EFFERENT (PARASYMPATHETIC) PUPILLARY DEFECTS
Recognizing an Efferent Pupillary Defect
A patient with a unilateral disorder affecting the final common parasympathetic pupil pathway, anywhere from the Edinger-Westphal segment of third cranial nerve nucleus in the midbrain to the iris, has a less reactive pupil than its fellow, normally innervated, pupil. Acutely, the pupil is also larger than the opposite pupil. Compared with the situation with an afferent pupillary defect, the reaction of a pupil affected by efferent damage appears impaired when the normal eye is stimulated with light. Most acute efferent pupillary defects are recognized by anisocoria, exaggerated when the eyes are exposed to bright light due to inability of the denervated iris sphincter to constrict the affected pupil. The anisocoria is minimized in darkness because dilator muscle function is preserved. A parasympathetically denervated pupil will not react any better to a near stimulus than it does to direct light because the final common pathway transmits efferent impulses to both the ciliary muscle and the pupillary sphincter.
Despite the extensive differential diagnostic possibilities and location of lesions that can produce parasympathetic dysfunction of the pupil (Table 3), most neurologically isolated efferent defects encountered in otherwise normal ambulatory patients are either Adie's tonic pupil or a pharmacologically dilated pupil.
TABLE 3. Differential Diagnosis of a Large and Poorly Reactive Pupil
Midbrain Syndromes of the Pupil
Equal-sized pupils are present in two special parasympathetic efferent disorders associated with midbrain lesions. The first, discussed earlier in the Afferent Pupillary Defects section, involves the contraction anisocoria rarely identified in a patient who has a lesion of the dorsal midbrain interrupting the pretectal pupillomotor fibers that innervate the Edinger-Westphal nuclei.
In this condition, the pupil of the directly stimulated eye constricts more than the pupil in the opposite eye, producing a consensual defect.
The second condition occurs as part of the dorsal midbrain or pretectal syndrome, also known as Parinaud's syndrome. In this condition, interruption of the pretectal pupillomotor fibers crossing the posterior commissure results in pupils that are of equal size, sometimes slightly dilated, and react poorly to light but promptly in response to accommodation (81), a pupillary sign referred to as light-near dissociation (Fig. 13). Because near reaction of the pupils is driven by an anatomically ventral supranuclear input to the Edinger-Westphal nuclei, the near response is generally not affected by lesions that injure the midbrain tectum. Common causes of the dorsal midbrain syndrome include dorsal compression from pineal and thalamic tumors, aqueductal dilation due to hydrocephalus, hemorrhages and infarcts affecting the rostral midbrain, encephalitis, and demyelinating disease.
Fig. 13 Light-near dissociation in a 51-year-old woman with multiple sclerosis who experienced double vision for 1 week. Her pupils are 5 mm in diameter in room light (top), react poorly in response to direct light reaction (middle), but constrict promptly in response to near stimulation (bottom). She also had a supranuclear pattern of impaired upward gaze and convergence-retraction "nystagmus" during attempted upward gaze, all consistent with Parinaud's syndrome.
In exceptional cases of severe rostral midbrain lesions, the pupils shift from their centered position in the iris to an eccentric position as they spontaneously dilate, a phenomenon referred to as midbrain corectopia. Postmortem examination of one affected patient revealed infarction involving the midbrain periaqueductal region but not affecting the parasympathetic or somatic oculomotor nuclei or the fascicular axons of the third cranial nerve (82). One explanation for this rare sign of severe midbrain dysfunction is that spontaneous and random inhibition of topographically arranged portions of the Edinger-Westphal nuclei result in segmental dilation and distortion of the pupil.
Bilateral dilation and impaired light reactivity of the pupils may also result from injury to the oculomotor parasympathetic nucleus, or to fascicular portions of both oculomotor nerves, in patients with midbrain or paramedian-thalamic distribution strokes (83). In such cases, however, the pupillary findings are overshadowed by other, more dramatic, signs of ocular motor dysfunction. More rostral injury to the diencephalon may interrupt the sympathetic pathway and cause bilaterally small pupils.
