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Pupillary light reflex (PLR) assessment is a crucial examination for evaluating brainstem function, particularly in patients with acute brain injury and neurosurgical conditions. The PLR is controlled by neural pathways modulated by both the sympathetic and parasympathetic nervous systems. Altered PLR is a strong predictor of adverse outcomes after traumatic and ischemic brain injuries. However, the assessment of PLR needs to take many factors into account since it can be modulated by various medications, alcohol consumption, and neurodegenerative diseases. The development of devices capable of measuring pupil size and assessing PLR quantitatively has revolutionized the non-invasive neurological examination. Automated pupillometry, which is more accurate and precise, is widely used in diverse clinical situations.
- neurocritical care
- outcome
- pupillometry
- traumatic brain injury
1. Introduction
Examination of brainstem reflexes is crucial for a comprehensive evaluation of neurosurgical patients, particularly in emergent situations. These reflexes include the PLR, corneal reflex, oculocephalic reflex, and gag reflex. The pupillary light reflex (PLR), which causes the pupil to constrict in response to bright light, is a routine assessment in the field of neurology [1] and emergency medicine [2]. Pupil size is regulated by two muscles: the circumferential sphincter muscle, which constricts the pupil in response to light and is innervated by the parasympathetic nervous system, and the iris dilator muscle, which dilates the pupil in low light intensity and is controlled by the sympathetic nervous system [3]. The integrity of the reflex arc passing through the brainstem is essential for PLR, making it a valuable tool for evaluating brainstem function. The PLR is particularly useful for monitoring cerebral dysfunction in patients with traumatic brain injuries and after neurosurgery, and deterioration of the PLR is a strong predictor of adverse outcomes after acquired brain injury [4].
The standard pupil examination involves assessing pupil size, shape, symmetry, and the PLR. The PLR is a strong predictor of outcome and survival after brain injury, such as traumatic brain injury (TBI) [5] or subarachnoid hemorrhage [6]. Furthermore, the shape of the pupil has been found to be significant in several intracranial pathological conditions, and adverse neurological outcomes have been associated with an oval or football-shaped pupil [7]. However, manual pupil assessment results are inconsistent and prone to inaccuracies due to variations in light intensity and exposure times with different light sources, as well as the skill levels and visual acuity of different examiners. The visual descriptions of manual PLR assessments are often subjective and imprecise, involving terms such as reactive, non-reactive, dilated, brisk, or sluggish [8]. Similar issues arise when evaluating pupil size and shape. To address these problems, modern automated pupillometry has been developed, which provides more accurate, reliable, and reproducible measurements by standardizing the distance between the light source and the eye, and the intensity of the light stimulus.
2. The Modulation of PLR
The pupil size is regulated by two groups of smooth muscle: the dilator iridis muscle and the sphincter pupillae muscle. The dilator muscle is innervated by the sympathetic system while the sphincter is innervated by the parasympathetic system [12]. The pathway of PLR on either side has an afferent limb and two efferent limbs. The afferent limb runs within the optic nerve (CN II), while the efferent limbs run within the oculomotor nerve (CN III). Photosensitive retinal ganglion cells, activated by light, transmit signals through the optic nerve (CN II) and across both optic tracts via the optic chiasm. From there, the signals travel to the Edinger–Westphal nuclei, which give rise to preganglionic parasympathetic fibers that innervate the sphincter pupillae muscles, causing pupil constriction.
Light stimulation in one eye causes a response in both eyes. The response of the pupil of the eye stimulated by light is called the direct light reflex, while the response of the pupil of the other eye to the light stimulation of the opposite eye is called the consensual light reflex. This reflex occurs due to the crossing over of the nasal retinal fibers at the optic chiasm, allowing each pretectal nucleus to receive signals from both eyes. The projections of each pretectal nucleus to both Edinger-Westphal nuclei contribute to the consensual light reflex.
The sympathetic system controls pupillary dilation. First-order neurons descend from the hypothalamus and synapse in the spinal cord at the T1 and T2 level. Second-order neurons then exit the spinal cord and synapse in the superior cervical ganglion. Third-order neurons then ascend with the carotid plexus and innervate the dilator iridis muscle. Horner syndrome, characterized by the triad of ptosis, miosis, and hemifacial anhidrosis, is caused by lesions affecting the first- and second-order neurons [13]. Hemifacial anhidrosis will not occur if a lesion affects only third-order neurons.
3. Automated Pupillometry
Measuring PLR and Pupillary Light Dilation (PLD)
The PLR and pupillary response to an alerting stimulus are measured as changes in pupil size. Several variables of these reflexes are assessed, including latency of onset, maximum amplitude, duration, and constriction and dilation velocities. The PLR has three key components: latency of the reflex, CV, and dilation velocity (DV). The conventional method of evaluating pupil reactivity involves using a penlight or flashlight to measure pupil size and the PLR, but this method is subjective and dependent on the skills of the technician. Values of pupil response parameters may vary due to differences in light intensity and duration, making it difficult to compare measurements between different examiners or even the same examiner at different times.
