillary light reflex of both eyes under scotopic conditions in all study participants.

Results. The pupillary dark reflex was strongly correlated with consciousness levels (r = 0.62, p < 0.001), the increase in pupillary diameters being smallest in unresponsive patients (mean ± SD: 20% ± 21%), followed by low-responsive patients (47% ± 26%) and healthy controls (67 % ± 17%; p < 0.001). Similar, yet less pronounced patterns were observed for the pupillary light reflex. Twenty-one of 25 unresponsive patients had preserved pupillary light reflexes, but only seven had preserved pupillary dark reflexes (p < 0.0001). Of these seven patients, five regained awareness.

Conclusion. The pupillary dark reflex is more sensitive to consciousness levels after brain injury than the pupillary light reflex. The clinical implications of this finding seem worthy of further investigation, particularly regarding possible benefits for neuromonitoring and prognostication after brain injury.

Brain injury

coma

consciousness

neuromonitoring

pupillometry

prognostication

The pupillary light reflex is a continuous physiological response that optimizes the amount of light reaching the retina, indicating integrity of the parasympathetic pupillary pathways,¹ and it is an essential component of neuromonitoring and -prognostication in intensive care.² Unlike the pupillary light reflex, the much lesser-known pupillary dark reflex involves pupil dilation in response to darkness and predominantly reflects sympathetic pathways.^3–5 The latter pathways include the hypothalamus and cervical sympathetic chain and are modulated by input from cortical brain areas. Psychosensory stimuli like sudden noise or squeezing the back of the neck may enhance the pupillary dark reflex.⁵ Fig. 1 provides an overview of the anatomical pathways of the pupillary light and the pupillary dark reflexes.

Disruptions to the pupillary dark reflex can occur with lesions that affect the sympathetic nervous system, even when the pupillary light reflex remains intact.^3,5–7 Because acute brain injury often involves diffuse damage to multiple neural circuits, the pupillary dark reflex may provide additional information about autonomic and higher-order brain functions after brain injury compared to the pupillary light reflex.^8–10 However, unlike the latter, the pupillary dark reflex is not clinical routine in the intensive care unit (ICU). To our knowledge, it has not previously been systematically studied in DoC patients with acute brain injury.

We investigated the pupillary dark reflex of DoC patients who were clinically unresponsive (coma or unresponsive wakefulness syndrome, UWS) or clinically low-responsive (minimally conscious states, MCS) and healthy controls. We hypothesized that the presence and strength of the pupillary dark reflex is correlated with levels of consciousness impairment after brain injury, and that these correlations are similar to those of the pupillary light reflex, but not necessarily identical.

Participants

We prospectively enrolled patients on a convenience base from two intensive care units (neurological/neurosurgical and cardiologic) at Rigshospitalet, Copenhagen University Hospital, a tertiary referral center. Inclusion criteria were age ≥ 18 years, acute traumatic or non-traumatic brain injuries, and impaired consciousness as previously described.^11–14 Age- (± 5 years) and sex-matched healthy controls were recruited from the community through word-of-mouth advertisement. Written informed consent was obtained from all participants or their surrogate decision-makers.

Clinical examination

Neurological assessments of consciousness were performed as described earlier, ^11–14 including three clinical scales: the Glasgow Coma Scale (GCS), the Full Outline of Unresponsiveness (FOUR) score,¹⁵ and the Simplified Evaluation of Consciousness Disorders (SECONDS).^16,17 Patients with a coma or UWS were categorized as clinically unresponsive; and patients in MCS or emerged from MCS were classified as being clinically low-responsive.¹⁸ In addition, MCS was subcategorized into those with (MCS +) and those without rudimentary language processing (MCS-).¹⁹ Individuals with active eye diseases or a history of eye injury were excluded. Clinical data such as medical history, admission etiology, diagnosis, and sedation were extracted from electronic health records. Sedation levels were stratified as described earlier into none; low to moderate (fentanyl < 500 µg/h, remifentanil < 1000 µg/h, propofol < 100 mg/h, midazolam < 10 mg/h, sevoflurane < 3%, or equivalent combinations); and high to very high (fentanyl ≥ 500 µg/h, remifentanil ≥ 1000 µg/h, propofol ≥ 100 mg/h, midazolam ≥ 10 mg/h, sevoflurane ≥ 3%, any dosage of sodium thiopental, or equivalent combinations). ^12–14