With unilateral fascicular injury of the oculomotor nerve, interruption of the parasympathetic function of the ipsilateral pupil usually, but not always, occurs. Rarely, a patient may develop a neurologically isolated, pupil-sparing, fascicular third cranial nerve palsy produced by brain-stem infarction that mimics the more typical extraaxial infarct of the third cranial nerve seen in patients with diabetes (84). A patient with neurologically isolated internal ophthalmoplegia generally does not have a midbrain lesion, although exceptional examples have been reported (85). Pupils affected in these midbrain syndromes do not demonstrate light-near dissociation because injury is to the final common pathway, which serves the efferent response to both light and near stimulation.
Argyll Robertson Pupils
In 1869, the Scottish ophthalmologist Douglas Argyll Robertson described pupillary findings in five patients with tabes dorsalis. Argyll Robertson pupils are small, irregularly shaped, and usually bilateral. They fail to dilate normally in darkness and react poorly or not at all to light stimulation, but they do react briskly and phasically to near stimulation (i.e., light-near dissociation) (Fig. 14). They redilate promptly following cessation of a near stimulus, in contrast to the slow, tonic redilation observed with Adie's pupils. Loewenfeld (86) concluded that the light-near dissociation and disinhibition of the Edinger-Westphal nuclei associated with Argyll Robertson pupils result from injury to the pupillomotor fibers of the rostral midbrain near the sylvian aqueduct.
Fig. 14 Argyll Robertson pupils in an elderly man treated for tabes dorsalis in 1952. His pupils are small and slightly irregular, constrict poorly in response to light stimulation (top), dilate poorly in darkness (middle), but constrict promptly in response to near stimulation (bottom).
Although Argyll Robertson pupils are usually associated with complications of late neurosyphilis, such as tabes dorsalis and general paresis, they do not necessarily reflect active disease. Nowadays, Argyll Robertson pupils, like the late stages of neurosyphilis themselves, are uncommon. They usually represent residual sequelae of remote and currently inactive central nervous system involvement from syphilis. From a practical point of view, pupils with some of the characteristics similar to those of Argyll Robertson pupils are more often associated with disorders other than neurosyphilis, most commonly long-standing, bilateral Adie's pupils and autonomic neuropathies (e.g., those resulting from diabetes and alcoholism). Therefore, one should carefully consider other causes of light-near dissociation and tonic pupils when evaluating a patient with bilateral, small, poorly reactive pupils, and reserve use of the term Argyll Robertson pupils for only those signs associated with definitive neurosyphilis. Conversely, it is reasonable to evaluate syphilis serology in a patient with pupils that have such characteristics (87).
Pupil and Preganglionic (Intracranial) Lesions of the Third Nerve
The pupil assumes its greatest clinical role in assisting the diagnosis of disorders that injure the extraaxial segment of the third cranial nerve, where it is susceptible to traction injury and compression by aneurysms and tumors of the base of the skull. The topographic arrangement of the pupillomotor fibers superficially along the oculomotor nerve determine which disorders are likely to affect the parasympathetic function of the pupil when the nerve becomes injured. This anatomic relationship, as well as certain consistent clinical observations, has resulted in the formulation of a so-called general rule of the pupil that serves as a useful guideline as it relates to the evaluation of a patient presenting with acute and neurologically isolated third cranial nerve palsy (88).
The anatomic basis for this rule is as follows. As the third cranial nerve exits the brain stem and enters the subarachnoid space, the pupillomotor fibers are concentrated peripherally on the superior to medial portion of the nerve along its course from the interpeduncular fossa to the cavernous sinus (see Fig. 3). The exposed position of these small fibers makes them particularly susceptible to early injury when the third cranial nerve is stretched or compressed in its subarachnoid segment by, most commonly, an aneurysm at the junction of the internal carotid and posterior communicating arteries, producing what is termed pupil-involving third nerve palsy." Ischemic injury of the third cranial nerve, conversely, generally causes weakness of the extraocular muscles without pupillary dilation ("pupil-sparing third cranial nerve palsy") because damage from infarction involves the central portion of the nerve trunk (89, 90).
These rules are broken in clinical practice often enough that one should always approach and observe a patient with acute third cranial nerve palsy with great trepidation. In particular, relative pupil-sparing and incomplete third cranial nerve palsy are two clinical presentations in which this rule of the pupil does not apply. Relative pupil-sparing implies complete or nearly complete external ophthalmoplegia with minimal (i.e., ipsilateral pupil diameter is larger by no more than a millimeter or so) pupil involvement. Incomplete palsy implies either that all extraocular muscles are paretic, but some or all incompletely so, or that only some of the extraocular muscles are affected. For example, roughly one third of patients with diabetes-associated infarction of the third cranial nerve show relative pupil sparing (91). However, the size of anisocoria is usually 1 mm or less and the involved pupil maintains reactivity to light. When the degree of pupil involvement is greater than these parameters, one should be highly suspicious that an aneurysm or other mass lesion is compressing the oculomotor nerve.
