Quantitative Assessments of Pupillary Light Reflexes in Hospital-Onset Unconsciousness

Abstract

Background

Patients who develop hospital-onset unconsciousness should be promptly managed in order to avoid clinical deterioration. Pupillary examination through pupillary light reflex is the mainstay method in the initial evaluation of unconscious patients, but the current method of light shedding and subjective description often shows poor reliability. The objective of this study is to explore whether a quantitative measurement of pupillary light reflexes is useful in detecting brain herniation syndrome and predicting neurological outcomes in non-neurological patients who developed hospital-onset unconsciousness.

Methods

This was a registry-based observational study on patients who activated the neurological rapid response team at Asan Medical Center (Seoul, Korea). Hospital-onset unconsciousness was defined as a newly developed stupor or comatose state during admission. Demographics, comorbidities, pupillometry parameters including Neurological Pupil index, brain herniation syndrome, in-hospital mortality, and modified Rankin Scale at 3-months were analyzed.

Results

In 214 consecutive patients with hospital-onset unconsciousness, 37 (17%) had brain herniation syndrome. The optimal cut-off value of Neurological Pupil index for detecting brain herniation syndrome was < 1.6 (specificity, 91% [95% confidence interval (CI) = 86−95]; sensitivity, 49% [95% CI = 32−66]). The in-hospital mortality rate was 28% (59/214); the Neurological Pupil index was negatively associated with in-hospital mortality after adjustments for the presence of brain herniation syndrome (adjusted odds ratio = 0.77, 95% CI = 0.62–0.96). Poor neurological outcomes (modified Rankin Scale ≥ 4) at 3 months was observed in 76% (152/201) of the patients; the Neurological Pupil index was negatively associated with poor neurological outcomes after adjustments for clinical variables (adjusted odds ratio = 0.67, 95% CI = 0.49–0.90).

Conclusions

Quantitative measurements of pupillary light reflexes may be useful for early detection of potentially life-threatening neurological conditions in patients with hospital-onset unconsciousness.

Introduction

Unconsciousness is one of the most common complaints in patients during emergency department visits and hospitalizations [1]. Various causes underlie unconsciousness, including metabolic encephalopathy, brain structural lesions, meningoencephalitis, and seizure disorders. Early management of the underlying causes as well as the clinical symptoms should be promptly provided in order to avoid clinical deterioration, morbidity, and mortality [2]. Hospitalized patients generally have more comorbidities and are sicker than the general population; hence, the etiologies and outcomes of sudden unconsciousness may differ between in-hospital patients and outpatients. Nevertheless, comprehensive studies on the early evaluations and long-term outcomes of hospital-onset unconsciousness (HOU) are lacking.

Pupillary examinations are the mainstay in the initial evaluation of unconscious patients [3]. The assessments of pupils include diameter, shape, symmetry, and light reflexes. Evaluation of the pupillary light reflexes (PLR) is conventionally performed by shedding light into the patient’s eye and subjectively described by examiners. However, such conventional assessments of PLR have low inter-rater and intra-rater correlations [4, 5]. Recently, quantitative pupillometery (QP) was introduced to the neurocritical care field to provide objective assessments of the PLR. QP is able to detect subtle early changes in the size and light reflexes of pupils [6]. This bedside tool is becoming popular in the routine evaluation of unconscious patients who are admitted to intensive care units and require serial measurements of pupils, especially for those with brain herniation syndrome (BHS) [7–10]. Moreover, QP was shown to be useful in neurological prognostication in unconscious patients after cardiac arrest [11–17]. Because the PLR is regulated by the autonomic nervous system, QP may also have a role in the assessment of autonomic dysfunction in critically ill patients [18, 19]. However, studies on the QP findings in patients who are hospitalized outside intensive care units are lacking. Moreover, the clinical implication of the findings of sluggish pupils remains largely uninvestigated in unconscious patients, although fixed dilated pupils inarguably suggest urgent situations and grave prognosis [3].

Here, we investigated whether quantitative assessments of the PLR through QP measurement indicates the presence of BHS in non-neurological patients who developed HOU. We also explored which QP parameters are related to clinical outcomes in such patients.

Methods

Results

Discussion

In this registry-based observational study, we showed that the application of QP was useful for detecting BHS and predicting clinical outcomes in patients with HOU. When the patients’ altered mental status activated the neurological rapid response team, the initial detection of reduced pupillary reactivity (lower values of NPi) as well as enlarged pupillary size (Max and Min) were significantly associated with later identifications of BHS. The specificity and negative predictive value of the finding of NPi < 1.6 were as high as ~ 90% in predicting the presence of BHS, while the sensitivity and positive predictive value were relatively low at ~ 50%. QP parameters indicating reduced pupillary reactivity were also significantly associated with in-hospital mortality (lower values of NPi, CH, CV, and DV, and higher values of Lat) and poor neurological outcome at 3 months (lower values of NPi, CH, and DV, and higher values of Lat). The addition of QP in considering the patients’ medical conditions enhanced the prediction value (larger area under the ROC curve) of mRS at 3 months. To the best of our knowledge, this is the first study to show the prognostic value of measuring QP in patients who are admitted for non-neurological illness and develop sudden unconsciousness.

