Recurrent unilateral pupillary dilation and transient visual blurring: A clinical challenge during hypoxia exposure in a male fighter pilot

Abstract

Hypoxia is an operational concern in military aviation, and fighter pilots should undertake altitude hypoxia training. Anisocoria is a significant clinical dilemma and may remain a diagnostic challenge for specialists. We present a case of atraumatic unilateral mydriasis during hypobaric chamber training. Our diagnostic dilemma is novel and unique because the authors reported no similar presentation yet, it occurred in a fighter pilot whose occupational future depends on having normal vision, and second, the presence of hypoxia seems to trigger symptoms.

Introduction

Military fighter pilots have complicated troublesome duties with different physical and mental stressors, which require perfect health, especially the visual system. Hypoxia is a significant operational concern in military aviation, and fast jet pilots expose to hypobaric (hypoxic) hypoxia during high-altitude flights. Unexpected severe hypoxia will prevent recognition of hypoxia and the performance of emergency recovery procedures before the loss of consciousness. Moreover, in-flight acceleration forces may impair cerebral perfusion and cause additional stagnant (circulatory) hypoxia. Military aviators should undertake altitude hypoxia training or hypoxia recognition training for improving emergency responses to hypoxic incidences and enhance their memory every 2 years. Flight surgeons and hypobaric chamber operators supervise the medically controlled hypoxia training in the Aviation Physiology Research Laboratory (APRL).^1,2 A pilot presenting with intermittent anisocoria, with or without vision changes, is a significant clinical dilemma and a diagnostic challenge for specialists that is a hazard for flight safety and may lead to incidents or accidents.³ Efficient personnel are the most important asset of the armed forces. Training experienced military pilots require a lot of resources and hence this manpower needs to be conserved well.⁴ We present a case of an active duty pilot with atraumatic unilateral mydriasis during altitude hypoxia training.

Case report

A 38-yr-old male patient fighter pilot presented with a transient episode of right-sided pupillary dilation, unilateral visual blurring, impaired near focusing, and without any headaches after the hypoxia training, detected by the flight surgeon within the post hypoxia medical evaluation (Fig. 1-A).⁵ The Oculus Sinister (OS) vision was 20/20, but the best-corrected Oculus Dexter (OD) vision was 20/40. He had difficulty in near focusing, the RAF near point rule (RNPR) examination demonstrated impairment in accommodation (binocular and right monocular) and convergence.

Fig. 1.

A) Islamic Republic of Iran Air Force (IRIAF) routine chamber flight program (profile type IV) and B) chamber flight profile for medically controlled exposure.

He had a history of 3 weeks of COVID-19 pneumonia 6 months ago, followed by getting two steps of COVID-19 vaccination. He was alert, oriented, afebrile, normotensive, and nontachycardic, without tachypnea or hypoxia in room air. The ophthalmologic examination demonstrated no ptosis, proptosis, ophthalmoplegia, diplopia, evidence of trauma, or facial tenderness. Pupil responses and accommodation to dim and bright light, directly and consensually, under light and dark conditions were normal. The slit-lamp examination showed normality of the anterior chamber, iris, and intraocular pressure. The swinging flashlight test indicated non-pathological findings. Visual acuity, visual field, color vision, convergence, and contrast sensitivity were normal. Fundoscopic examination revealed optic discs that were round with clear margins, no cupping, and no pallor. There was no macular edema, retinal detachment, arteriovenous nicking, or copper-wiring (Fig. 2-A).

Fig. 2.

A) Normal fundoscopy, B) normal brain MRI, and C) normal brain MRA.

Bilateral median, ulnar and sural motor and sensory nerve conduction studies, autonomous testing results, and deep tendon reflex were unremarkable (Table 1).⁶

Table 1.

The brief list of performed autonomic function tests.