If all the extraocular muscles are totally paralyzed and the pupil is completely spared, the likelihood that aneurysmal compression is the underlying cause of the third cranial nerve palsy is extremely low. These patients can generally be observed during follow-up without the need to exclude aneurysm using screening (e.g., magnetic resonance angiography) or invasive (i.e., catheter angiography) neuroradiologic procedures (92). The same level of confidence cannot be applied to a patient whose extraocular muscles are only partially paretic, or one in whom not all are involved, as seen in a patient with a superior division third cranial nerve palsy. Mydriasis may not develop with certain aneurysms, including some of the basilar tip that compress or stretch the oculomotor nerve at a point below the concentration of the more dorsally positioned pupillomotor fibers (93-96).
A small percentage of patients with aneurysmal third cranial nerve compression do not have a dilated pupil when they are first evaluated for their ophthalmoplegia (93, 97). These patients generally have incomplete ophthalmoplegia, again emphasizing a clinical exception to the rule of the pupil. However, most such patients develop pupil involvement within 1 week from that time, indicating that any patient with a pupil-sparing third cranial nerve palsy should be observed carefully during the subsequent 1 to 2 weeks for development of anisocoria, a sign that may indicate aneurysm.
Within the cavernous sinus, the pupillomotor fibers remain peripherally located along the oculomotor nerve but are concentrated along the inferior surface. A mass lesion within the cavernous sinus compressing or stretching the oculomotor nerve may not injure the pupillomotor fibers. More often than not, however, the pupil is involved with cavernous sinus tumors and aneurysms compressing the oculomotor nerve (98). The pupil may be smaller than its fellow pupil and poorly reactive to light if aberrant regeneration of the iris sphincter has occurred as a result of chronic compression with degeneration and regeneration of the oculomotor nerve (see next section). Less often, the pupil may be small, poorly reactive to light, and also fail to dilate in darkness if the oculosympathetic fibers are injured along with the pupillomotor fibers. Topical cocaine can be used to confirm the presence of oculosympathetic paresis, because the affected pupil does not dilate as fully as its fellow pupil in this setting.
In summary, there are four clinical situations in which the pupil may not be involved when a patient is harboring an aneurysm compressing the oculomotor nerve:
1. When the degree of external ophthalmoplegia is incomplete
2. When the inferior division of the third cranial nerve is spared (another form of incomplete third cranial nerve palsy)
3. When third cranial nerve palsy and Horner's syndrome are combined
4. When the injured oculomotor nerve has undergone aberrant regeneration
These patients must emergently undergo further diagnostic tests to exclude aneurysm if computed tomography or magnetic resonance imaging does not identify the responsible lesion (92).
Isolated mydriasis generally is not the initial manifestation of oculomotor nerve compression. However, exceptional single reports of this phenomenon exist (99).
The superficially located pupillomotor fibers of the third cranial nerve are also susceptible to injury by disorders involving leptomeningeal infiltration (e.g., metastasis), infection (e.g., fungi), or inflammation (e.g., Guillain-Barr� or Fisher's syndrome). In the case of inflammatory disorders, leptomeningeal involvement tends to be diffuse so that bilateral oculomotor nerve involvement, and therefore bilateral mydriasis, is common.
Aberrant Regeneration of the Third Nerve and the Pupil
The iris sphincter and extraocular muscles may become reinnervated by misdirected fibers several weeks following an acute, pupil-involving injury of the oculomotor nerve. The most commonly observed synkinetic movements that result from misdirected regeneration involve the upper eyelid, which will elevate when the globe is adducted or depressed.
When fibers originally destined to innervate the extraocular muscles become miswired into the iris sphincter, its parasympathetic tone increases, resulting in a pupil that is often smaller than normal and poorly reactive to light. Additional signs of aberrant regeneration of the iris sphincter include pupillary constriction during elevation, depression, or medial rotation of the globe (100) (Fig. 15). When the iris sphincter constricts better during convergence (i.e., medial rotation) than it does in response to direct light, the pupil is demonstrating a form of light-near dissociation. However, unlike Adie's pupil, the pupil affected by aberrant regeneration of the oculomotor nerve does not show a tonic near response.
