NEUROTRAUMA/COLLECTIVE REVIEW neurotraum~

Evaluation and Significance of the Pupillary Light

Reflex in Trauma Patients

From the Department of Surgery, University of Washington Harborview Medical Center, Seattle, Washington.

Received for publication April 23, i992. Revision received December 16, 1992. Accepted for publication January 19, 1993.

Scott Meyer, MD Tyler Gibb, MD Gregory J Jurkovich, MD

The pupillary light reflex is an important component of the neu- rologic examination of the trauma victim. Although the normal reflex can be predictably altered by specific head injuries, a variety of other factors common to trauma patients such as alco- hol, illicit drugs, narcotics, paralyzing agents, hypothermia, and orbital or ophthalmic injury can confound the evaluation of the pupillary light reflex. This report reviews the anatomy and neuro- physiology of the pupillary light reflex and discusses the impact these confounding variables may have on this key component of the initial trauma evaluation.

[Meyer S, Gibb T, Jurkovich G J: Evaluation and significance of the pupillary light reflex in trauma patients. Ann Emerg Med June 1993;22:1052-1057.]

INTRODUCTION

The pupillary light reflex is an important part of the neu- rologic examination of trauma victims. After management of the airway, breathing, and circulation, a concise yet thorough evaluation of the central nervous system is required to identify victims with potential head or spinal cord injury, The pupillary light reflex is a quick screening tool in the diagnosis of intracranial mass lesions and damage to the hypothalamus, midbrain, or pons.~ It also is helpful in predicting awakening after cardiac arrest 2-~ and in determining terminal anoxia, which results in bilaterally wide and fixed pupils. 5-r

After severe head injury, the initial neurologic examina- tion is the crucial baseline against which all subsequent changes are compared. The pupillary light reflex, along with an assessment of level of consciousness and brain stem reflexes, plays a key role in determining the presence of intracranial pathology. It is important to realize, how- ever, that this reflex is a physiologic response that can be affected by several factors not necessarily associated with the pathology caused by the injury itself. Alcohol, illicit drugs, narcotics, paralyzing agents, hypothermia, acute

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PUPILLARY LIGHT REFLEX Meyer, Gibb & Jurkovich

or previous present ophthalmic pathology, and associated orbital injury all can confound the evaluation of the pupil- lary light reflex.

Understanding which agents affect the pupillary response can assist the physician in discerning a reliable pupillary light reflex examination from one that has been altered pharmacologically. The purpose of this report is to review the anatomy and neurologic events that comprise the pupillary light reflex and discuss the impact that confounding factors may exert in interpreting this reflex in trauma patients.

ANATOMY

• The pupfllary light reflex is elicited by shinging a bright light into the eye. This triggers a complex neural reflex that normally leads to pupillary constriction in both the ipsflateral eye (direct response) and the contralateral eye (consensual response). Correctly interpreting this response requires a fundamental understanding of the anatomy and physiology of the regulating pathways.

Pupillary dilatation is controlled by the sympathetic nervous system. Sympathetic discharges, originating in the hypothalamus, enter the upper thoracic spinal cord and synapse in the intermediolateral cell column of spinal segments T1-3 (Figure 1A). The preganglionic fibers then leave the cord, enter the sympathetic chain, and synapse in the superior cervical ganglion. The postganglionic fibers ascend along the internal carotid artery and follow the ophthalmic division of the trigeminal nerve (cranial nerve V) into the orbit, where they continue with its nasociliary division to finally innervate the pupillodflator muscle.

Although the exact sympathetic pathways from the hypothalamus are not known, they have been studied extensivelyS-1 t The considerable data on these illusive pathways will not be completely reviewed here, except to note that evidence suggests that the sympathetic regula- tion of pupillary dilatation actually begins in the cortex with descent to the hypothalamus. 12-14 This is important for the consideration of unilateral, fixed pupils resulting from seizures because cortical seizure activity could be responsible for the interruption of the sympathetic input to the pupil.15,16

The parasympathetic regulation of pupillary constric- tion occurs along a simpler pathway (Figure 1B). Pregan- glionic fibers originate in the Edinger-Westphal nucleus adjacent to the oculomotor nucleus in the midbrain. These fibers travel with the oculomotor nerve (cranial nerve III) to synapse in the ciliary ganglion located in the

posterior orbit. The postganglionic fibers innervate the sphincter pupillae controlling constriction and innervate the ciliary smooth muscle regulating accommodation.

