Although it is arguable that the eyes are the mirror to the soul, it is certain that the eyes reveal a great deal of information with regard to toxicology. In addition to exhibiting findings of systemic toxicity, they are also subject to the direct effects of xenobiotics and serve as a portal of entry for systemic absorption. An understanding of ophthalmic principles will allow the clinician to make timely and more accurate diagnoses that can be sight-saving or lifesaving and is essential to efficient, organized patient care.

As a matter of convention, the routine eye examination is performed in the following sequence: visual acuity, pupillary response, extraocular muscle function, funduscopy, and, when indicated, a slit-lamp examination. Examination of the pupillary size and response to light can help determine the presence of a toxic syndrome. For example, opioids and cholinergics produce miosis, whereas anticholinergics and sympathomimetics produce mydriasis. Assessment of the extraocular muscles often reveals xenobiotic-induced nystagmus or cranial nerve abnormalities. Funduscopy typically reveals pink discs characteristic of poisoning by methanol or carbon monoxide. The slit-lamp examination allows for evaluation of toxic exposure to the lids, lacrimal systems, conjunctiva, sclera, cornea, and anterior chamber. However, before considering specific xenobiotic exposures in detail, it is important to review the anatomy and physiology of the visual pathways and how alteration of the normal physiology and anatomy correlate with clinical signs and symptoms.

The eye is a spherical structure referred to as a globe. The globe is divided into anterior and posterior structures (Fig. 24–1). The most anterior structures are the cornea, conjunctiva, and sclera. Posterior to the cornea are the iris, the lens, and the ciliary body. The space between the cornea and the iris is the anterior chamber, and the space between the iris and the retina is the posterior chamber. The anterior chamber contains aqueous humor, which is produced by the ciliary processes; this fluid nourishes the cornea, iris, and lens. The iris, the ciliary processes, and the choroid compose the uvea. The posterior chamber is filled with a transparent gelatinous mass termed the vitreous humor. The vitreous humor is an important body fluid in forensic toxicology as it is less susceptible to postmortem redistribution (Chaps. 139 and 140). The fundus is the most posterior structure and includes the retina, retinal vessels, and the head of the optic nerve or disc.

Visual Acuity and Color Perception

Normal vision is dependent on light transmission through the globe reaching intact posterior neural elements. As such, appropriate light transmission requires a clear cornea, clear aqueous humor, proper pupil size, an unclouded lens, and clear vitreous. The posterior neural elements include the retina, optic nerve, and the optic cortex; in turn, all of these structures require intact blood circulation for proper function. Decreased acuity results from abnormalities anywhere in the visual system that affect either light transmission or the neural elements.^4,12,22 Corneal injury or edema results in blurring of vision, characteristically described as “halos” around lights. Toxicologic causes of corneal abnormalities include direct exposure to chemicals, failure of corneal protective reflexes because of local anesthetic effects or a profoundly decreased level of consciousness, and incomplete eyelid closure during coma. Mydriasis (Table 24–1) interferes with the pupillary constriction necessary for accommodation, thereby resulting in decreased acuity for near objects. Lens clouding or cataract formation causes blurred vision and decreased light perception, as does blood (hyphema), pus (hypopyon), or other deposits in the aqueous humor or vitreous humor (vitreous hemorrhage). Many xenobiotic-induced lens abnormalities are caused by chronic systemic exposures (Table 24–2).^17,22,30 Even if light reaches the retina without distortion, ischemia or injury to any neural element from the retina to the optic cortex will result in abnormal reception or transmission. Direct, acute, visual neurotoxic injury is rare and is caused almost exclusively by methanol or quinine.^17,43 Indirect injury following xenobiotic-induced central nervous system (CNS) ischemia or hypoxia is far more common. Alterations in color perception generally result from abnormalities in retinal or optic nerve function. Color–vision abnormalities are attributed to numerous xenobiotics, but most are caused by chronic xenobiotic exposure and rarely are features of acute toxicity.^17,22

Pupil Size and Reactivity

Generally, pupils are round and symmetric with an average diameter of 3 to 4 mm under typical light conditions. Physiologic anisocoria (unequal pupils) is a normal variant and is defined as a difference in pupil size of 1 mm or less. However, in the absence of a history of physiologic anisocoria, any asymmetry in pupil size should be considered an abnormal finding. Pupils react directly and consensually to light intensity by either constricting or dilating. Constriction is also a component of the near reflex (accommodation) that occurs when the eye focuses on near objects. The iris controls pupil size through a balance of cholinergic innervation of the sphincter (constrictor) muscle by cranial nerve III and sympathetic innervation of the radial (dilator) muscle.¹²

