TONIC PUPIL

Signs and Symptoms

Tonic pupils (sometimes referred to as internal ophthalmoplegia) result from damage to the parasympathetic innervation to the eye, resulting in decreased function of the iris sphincter as well as the ciliary body.1-10 A tonic pupil responds to both light and near stimuli with extremely slow constriction and re-dilation. Patients typically present with a chief complaint of unilaterally reduced near vision and anisocoria. When first noted by the patient in ambient light, the tonic pupil is often the larger of the two. However, if viewed in dim illumination, it may reverse and become the smaller pupil.1,2 Interestingly, the anisocoria may diminish as the tonic pupil becomes more miotic over time.1-3,5-7,9 The tonic pupil is typically unilateral (90%), but may become bilateral at a rate of 4% per year.1-3,7 The iris margin may be irregular and the pupil misshapen due to a sector paralysis of the iris.

Along with the pupil anomaly, parasympathetic damage may result in dysfunction of the ciliary body, causing accommodative spasm, accommodative insufficiency and induced astigmatism, generating complaints of blur at both distance and near.1,2 Accommodation, like pupillary responses, is tonic as the patient changes fixation from distance to near and back again. As a result, patients with tonic pupil often complain that vision transiently blurs (until the ciliary muscle catches up or relaxes) during attempts at focusing. Accommodative amplitude is also found to be reduced.1,2 Over time, the tonicity of both the accommodative and pupillary responses increase.

Tonic pupils can be found at any age and in both sexes; however, 70% are found in otherwise healthy females between the ages of 20 and 50.1-7

Pathophysiology

Afferent input to the parasympathetic pathway results in pupillary constriction (the direct light reaction). The pathway originates in the photoreceptors and retinal ganglion cells and travels via the optic nerve, chiasm and optic tract. Some fibers leave the tract prior to the lateral geniculate body via the superior colliculus and the brachium conjunctivum. These fibers synapse in the pretectum and are distributed bilaterally to the Edinger-Westphal nucleus adjacent to the oculomotor nerve in the dorsal mesencephalon.1-7

Parasympathetic tone of the irides originates in this complex group of paired midline nuclei. The efferent fibers travel with the third cranial nerve, entering the orbit and synapsing in the ciliary ganglion.1-7 Postsynaptic fibers leave the ganglion traveling as the short ciliary nerves, piercing the sclera to arrive at their end organ destinations, the iris and ciliary body.1,2

The vast majority (93-97%) of these parasympathetic fibers go on to supply the ciliary body, resulting in the stimulation of accommodation. The remaining 3-7% of parasympathetic fibers innervate the pupillary sphincter, allowing constriction of the pupil in response to light.1,2,5-7 The hypothesized reason for this uneven distribution is the unequal masses of the ciliary muscle and the iris sphincter.1,2,5,6

Interruption of the above pathway anywhere along its route can result in incomplete parasympathetic innervation, causing pupillary dilation, decreased speed and amplitude of constriction and decreased speed and amplitude of accommodation. Since the input to the Edinger-Westphal nucleus is crossed and innervation of the pupillary sphincters is bilateral, the pupils are expected to be equal in size.5 Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system. The parasympathetic system conducts the light reaction. The sympathetic nervous system acts either directly on the dilator muscle or by inhibiting the Edinger-Westphal nucleus.11 Acquired anisocoria indicates a lesion in one of the efferent pathways or the iris muscle.

Also playing a role in pupillary constriction are three synkinetic reactions: (1) the near reflex (miosis, accommodation and convergence), (2) Bell’s phenomenon (levator inhibition, superior rectus activation and miosis) and (3) the Westphal-Piltz reaction (orbicularis contraction and miosis).2,3,5,7

Following injury to the ciliary ganglion or the short ciliary nerves, clinical signs may be seen. These include light-near dissociation, tonicity of both the pupillary light reaction and accommodation, segmental palsy of the iris sphincter, and denervation hypersensitivity to dilute cholinergic agents.1-10 In the 8-12 weeks following injury to the ciliary ganglion, surviving nerve cells sprout collaterals to re-innervate both the ciliary body and the pupil.1,2,4,6 Because of the unequal ratio of fibers originally favoring the ciliary muscle, this re-innervation results in a pupil that constricts more when accommodation is stimulated (a target held near) than to light and is termed a light-near dissociated pupil.1-7 Unlike light-near dissociation, which takes weeks to months to develop, hypersensitivity can be observed in days to weeks.1,2,5,6

In addition, the re-established connections are less efficient, further contributing to the latency and slow pupillary constriction.1,2 The tonic pupil also dilates poorly due to inappropriate tone secondary to aberrant reinnervation.5,6 The tonic characteristic of both constriction/redilation is also in part due to the decreased number of intact neuromuscular junctions following injury. Segmental palsy results from the fact that the sphincter is made up of 70-80 separate motor units, each served by a separate parasympathetic nerve fiber.8 Partial denervation will then result in partial or segmental constriction of the iris in response to both light and near stimuli.

