NORD gratefully acknowledges Helmut Wilhelm, Prof. Dr. med, Centre for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany, for assistance in the preparation of this report.
Adie syndrome, or Holmes-Adie syndrome, is a rare neurological disorder affecting the pupil of the eye. In most patients the pupil is larger than normal (dilated) and slow to react in response to direct light. Absent or poor tendon reflexes are also associated with this disorder. In most individuals, the cause is unknown (idiopathic), but Adie syndrome can occur as due to other conditions such as trauma, surgery, lack of blood flow (ischemia) or infection. In rare cases localized disturbance of sweat secretion is associated with Adie syndrome (Ross syndrome). Adie syndrome involves a usually non progressive and limited damage to the autonomic nervous system, which is the portion of the nervous system that controls or regulates certain involuntary body functions including the reaction of the pupils to stimuli.
The term Adie syndrome is used when both abnormalities of the pupil and loss of deep tendon reflexes are present. However, these findings may not develop at the same time. When only abnormalities affecting the pupil are present, the disorder may be referred to as Adie’s pupil, Adie’s tonic pupil or, most commonly, tonic pupil. When a person’s pupils are of unequal size, the term anisocoria may be used.
Normally the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited.
In most patients with Adie syndrome the affected pupil is larger than normal (dilated) all the time and does not constrict very much or not at all in response to direct light. In many cases it is not ideally round but slightly ovally distorted. The pupil will constrict slowly when focusing (=accommodating) on objects close at hand (normally referred to as near response). If the pupil is observed with a loupe or microscope a typical behavior can be observed both spontaneously or during near response: Some sectors of the sphincter muscles constrict and others don’t. This reminds of the movement of an earthworm. Eventually, after months or years, the pupil, which was initially larger than the unaffected pupil, will become smaller than the unaffected pupil. When no longer focusing on the close at hand object, the affected pupil may remain smaller than normal or grow larger (re-dilate) at an abnormally slow rate, sometimes taking as long as several minutes to return to its original (i.e. dilated) size. Some individuals may not have symptoms associated with the affected pupil. Sometimes blurry vision or sensitivity to bright lights (photophobia) can occur.
Individuals with Adie syndrome have absent or poor (sluggish) deep tendon reflexes as well. Deep tendon reflexes are involuntary muscle contractions that occur to a sudden stimulus. For example, the patellar reflex occurs in the area just below the kneecap (patella). A physician may tap this area with a small rubber hammer, which should cause the lower leg to kick out; in individuals with Adie syndrome this reflex response is poor or does not occur.
Headache, facial pain, or emotional fluctuations may occur in some patients. The disorder does not ordinarily cause severe disability. Adie syndrome usually affects the pupil of one eye, although the other eye may eventually become affected as well.
There have been some reports in the medical literature that individuals with Adie syndrome may experience other abilities of autonomic function such as issues with cardiovascular function.
In most instances, the exact cause of Adie syndrome is unknown (idiopathic). It is believed that most cases result from inflammation or damage to the ciliary ganglion, a cluster of nerve cells found in the eye socket (orbit) just behind the eyes, or damage to the post-ganglionic nerves. The ciliary ganglion is part of the parasympathetic nervous system, which is itself part of the autonomic nervous system. The parasympathetic nervous system relaxes the body and inhibits or slows down high energy functions.
The ciliary ganglion supplies nerves (innervates) to the eye. These nerves carry signals that help to control the pupil’s response to stimuli such as growing smaller or larger in response to light, dark or other stimuli. These nerves communicate with the iris sphincter muscle, the muscle that controls how much light enters the pupil (causing the pupil to either contract or grow larger). However, most of the cells of the ciliary ganglion (97%) serve accommodation and supply the ciliary muscle which adjusts the crystalline lens of the eye to near vision.
In Adie syndrome, both these nerve cells are damaged. Because there are so many nerve cells serving accommodation usually a sufficient amount survive. Therefore, accommodation difficulties are not obvious or less obvious. Eventually, the damaged nerves may regenerate, but some do so improperly (aberrant regeneration). Because the nerve cells serving the pupillary sphincter are very few it is unlikely that many of them regenerate and restore the pupillary light reflex. However, cells that supply the ciliary muscle may regenerate and innervate not only the ciliary muscle but also the pupillary sphincter muscle (aberrant regeneration). This explains why the near response in a tonic pupil is present but slow. It is being elicited by nerve cells that were designed for accommodation, a slower movement than pupillary constriction. In most instances, damage to the ciliary ganglion or the postganglionic nerves is believed to be caused by a viral infection. There is evidence that also autoimmune processes may play a role. Tumor, trauma, and inflammation (especially syphilis) have also been linked to Adie syndrome. The syndrome has also occurred as a complication of surgery to the area of the eye socket. It is also seen in giant cell arteritis, a severe vasculitis of the elderly. There are rare cases where a tonic pupil has occurred as a paraneoplastic disorder, but so far only in patients were the malignant disease already was known.
The loss of deep tendon reflexes is believed to be caused by damage to the dorsal root ganglions, a cluster of nerve cells in the root of spinal nerves.
Adie syndrome affects females more often than males by a ratio by some estimates of 2.6:1 for cases where the cause is unknown. Young adults usually between the ages of 25 to 45 are most commonly affected. The prevalence of Adie’s pupil (not the full syndrome) is approximately 2 people per 1,000 in the general population. The exact incidence or prevalence of Adie syndrome itself is unknown.
A diagnosis of Adie syndrome can be made by a thorough clinical evaluation and a detailed patient history. A complete eye examination by an ophthalmologist is recommended. An eye doctor may use water-downed (diluted) pilocarpine to test the pupil’s reaction. Pilocarpine, given in the form of eye drops, is a drug that causes the pupils to grow smaller (constrict). In individuals with Adie syndrome, the affected pupil, which does not constrict in response to light, will constrict in response to dilute pilocarpine (0.05 – 0.1%) to which a normal pupil would not constrict. If the pupil dilation is caused by contact with scopolamine or atropine, the pupil will not constrict even to higher concentrations (0.5 – 1%) which cause normal pupils to constrict vigorously.
In some patients with tonic pupils constriction is observed when the conjunctiva is touched or irritated e.g. when grating onions.
An eye doctor may also compare the size of the affected eye versus the unaffected eye in darkness and light as well as evaluating the response of the pupil when focusing on an object close at hand.
An eye doctor may use a slit-lamp, a device that allows an eye doctor examine the eyes under high magnification, to detect segmental paralysis and a flattened border of the pupil so that the pupil appears irregularly-shaped. In some instances, worm-like (vermiform) movements of the iris can be seen under slit-lamp examination. In most cases the pupil seems slightly ‘ovally’ distorted.
In most instances, treatment will not be necessary. Glasses may be prescribed to correct blurred vision; sunglasses can help individuals with sensitivity to light. Therapy using dilute pilocarpine may improve poor depth perception and relieve glare in some patients. The loss of deep tendon reflexes is permanent.
Research on Adie syndrome is ongoing. Scientists are trying to identify the underlying cause of the disorder so that better treatments may be developed.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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