In terms of the etiologies of HOU, we found that metabolic encephalopathy was the most common cause, followed by seizure-related events, ischemic and hemorrhagic strokes, and metastatic and primary brain tumors. Approximately 43% of our study population had acute diseases of the brain such as stroke, intracranial bleeding, brain tumor, meningoencephalitis, and hypoxic-ischemic brain injury. BHS, one of the most severe life-threatening neurologic emergencies, was found in 17% of patients with HOU and was caused by massive cerebral infarcts, subdural hemorrhage, or diffuse brain swelling related to metabolic conditions (eg, acute liver failure). Seizure-related events including convulsive seizure, nonconvulsive status epilepticus, and postictal state were also as frequent as 29%.

We found that the use of QP may be useful for the early detection of BHS. The pupillary examination is a crucial component in the initial evaluation of unconscious patients, but early signs of pupils relevant to BHS can be nonspecific or elusive despite careful examination. In emergency situations, it is challenging to quickly perform and properly interpret neurological examinations, especially in hospitalized patients with multiple comorbidities. According to the experience of our rapid response team, QP is a practical tool when used in addition to routine neurological examination, because it is portable and can be quickly performed at bedside. In a previous preliminary observational study, midline shift and increased intracranial pressure were associated with a decrease of CV below 0.6 mm/sec; however, patients with diffuse brain edema and without midline distortion did not show such a decrease in CV until the intracranial pressure exceeded 30 mmHg [10]. In our study, 13 of 37 patients with BHS had diffuse brain swelling but did not have midline shifts, which may account for the absence of differences in CV between the BHS and non-BHS groups. Nevertheless, we demonstrated that the NPi value of less than 1.6 has a high specificity and a high negative predictive value for detecting BHS in patients with HOU. Collectively, these findings suggest that patients who develop unconsciousness during the hospital admission and show decreased NPi value on QP measurements would benefit from undergoing expeditious neuroimaging studies to detect BHS.

Traditionally, the PLR has been rather subjectively assessed by using a variety of non-standardized light sources by practitioners with varying levels of skills in neurological examinations. Recent studies have shown that such subjective assessments of pupillary reactivity have subpar reliability, with low inter-rater and intra-rater correlations [4, 5]. Recently, the QP has become popular as it provides a non-invasive, hand-held implementation of neuro-monitoring. QP also offers an objective and standardized measurement of the PLR, and mean QP values in healthy volunteers (Max 3.5–5.3 mm, Min 2.4–3.4 mm, CH 29–36%, Lat 0.22–0.27 sec, CV 1.5–2.9 mm/sec, and DV 0.9–2.2 mm/sec) have been suggested in prior studies [7, 10, 24–26]. Additionally, the automated algorithm of QP provides an NPi value derived from a combination of QP variables. An NPi score below 3.0 is generally considered an abnormal finding of sluggish light reflex [8]. Preliminary studies conducted in intensive care units reported the usefulness of QP for detecting a wide range of conditions including increased intracranial pressure [7–10]. response to osmotherapy [27], discrimination between compressive lesions and microvascular ischemic oculomotor nerve palsy [28], assessment of disease severity of aneurysmal subarachnoid hemorrhage [29], the depth of sedation and analgesia [30], and neurological prognostication in comatose resuscitation-of-spontaneous-circulation following cardiac arrest [11–17]. The prognostic implication of QP has been only investigated in patients with cardiac arrest [11–17], in whom a decrease in NPi values less than 2.0 was associated with unfavorable neurological outcomes [13]. Our results showed that the QP was useful in detecting BHS and predicting clinical outcomes in patients with HOU, and that decreased NPi values and increased pupillary sizes were significantly related to BHS. Decreased NPi values were also associated with in-hospital mortality and unfavorable neurological outcomes at 3-months. In terms of QP variables, the pupillary size (Max and Min) was not significantly related to mortality rate or neurological outcomes, whereas other QP variables such as CH, Lat, and DV were associated with clinical outcomes including in-hospital mortality and neurological status at 3-months. Therefore, a combination of QP variables may be more reliable than the NPi alone in the prediction of neurological outcomes, despite the high predictive value of the NPi. In summary, our results show that measurements of PLR with QP may be useful in the early detection of life-threatening neurological conditions and neuro-prognostication for patients with HOU.