Pupillary dilation (mydriasis) results from increased sympathetic stimulation of the radial muscle by endogenous catecholamines, or from the use of cocaine, amphetamines, and other sympathomimetics and ophthalmic instillation of sympathomimetics such as phenylephrine. Mydriasis also results from inhibition of muscarinic cholinergic-mediated innervation of the sphincter secondary to systemic or ophthalmic exposure to anticholinergics (Chap. 49). Because pupillary constriction in response to light is a major determinant of normal pupil size, blindness from ocular, retinal, or optic nerve disorders also leads to mydriasis as exemplified by methanol and quinine toxicity. As such, the reactivity of mydriatic pupils to light varies with the etiology of the mydriasis.²² Although often difficult to appreciate, constriction to light is often elicited after sympathomimetic exposures because constrictor function is preserved, whereas this is often not the case when mydriasis results from anticholinergic excess since constrictor function is potently antagonized. Light reactivity is absent in complete blindness but is preserved if light perception persists.

Miosis results from either increased cholinergic stimulation such as opioids, pilocarpine, and cholinesterase inhibitors, such as organic phosphorus compounds, or inhibition of sympathetic dilation caused by clonidine. Miosis was the most common finding in victims of the Tokyo subway sarin attack of 1995 and was used to distinguish between mild and moderate exposure.³⁶

There are conflicting reports regarding the pupillary reactions to many xenobiotics. Depending on the stage and severity of toxicity, the presence of coingestants or coexistent hypoxemia, and numerous other factors, many individual xenobiotics such as clonidine, nicotine, phencyclidine, and barbiturates cause mydriasis, miosis, or hippus, which is defined as a spasmodic and rhythmic, but regular, alteration between miosis and mydriasis.^22,31 For some xenobiotics, the pupillary examination provides consistent information (Table 24–1), but many factors are involved, and the significance of the pupil size and reactivity must always be considered in the context of the remainder of the patient evaluation.

Extraocular Movement, Diplopia, and Nystagmus

Maintenance of normal eye position and movement requires a coordinated function of a complex circuit involving bilateral frontal and occipital cortices, multiple brain stem nuclei, cranial nerves, and extraocular muscles.^2,12 Because of the many elements necessary for normal function, abnormalities of eye movement result from several causes and are extremely common.²² Probably the most common abnormality is reversible nystagmus or rhythmic oscillations of the globes (Table 24–1). Nystagmus is divided into 2 types: jerk nystagmus, which has a slow phase and a fast phase, and pendular nystagmus, which has rhythmic oscillation. Either type can be torsional (rotatory) or in a horizontal or vertical direction. Xenobiotic-induced nystagmus takes many forms but is most commonly jerk nystagmus, as opposed to pendular. The nystagmus may be evident at rest but is accentuated by visual pursuit and extreme lateral gaze. Although nystagmus with extreme lateral gaze is a normal finding, it extinguishes within 2 to 5 beats; if nystagmus persists, it is evidence of underlying pathology. Vertical nystagmus in other settings is usually associated with a structural lesion of the CNS. However, xenobiotic-induced vertical nystagmus occurs with phencyclidine, ketamine, dextromethorphan, or phenytoin toxicity. Loss of conjugate gaze commonly results from CNS depression of any etiology, typically after sedative–hypnotic or ethanol poisoning. Except after extremely rare exposures to neurotoxins (Table 24–1), diplopia without a decreased level of consciousness should not be attributed to an acute toxicologic etiology. In addition to the transient effects of some xenobiotics, thallium, carbon disulfide, and carbon monoxide cause sustained gaze disorders as a consequence of residual cranial nerve and CNS injury.²² Nystagmus and ophthalmoplegia caused by thiamine deficiency (Wernicke encephalopathy) usually improves after therapy, but on occasion the nystagmus completely resolves.⁴⁶

Chemical Ophthalmic Injury

Chemical injury to the eye from a number of xenobiotics occurs in both residential and industrial settings, and also results from warfare or acts of terrorism. A recent study demonstrated that over a 4-year period there were more than 144,000 ophthalmic burns recorded in emergency departments in the United States.²³ Although injuries were more common in men than women, children aged 1 to 2 years had the highest incidence of injury. Alkaline injuries resulted in more severe injuries than acids, and were more common.²³ Vision loss is associated with an increased risk for subsequent serious injuries, and will have long-lasting impact on general health.²⁹