Pupillometry

Pupillary reflexes were investigated under scotopic conditions as described earlier.^11,20 Before pupillometry assessments, we reduced ambient light levels to below 10 lux, which was monitored using the LUX Light Meter app on a conventional iPhone. We first used the NeurOptics PLR®-3000 pupillometer to measure the pupillary dark reflex. The protocol entailed a negative pulse stimulus (pulse intensity = 0 µW, background intensity = 180 µW, measurement duration = 8.02 s, pulse duration = 7.02 s, pulse onset = 1.00 s). The light source was directed at the pupil for at least three seconds before initiating the measurement sequence. After the initial pulse, the light was deactivated, and the pupil was continuously measured for an additional 7 s. We subsequently used the NeurOptics NPi®-200 Pupillometer to assess the pupillary light reflex in both eyes. For both pupillary light and pupillary dark reflexes, we investigated changes in pupillary diameter, dilation velocity, and latency among unresponsive patients, low-responsive patients, and healthy controls. In addition, we quantified the pupillary light reflex using the Neurological Pupil index (NPi), which ranges from 0 (non-reactive) to 5 (normal), with an NPi of 3 or higher considered within normal physiological limits.¹ All data underwent visual inspection to identify and remove anomalies, e.g., blinking artifacts, as described earlier.¹³

Outcomes

The primary outcome was the magnitude and reactivity of the pupillary dark reflex assessed in both eyes of unresponsive and low-responsive DoC patients, and a comparison between DoC patients and healthy controls. Secondary outcomes included (i) the correlation between the pupillary dark reflex and levels of consciousness impairment in patients, (ii) differences in the pupillary light reflex among all groups, and (iii) the proportion of patients exhibiting discordance between pupillary dark and light reflexes.

Statistical analyses

Differences in demographic and pupillometry characteristics among unresponsive and low-responsive patients and healthy controls were assessed using a chi-squared or Fisher’s exact test for categorical data and a one-way ANOVA with a post-hoc Tukey test to account for multiple comparisons for numeric data. Comparisons between unresponsive and low-response patients were made using Student’s t-test, Mann-Whitney U-test, or Fisher’s exact test, as appropriate. A significant pupillary light reflex was defined as an NPi of 3 or higher.¹ In the absence of a specific cut-off for significant pupillary dilation, this was defined as being within 2 standard deviations of the mean pupillary dilation response (% change from initial size) observed in healthy controls. McNemar's test was used to analyze the discordance between binary pupillary dark and pupillary light reflexes in unresponsive patients. Spaghetti, scatter, and box plots were used to visualize initial and final pupillary diameters during pupillary reflex measurements. The association between mean pupillary dilation (relative change across left and right eyes) and consciousness levels (coma, UWS, MCS, fully conscious) across all study participants was assessed using Spearman’s Rank correlation coefficient and an ordinal regression model. Missing data were reported and excluded from the analyses. All analyses were conducted using R statistical software v. 4.3.2 (R Core Team, Vienna, Austria, 2022).

Ethical approval

The study adhered to the Declaration of Helsinki and received approval from the regional Danish Research Ethics Committee (H-21022096).

Between November 2022 and March 2023, we enrolled 100 study participants, including 50 patients with DoC and 50 healthy controls. Among the DoC patients, 25 were clinically unresponsive, and 25 were low-responsive. Demographic and clinical characteristics are provided in Table 1. There were no significant differences between the patient groups in terms of age (F(2,97) = 0.31, p = 0.73) or sex (χ² = 1.39, p = 0.50). In both patient groups, hemorrhagic stroke was the leading cause of brain injury (52% in unresponsive and 32% in low-responsive patients), followed by traumatic brain injury (20%) in unresponsive patients and cardiovascular causes (28%) in low-responsive patients.

