Adie syndrome is also called the Holmes-Adie Syndrome (HAS). It is named after William John Adie, the British neurologist of Australian descent, and Sir Gordon Morgan Holmes, an Irish neurologist. They reported it in 1931. Earlier in 1881, Hughlings Jackson had described mydriasis with pupillary paralysis. In 1914, Oloff had shown that tonic pupils could be caused by factors other than syphilis.
Adie syndrome is a rare neurological disorder of unknown etiology comprising unilateral or bilateral tonically dilated pupils with near light 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, to bilaterality (4% each year) and progressive loss of deep tendon reflexes.
Adie syndrome is mostly idiopathic and may rarely be caused by local disorders within the orbit affecting the ciliary ganglion including infection (syphilis, varicella, human parvovirus (B19) infection, Lyme disease), ischemia (lymphomatoid granulomatosis, migraine, giant cell arteritis), autoimmune disorders (Sjogren syndrome, polyarteritis nodosa, sarcoidosis, amyloidosis, Guillain-Barre syndrome, Vogt-Koyanagi-Harada disease), cardiovascular disorders (carotid dissection), local or general anesthesia, orbital or choroidal tumor, orbital surgery or laser therapy, orbital floor fracture, paraneoplastic (Lambert-Eaton myasthenic syndrome, congenital neuroblastoma with Hirschsprung disease and central hypoventilation syndrome, anti-Hu antibodies).
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. It is unilateral in 80% of the cases. The exact incidence and prevalence rates have not been reported.
Pupillary symptoms of Holmes-Adie syndrome result from infections causing inflammation and damage to the parasympathetic neurons in the ciliary body and iris which travel along with the oculomotor nerve to synapse at the ciliary ganglion. As a result of damage to the dorsal root ganglion of the spinal cord, many patients experience the problems with autonomic control of the body. Reinnervation and upregulation of the postsynaptic receptors after damage to the ciliary ganglion results in a condition called denervation supersensitivity. The number of axons devoted to the ciliary body is much larger as compared to the ones for the pupil. Most often due to aberrant reinnervation after an injury or insult, the fibers which were previously devoted to the ciliary body get diverted to the pupil (aberrant regeneration). A tonic reaction with light-near dissociation of the pupils is caused by activation of the near response after aberrant regeneration. The quantity (the number of nerve cells) and the quality (reduced myelin sheath in the gray and white matter) of neurons in the thoracic and lumbar ganglia of the posterior root and the medial region of the spinal cord decreases in patients with 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 (Ross variant). The Achilles tendon reflex is most commonly affected. Other signs may include difficulty reading due to hyperopia (accommodative paresis), segmental palsy of the sphincter, photophobia, cholinergic supersensitivity of the denervated muscles, and cardiovascular abnormalities (orthostatic hypotension).
The Adie pupil has a hallmark strong and tonic response of the near reaction with a slow and sustained relaxation due to iris sphincter 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 (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 from mydriasis due to a general neuropathy.
Adie's syndrome is a clinical diagnosis. Low-Dose pilocarpine (one-eighth to one-tenth percent) test may be useful to demonstrate the cholinergic denervation supersensitivity (80% prevalent) in the tonic pupil. After the administration of the dilute pilocarpine, a more miotic response will be seen compared with the fellow eye.
Systemic dysautonomia, syphilis, diabetes, chronic alcoholism, encephalitis, multiple sclerosis, peripheral nerve disease (for example, Charcot-Marie-Tooth), rare midbrain tumors, herpes zoster, and neurosarcoidosis need to be ruled out. CT and MRI 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.
Systemic autonomic neuropathies like Ross and Harlequin syndromes can also affect the ciliary ganglion and produce the tonic pupil. Ross syndrome is characterized by a triad of a tonic pupil, hyporeflexia, and segmental anhidrosis. Harlequin syndrome is a rare disorder of sympathetic nervous system characterized by the unilateral decreased or absence of flushing and sweating, particularly in the face, neck, arm, and chest in response to heat, exercise, or emotional factors. 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.
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. 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").
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.
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