4. Clinical Application of Pupillometry
Pupillometry has found its most well-established application in the postacute care of cardiac arrest patients. The 2020 American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care have been recently included automated pupillometry and the NPi as a standard and reproductible assessment when performed in conjunction with other prognostic tests [52]. Pupillometry is classified as a class IIb recommendation and can be performed at 72 h or longer after cardiac arrest to aid in predicting the neurological outcome in patients who remain comatose.
5. Role of Pupillometry in Neurocritical Care
Pupillometry has emerged as a crucial tool in neurocritical care, enabling clinicians to detect elevated intracranial pressure and impending neurological deterioration at an early stage [44,46,53,54,55,56,57]. Pupil evaluation using a penlight for reactivity and a pupil gauge for size is often performed, but the results are often heterogenous and inconsistent, with variations in the intensity and duration of ambient light, as well as with different examiners. Furthermore, subjective and imprecision description of the PLR, including terms such as reactive, non-reactive, dilated, brisk, or sluggish contribute to the lack of consistency in repeated measurements. A previously observational study by Chen and Colleagues [42] revealed only moderate inter-rater reliability between practitioners for pupil size, shape, and reactivity.
6. Prognostic Indicator in Intracranial Pathology
Several studies have demonstrated the potential use of pupillometry as a prognostic indicator, particularly in cases of cardiac arrest and acute brain injuries. Taylor et al. [62] prospectively analyzed collected pupillometry data from 117 patients with various acute brain injuries, including aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage, and found that the NPi score on admission was significantly different between patients with poor and favorable progress (Glasgow Outcome Scale (GOS) 0.88 ± 1.68 vs. 3.89 ± 0.97, p < 0.001). An initial NPi cutoff of 3.4 was able to predict outcome at 1 month with a specificity of 84.6% and sensitivity of 86% [62]. The observational study by Lee et al. [63] in their hospital-onset unresponsive patients found that brain herniation syndrome could be detected with a NPi cut-off set below 1.6 with a specificity of 91% and a sensitivity of 49%. The study also found that the NPi was negatively associated with in-hospital mortality (odds ratio (OR): 0.77; 95% CI: 0.62–0.96) and poor neurological outcomes (modified Ranking scale ≥ 4) at 3 months (OR: 0.67; 95% CI: 0.49–0.90) after adjustments. Another three case series by Papangelou et al. showed that the NPi can be used to predict transtentorial brain herniation, with 73% of NPi values being abnormal (NPi < 3) prior to the occurrence of transtentorial herniations [64]. These studies suggest the potential value of pupillometry as a prognostic tool in neurocritical care.
7. Increased Intracranial Pressure
Intracranial pressure (ICP) monitoring is an important method for evaluating and managing patients with neurocritical conditions. While intracranial catheter placement remains the gold standard for measuring ICP, several non-invasive techniques are being advocated to provide useful information, including optic nerve sheath diameter, pulsatility index, estimated ICP using transcranial Doppler, and the NPI [66]. Pupillometry, which assesses changes in pupil size and reactivity, has been increasingly recognized as an effective tool for detecting ICP. Several studies have been conducted in the past on the association between pupillometry and increased ICP.
The relationship between increased ICP and pupillometry (decreased NPi) was first described in a case series back in 2002 [67], and subsequent studies have confirmed this association [68,69,70]. In 2003, Taylor et al. conducted a study involving 310 normal volunteers and 26 patients with acute brain lesions [23]. They found that a CV falling below 0.6 mm/second might be a useful cut point for detecting increased ICP. Additionally, they noted that when patients had diffuse brain swelling without a midline shift, the CV started to drop when ICP increased above 30mmHg. An asymmetry of the pupil size greater than 0.5 mm was also recognized when the ICP increased above 20 mmHg [23].
8. Traumatic Brain Injury
Quantitative pupillometry has been increasingly recognized as a valuable non-invasive tool for detecting ICP in patients with acute brain injuries. The measurement of the PLR has been used to triage patients with TBIs and evaluate the severity of the injury.
El Ahmadieh et al. found that an NPi < 3 in comatose patients with a GCS score ≤ 8 could indicate that the PLR pathway is compromised, and the patient might require intervention even when the brain CT did not show signs of herniation or midline shift [72]. Singer et al. sought to develop a non-invasive method to evaluate the severity of TBIs and measure ICP [73]. They found that optic nerve sheath diameter and pupillometry were suitable supplementary screening tool for severe TBIs. The study demonstrated that patients with severe TBIs had a significantly large optic nerve sheath diameter and decreased NPi compared to controls.