Fig. 15 Aberrant regeneration of the right pupil in a man with a large intracavernous sinus meningioma causing a pupil-involving, incomplete third cranial nerve palsy. His pupil is round when he gazes straight ahead (top). When he tries to rotate the eye medially, the pupil constricts, but a segment of the iris from around 3- to 6-o' clock (black arrow) constricts much better than other segments of the iris (bottom). This phenomenon of segmental constriction of the pupil in response to gaze, one of the signs of aberrant regeneration, is referred to as Czarnecki's sign.
These synkinetic pupil movements may occasionally be observed clinically without magnification if they are large. Use of a hand-held magnifying glass, of a direct ophthalmoscope focused on the iris, or ideally of a slit-lamp biomicroscope will facilitate observation of subtler movements of the iris during eye movement. Under these magnified conditions, sectors of the iris sphincter constrict in response to eye movement or light. This is referred to as Czarnecki's sign (101).(Video 2 )
Video 2. Aberrant regeneration of the iris sphincter, Czarnecki's sign, in a patient with a cavernous sinus meningioma.
The phenomenon in which synkinetic movements of the extraocular muscles and iris sphincter occur following an acute, clinically obvious third cranial nerve palsy is referred to as secondary aberrant regeneration. Secondary aberrant regeneration most commonly occurs following head trauma or direct neurosurgical injury of the third cranial nerve. Aberrant regeneration does not occur during recovery of ischemic third cranial nerve palsy because the axons in this condition do not undergo the same degree of injury or disruption of their connective tissue support.
Primary aberrant regeneration is that condition in which synkinetic movements of muscles innervated by the oculomotor nerve develop in a patient who never had a clinically obvious acute third cranial nerve palsy. This phenomenon typically occurs in the setting of a slowly expanding mass lesion within the cavernous sinus, most often a giant internal carotid artery aneurysm or meningioma (102, 103). The chronic compressive injury to the oculomotor nerve causes slowly progressive simultaneous degeneration and regeneration of nerve fibers. The pupil findings are the same whether the aberrant regeneration is primary or secondary.
Inferior Division Oculomotor Nerve Lesions
The third cranial nerve bifurcates into superior and inferior divisions in the anterior cavernous sinus. The inferior division passes through the superior orbital fissure and supplies the medial rectus, inferior rectus, and inferior oblique muscles, as well as the two intraocular muscles innervated by the parasympathetic fibers, the ciliary muscle, and the iris sphincter. Although uncommon, selective involvement of the inferior division can occur with lesions of the cavernous sinus or orbital apex, such as trauma to the orbit or skull base, an inflammatory process (e.g., Tolosa-Hunt syndrome or orbital pseudotumor), with neoplastic infiltration or with vascular anomalies (104-106). In such cases, although the pupil is dilated and poorly reactive to light, it will not exhibit light-near dissociation or tonic redilation following accommodation. In the absence of optic nerve dysfunction or proptosis, one cannot clinically differentiate whether a lesion causing inferior division oculomotor nerve palsy is located within the cavernous sinus or the orbital apex. In fact, the localizing value of this sign is further reduced by rare reports of a lesion involving the midbrain fascicles of the third cranial nerve that preferentially affect the muscles innervated by the inferior division (107).
Pupil and Postganglionic (Intraorbital) Lesions: Adies' Pupil
Parasympathetic denervation of the pupil from injury to either the ciliary ganglion or the postganglionic short ciliary nerves produces a tonic pupil, which refers to the behavior of a pupil that has undergone postganglionic parasympathetic denervation whereby it exhibits slow constriction and slow redilation after light or near stimulation. Adie's pupil specifically refers to an idiopathic tonic pupil, frequently associated with impaired muscle stretch reflexes, a combination often referred to as Adie's syndrome, or the Holmes-Adie syndrome to acknowledge the additional contributions of the English neurologist, Gordon Holmes.