Pupillary dark and pupillary light reflexes indices

Data regarding the pupillary dark reflex are summarized in Table 2. During the pupillary dark reflex, the absolute and relative increase in pupillary diameter was smallest in unresponsive patients (mean ± SD: 0.5 mm ± 0.6 mm or 20 % ± 21%), followed by low-responsive patients (1.1 mm ± 0.7 mm or 47 % ± 26%) and healthy controls (1.8 mm ± 0.5 mm or 67 % ± 17.4%). This difference in pupillary dilation was significant across the groups (F(2,97)=43.1, p<0.001). Specifically, the increase in pupillary diameter was smaller in unresponsive patients compared to low-responsive patients (M=-20, p<0.001) and healthy controls (M=-47, p<0.001) and smaller in low-responsive patients compared to healthy controls (M=-27, p<0.001). Figures 2a and 3a provide details. Significant differences in dilation velocity were observed for the left (but not the right) pupil across groups (F(2,86) = 6, p = 0.004), with unresponsive patients showing slower dilation velocity compared to healthy controls (M = -1.1, p = 0.006). There were no differences in latency to dilation across any groups.

Similar patterns were observed for the pupillary light reflex (Table 3, Figures 2b and 3b). The decrease in pupillary diameter was smaller in unresponsive patients (M = 17.5 ± 10.6%) compared to low-responsive patients (M = 27 ± 10.5%) and healthy controls (M = 37.5 ± 5.5%). This difference in pupillary constriction was significant across all groups (F(2,93) = 46, p < 0.001). Significant differences in NPi scores were also observed (F(2,97) = 12.3, p < 0.001). NPi scores were lower in unresponsive patients (3.3 ± 1.7) than in low-responsive patients (4.3 ± 0.6, p < 0.001) and healthy controls (4.4 ± 0.4, p < 0.001), but there was no significant difference between low-responsive patients and healthy controls. Constriction velocity varied significantly across groups (F(2,93) = 45, p < 0.001), being smallest in unresponsive patients (1.0 ± 0.7), followed by low-responsive patients (1.7 ± 0.9) and healthy controls (2.6 ± 0.6). There were no significant differences in latency to constriction (F(2,92) = 0.09, p = 0.092). Table 2 and Figures 2a and 3a provide details regarding pupillary dark reflex data.

Pupillary dark and pupillary light reflexes in DoC in the ICU

The association between pupillary reflexes and consciousness levels was assessed using Spearman's rank correlation coefficient and an ordinal regression model. Spearman's rank correlation was 0.62 (p < 0.001) for the pupillary dark reflex, indicating a positive association between greater pupillary dilation and higher consciousness levels. The ordinal regression model confirmed this, showing a significant association between greater pupillary dilation and higher consciousness levels (estimate = 0.051, SE = 0.013, p<0.001). This association remained significant after accounting for sedation, with higher consciousness levels linked to greater pupillary dilation (estimate = 0.032, SE = 0.01, p = 0.021) and increased sedation linked to lower consciousness levels (estimate = -1.24, SE = 0.45, p = 0.006). There was a similar, but less pronounced association between the pupillary light reflex and consciousness levels (r = 0.39, p = 0.005; estimate = 0.089, SE = 0.35, p = 0.02), which remained significant when accounting for sedation (estimate = 1.02, SE = 0.37, p = 0.006).

