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Adie syndrome, also referred to as "Holmes–Adie syndrome," is a rare neurological disorder characterized by tonic pupillary dilation with light–near dissociation and diminished or absent deep tendon reflexes. The condition most frequently affects young to middle-aged adults and has a female predominance. Although the precise etiology remains uncertain, Adie syndrome is thought to result from postganglionic parasympathetic denervation of the ciliary ganglion, often presumed to be immune-mediated or postinfectious. Risk factors are poorly defined, although antecedent viral illness or autoimmune conditions have been reported. The pathophysiology reflects postganglionic parasympathetic fiber injury to the iris sphincter, causing loss of the pupillary light reflex and aberrant reinnervation responsible for the tonic near response. Clinical presentation typically includes anisocoria, photophobia, blurred vision, and hyporeflexia, with symptoms often unilateral at onset. Diagnosis is primarily clinical and may be supported by dilute pilocarpine testing demonstrating cholinergic supersensitivity. Management is largely symptomatic, focusing on visual correction and photophobia relief. Complications are uncommon, and the prognosis is generally benign, with stable or slowly progressive findings over time. This activity focuses on evaluating and managing Adie syndrome, including understanding its etiology, risk factors, pathophysiology, clinical presentation, and evidence-based diagnostic and therapeutic practices. This activity also emphasizes effective collaboration among interprofessional healthcare teams caring for patients with this neurological condition. Objectives: Identify the characteristic clinical features of Adie syndrome, including tonic pupillary dilation, light–near dissociation, and absent or reduced deep tendon reflexes. Apply evidence-based strategies for symptomatic management, including pharmacologic testing, visual correction, and symptom mitigation when indicated. Select interventions for autonomic complications, such as diaphoresis, based on patient response and risk factors. Collaborate with the interprofessional healthcare team to treat and monitor patients with Adie syndrome, ensuring follow-up for progressive findings and ongoing patient support. Access free multiple choice questions on this topic.

Adie syndrome, also known as Holmes–Adie syndrome, is named after William John Adie, a British neurologist of Australian descent, and Sir Gordon Morgan Holmes, an Irish neurologist. Both independently reported the condition in 1931, with Adie naming it Pseudo-Argyll Robertson pupil.[1] Earlier, in 1881, Hughlings Jackson described mydriasis with pupillary paralysis. In 1906, Markus first characterized the tonic pupil. In 1914, Oloff demonstrated that tonic pupils could result from causes other than syphilis. Adie syndrome is a relatively common neurological disorder of uncertain etiology, characterized by unilateral or bilateral tonic pupillary dilation with light–near dissociation and tendon areflexia. Symptoms arise from autonomic disturbances that affect vasomotor and sudomotor functions. The disorder demonstrates a female predominance and is associated with absent or reduced deep tendon reflexes (DTRs). Progressive miosis, bilateral involvement (approximately 4% per year), and continued loss of DTRs are frequently observed.[2] When associated with hypohidrosis, the condition defines the variant known as Ross syndrome.[3][4]

Adie syndrome often has no identifiable cause. In rare cases, the condition may result from local disorders affecting the ciliary ganglion, including infections such as syphilis, varicella, human parvovirus B19, HIV, and Lyme disease.[5][6][7] Ischemic processes related to lymphomatoid granulomatosis, migraine, or giant cell arteritis have also been reported.[8][9] Autoimmune disorders associated with Adie syndrome include Sjögren syndrome, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, amyloidosis, Guillain-Barré syndrome, and Vogt-Koyanagi-Harada disease.[10][11][12] Cardiovascular disorders, exposure to local or general anesthesia, orbital or choroidal tumors, and orbital surgery for orbital floor fractures have been implicated as well.[13][14][15][16] Neuromuscular conditions, such as Lambert-Eaton myasthenic syndrome, and paraneoplastic syndromes associated with anti-Hu antibodies have also been documented.[17][18][19] Retinal photocoagulation may damage ciliary nerves within the suprachoroidal space, resulting in tonic pupil formation.[20][21] An association with familial dysautonomia has been described.[22] Two cases of Adie syndrome associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have recently been reported.[23][24] Proposed mechanisms include direct viral invasion of the ciliary nerves or ganglion due to neurotropism or a delayed immune-mediated response.[25]

The incidence of Adie syndrome is approximately 4.7 per 100,000 people per year, with a prevalence of approximately 2 per 1000 individuals. Young adults, typically aged between 25 and 45 (mean age 32), are the most commonly affected population. A female predominance is observed, with a ratio of 2.6:1. Most cases are sporadic, while familial associations are rare.[26] The disorder is unilateral in approximately 80% of cases.

