Continuing Education Activity

Adie syndrome, also known as the Holmes-Adie syndrome, is a neurological disorder of unknown etiology comprising unilateral or bilateral tonically dilated pupils with light-near dissociation and tendon areflexia. This activity outlines the evaluation and management of Adie syndrome and highlights the role of the interprofessional team in treating patients with this condition.

Objectives:

• Review the potential etiologies of Adie syndrome that should be ruled out when Adie syndrome is present.
• Describe the pathophysiology of Adie syndrome.
• Outline the evaluation of Adie syndrome.
• Summarize the importance of collaboration and communication amongst interprofessional team members to enhance care coordination for patients with Adie syndrome.

Introduction

Adie syndrome, also called the Holmes-Adie Syndrome, is named after William John Adie, the British neurologist of Australian descent, and Sir Gordon Morgan Holmes, an Irish neurologist. They both reported the condition in 1931, where Adie named it Pseudo-Argyll Robertson pupil.[1] Earlier in 1881, Hughlings Jackson had described mydriasis with pupillary paralysis, while in 1906, Markus first described the tonic pupil. In 1914, Oloff had shown that tonic pupils could be caused by factors other than syphilis.

Adie syndrome is a relatively common neurological disorder of unknown etiology comprising unilateral or bilateral tonically dilated pupils with light-near dissociation and tendon areflexia. The symptoms result from autonomic disturbances, affecting vasomotor and sudomotor functions. It has a female preponderance with absent or reduced deep tendon reflexes. The patient tends to have progressive miosis, bilateral affection (4% each year), and progressive loss of deep tendon reflexes.[2] It can be associated with hypohidrosis, in this case, it is known as Ross syndrome.[3][4]

Etiology

Adie syndrome is mostly idiopathic with no identifiable cause but may rarely be caused by local disorders involving the orbit that affect the ciliary ganglion including infections such as syphilis, varicella, human parvovirus-B19, human immunodeficiency virus, and Lyme disease,[5][6][7] ischemia due to lymphomatoid granulomatosis, migraine, and giant cell arteritis,[8][9] autoimmune disorders such as Sjogren syndrome, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, amyloidosis, Guillain-Barre syndrome, and Vogt-Koyanagi-Harada disease,[10][11][12] cardiovascular disorders,[13] local or general anesthesia,[14] orbital or choroidal tumors,[15] orbital surgery for orbital floor fractures,[16] neuromuscular conditions such as Lambert-Eaton myasthenic syndrome, and paraneoplastic in association with anti-Hu antibodies.[17][18][19] It may also be caused by retinal photocoagulation that results in damage to the ciliary nerves within the suprachoroidal space.[20][21] An association with familial dysautonomia has also been reported.[22]

Recently, 2 cases of Adie syndrome associated with severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) have been reported.[23][24] This is thought to occur due to a direct invasion of the ciliary nerves or ganglion by the virus due to its neurotropism, or due to a delayed immune-mediated mechanism.[23]

Epidemiology

The incidence of Adie syndrome is approximately 4.7/100,000 population/year with a prevalence of two cases/1000 population (approximately). Young adults usually between the ages of 25 to 45 (mean age of 32 years) are most commonly affected. There is a female predominance (2.6:1). Sporadic Adie syndrome is commonly reported with rare reports of familial association.[25] It is unilateral in 80% of the cases. The exact incidence and prevalence rates have not been reported.

Pathophysiology

The pathophysiology of Adie syndrome involves damage to the ciliary ganglion most commonly by an inflammatory process. Pupillary symptoms result from damage to the postganglionic parasympathetic supply innervating the ciliary body and iris which first travel as preganglionic fibers along with the oculomotor nerve to synapse at the ciliary ganglion within the orbit. As a result of damage to the dorsal root ganglion of the spinal cord, many patients also experience problems with autonomic control of the body. The number of parasympathetic axons devoted to the innervation of the ciliary body for accommodation in humans is about 30 times the number devoted to pupillary function.[21] Therefore, following an injury or insult, the fibers which were previously devoted to the ciliary body function have a much higher chance of becoming diverted to the pupil compared to regular regeneration of the pupillary fibers. This usually results in aberrant regeneration with resultant impairment in the normal pupillary light response leading to light-near dissociation.[26] A tonic reaction thus occurs following activation of the near response leading to an abnormal and prolonged tonic pupillary reaction that resembles accommodation. Reinnervation and upregulation of the postsynaptic receptors after damage to the ciliary ganglion also occur and result in a condition known as denervation hypersensitivity with an exaggerated response to cholinergic stimulation. The number of neurons in the thoracic and lumbar ganglia of the posterior root and the medial region of the spinal cord is also found to decrease in patients with Adie syndrome with impaired axonal myelination. The condition may also be associated with chronic coughing due to the involvement of the afferent or efferent pathways of the vagus nerve.[27]

Histopathology

Post-mortem studies of patients with Adie syndrome have shown that the ciliary ganglion on the affected side has degenerated with associated partial atrophy of the sphincter pupillae muscle. There was also minimal neuronal degeneration affecting the superior cervical ganglion, the sacral dorsal root ganglion, and the sciatic nerve.[28] No underlying cause for these abnormalities, however, has been found in the studied cases.

History and Physical

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.[21] 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][29] Adie syndrome may also be associated with chronic coughing.[27][30] Signs and symptoms of associated conditions may be present such as infections, autoimmune diseases, or malignancy.

Evaluation

Examination

The hallmark of the 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.[21]

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.[31][32] 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.[32] 

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.[33][34]

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.

Treatment / Management

Most patients with 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.[35]

Differential Diagnosis

The differential diagnoses of Adie syndrome include other causes of light-near dissociation such as Argyll Robertson pupil that is found in late-stage syphilis and is associated with miosis.[36] 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.[37] Ross syndrome is characterized by a triad of a tonic pupil, hyporeflexia, and segmental anhidrosis.[4][38] 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.[39][40] 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.[41]

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.[42] 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.[43] This, however, is usually followed by pupillary dilatation.

Prognosis

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.[44][45] 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").

Complications

Adie syndrome may rarely result in angle-closure glaucoma that leads to episodes of blurring of vision and ocular pain.[45] 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.[28][46] This has been effectively managed by correction of the refractive error and occlusion therapy.[28]

Deterrence and Patient Education

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.

Enhancing Healthcare Team Outcomes

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]