The pupillary light reflex is mediated entirely through the parasympathetic pathway (Figure 1B). Afferent impulses for the light reflex begin in retinal ganglion ceils, which fire in response to a light stimulus. The signal then travels by way of the optic nerve to the chiasm where, like visual fibers, they either travel in the ipsilateral optic tract or cross and travel in the contralateral optic tract. Unlike visual fibers, however, the impulse travels through, but does not synapse in, the lateral geniculate body and instead synapses in the pretectal nucleus of the midbrain. Here, the anatomy of the direct and consensual response is established as the pathway projects to both the ipsilateral and contralateral Edinger-Westphal nuclei. The efferent arc of the reflex then ensues, as discussed above.

An understanding of the anatomy of the pupillary light reflex is required to appreciate its evaluation in the patient with a closed-head injury, particularly because the brain stem areas controlling consciousness anatomically are adjacent to those controlling the pupils. With supratento- rial lesions, intracranial shifts can lead to coma as a result of brain herniation. Uncal herniation is the classic presen- tation of an acute traumatic epidural or, occasionally, sub- dural hemorrhage. As the intracranial hematoma expands, the medial edge of the uncus is pushed over the lateral " edge of the tentorium and the ipsilateral third nerve is

Figure 1. The sympathetic pathway (A) controls pupillary dilatation, whereas the parasympathetic pathway 07) controls pupillary constriction and mediates the pupillary light reflex. (Modified with permission from Plum F, PosnerJP: The Diagnosis of Stupor and Coma, ed 3. Philadelphia, FA Davis, 1980.)

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PUPILLARY LIGHT REFLEX Meyer, Gibb & Jurkovich

compressed, compromising the efferent parasympathetic pathways to the pupil and resulting in dilation. Evaluation of the pupillary light reflex will show that this pupil is dilated, fixed, and unresponsive to direct and consensual light stimuli. Because the afferent arc of the pathway is still intact, however, shining a light in the affected eye will still lead to a consensual response. Although uncal hernia- tion usually is accompanied by rapidly developing stupor or coma, the changes in the pupillary response occasion- ally can be diagnosed early (eg, the patient with a slowly expanding intracranial tumor), even before the patient becomes stuporous. 1

PHYSIOLOGY

The chemistry and physiology of neurotransmission also are important in understanding the pupillary light reflex. Both the parasympathetic and sympathetic nervous systems use nicotinic ace@choline receptors at their ganglionic synapses (eg, superior cervical ganglion, ciliary ganglion). However, the postganglionic synapses of these systems differ (Figure 2). Postganglionic receptors of the sympa- thetic system (with the exception of innervation to sweat glands) use adrenergic synapses with norepinephrine as the transmitter. The parasympathetic system continues to use ace@choline as the postganglionic transmitter but with a muscarinic type receptor. The efferent arc of the parasympathetic pupillary light reflex, therefore, uses

Figure 2. Schematic representation of the neurotransmitters used in the autonomic and somatic nervous systems. Ach, acetylcholine; NE, norepinephrine. (Adapted with permission from Katzung BG: Introduction to autonomic pharmacology, in Katzung BG (ed): Basic and Clinical Pharmacology, ed 3. Norwalk, Connecticut, Appleton & Lange, 1987, p 53.)

\ Parasympathetic (

Sympathetic

Somatic

Muscarinic Ach Receptor

V

nicotinic ace@choline receptors at the ciliary ganglion, whereas the postganglionic synapse at the pupillary con- strictor muscle is equipped with muscarinic ace@choline receptors. These receptor differences are particularly sig- nificant in view of the pharmacologic action of modern neuromuscular blocking agents, as discussed below.

PUPILLARY LIGHT REFLEX IN TRAUMA VICTIMS

Neuromuscular blocking agents frequently are used in some prehospital systems to assist in intubation and air- way control and occasionally are used to prevent motion that may cause further injury in the combative trauma patient. These agents primarily block the action of ace@choline at the nicotinic receptors of the somatic neuromuscular junction, thereby causing skeletal muscle paralysis (Figure 2). However, there is potential for "spillover" to other receptor types, including ganglionic and end organ receptors, which may result in side effects other than muscle relaxation.