Bilateral tonic pupils have been found in association with other dysfunctions of the autonomic nervous system including Ross syndrome (hyporeflexia, tonic pupil and progressive segmental anhidrosis), orthostatic hypotension, and Riley Day Syndrome (familial dysautonomia).1,2,12-15 There appear to be reports of Ross syndrome variants, including tonic pupil and anhydrosis with preservation of deep tendon reflexes as well as tonic pupil, hyporeflexia and segmental compensatory hyperhidrosis where hypohidrosis or anhidrosis is not even noticed.15,16

William John Adie has long been credited with describing benign non-syphilitic tonic pupils (Adie’s tonic pupil) and a syndrome involving tonic pupil and absent deep tendon reflexes (Adie’s syndrome). However, Adie was not the first to describe the pupil abnormality and it is more appropriate to refer to tonic pupils simply as such and leave the Adie name to describe the syndrome.17 It is important to note that this benign pupil abnormality and syndrome are largely isolated and have no discernible cause. There are numerous etiologies that can result in a tonic pupil, either unilaterally or bilaterally. The discovery of a tonic pupil should not be presumed to be benign.

It is well known that migraine can result in a tonic pupil.18-23 The pathophysiology is not well understood, but this association may be caused by infarction of parasympathetic fibers secondary to prolonged vasospasm which sometimes occurs in migraine.

Damage to the ciliary nerves through surgery or laser photocoagulation can also cause tonic pupil to develop.24 Infectious diseases such as herpes zoster, HIV, neurosyphilis and cytomegalovirus have been implicated as causes of tonic pupil.25-27 Obstructive hydrocephalus has been noted to cause tonic pupil.28 Iris and ciliary body ischemia occurring from giant cell arteritis has also been implicated in tonic pupil development.29 Various reports have also implicated sarcoidosis as a causative etiology.30,31 Blunt trauma to the globe may cause segmental iridoplegia, which can be mistaken for a tonic pupil.8 Thus, it is important to try to discern a cause when encountering a patient with a tonic pupil(s).

Management

The first step in proper diagnosis is determining if the anisocoria is benign and physiologic or acquired and pathologic. This is accomplished by comparing the amount of anisocoria in bright and then dim illumination. Pupils that possess physiological anisocoria will show a relative size difference that typically does not vary from one illumination level to the next. However, in very bright illumination, the degree of anisocoria may become so imperceptible that the pupils may seem isocoric. Pupils suffering from sympathetic pathway lesions (i.e., Horner’s syndrome) will possess anisocoria that is greater in dim illumination, due to failure of the iris dilator.1-5,9,10 There will also be a dilation lag in dim light, further separating this from physiologic anisocoria. Pupils suffering from parasympathetic pathway interruptions will demonstrate anisocoria that measures larger in bright light.1-5,9,10

The second step is to measure the pupil’s ability to react to light (both the direct and consensual response). The third step is to measure the amount of constriction accompanying an accommodative effort compared to the light response, checking for light-near dissociation. It is also helpful to know how long the anisocoria has been present, as a more acute onset is more likely to warrant evaluation. If the patient cannot delineate a time frame, inspection of old photographs may be helpful.

A tonic pupil can be diagnosed upon examination with the biomicroscope.8 With the slit beam opened wide and directed from a 60° angle, the details of the iris can be easily observed. When a tonic pupil is present, as the light source is turned on and off, sectors of the iris will be found paralyzed and not constricting to light. These fibers can be observed being dragged by neighboring functional segments.8 This phenomenon, referred to as “stromal streaming,” is due to sectoral palsy of the sphincter muscle.1,2,4,6-9

Thompson observed 122 patients with tonic pupil, noting that every pupil exhibited this sectoral paralysis.8 He also observed a tendency for sphincter function to decrease over time. The near reaction in tonic pupils is often segmental as well. Segments which are reactive during accommodation may not be the same segments that react to light.8 The pupillary constriction that accompanies accommodation is slow and after the near effort is relaxed, redilation may take minutes to hours.2

Pharmacological testing aids tonic pupil diagnosis. In 80-90% of patients with tonic pupil, dilute pilocarpine (0.125%) will induce pupillary constriction after 30-45 minutes while normal pupils will not respond.1,2,5-7 To accurately test for hypersensitivity, the corneal epithelium must be intact. Any compromise to integrity may produce a false positive result. Alternatively, profuse tearing or blinking may dilute the already weak pilocarpine, resulting in false negative findings.1-3 Observations of pupil diameter should be made while fixation is directed at distance to eliminate any contribution of the near synkinetic response.1,2