The pathophysiology of Adie syndrome involves damage to the ciliary ganglion, most often caused by an inflammatory process. Pupillary symptoms result from injury to the postganglionic parasympathetic fibers supplying the ciliary body and iris. These fibers originate as preganglionic fibers that travel along the oculomotor nerve to synapse at the ciliary ganglion within the orbit. Damage to the dorsal root ganglia of the spinal cord may also occur, resulting in impaired autonomic control throughout the body. Parasympathetic axons for ciliary body accommodation are approximately 30 times more numerous than those for pupillary function. Following injury, fibers previously dedicated to ciliary body function are more likely to divert to the pupil, leading to aberrant regeneration. This process impairs the normal pupillary light response and produces light–near dissociation.[27] Activation of the near response elicits a tonic pupillary reaction, characterized by an abnormal and prolonged constriction resembling accommodation. Reinnervation and postsynaptic receptor upregulation after ciliary ganglion damage lead to denervation hypersensitivity, manifesting as exaggerated responses to cholinergic stimulation. Patients with Adie syndrome show reduced neuronal counts in the thoracic and lumbar dorsal root ganglia and medial spinal cord, along with impaired axonal myelination. The condition may also present with a chronic cough due to involvement of afferent or efferent vagal pathways.[28]

Postmortem studies of patients with Adie syndrome demonstrate degeneration of the ciliary ganglion on the affected side, accompanied by partial atrophy of the sphincter pupillae muscle. Minimal neuronal degeneration has also been observed in the superior cervical ganglion, sacral dorsal root ganglion, and sciatic nerve.[29] No underlying cause for these abnormalities has been identified in the studied cases.

Adie syndrome typically presents with at least one mydriatic pupil exhibiting poor or absent pupillary light reaction, a tonic pupillary near response with light–near dissociation, and decreased or absent DTRs. The disorder is additionally associated with sudomotor abnormalities in Ross syndrome. The Achilles tendon reflex is most commonly affected. Patients may report difficulty reading and photophobia. Additional findings may include increased manifest hyperopia, anisometropia, segmental sphincter palsy, cholinergic supersensitivity of denervated muscles, and cardiovascular abnormalities such as orthostatic hypotension.[30] Adie syndrome may also be associated with chronic coughing.[31] Signs and symptoms of comorbid conditions, such as infections, autoimmune disorders, or malignancy, may also be observed.

Examination The hallmark of the Adie pupil is a strong, tonic response to near stimulation with slow and sustained relaxation, resulting from aberrant regeneration of the iris sphincter and hypersensitivity to muscarinic receptor agonists (eg, pilocarpine). Over time, the tonic pupil, typically larger than the uninvolved fellow eye, may decrease in size, a condition referred to as the “little old Adie” pupil. The little old Adie pupil is characterized by poor light reaction and preserved tonic near response. Approximately 20% of patients with Adie pupils demonstrate bilateral involvement, with an annual incidence of 4%. Anisocoria greater than 1 mm and the presence of sectoral palsy on slit-lamp examination aid in differentiating Adie syndrome from mydriasis caused by generalized neuropathy.[32] Pharmacologic Testing Adie syndrome is primarily a clinical diagnosis. Low-concentration pilocarpine (0.125%–0.1%) may be used to demonstrate cholinergic denervation supersensitivity, which is present in approximately 80% of tonic pupils.[33] Following administration, the affected pupil exhibits a greater miotic response than the normal fellow eye; thus, these low concentrations are typically ineffective in normal pupils. However, some pupils with third nerve palsy also respond to 0.1% pilocarpine. Therefore, pharmacologic testing alone is insufficient for definitive diagnosis of an Adie pupil.[34] Sweat Testing Additional assessments that can help rule out Ross or Harlequin syndrome include the starch–iodine and spoon tests. Both evaluations aid in detecting anhidrosis.[35][36] Etiologic Evaluation Conditions that may mimic or contribute to Adie syndrome, including systemic dysautonomia, syphilis, diabetes, chronic alcoholism, encephalitis, multiple sclerosis, peripheral neuropathies (eg, Charcot–Marie–Tooth disease), rare midbrain tumors, herpes zoster, and neurosarcoidosis, should be considered and excluded. Specific workup should be tailored based on the patient's other clinical manifestations. Computed tomography and magnetic resonance imaging may aid in the evaluation of focal hypoactive reflexes.