All neuromuscular blocking agents have the potential for autonomic ganglion blockade at nicotinic ace@choline receptors. Although both the sympathetic and parasympa- thetic inputs to the pupil would be blocked in this case, it is the parasympathetic blockade at the ciliary ganglion that would prevent constriction and interrupt the pupillary light reflex. Autonomic ganglion blockade usually requires a much higher dose of the neuromuscular blocking agent than muscular blockade. Kharkevich and Shorr reviewed the ganglion-blocking effects of neuromuscular blocking agents. 17 They defined an index of ganglion-blocking safety as the ratio between the dose inducing a 50% ganglionic block (EDsoGB) and the dose required for a 50% inhibi- tion of neuromuscular transmission (EDsoNMB). Their analysis suggested that ganglion-blocking activity is clini- cally significant in those agents whose experimental EDsoGB/EDsoNMB is less than 10. That is, the autonomic ganglion-blocking capacity of an agent may be clinically significant if less than a tenfold dose increase above the level producing muscle relaxation will block autonomic ganglion (eg, the ciliary ganglion). As an example, if a 1-mg/kg dose of a paralyzing agent will block the neuro- muscular junction, then this agent is considered to have clinically significant ganglion-blocking activity (and poten- tially affect the pupfllary response) if less than 10 mg/kg will block autonomic ganglion transmission.

The classic nondepolarizing blocking agent d-tubocu- rare has been shown to have significant ganglionic blockade with an index of ganglion-blocking safety of much less than 10. ls-23 Thus, therapeutic doses of

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PUPILLARY LIGHT REFLEX Meyer, Gibb & Jurkovich

curare are expected to interfere with the evaluation of the pupillary light reflex by blocking its efferent arc. Other nondepolarizing agents such as pancuronium bromide (Pavulon ®) 17,21,23,24 and vecuronium bromide (Norcuron®) 24 and depolarizing agents such as succinyl- cholinel9,20, 25 have been shown to be essentially devoid of ganglion-blocking activity and thus do not interfere with the pupillary light reflex.

Neuromuscular blocking agents also have the potential for antimuscarinic (atropinelike) activity With spillover to muscarinic receptors at the sphincter pupillae, one would expect to see pupillary dilatation with the use of these agents. Studies have shown that only experimental neuro- muscular blocking agents, which are not used clinically, have nonselective atr0pinelike activity26, 2r The clinically used agent pancuronium bromide does have atropinelike activity but only at the cardiac muscarinic receptors.25, 28 Use of this agent, therefore, commonly causes tachycardia, but the sphihcter pupi!lae is not blocked, and evaluation of the pupillary light reflex is not affected.

Therefore, commonly used neuromuscular blocking agents do not affect the pupillary light reflex, and it remains a reliable component of the neurologic examina- tion in paralyzed patients. The exception to this is curare, with which significant autonomic ganglionic blockade might occur, resulting in parasympathetic (constriction) paralysis and bilateral dilated and fixed pupils to light.

Antimuscarinic agents block muscarinic receptors at the pupillary constrictor muscle and are expected to cause dilated, fixed pupils. Atropine frequently is given during CPR, especially in attempts to reverse bradycardia. It is widely believed that such systemic administration causes mydriatic (dilated) pupils that are fixed to light. 29-31 A recent study in children, however, showed that conven- tional doses of atropine given before endotracheal intuba- tion or during cardiac arrest caused only mild mydriasis but did not abolish the pupillary light reflex. 32 Despite these discrepancies, the physician should be aware that both topical ocular administration and high systemic doses of antimuscarinics (eg, atropine) probably will cause widely dilated, fixed pupils. 1,33

To distinguish anticholinergic mydriasis from pupillary paralysis of neurologic origin, the pilocarpine instillation test can be performed. 34 Topical instillation of 0.5% pilocarpine into the affected eye will cause the pupil to constrict in pupillary paralysis associated with third nerve palsy but will have no effect in cases of anticholinergic mydriasis.

The cardiac inotropic agents dopamine and ibopamine 35 and the antihypertensive drugs clonidine 36,37 and

c~-methyldopa 38 all have been reported (mostly in animal models) to have the possible side effect of fixed, dilated pupils. The mechanism of action is similar for all of these drugs. Centrally acting agonism at %-adrenoreceptors causes parasympathetic blockade and interruption of the efferent arc of the pupillary light reflex.