If denervation hypersensitivity is present, one of two things will be observed: The involved pupil will constrict more than 0.5mm relative to the fellow eye, or the suspicious pupil, larger in size prior to the instillation of the drop, will become the smaller pupil following instillation.1,2 If the pupil fails to constrict to 0.125% pilocarpine, the next step is to instill a 1% pilocarpine solution. If the pupil also fails to constrict to 1% pilocarpine, the dilation is likely due to pharmacological mydriasis, traumatic iridoplegia, sphincter ischemia or iatrogenic damage from prior intraocular surgery.1,2,4-6,10

No definitive treatment for the tonic pupil exists. Patients primarily seek relief from glare associated with mydriasis and cosmetic improvement related to anisocoria. In these cases, an opaque cosmetic contact lens may provide the solution. Visual complaints associated with ciliary body dysfunction occasionally respond to low concentrations of cholinergic drugs. In some cases, accommodative lag can be helped by a near addition.

Clinical Pearls

Light-near dissociation, irregular pupil shape and miosis with dilute concentrations of pilocarpine are characteristic of tonic pupils.

The light-near dissociation response may be difficult to observe. It is best to examine the suspect pupil biomicroscopically. In this manner, it is easier to see the stromal streaming and poor light response. While at the biomicroscope, direct the patient to look at an accommodative target with the fellow eye. You should see a brisk near response compared to a minimal light response.

Most cases of isolated internal ophthalmoplegia (tonic pupil) are found to be idiopathic and referred to as Adie’s tonic pupil, though it may be more appropriate to simply call them ‘tonic pupils.’

An idiopathic tonic pupil in concert with loss of deep tendon reflexes is termed Adie’s syndrome.

In the absence of other signs and symptoms, a tonic pupil is a benign finding. However, until other etiologies have been ruled out, it is inappropriate to refer to the tonic pupil as Adie’s tonic pupil. This is actually a diagnosis of exclusion.

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16. Kalapesi FB, Krishnan AV, Kiernan MC. Segmental facial anhidrosis and tonic pupils with preserved deep tendon reflexes: a novel autonomic neuropathy. J Neuroophthalmol. 2005;25(1):5-8.

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18. Sobreira I, Sousa C, Raposo A, et al. Ophthalmoplegic migraine with persistent dilated pupil. J Child Neurol. 2013;28(2):275-6.

19. Tafakhori A, Aghamollaii V, Modabbernia A, Pourmahmoodian H. Adie’s pupil during migraine attack: case report and review of literature. Acta Neurol Belg. 2011;111(1):66-8.

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21. Barriga FJ, López de Silanes C, Gili P, Pareja JA. Ciliary ganglioplegic migraine: migraine-related prolonged mydriasis. Cephalalgia. 2011;31(3):291-5.

22. Iannetti P, Spalice A, Iannetti L, et al. Residual and persistent Adie’s pupil after pediatric ophthalmoplegic migraine. Pediatr Neurol. 2009;41(3):204-6.

23. Drouet A, De Carvalho A, Mage F, et al. Adie’s tonic pupil and migraine: a chance association? J Fr Ophtalmol. 2008;31(2):e5.

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25. Nagane Y, Utsugisawa K. Ross syndrome associated with cytomegalovirus infection. Muscle Nerve. 2008;38(1):924-6.

26. Cerny R, Rozsypal H, Kozner P, Machala L. Bilateral Holmes-Adie syndrome as an early manifestation of the HIV neuropathy. Neurol Sci. 2010;(5):661-3.

27. Camoriano GD, Kassab J, Suchak A, Gimbel HV. Neurosyphilis masquerading as an acute adie’s tonic pupil: report of a case. Case Report Ophthalmol. 2011;2(2):205-10.

28. Han SW, Ryu JH, Baik JS, et al. Early dorsal midbrain syndrome mimicking an Adie’s tonic pupil. J Clin Neurol. 2010;6(1):38-40.

29. Prasad S, Baccon J, Galetta SL. Mydriatic pupil in giant cell arteritis. J Neurol Sci. 2009;15;284(1-2):196-7.

30. Koczman JJ, Rouleau J, Gaunt M, et al. Neuro-ophthalmic sarcoidosis: the University of Iowa experience. Semin Ophthalmol. 2008;23(3):157-68.

31. Lamirel C, Badelon I, Gout O, et al. Neuro-ophthalmologic initial presentation of sarcoidosis. J Fr Ophtalmol. 2006;29(3):241-9.