Tonic pupils are recognized by a constellation of associated clinical signs that reflect both degeneration and regeneration of the iris sphincter (Table 4) (108). Following acute injury to the ciliary ganglion or short ciliary nerves, the iris sphincter becomes denervated, producing a large, poorly reactive pupil (Fig. 16). During subsequent regeneration, postganglionic parasympathetic fibers then reinnervate discrete segments of the iris. However, since approximately 97% of the postganglionic fibers are dedicated to the ciliary muscle, a greater proportion of them become aberrantly misdirected to innervate the iris sphincter, so that the pupil constricts during accommodation or near efforts better than it does in response to light stimulation, referred to as light-near dissociation. The denervated pupil constricts very weakly, if at all, to light, and much more completely, although slowly and tonically, to near efforts (Fig. 17). Following a near response, a tonic pupil then redilates slowly (i.e., tonically). The slow nature of the pupillary constriction and redilation distinguish a tonic pupil from most other efferent pupil disorders that might be confused with it. Due to increased tone of the iris sphincter, a tonic pupil also dilates poorly in darkness and may be smaller than the normal pupil in this ambient light condition.
TABLE 4. Clinical Features of a Tonic Pupil
Fig. 16 Pathophysiology of signs associated with a tonic pupil. Normally, all parasympathetic fibers of the third cranial nerve synapse in the ciliary ganglion (top). Most postganglionic fibers innervate the ciliary muscle (dashed lines). After injury to the ciliary ganglion, the pupil becomes denervated and larger (bottom). Denervation supersensitivity of the iris sphincter develops (depicted as an increase in the number of oval-shaped receptors). Some fibers never reinnervate the pupil (depicted as open circle neurons within the ciliary ganglion), whereas others reinnervate segments of the iris sphincter they had not innervated before injury. This haphazard process of denervation and reinnervation results in a poorly reactive pupil with segmental palsies of the iris sphincter. A greater proportion of postganglionic fibers that originally innervated the ciliary muscle become miswired and aberrantly reinnervate the iris sphincter muscle, resulting in more efficient pupillary constriction during accommodation than in response to light (i.e., light-near dissociation).
Fig. 17 Pupil signs in a 32-year-old woman with right-sided Adie's pupil. The right pupil is larger than the left pupil (top), reacts poorly to direct light stimulation (second panel), and better in response to near stimulation (third panel). The right pupil also shows a supersensitive response 30 minutes after pilocarpine 0.1% was applied to both eyes (bottom).
Segmental reinnervation of the iris sphincter is difficult to observe without magnification. This phenomenon is best seen using slit-lamp biomicroscopy, where some segments of the iris sphincter constrict a variable amount, an occasional segment might be seen to constrict normally, and other segments constrict not at all and are dragged toward constricting segments (109). These movements are sometimes referred to as "vermiform". One can use a direct ophthalmoscope to identify segmental palsies of the iris sphincter by observing portions of the iris while quickly directing the light back and forth onto the iris in darkness.
Finally, the denervated pupil constricts significantly more than the normally innervated fellow pupil in response to a dilute solution of a cholinergic agonists, such as pilocarpine 1/10% or 1/16%, applied to both eyes (110) (see Fig. 17). This phenomenon, referred to as denervation cholinergic supersensitivity of the iris sphincter, is discussed in greater detail in the next section.
Although tonic pupils occur in various conditions associated with orbital, neuropathic, and systemic disorders (Table 5), most patients with this pupil abnormality presenting to a neurologist have an isolated Adie's syndrome (111). In the case of tonic pupils associated with orbital disorders, the primary cause should be apparent after reviewing the history and performing an ophthalmologic examination because the pupil signs are not likely to be an isolated finding in this setting. In the case of tonic pupils occurring with peripheral neuropathy, the pupil signs occur in association with other symptoms and findings consistent with a peripheral neuropathy, systemic disease, or in conjunction with features of autonomic dysfunction.
TABLE 5. Causes of Tonic Pupils
Ross' syndrome deserves special mention as a disorder that might be thought of as a "tonic pupil plus" syndrome (112, 113). This unusual disorder of the peripheral nervous system is associated with tonic pupils, hyporeflexia, and a progressive and symptomatic abnormality of sweating. Features of sweat dysfunction include segmental or regional areas of anhidrosis and, not uncommonly, excessive sweating in preserved regions of sudomotor function. The tonic pupil in Ross' syndrome is bilateral in one half of affected patients. Pharmacologic and noninvasive physiologic evaluation of autonomic function in affected patients indicates that the tonic pupil and sudomotor dysfunction result from degeneration of the parasympathetic and sympathetic cholinergic ganglion cells or the postganglionic nerves (114).
