Adie Syndrome

Adie syndrome presents with at least one mydriatic pupil with poor or absent pupillary light reaction, tonic pupillary near response with light-near dissociation, decreased or loss of deep tendon reflexes, and abnormalities of sweating in Ross syndrome.[20] The Achilles tendon reflex is most commonly affected. Patients may complain of difficulty in reading and photophobia. Other signs may include increased manifest hyperopia, anisometropia, segmental palsy of the sphincter, cholinergic supersensitivity of the denervated muscles, and cardiovascular abnormalities such as orthostatic hypotension.[2][26] Adie syndrome may also be associated with chronic coughing.[27][24][27] Signs and symptoms of associated conditions may be present such as infections, autoimmune diseases, or malignancy.

Examination

The hallmark of Adie pupil is a strong and tonic response to near stimulation with a slow and sustained relaxation due to iris sphincter aberrant regeneration and hypersensitivity to muscarinic receptor agonists (e.g., pilocarpine). Over time, the tonic pupil, which is usually larger than the uninvolved fellow eye, tends to become smaller, a condition that is known as the "little old Adie" pupil. The little old Adie pupils can be diagnosed by the poor light reaction and the tonic near response. Approximately 20% of Adie pupils are bilateral with a 4% incidence of bilateral involvement per year. Anisocoria greater than 1 mm and the presence of sector palsy on slit-lamp examination help to differentiate Adie syndrome from mydriasis due to a general neuropathy.[20][20][20]

Pharmacologic Testing

Adie's syndrome is a clinical diagnosis. Low-concentration pilocarpine (one-eighth to one-tenth percent) test may be useful to demonstrate the cholinergic denervation supersensitivity (80% prevalent) in the tonic pupil.[28][29] After the administration of the dilute pilocarpine, a more miotic response will be seen in the affected eye compared with the normal fellow eye since these low concentrations are usually ineffective in normal pupils. Some pupils in third nerve palsy, however, also respond to 0.1% pilocarpine, and therefore, the diagnosis of an Adie pupil should not be based on pharmacologic testing of pupils alone.[29] 

Sweat Testing

Other tests that can be used to exclude Ross or Harlequin syndromes include the starch iodine test and the spoon test which help in the detection of anhidrosis.[30][31]

Etiologic Evaluation

Conditions that could mimic or cause Adie syndrome including systemic dysautonomia, syphilis, diabetes, chronic alcoholism, encephalitis, multiple sclerosis, peripheral nerve disease (for example, Charcot-Marie-Tooth), rare midbrain tumors, herpes zoster, and neurosarcoidosis should be ruled out. However, the specific workup for each patient will depend on the associated manifestations. Computed tomography and magnetic resonance imaging scans may be useful in the diagnostic testing of focal hypoactive reflexes.

Most patients with an idiopathic Adie syndrome do not require any treatment. Patients with an underlying systemic cause should have treatment directed at their other autonomic neuropathies. The treatment for impairment of the eyes (due to accommodative paresis) is to prescribe reading glasses. Topical low-dose pilocarpine or physostigmine drops may be administered as a treatment as well as a diagnostic measure. For those failing conservative management with drug therapy, thoracic sympathectomy is the treatment of choice for diaphoresis.[32]

Differential diagnoses of Adie syndrome include other causes of light-near dissociation including Argyll Robertson pupil that is found in late-stage syphilis and is associated with miosis.[33] Other causes of mydriasis including pharmacological dilation which lacks light-near dissociation, oculomotor nerve palsy which may be associated with ophthalmoplegia and ptosis, and optic nerve diseases which are associated with a relative afferent pupillary defect and diminution of vision should be excluded.

Systemic autonomic neuropathies like Ross and Harlequin syndromes can also affect the ciliary ganglion and produce the tonic pupil.[34] Ross syndrome is characterized by a triad of a tonic pupil, hyporeflexia, and segmental anhidrosis.[4][35] Harlequin syndrome is a rare disorder of the sympathetic nervous system characterized by the unilateral decrease or absence of flushing and sweating with an exaggerated response on the contralateral normal side, particularly in the face, neck, arm, and chest in response to heat, exercise, or emotional factors.[36][37][36] Some patients (13% in one series) also have a tonic pupil, although a Horner syndrome is more common and may coexist with a tonic pupil.[38]

Little old Adie with a miotic pupil should be differentiated from other causes of miosis. Horner syndrome is another cause of a miotic pupil, however, ptosis and apparent enophthalmos are usually present.[39] Miosis may also be present as an early sign in temporal lobe herniation following head injury due to oculomotor nerve irritation, which is known as Hutchison's stage I.[40] This, however, is usually followed by pupillary dilatation.

Adie syndrome does not have a progressive course. It is not a life-threatening condition and does not cause disabilities. It is not associated with any mortality rate. The loss of deep tendon reflexes is permanent and may progress over time. Most patients require reassurance after confirmation of the diagnosis. There have been rare associations of angle-closure glaucoma with Adie pupil.[41][42] The accommodative paresis gets better spontaneously over time. The pupil light reaction becomes weaker over time with an increasing light-near dissociation, and the pupil becomes smaller with time ("little old Adie").

Adie syndrome may rarely result in angle-closure glaucoma that leads to episodes of blurring of vision and ocular pain.[42] Management includes medical treatment to lower the intraocular pressure and laser iridotomy to prevent pupillary block.

Previously, Adie syndrome has also been reported to result in amblyopia in children due to the conversion of latent hypermetropia into manifest hypermetropia as a result of accommodative paresis.[25][43] This has been effectively managed by correction of the refractive error and occlusion therapy.[25]

Patients should be reassured regarding the commonly benign nature of the condition, however, predisposed patients should be informed of the possibility of developing angle-closure glaucoma and educated about its symptoms and precipitating factors.

Parents of children with Adie syndrome should be educated about the importance of the continuous follow-up of their children to detect refractive errors and anisometropia which may lead to amblyopia if not properly treated.

Care coordination by an interprofessional team of neurologists and ophthalmologists is needed for earlier detection and improvement in the care of the patient. The involvement of infectious disease and rheumatology specialists early on in the management of patients with tonic pupils can lead to a significant reduction in the time to diagnosis while ruling out other causes. Cardiovascular involvement in some patients requires the assistance of a cardiology team. Care of the pediatric patient is particularly important to help prevent or treat amblyopia. Most of the evidence regarding the management of Adie syndrome is currently derived from case series and expert opinion (Level 5 evidence).