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].