The nosologic distinction between Ross' syndrome, Adie's syndrome, and some other idiopathic degenerative and systemic disorders associated with dysautonomia is not always clear. Some patients with Ross' syndrome have additional evidence of autonomic dysfunction, including orthostatic hypotension and Horner's syndrome. Many patients with Adie's syndrome have subclinical abnormalities of sweat function, including segmental hypohidrosis, demonstrable using noninvasive techniques (115-117). If abnormalities of sweat function were symptomatic or progressive, then the diagnosis of Ross' syndrome, not Adie's syndrome, would probably be entertained. When more widespread evidence of autonomic failure occurs in a patient with hypohidrosis and tonic pupils, then a systemic degeneration of the autonomic nervous system, not Ross' syndrome, would likely be the diagnosis.
In addition, various overlapping syndromes involve patients with tonic pupils and abnormal sweat function, including an idiopathic condition of progressive widespread loss of sudomotor function without other features of autonomic dysfunction, called chronic idiopathic anhidrosis (118). Harlequin's syndrome is an idiopathic disorder characterized by sudden onset of loss of sweating and flushing on one side of the face (119). Many patients with either of these conditions frequently have, in addition to tonic pupils, Horner's syndrome. Finally, the sensory neuronopathic presentation of Sj�gren's syndrome can rarely produce, in addition to dry eyes and dry mouth, tonic pupils, hyporeflexia, and segmental anhidrosis (120).
In 1932, the Australian ophthalmologist, William Adie, drew attention to the constellation of pupillary signs and clinical characteristics of patients harboring the disorder that now bears his name (121). Adie's pupil occurs in women more often than men, usually between their third and fourth decades (111). Most patients are asymptomatic and the large pupil is recognized by a family member, friend, or during an evaluation for some other problem that requires an examination of the eye. In some cases, a tonic pupil is first identified when a patient seeks assistance from an optometrist or ophthalmologist for symptoms referable to ciliary muscle dysfunction, such as blurred vision when reading, or an annoying intraorbital or brow ache when reading ("ciliary cramp") (Table 4). When one evaluates a patient for what appears to be an acute presentation, it is helpful to inspect available photographs (e.g., driver's licenses) to determine whether a large pupil may have been present longer than the patient realized. Identification of long-standing mydriasis lends support to the benign nature of the current symptomatic presentation.
The diagnostic signs associated with Adie's pupil, reviewed in the preceding section and summarized in (Table 4), are the result of progressive degeneration and simultaneous aberrant regeneration of the short ciliary nerves following injury to the ciliary ganglion (see Fig. 16) Postmortem examination of patients affected with this condition have revealed marked loss of neurons in the ciliary ganglion, with the remaining neurons showing various stages of degeneration (122, 123). No significant inflammation is observed. Within the globe, postganglionic fibers are reduced in number and the iris sphincter muscle shows patchy partial atrophy. The oculomotor nerve is normal from the midbrain to the orbit.
In 1940, Adler and Scheie (124) reported that patients with unilateral tonic pupil showed marked constriction of that pupil in response to topically applied dilute methacholine, whereas the unaffected, fellow pupil showed no significant response to application of the same solution (124). This phenomenon is called denervation cholinergic supersensitivity of the iris sphincter and has become a standard diagnostic test to help confirm Adie's pupil (see Fig. 17). A dilute solution of pilocarpine (1/8%, 1/10%, or 1/16%) is currently the favored cholinergic agonist to demonstrate such supersensitivity.
Although it is true that most, but certainly not all, Adie's pupils demonstrate substantial constriction to a dilute solution of pilocarpine (110, 111), there are several problems inherent in depending only on supersensitivity test results to establish the diagnosis of Adie's pupil (Table 6). Not the least of which is the physiologic principle that large pupils from any cause, other than mechanical disorders of the iris or anticholinergic blockade, will constrict more than smaller pupils in response to the same dose of a dilute cholinergic agonist applied to both eyes. This occurs because a larger pupil encounters relatively less resistance by the iris tissue when it contracts than does a smaller pupil. Accordingly, a unilateral, large pupil that constricts more than its smaller fellow pupil in response to the same dose of dilute pilocarpine applied to both eyes is not a response specific to Adie's pupil. In fact, many patients with pupil-involving compressive, traumatic, congenital, but not ischemic, third cranial nerve palsies also demonstrate supersensitive responses of the affected pupil (125-128). In patients with long-standing oculomotor nerve palsies, transsynaptic degeneration of postganglionic parasympathetic fibers might occur, resulting in denervation supersensitivity of the iris sphincter. In acute cases, biochemical denervation of the iris sphincter due to reduced cholinergic transmission, independent of transsynaptic degeneration, might be responsible for such apparent supersensitivity due to a preganglionic lesion (128).