Scopolamine, the belladonna alkaloid with central anticholinergic activity, commonly is used in ophthalmic preparations or transdermally for its antiemetic properties in motion sickness. Its use has been associated with the development of unilateral fixed and dilated pupils, pre- sumably due to inadvertent self-inoculation of one eye. 39-42

A unilateral fixed and diIated pupil also has been asso- ciated with overdose of the sedative and hypnotic glute- thimide (Doriden®).43, 44 Although the mechanism is not known, the reversible mydriatic pupil can appear indistin- guishable from the syndrome of uncal herniation.

Interpretation of the pupillary light reflex in an intoxi- cated patient can be highly variable and confusing. High blood alcohol levels (300 to 400 mg/dL) can cause dilated, sluggishly reactive pupils. This may be interpreted as non- reactive in the acute trauma situation. ~,45-47

Varying degrees of hypothermia have been associated with sluggish or absent pupillary responses.48, 49 Pratt reported that the light reflex becomes sluggish as core body temperature fails below 28 C and may become nonreactive.50

As previously noted, seizures in the absence of other pathology can cause a unilateral, fixed, dilated pupil. 15,~6 Although pupillary responses during seizures are rarely observed, a seizure in a trauma victim may present only with pupillary abnormalities because the other neurologic responses may be masked by paralyzing agents used for intubation and airway control.

A sluggish or latent pupillary response also may be due to underlying retinal or optic nerve pathology indepen- dent of recent trauma. Optic neuritis, optic atrophy, or retinal disease can interrupt the afferent arc of the pupil- lary light reflex (and visual acuity) and cause a relative afferent pupillary defect (the Marcus-Gunn pupil).ss Similarly, any orbital trauma that injures the iris, destroys the retina, or interrupts nerves of either the afferent or efferent arc may alter the reflex in the trauma victim.

Adie's syndrome, an idiopathic lesion in the ciliary ganglion, usually causes a unilateral, tonic pupil 52 This syndrome typically is seen in women aged 20 to 40 and may be mistaken as an ominous sign in the emergency patient. An Adie's syndrome pupil may be distinguished from the tonic pupil due to pharmacologic autonomic blockade or a third nerve lesion by using dilute (0.125%)

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PUPILLARY LIGHT REFLEX Meyer, Gibb & Jurkovi.ch

40. Verdier DD, Kennerdell JS: Fixed dilated pupil resulting from transdermal scopolamine (letter). Am J Ophthalmo11982;93:803-804.

41. Rosen NB: Accidental mydriasis from scopolamine patches. JAm Optom Assoc 1986;57:541- 542.

42. Bienia RA, Smith M, Pellegrine T: Scopolamine skin-disks and anisocoria. Ann Intern Med 1983;99:572-573.

43. Mayer JF, Schreiner GE, Westervelt FB Jr: Acute glutethimide intoxication. Am J Med 1962;33:70-81.

44. Brown DG, Hammill JF: Glutethirnide poisoning: Unilateral pupillary abnormalities (letter). N Engl Med J 1971;285:806.

45. Imria JA: Emergencies in general practice: Acute alcoholic poisoning. BMJ 1955;13:428-430.

46. Simpsan-Crawford T, Slater SW: Eye signs in suspected drinking drivers: Clinical examination and relation to blood alcohol. NZMedJ1971;74:92-96.

47. Rubin SR, Getthei[ E, Roberts A, at ah Effects of alcohol an autonomic reactivity in alcoholics. Pupillemetfic studies. III. J StodAIceho11980;41:611-622.

48. Tolrnan KG, Cohen A: Accidental hypothermia. Can MedAssoc J 1970;103:1357-1361.

49. Jurkovich G J: Hypathermia in the trauma patient. Adv Trauma 1989;4:111-140.

50. Pratt RS: Hypotherm ia: The chili that need net kill. ACS Bull 1980;10:26-35.

51.6ittinger JW: Ophthalmology: A Clinical Introduction. Boston, Little, Brown, & Company, 1984.

52. Thompson HS: Adie's syndrome: Some new observations. TransAm Ophthal Sac 1977;76:587-626.

Address for reprints:

Gregory J Jurkovich, MD

Department of Surgery

University of Washington

Harborview Medical Center

Seattle, Washington 98104

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