Among unresponsive patients, three of 25 (12%) exhibited bilaterally preserved pupillary dark reflexes, while an additional four patients (16%) had a pupillary dark reflex in one eye (Figure 4). The clinical and pupillometry characteristics of the seven patients with a unilaterally or bilaterally preserved pupillary dark reflexes are detailed in Supplementary Table S1. All these seven patients were male; four had hemorrhagic stroke, two had traumatic brain injury, and one had post-cardiac arrest ischemic-anoxic brain damage. Four patients received high to very high levels of sedation, while three received none to minimal. Except for two patients diagnosed with UWS/vegetative state, all were diagnosed with coma and were either orally intubated or tracheostomized at the time of measurement. All seven unresponsive patients with preserved pupillary dark reflexes also had preserved pupillary light reflexes in the eye(s) with a pupillary dark reflex. More unresponsive patients had preserved pupillary light reflexes than pupillary dark reflexes: 18 of 25 (72%) had bilateral light reflexes, while an additional three (12%) had pupillary light reflexes in one eye. McNemar's test indicated a significant discordance of 60% between pupillary dark and light reflexes in the unresponsive patient group (p < 0.001). In sum, 21 of 25 clinically unresponsive patients had preserved pupillary light reflexes, but only seven had preserved pupillary dark reflexes (Fisher exact test, p-value < 0.0001).

In the low-responsive patient group, pupillary reflexes were more commonly preserved. Nineteen of 25 (76%) low-responsive patients had preserved pupillary dark reflexes (16 bilaterally, two only in the left eye, and one only in the right eye). All 25 (100%) low-responsive patients had preserved pupillary light reflexes, resulting in a non-significant discordance of 28% between the light and dark reflexes (p = 0.131).

Three months after assessment, 23 of 25 unresponsive patients and 24 of 25 low-responsive patients could be followed up. Fourteen of 23 (75%) unresponsive patients and 21 of 24 (88%) low-responsive patients survived (Fisher’s exact test, p = 0.049). Six of the seven unresponsive patients with a preserved pupillary dark reflex in at least one pupil were available for follow-up: Five regained awareness, with the first signs of clinical awareness appearing after 9±5 days. In four of these five patients, the first sign of awareness was visual fixation as noted by the attending clinicians. The one patient who did not regain consciousness had life-supporting treatment withdrawn on the same day as the pupillometry.

Our study demonstrates that the pupillary dark reflex is diminished in DoC patients with acute brain injury, especially in those who are clinically unresponsive, and that it correlates with the levels of consciousness. We have shown that the pupillary dark reflex may be abolished in patients who have preserved pupillary light reflexes, thereby adding potentially important prognostic information. The pupillary dark reflex may serve as an indicator of sympathetic pathway integrity in acute DoC patients in the ICU.

The pupillary dark reflex compared to the pupillary light reflex in DoC patients

Both relaxed and dilated pupillary diameters were smaller in patients with DoC compared to healthy controls, with the lowest increase in pupillary dilation and preserved dark reflexes observed in unresponsive patients, followed by low-responsive patients. Although the pupillary light reflex showed similar patterns, these appeared to be less pronounced than what we found for the pupillary dark reflex, suggesting that sympathetic input to the pupils is overall more severely compromised than parasympathetic input. While the exact reasons require further investigations, these findings are consistent with previous research: We recently showed that eye drops containing brimonidine, an alpha-2 agonist reducing sympathetic pupillary tone, do not significantly change pupil size in deeply comatose patients, indicating the absence of sympathetic innervation.¹¹ The present study extends these findings by demonstrating the sympathetic system’s influence (or lack thereof) on the association of the pupillary dark reflex with levels of consciousness.