TABLE 6. Problems with Cholinergic Supersensitivity Testing for Adie's Pupil
The ideal technique for performing supersensitivity testing is to apply the same dose of dilute pilocarpine in both eyes so that the normal, fellow pupil can serve as an internal control with which the response of the abnormal pupil can be compared (110, 111) (Table 7). Many patients with Adie's syndrome have bilateral involvement, which precludes comparing responses of an affected pupil with a normal pupil.
TABLE 7. Testing for Cholinergic Supersensitivity of the Iris Sphincter
What concentration of dilute cholinergic agonist should be used? In general, the ideal concentration is the lowest dose that will just constrict a normal pupil. This provides the largest difference in the amount of constriction between an Adie's pupil and normal fellow pupil (129). Because there exists a large amount of interindividual difference in sensitivity to dilute cholinergic agonists, however, very dilute solutions may not constrict all normal pupils. In that setting, you cannot reliably conclude that the test result was negative if the abnormal pupil does not constrict, either. You must then repeat the procedure using a slightly greater concentration to ensure that sufficient drug penetrated the cornea, as evidenced by observing constriction of the normal pupil. Conversely, too strong a concentration will produce too many false-positive results.
I recommend using pilocarpine 0.1%, a solution the concentration of which represents a reasonable compromise. It is easy to prepare by mixing one drop of a commercially available preparation of pilocarpine 1% with nine drops of a sterile diluent into a 1-ml tuberculin syringe. Even the type of diluent used can influence the potency of the solution and, therefore, the amount of pupillary constriction. For example, pupils constrict most when methylcellulose is the diluent, followed by saline, and the least with bacteriostatic water (130). The reason for this likely results from differences in pH of the solutions and the effect this has on the amount of pilocarpine that is absorbed across the cornea.
Finally, what degree of pupillary constriction constitutes a positive pilocarpine test for supersensitivity? The absolute interocular difference of pupillary constriction that occurs in normal subjects following instillation of pilocarpine 0.1% applied to both eyes is roughly 0.5 mm when measured in darkness. Therefore, if an abnormal pupil constricts more than the normal, fellow pupil by any amount exceeding this cutoff, that response is greater than one that would occur by chance, and likely represents a supersensitive response. One should test for cholinergic supersensitivity in as dim an ambient environment as possible because the pupillary responses induced by the cholinergic agonist in this setting are relatively independent of any additional miotic influence of the light reflex (8). Additionally, testing pupil responses in darkness maximizes the starting pupil size so that mechanical resistance of the iris tissue during miosis is minimized. However, measuring pupil sizes in darkness is difficult without the assistance of photographic equipment or infrared pupillometry. An empirically defined valid endpoint that obviates the need for such equipment can be used if the starting size of the abnormal pupil is larger than the fellow pupil using the dimmest possible light. In that setting, if the larger pupil clearly becomes the smaller pupil after the same dose of pilocarpine has been applied to both eyes, then it is likely that the larger pupil exhibited a supersensitive response because it overcame the resistance of the iris tissue that would normally restrict that pupil from constricting to that degree (8).
In summary, diagnosing Adie's pupil primarily requires identification of the characteristic signs of a tonic pupil (see Table 4) and clinical judgment to determine whether the pupil disorder is isolated or associated with a local ocular or orbital process, peripheral or autonomic neuropathy, or a systemic disorder (see Table 5). Supersensitivity testing is not required to confirm a suspected Adie's pupil. However, supersensitivity testing can provide important additional objective documentation of the nature of an efferent pupillary defect, if properly performed and interpreted (Table 8). In addition, it may be a useful test in patients with ambiguous clinical signs, such as little or no segmental palsies of the iris sphincter or equivocal light-near dissociation.