Most patients with idiopathic Adie syndrome do not require treatment. Management of underlying systemic causes should focus on addressing any underlying systemic causes and associated autonomic neuropathies. Accommodative paresis may be corrected with reading glasses. Topical low-dose pilocarpine or physostigmine drops may be administered for both diagnostic and therapeutic purposes. Thoracic sympathectomy is the preferred intervention for diaphoresis in patients who fail to respond to conservative pharmacologic management.[37]

The differential diagnoses of Adie syndrome include other causes of light–near dissociation, such as Argyll Robertson pupil, which occurs in late-stage syphilis and is associated with miosis.[38] Other etiologies of mydriasis should be excluded, including pharmacologic dilation, which lacks light–near dissociation; oculomotor nerve palsy, which may be accompanied by ophthalmoplegia and ptosis; and optic nerve diseases, which present with a relative afferent pupillary defect and diminished vision.[39] Systemic autonomic neuropathies, such as Ross and Harlequin syndromes, may also affect the ciliary ganglion and produce a tonic pupil.[40] Ross syndrome is characterized by the triad of tonic pupil, hyporeflexia, and segmental anhidrosis.[41][42] Harlequin syndrome is a rare sympathetic disorder characterized by unilateral decreased or absent flushing and sweating, with exaggerated responses on the contralateral normal side, particularly in the face, neck, arm, and chest, in response to heat, exercise, or emotional stimuli.[43][44] Some patients (13% in a series) also exhibit a tonic pupil, although Horner syndrome is more common and may coexist with a tonic pupil.[45] A "little old Adie" pupil with miosis should be distinguished from other causes of constricted pupils. Horner syndrome, for example, presents with a miotic pupil, usually accompanied by ptosis and apparent enophthalmos.[46] Miosis may also appear as an early sign of temporal lobe herniation following head injury due to oculomotor nerve irritation (Hutchison stage I), although this finding is typically followed by pupillary dilatation.[47]

Adie syndrome usually follows a nonprogressive course. The condition is not life-threatening and does not cause disability or affect mortality. Loss of DTRs is permanent and may progress gradually. Most patients require only reassurance after the diagnosis is confirmed. Rare associations of an Adie pupil with angle-closure glaucoma have been reported in individuals.[48] Accommodative paresis typically improves spontaneously over time. The pupillary light reaction weakens progressively, accompanied by increasing light–near dissociation. The pupil may gradually decrease in size, resulting in the "little old Adie" pupil.

Adie syndrome may rarely result in angle-closure glaucoma, leading to episodes of blurred vision and ocular pain.[49] Management involves medical therapy to lower intraocular pressure and laser iridotomy to prevent pupillary block. Adie syndrome has also been reported to cause amblyopia in children, resulting from the conversion of latent hypermetropia to manifest hypermetropia secondary to accommodative paresis.[50] Correction of the refractive error, combined with occlusion therapy, has been shown to be effective in managing this complication.

Patients should be reassured regarding the typically benign nature of Adie syndrome. Individuals at risk for angle-closure glaucoma should be informed of its potential development and educated about associated symptoms and precipitating factors. Parents of children with Adie syndrome should be counseled on the importance of ongoing follow-up to monitor for refractive errors and anisometropia, which can lead to amblyopia if not appropriately managed.

Care coordination by an interprofessional healthcare team, including neurologists and ophthalmologists, facilitates earlier detection and optimizes patient care. Early involvement of infectious disease and rheumatology specialists in patients presenting with tonic pupils can reduce time to diagnosis and help exclude alternative causes. In cases with cardiovascular involvement, select patients may necessitate consultation with a cardiology team. Pediatric care is particularly important for preventing or managing amblyopia. Most evidence guiding the management of Adie syndrome is derived from case series and expert opinion.