Notably, among the 25 clinically unresponsive patients, only three had preserved pupillary dark reflexes bilaterally and four unilaterally, all of whom had preserved light reflexes. Of the six patients who could be followed up, five regained clinical awareness. Interestingly, it has been argued that sympathetic pupillary innervation requires consciousness to be preserved to at least some degree,¹¹ and the proportion of clinically unresponsive patients with a preserved pupillary dark reflex is of the same order of magnitude as the proportion of unresponsive patients with covert consciousness (15-20%).^13,21–23 In future studies it will be interesting to investigate whether the pupillary dark reflex could be a sign of covert consciousness. Notably, automated pupillometry assessing the pupillary dark reflex distinguishes between clinically unresponsive and low-responsive patients with better precision than other technological approaches that require much greater computational expertise like, for example, arterial spin labeling MRI evaluating cerebral blood flow measurements.²⁴

Uncertainties about the pupillary dark reflex in terms of physiology and pathophysiology

The exact physiologically underpinnings of the pupillary dark reflex are not fully understood. It must be noted, for example, that the "light off" dilation is not entirely sympathetically generated. As Omary has demonstrated,²⁵ the pupillary dark reflex may still be present in patients with Horner’s syndrome. Loewenfeld discusses how "light off" activates neurons in the pretectal nucleus that are then inhibitory to the Erdinger Westphal nucleus and argues that the pupillary dark reflex is a combination of sympathetic activation and inhibition of the parasympathetic nucleus.⁶ Sillito et al. shows how the pupillo-constrictor neurons are inhibited at “light off”.²⁶ Loewenfeld also discusses a pathway from the retina to the suprachiasmatic nucleus.⁶ That nucleus increases the activity of the preganglionic sympathetics at “light off”. Pupillary dilation then follows as the sympathetic tone is augmented. Although this pathway might not be present in primates,⁶ it is important to realize that the anatomical pathways of the pupillary dark reflex outlined Figure 1A may not be complete, but a proper diagram is not yet available. (Samuels and Szabadi also show a complex figure, but the pathways they outline are not proven.²⁷)

Furthermore, in terms of pathophysiology, future research must meticulously investigate the effects of opioids and general anesthesia on the pupillary dark reflex and how this reflex may reemerge (or not) when sedation is stopped in people with acute brain injury. Opioids appear effective in blocking pupillary reflex dilation (which is not the same as the pupillary dark reflex) without altering the light reflex.²⁸ As opioids block inhibitory pathways into the Erdinger Westphal nucleus,²⁹ do unresponsive patients lack a pupillary dark reflex because of the drugs or because of CNS injury? Of the seven unresponsive patients with a preserved pupillary dark reflex, four received high to very high levels of sedation, showing that at least in a subset of sedated patients the pupillary dark reflex remains intact. Complicating this matter further, however, tolerance to the effects of opioids on the pupil does occur.³⁰ The effects of opioids on the pupillary dark reflex after brain injury may thus change over time (and perhaps with the etiology of the brain injury). Although we accounted for sedation in the statistical analysis, all these considerations must be addressed by replication studies with serial pupillary measurements of DoC cohorts with large enough numbers to account for the heterogeneity of sedation and brain injury etiologies.

Strength and limitations

This study has several strengths. First, we introduced a potentially novel clinical biomarker that is easy to collect at the bedside. Second, the study was conducted in a real-life setting in a comparably large ICU cohort. Third, we included an equally large age- and sex-matched healthy control group helped establish normal reference values for the pupillary dark reflex. Evaluating the pupillary dark reflex in addition to the pupillary light reflex may enable a more comprehensive assessment of autonomic and higher-order brain functions after acute brain injury. However, as already outlined, some limitations must be acknowledged. For example, while we controlled for ambient light intensity, environmental factors such as noise and temperature were not systematically controlled for. In the same vein, DoC patients may experience changes in intracranial pressure; they have various types and locations of brain lesions; and as stated, these patients are commonly treated with sedatives and sympathomimetics; all of which can affect pupillary function of one or both eyes. Even though we accounted for sedation, future studies must investigate the influence of all these potentially confounding factors on the pupillary dark reflex.