TABLE 8. Pupil and Eyelid Disorders Commonly Confused with the Miosis and Ptosis Associated with Horner's Syndrome
The pupil signs and impairment of muscle stretch reflexes in patients with Adie's syndrome are not static, suggesting that this condition is a progressive degenerative disorder (111). The light reaction tends to worsen over time, so that larger segments of the iris sphincter show sector palsies. The pupil becomes gradually smaller and dilates increasingly poorly in darkness. Accordingly, a patient with an Adie's pupil that has been present for longer than 5 years or so will often have an affected pupil that is smaller, not larger, as seen with an acute or early presentation. Thompson and Kardon (131) refer to such small Adie's pupils as "little old Adie's". The uninvolved eye in unilateral cases will commonly become affected several years later. The pupils of a patient with long-standing bilateral Adie's syndrome appear small, irregular, asymmetric, and react poorly to light, all findings similar to those associated with Argyll Robertson pupils. Therefore, obtaining syphilis serology is reasonable in a patient with bilateral tonic pupils, especially those that are small (87).
Most patients with Adie's pupil have impaired muscle stretch reflexes in the absence of symptoms or other signs indicative of a peripheral neuropathy (111). Absence or depression of ankle jerks is the most common finding, although the patellar and tricep reflexes may be involved, as well. Impairment of muscle stretch reflexes is frequently asymmetric and not predictive of the side of the affected pupil in unilateral cases. Additionally, there is no correlation between the degree or distribution of reflex impairment and the degree of pupil dysfunction or frequency of bilateral pupil involvement.
Electrophysiologic findings in the lower extremities of patients with Adie's pupils who have impaired muscle stretch reflexes include absent H reflexes in association with normal nerve conduction velocities, normal muscle compound action potentials, intact F waves, and normal somatosensory evoked potentials (132). Miyasaki and colleagues (132) concluded that depressed reflexes result from loss of large spindle afferent input to spinal motoneurons because they additionally found that patients with Adie's syndrome also had reduced estimated evoked postsynaptic potentials. Other investigators consider the site of impairment to be the dorsal root or dorsal root ganglion since affected patients also demonstrate impaired vibration sense when tested using quantitative methods (133). In fact, postmortem examination of patients with Adie's pupils and affected muscle-stretch reflexes shows evidence of degeneration of the dorsal root ganglia with secondary loss of myelin in the posterior roots and axons of the posterior columns (123).
Many patients with Adie's pupil have symptoms that are annoying, but not intrusive enough to interfere with normal activities of daily living (see Table 4). Symptoms of accommodation paresis tend to improve over time and are not usually a chronic problem for most patients (134). An occasional patient does find that photosensitivity and instability of accommodation sufficiently impair the ability to perform in his or her work or social setting to justify treatment. For photosensitivity, a weak solution (e.g., 1/16%) of pilocarpine may be used to constrict the pupil. Its effects are short-lived and many patients find the blurred vision or ciliary cramp resulting from its use are just as annoying as the symptom it was trying to relieve. Sunglasses or tinted spectacles are a more practical option. Some patients bothered by loss of accommodation, causing blurred vision for near work, find partial relief by using inexpensive over-the-counter magnification spectacles during those activities. A patient should be encouraged to avoid more costly approaches (e.g., frequent new prescription glasses) because the loss of accommodation is usually not chronic, and because expensive spectacles will not eliminate other symptoms of ciliary muscle dysfunction, such as tonicity or instability of accommodation (see Table 4).
Disorders Affecting the Neuromuscular Junction
Ten percent of patients with Eaton-Lambert syndrome have large, poorly reactive pupils as well as other signs of autonomic dysfunction (135). However, these are not tonic pupils because they do not demonstrate light-near dissociation, segmental palsies of the iris sphincter, or tonic near and redilation responses. Their large size and poor reactivity result from presynaptic parasympathetic denervation of the iris sphincter due to the neuromuscular junction defect associated with this condition (136).
In contrast to the efferent pupillary signs occasionally observed in patients with Eaton-Lambert syndrome, myasthenia gravis is not associated with an efferent pupil defect because this disorder involves postsynaptic neuromuscular junction failure of striated, not smooth, muscles. Although abnormalities of the pupillary light reflex have been measured using pupillometry (137) and the pupil cycle time (138) in some patients with myasthenia gravis, the clinical significance of these experimental findings is doubtful. When an efferent pupil defect is seen in a patient with presumed myasthenia gravis, the examiner should consider an alternative diagnosis or explore the possibility that the patient also has tonic pupils.
An efferent pupillary defect, along with impairment of accommodation and external ophthalmoplegia, occurs frequently in patients suffering from botulism due to a wound or food contamination (139, 140). Friedman and colleagues (141) described a patient who developed typical bilateral tonic pupils following recovery from botulism.