Clinical symptoms	Lightheadedness resulting from postural changes, dry mouth, dry eyes, impotence, gastroparesis, bowel or urinary incontinence, neuropathies
Clinical tests	Autonomic sudomotor function tests (sweat testing)	Quantitative sudomotor axon reflex test
		Thermoregulatory sweat test
	Cardiovagal function test	Heart rate variability
		Valsalva ratio
	Adrenergic function tests	BP and heart rate responses to the Valsalva maneuver
		Head-up tilt study
		Plasma norepinephrine at the supine position and after a period of standing
		Meta-iodobenzylguanidine cardiac uptake

Electroencephalography (ECG) and visual evoked potential results provided no significant finding. Complete blood count, coagulation studies, metabolic profile, thyroid function test, and urinalysis were within normal limits. Magnetic resonance imaging (MRI) of the head and neck did not reveal any signs of intracranial hemorrhage, ischemic stroke, mass lesion, herniation, or other structural abnormalities (Fig. 2-B). Magnetic resonance angiography (MRA) excluded dissection, thrombus, occlusion, or other vascular pathology of the ophthalmic, cerebral, or cerebellar arteries (Fig. 2-C). The psychological assessment indicated that he complained of recent anxiety and insomnia related to his future occupational status. The APRL instructor and flight surgeon planned a medically controlled hypoxia exposure in the hypobaric chamber (Fig. 1-B). The patient's clinical changes were closely monitored by the automated pupillometer, pulse oximeter, and chronometer. The same episode occurred after 186 s from mask drop at 25,000 ft with oxygen saturation of 71 percent. The patient was assessed immediately after the occurrence of anisocoria in the hypobaric chamber. He had right-sided pupillary dilation, right eye visual blurring, and impaired near focusing without any headaches. Automated pupillometry indicated that the right and left pupils were 7 mm and 4 mm in diameter, respectively. The anisocoria was more pronounced during examination under the light. The right pupil was nonreactive to light, while the left pupil had a normal response to light (Fig. 3).

Fig. 3.

During the ictal phase, anisocoria was more pronounced under bright light. A) Bright light and B) dim light.

The OS vision was 20/20, but the best-corrected OD vision was 20/40. The RNPR examination demonstrated impairment in accommodation (binocular and right monocular) and convergence. In addition, 0.125% pilocarpine did not constrict the pupil, whereas 1% pilocarpine constricted both pupils well. Other neuro-ophthalmic examinations had no significant abnormality. His problem resolved completely 728 s after reaching normoxia with oxygen saturation of 97 percent. Ophthalmological examinations were normalized when the anisocoria was resolved.

We found no significant etiology during complete ophthalmological, neurological, psychological, laboratory, and imaging assessments. In addition, he may have had similar episodes in the past that have not been diagnosed due to operational busy or mild transient conditions. Thus, we offered the isolated-benign episodic unilateral mydriasis as his primary diagnosis, and our plan for him was more investigation and exact follow-ups in the future. He was reassured and suspended from the flying duties until the accurate cause was identified, the symptoms completely resolved, and confirmation of recovery in the hypoxic challenge. Patient consent for inclusion in study was also obtained.

Discussion

Anisocoria is an unequal size of pupils that often presents as a diagnostic dilemma and clinical challenge with benign or life-threatening causes. Up to 20 percent of the population may have physiologic anisocoria with a difference in the size of 0.4 mm. Anisocoria with more than 1 mm difference and unilateral mydriasis are atypical, accompanies more risk of the underlying abnormality, and each patient deserves individualized decision making. However, episodic isolated anisocoria accompanying no symptoms or signs is much more likely to be benign.^3,7,8

A practical diagnostic approach to Anisicoria or unilateral mydriasis in a stable patient includes a detailed history, complete physical, neurological, and ophthalmological examination and use of imaging methods that exclude other possible life-threatening reasons. History may contain important points about migraine or intermittent headaches, underlying diseases, systemic or topical medication use, recent trauma, and accompanying symptoms.9, 10, 11

Pupil responses and accommodation to dim and bright light, directly and consensually, under light and dark conditions in ictal and inter-ictal phases determine the affected pupil. The pupil diameter is mainly influenced by the amount of light entering the eye and controlled by the pupillary light reflex. During pupillary light reflex in anisocoria, the bright light causes full miosis in the normal eye and relative response in the affected eye. The difference between pupils' reactivity and diameter is more pronounced and facilitates discerning an abnormal pupil. So, the bright light examination is more sensitive than ambient light for discerning an abnormally dilatated pupil.¹²

The larger pupil is likely to be affected if the anisocoria is more prominent in light. The ophthalmologists recommend the following investigations during and between episodes of anisocoria: slit-lamp exam, tonometry, fundoscopy, swinging flashlight test, pilocarpine phenylephrine provocative test, and assessment of visual acuity, visual field, color vision, contrast sensitivity, and convergence. Ptosis, proptosis, ophthalmoplegia, diplopia, evidence of trauma, or facial tenderness eye pain, visual floaters and infrequent flashes of light, discharge, itchiness, or excessive tear production must be noticed too. Neurological examination, laboratory tests, and neuroimaging may provide valuable findings.