We did a systematic investigation of the pupillary dark reflex in the ICU. We found that this reflex can reliably distinguish between clinically unresponsive and low-responsive DoC patients with acute brain injury. Compared to the pupillary light reflex, the absence of the pupillary dark reflex appears more specific to the absence of consciousness. The pupillary dark reflex therefore provides insights into sympathetic pupillary function (or lack thereof) and reveals indices of autonomic function after brain injury that are unavailable from the light reflex. Caveats include the incomplete knowledge of the mechanisms behind the pupillary dark reflex in the healthy and the diseased brain. Future research is required to investigate these issues further, including possible benefits of the pupillary dark reflex for neuromonitoring and prognostication after acute brain injury.

Ethics permission: Danish Research Ethics Committee (H-21022096)

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The authors confirm the following: The manuscript complies with all instructions to authors; authorship requirements have been met; all authors approved the final manuscript; this manuscript has not been published elsewhere (but may be submitted to a preprint server, i.e. MedRxiv) and is not under consideration by another journal; ethical guidelines were adhered to and we indicate ethical approvals (IRB) and use of informed consent, and we confirm the use of an appropriate reporting checklist.

Author Contributions: DK, MDL and MHO were involved in conceptualization and design. PZ and DK were involved in the data analysis. PZ and DK were involved in writing the article. All authors were involved in data acquisition, important intellectual contribution and approved the manuscript.

Approval of the manuscript before submission: All authors.

Conflict of Interest Disclosures: The authors report no competing interests.

Funding/Support: This study was funded by Offerfonden, Region Hovedstadens Forskningsfond, Lundbeck Foundation and Rigshospitalets Forskningspuljer. Funding was given to support PhD students and research scholarship students. Open access funding was provided by Royal Danish Library.

Figures. The authors are solely responsible for the material, content, and results. The views expressed in the material are the authors’ own and do not necessarily reflect those of the funders.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Table 1: Demographic and clinical characteristics

	Healthy controls	Unresponsive patients*	Low-responsive patients*	P-value**
Number of participants	50	25	25	-
Age (mean ± standard deviation)	62 ± 15	59.8±16.6	63.2±13.0	0.73
Male sex, n (%)	32 (64%)	18 (72%)	14 (56%)	0.50
Pre-morbid mRS 0-2, n (%)	-	19 (76%)	24 (96%)	0.37
Brain injury etiology, n (%)
Subarachnoid hemorrhage	-	3 (12 %)	5 (20%)
Intracerebral hemorrhage	-	10 (40%)	3 (12%)
Ischemic stroke	-	2 (8%)	1 (4%)	-
Traumatic brain injury	-	5 (20%)	1 (4%)	-
Ischemic-anoxic brain damage of cardiac origin	-	3 (12)	7 (28)	-
Other	-	2 (8%)^#	8 (32%)^##	-
Airway management, n (%) p<0.001
Non-invasive	-	2 (8%)	16 (64%)	-
Tracheostomy	-	4 (16%)	3 (12%)	-
Oral intubation	-	19 (76%)	6 (24%)	-
Sedation***				p<0.001
None to minimal	-	9 (36%)	21 (84%)	-
Low to moderate	-	1 (4%)	2 (8%)	-
High to very high	-	15 (60%)	2 (8%)	-
* Patients categorized as unresponsive were in a coma or unresponsive wakefulness syndrome; those categorized as low-responsive were in the minimally conscious minus state or better. P-values regarding age and sex denote all three groups. See Methods for statistical analysis used. * See Methods for details about sedation. ^# Status epilepticus, herpes simplex encephalitis. ^##Carbon monoxide poisoning, non-convulsive status epilepticus following cerebral shunt malfunction, respiratory arrest due to Guillain-Barré, respiratory arrest due to myasthenia gravis, cerebral tumor and three aorta dissections.