Fixed or dilated pupils are generally ominous neurological signs, as sluggish or absent PLR may indicate the compression or stretching of the dorsal midbrain in which the Edinger-Westphal nuclei is located, or of the efferent oculomotor nerve that carries parasympathetic fibers [31]. Some studies suggested that the integrity and function of PLR may also be affected by the perfusion defect to the brainstem or alterations of neurotransmitter release [32, 33]. Furthermore, even though pupillary constriction by light stimulus is predominantly integrated by the parasympathetic nervous system, it is possible that sympathetic activities are also engaged in the regulation of the pupillary reactivity. First, the sympathetic nerves are involved in the dilation phase of PLR: the supranuclear inhibition via sympathetic neurons suppresses the pre-ganglionic parasympathetic neurons at the Edinger-Westphal nucleus, resulting in relaxation of the pupil sphincter muscle; also, the sympathetic neurons contract the iris dilator muscle via peripheral sympathetic innervation [31]. Second, the reticular activating system affects the pupil size and PLR by tonic inhibitory input of the Edinger-Westphal complex through releasing norepinephrine [34]. Third, cognitive and emotional processes may result in mydriatic reaction by the input of cortical innervation into the brainstem, although the exact circuits remain poorly understood [34, 35]. Thus, the dynamics of the pupil reactivity may be indicative of lesions or dysfunctions of the cortex, subcortex, and brainstem that affect the parasympathetic system, sympathetic system, neurotransmitters, and their complex interactions.

Further studies are needed to clarify the mechanism underlying the association between QP values and clinical outcomes in patients with HOU in the absence of BHS. It is possible that autonomic dysfunction, as well as multiorgan dysfunction and brain dysfunction (eg, metabolic encephalopathy and BHS) may underlie such association. Autonomic dysfunction mediated by inflammatory response likely has an important role in the pathogenesis of the dysfunction of the brain or other organs [36]. Neurotransmitter imbalance such as cholinergic deficiency due to inflammation and multiorgan dysfunction in critically ill patients can lead to pupillary dysfunction [18, 33]. In this context, although there is limited evidence on the association between QP values and the severity of encephalopathy [37], QP as an indicator of autonomic and brain dysfunction may play a role in assessing the severity of metabolic encephalopathy as the cause of HOU (Fig. 3).

In addition to the inherent limitations of its single-center retrospective design, the present study has the following limitations. First, we did not assess the pupillary dilation reflex, which may be evoked by sensory stimulation and predominantly mediated by the sympathetic nervous system. Instead, we measured the DV, which could reflect sympathetic activity during the dilation phase of the PLR. Second, concurrent use of drugs that could confound the evaluation of the PLR such as opioids, anticholinergics, or sedative agents was not evaluated. Although a previous study showed that the use of these medications within therapeutic doses does not significantly suppress the PLR [38], we cannot exclude the possibility that other medications such as propofol may have affected the PLR [39]. Third, we did not analyze confounders such as underlying pathology of the retina or optic nerve as well as the influence of ambient lights on the PLR [40].

Conclusions

In conclusion, reduced reactivity and increased size of pupils were related to BHS in patients with HOU. Moreover, reduced pupillary reactivity was associated with in-hospital mortality and poor neurological outcomes at 3-months. These findings suggest that QP measurement may be useful for early detection of potentially life-threatening neurological conditions in non-neurological in-patients who develop unconsciousness.

Abbreviations

BHS brain herniation syndrome

CH percentage of change

CI confidence interval

CT computed tomography

CV constriction velocity

DV dilation velocity

EEG electroencephalography

GCS Glasgow Coma Scale

HOU hospital-onset unconsciousness

Lat latency of constriction

Max maximal pupillary diameter

Min minimal pupillary diameter

MRI magnetic resonance imaging

mRS modified Rankin Scale

NAT Neurological Alert Team

NPi Neurological Pupil index

OR odds ratio

PLR pupillary light reflexes

QP quantitative pupillometery

Declarations

Manuscript complies with all instructions to authors. Authorship requirements have been met and the final manuscript was approved by all authors. This manuscript has not been published elsewhere and is not under consideration by another journal.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics approval

This study was approved by the institutional review board of Asan Medical Center and the need for written informed consent was waived considering the retrospective nature of the study.

Conflicts of interest

The authors declare that they have no conflict of interest

Funding

This study was supported by grants of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant numbers: HI18C1487 and HI18C2383).

Authors' contributions

H.L., S.H.C. and S.-B.J. contributed to the conception and design of the study; H.L., S.H.C., B.P., Y.-H.H., H.B.L., and S.-B.J. recruited the participants and collected the data; H.L. and S.-B.J. analyzed and interpreted the data, performed literature search, and wrote the manuscript; H.L. prepared the figures; all authors appraised and edited the manuscript, and approved its final version for submission.

Acknowledgements

None

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