Benign episodic unilateral mydriasis (BEUM) is a relatively common physiologic syndrome that generally affects young women with a history of migraine or intermittent headache, which displays features of migraine but does not strictly fulfill diagnostic criteria. Patients typically report multiple, stereotyped, recurrent episodes of unilateral mydriasis that may last from seconds to weeks without clear etiology. They may experience episodes that vary between several times a week to once every few years. The anisocoria is more pronounced during examination under the light. Although BEUM predominantly occurs unilaterally, authors reported bilateral forms too (such as bilateral juvenile internal ophthalmoplegia).^9,10

The commonly associated symptoms include visual blurring, headache, orbital pain, and photophobia, while red-eye, diplopia, confusion, neck pain, third cranial nerve palsy, and scotoma are less common. Although the pathophysiology BEUM is not exactly clarified yet, it is supposed to be due to transient abnormal parasympathetic or sympathetic activity in the iris sphincter or iris dilator, respectively. Many scientists believe that the BEUM is a limited form of ophthalmoplegic migraine (recurrent painful ophthal moplegic neuropathy), and some authors think against it.^8,11

It is important to note that patients with BUEM must not have any associated structural lesions. Except for the non-neurological isolated diseases, vasculopathy, history of recent trauma, no migraine history, male or elder patients, BUEM has a good neurological prognosis typically does not require any further evaluation or imaging studies.⁹

Hypobaric hypoxia causes a broad spectrum of signs and symptoms, especially neurological manifestations. They are specific for each person that may change over time and named hypoxic signature.^1,2

The vision has been recognized as being highly sensitive to hypoxia and hypobaric hypoxia is known to cause several visual problems. The iris muscles receive the sympathetic (cervical ganglion) and parasympathetic (third cranial nerve) neurons that affect the pupil diameter. The pupil diameter depends on the amount of light entering the eye, central inhibition of the parasympathetic input by the sympathetic, level of alertness, occipital cortex control, psychosensory reactions, and age. The autonomous nervous system is part of the central nervous system (CNS) receives further input from large parts of the brain.¹²

Hypoxia alters the cellular metabolism and has depressive effects on the CNS leading to impairment of the autonomic nervous system. Pupillary diameter instability occurs due to fluctuation in the activity of sympathetic and parasympathetic innervations of the iris muscles. This might be the result of a direct, transient, and inhibitory effect of hypoxia on specific components of the CNS as well as an indirect stimulatory effect due to an increase in peripheral humoral factors. Some studies have shown that exposure to hypoxic stress and operational anxiety stimulates sympathetic pathways, releases catecholamines, produces the fight-or-flight response, and mydriasis. Other authors believe that pupillary reflex and oculomotor performance metrics are significantly altered during hypoxia exposure, manifesting as decreased pupil diameter. However, mydriasis or miosis, both of them, can occur during acute hypoxia exposures that usually rapidly reverse with appropriate ventilation.¹³

This patient is a talented fighter pilot who had no past fault or error in his simulator or actual operations. He had no past medical (physical or mental) problem, disease, disorder, or drug use/abuse except for COVID-19 pneumonia and two steps of COVID-19 vaccinations. He passed all his medical annual assessments successfully and had no problem in the last hypoxic chamber training in October 2018. In addition, SARS-CoV-2 is a neurotrophic and neuro-invasive virus. COVID-19 pneumonia and COVID-19 vaccination have many different extra respiratory multisystemic (neurological) involvement and complications.⁴ In this case, it is better to keep in our mind that the COVID-19, directly or indirectly, may be involved in the activity fluctuation of the sympathetic and parasympathetic innervations of the iris muscles.

Conclusion

Our diagnostic dilemma is novel and unique because the authors reported no similar presentation yet, it occurred in a fast jet military pilot whose occupational future depends on having normal vision, and second, the presence of hypoxia seems to trigger symptoms. We want to inform our colleagues about the risk of anisocoria-related visual impairment in pilots and insist that the possible role of hypoxia, COVID-19 pneumonia, and COVID-19 vaccination in these patients need more attention and research in the future.

Disclosure of competing interest

The authors have none to declare.