Table 2: Pupil diameter changes during the pupillary dark reflex

Healthy controls

Unresponsive

patients*

Low-responsive

patients*

P-value**

Initial diameter (mm)

L: 2.8±0.6

R: 2.8±0.6

L: 2.5±1.2
R: 2.2±0.7

L: 2.3±0.5

R: 2.3±0.4

L: 0.05

R: <0.001

End diameter (mm)

L: 4.6±0.9

R: 4.6±0.9

L: 2.8±1.3

R: 2.7±1.2

L: 3.4±1.0

R: 3.4±1.0

L: <0.001

R: <0.001

Change in pupillary diameter: dilation (mm)

L: 1.9±0.5

R: 1.8±0.5

L: 0.4±0.5

R: 0.5±0.7

L: 1.0±0.7

R: 1.1±0.7

L: <0.001

R: <0.001

Relative change in pupillary diameter: dilation (%)

L: 68.9±18.8
R: 65±20.0

L: 16.6±21.9

R: 23±24.7

L: 44.5±28.5

R: 49.5±28.8

L: <0.001

R: <0.001

Dilation velocity (mm/sec)

L: 1.0 (0.42-10.2)

R: 1.5±2.1

L: 0.3 (0.1-1.2)

R: 0.4±0.2

L: 0.6 (0.3-1.6)

R: 1.2±1.2

L: 0.004

R: 0.07

Latency (sec)

L: 0.45±0.13

R: 0.40±0.12

L: 0.39±0.13

R: 0.39±0.19

L: 0.37±0.12

R: 0.46±0.20

L: 0.048

R: 0.24

Pupillometry results are presented as mean ± standard deviation.

* Patients categorized as unresponsive were in a coma or unresponsive wakefulness syndrome; those categorized as low-responsive were in the minimally conscious minus state or better.

**One-way ANOVA tests with post-hoc Tukey adjustments for multiple comparisons. Bolded values indicate significant differences.

Abbreviations: L, left; R, Right

Table 3 Pupil diameter changes during the pupillary light reflex

Initial diameter (mm)

L: 4.7±0.9

R: 4.8±1.0

L: 2.9±1.2

R: 2.8±1.2

L: 3.3±1.1

R: 3.4±1.2

L: <0.001

R: <0.001

End diameter (mm)

L: 2.9±0.6

R: 3.0±0.7

L: 2.3±0.9

R: 2.2±0.7

L: 2.4±0.7

R: 2.4±0.6

L: <0.001

R: <0.001

Change in pupillary diameter: constriction (mm)

L: 1.7±0.4

R: 1.8±0.5

L: 1.0±1.4

R: 1.1±1.1

L: 0.9±0.6

R: 1.0±0.7

L: <0.001

R: <0.001

Relative change in pupillary diameter: constriction (%)

L: 37±5.6

R: 38±6.0

L: 16±12

R: 21±12

L: 26±10

R: 28±12

L:<0.001

R:<0.001

Constriction velocity (mm/sec)

L: 2.6±0.6

R: 2.6±0.6

L: 0.9±0.8

R: 1.2±0.8

L: 1.7±0.9

R: 1.7±0.9

L: <0.001

R: <0.001

Latency (sec)

L: 0.24±0.03

R: 0.24±0.04

L: 0.25±0.12

R: 0.25±0.04

L: 0.25±0.05

R: 0.24±0.05

L: 0.72

R: 0.92

NPi

L: 4.4±0.4

R: 4.4±0.4

L: 3.3±1.7

R: 3.2±1.9

L: 4.3±0.7

R: 4.4±0.6

L:<0.001

R: <0.001

Pupillometry results are presented as mean ± standard deviationss.

* Patients categorized as unresponsive were in a coma or unresponsive wakefulness syndrome; those categorized as low-responsive were in the minimally conscious minus state or better.

**One-way ANOVA tests with post-hoc Tukey adjustments for multiple comparisons. Bolded values indicate significant differences.

Abbreviations: L, left; NPi, Neurological Pupil index; R, Right

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The pupillary dark reflex in acute disorders of consciousness

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Abstract

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INTRODUCTION

METHODS

Participants

Clinical examination

Pupillometry

Outcomes

Statistical analyses

RESULTS

DISCUSSION

Conclusion

Declarations

References

Tables

Supplementary Files

Status:

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