9. Intracerebral Hemorrhage (ICH)
Recent studies have evaluated the use of pupillometry in predicting increased ICP and the correlation between computed tomography (CT) indicators of intracerebral hemorrhage and pupillometry parameters. Giedde-Jeppe et al. [57] conducted a retrospective study on 23 sedated nontraumatic supratentorial ICH patients. The study found that PLR parameters, such as CV, DV, latency, and percentage change of aperture, had high negative predictive values (around 97% to 99.2%) but low positive predictive values (only 7.2% to 8.3%) for predicting increased ICP (defined as >20 mmHg). These findings suggest that automated pupillometry may facilitate the avoidance of routine invasive ICP monitoring.
10. Aneurysmal Subarachnoid Hemorrhage
Aneurysmal subarachnoid hemorrhage is a serious condition that requires careful monitoring of neurological function. Several studies have been conducted on the use of pupillometry in evaluating disease severity and predicting clinical outcomes in patients with aSAH. Natzeder et al. collected 4456 NPi data points from 18 patients with aSAH and found that the mean NPi tended to be lower in patients with clinically severe (World Federation of Neurological Surgeons (WFNS) grade 4–5) compared with non-severe (WFNS grade 1–3) aSAH (3.75 ± 0.40 vs. 4.56 ± 0.06, p = 0.171) [74]. The mean NPi also tended to be lower in patients with an unfavorable outcome (GOS 1–3) compared to those with a favorable outcome (GOS 4–5) at the time of discharge (3.64 ± 0.48 vs. 4.50 ± 0.08, p = 0.198). However, the application of the mean NPi to predict severity and outcome was not statistically significant. The study did find a statistically significant difference in the frequency of pathological NPi values in clinically severe (WFNS grade 4–5) and non-severe (WFNS grade 1–3) aSAH (16.3% ± 8.8% vs. 0.0% ± 0.0%, p = 0.002). Pathological NPi values were also noted more frequently in patients with unfavorable outcomes compared to those with favorable outcomes (19.2% ± 10.6% vs. 0.7% ± 0.6%, p = 0.017) [75]. In summary, the study demonstrated that the frequency of pathological NPi values was significantly different between severe and non-severe aSAH patients and between patients with favorable and unfavorable outcomes.
11. Non-Convulsive Status Epilepticus
Research about pupillometry in seizure is relatively limited compared to other neurocritical diseases. Compared with other types of seizure, making the correct diagnosis of non-convulsive status epilepticus (NCSE) in a neurocritical unit is much more challenging. Godau et al. [76] found a reduction in the NPi or a significant difference between the left and right NPi might be a useful quantitative modality to evaluate NCSE. Another study also conducted by Godau revealed the potential of the NPi to assess treatment responses of NCSE [45]. In addition to the NPi, decreased dilation velocity (DV) was also discovered to have association with unreactive electroencephalography (EEG) signals, which is a possible utility in patients with seizure or critical illness [77].
12. Ischemic Stroke
The Establishing Normative Data for Pupillometer Assessment in Neuroscience Intensive Care (END-PANIC) registry [78] is a database of pupillometry data that has been used to evaluate the relationship between pupillometry and various neurocritical conditions. The authors measured the midline shift of septum pellucidum in serial brain images and collected pupillometric data from 134 patients with acute ischemic stroke and intracerebral hemorrhage (70.1% ischemic, 29.9% hemorrhagic) from the END-PANIC registry. They found a significant correlation between the midline shift, the NPi (left (p < 0.001), right (p < 0.001)), coefficient of variation (left (p < 0.005), right (p < 0.001)), and pupillary asymmetry (absolute difference between right and left; p < 0.05). However, there was no significant correlation between the midline shift and pupil size.
13. Pain Assessment in Neurocritical Care
A self-rated score is the most common and intuitive method to assess patients’ pain intensity. However, in certain circumstances, such as facing noncommunicating patients, and patients who are usually critically ill, consciousness-disturbed, or mechanically ventilated, a self-rated score is impractical. A noxious stimulus could evoke sympathetic system and lead to pupillary dilation. As a result, pupillometry had been applied to investigate as an indicator of pain and effect of analgesia [9,83,84]. Specifically, Guglielminotti et al. [85] reported the utility of pupillometry in assessment of the degree of analgesia by epidural anesthetics for pregnant patients suffered from labor pain and uterine contraction. In addition to adult patients, pupillometry was also reported as a useful and effective tool for assessment of pain in the sedation of pediatric patients [86].
14. Smartphone-Based Pupillometry
Pupillometry has been established as a reliable method for examining patients’ pupils in various clinical settings. However, its cost and accessibility can pose obstacles, particularly in low-resource or developing countries. To address this, several studies have focused on developing smartphone-based pupillometry, which offers a promising alternative approach that is more affordable and accessible.
15. Conclusions
Pupillometry has become an important tool in the management of intracranial pathology, with increasing evidence supporting the role of automated pupillometry. Although there are currently no guidelines regarding the routine application of pupillometry, automated pupillometry offers several advantages over traditional subjective manual pupil examination. It provides more precise, objective, and quantitative measurements, with better reliability, and reproducibility.
This entry is adapted from the peer-reviewed paper 10.3390/jpm13071100
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