Holmes-Adie syndrome (HAS) is a neurological disorder affecting the pupil of the eye and the autonomic nervous system. It is characterized by one eye with a pupil that is larger than normal and constricts slowly in bright light (tonic pupil), along with the absence of deep tendon reflexes, usually in the Achilles tendon. HAS is thought to be the result of a neurotrophic (acting on neurons, or nerve cells) viral infection that causes inflammation and damage to neurons in the ciliary ganglion, an area of the brain that controls eye movements, and the dorsal root ganglion, an area of the spinal cord involved in the response of the autonomic nervous system. HAS begins gradually in one eye and often progresses to involve the other eye. At first, it may only cause the loss of deep tendon reflexes on one side of the body but then progress to the other side. The eye and reflex symptoms may not appear at the same time. People with HAS may also sweat excessively, sometimes only on one side of the body.
Injury to the cells of the ciliary ganglion or to the short ciliary nerves may result in denervation of the pupil. The subsequent reinnervation from surviving ganglion cells is such that the majority of regenerating nerve fibers reach the ciliary muscle. This leaves the iris relatively denervated and produces a condition known as the tonic pupil. The condition is usually unilateral. The pupil is large and fails to contract, or shows a very slow, delayed contraction of light and to near vision. In each case, the pupil contracts slowly and then remain small for some time before returning to normal size with an equally slow movement.
The combination of these 3 symptoms – abnormal pupil size, loss of deep tendon reflexes, and excessive sweating – is usually called Ross’s syndrome, although some doctors will still diagnose the condition as a variant of HAS. Some individuals will also have cardiovascular abnormalities. The HAS symptoms can appear on their own, or in association with other diseases of the nervous system, such as Sjogren’s syndrome or a migraine. It is most often seen in young women. It is rarely an inherited condition.
The tonic pupil is exquisitely sensitive to local application of 0.125% fresh solution of pilocarpine with prompt constriction.
A similar application would not affect a normal pupil.
Differential diagnosis of Holmes-Adie or Adie Syndrome
Symptoms of the following disorders can be similar to those of Adie syndrome. Comparisons may be useful for a differential diagnosis
- Ross syndrome
- Argyll Robertson pupil
- paralysis of the third facial nerve (third nerve palsy)
- Guillain-Barre syndrome
- Charcot-Marie-Tooth disease
- Parry-Romberg syndrome
- chronic alcoholism
- multiple sclerosis
- multiple system atrophy.
- Use of transdermal scopolamine
- lesions of the dorsal midbrain
How to Diagnose The Tonic Pupil/Holmes-Adie or Adie Syndrome
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.
Adie’s syndrome is not life-threatening or disabling. As such, there is no mortality rate relating to the condition; however, loss of deep tendon reflexes is permanent and may progress over time.
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.
Signs & Symptoms of The Tonic Pupil/Holmes-Adie or Adie Syndrome
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. The pupil will constrict slowly when focusing (accommodating) on objects close at hand (normally referred to as near response). Eventually, 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.
Adie syndrome presents with three hallmark symptoms, namely at least one abnormally dilated pupil (mydriasis) which does not constrict in response to light,
- loss of deep tendon reflexes,
- And abnormalities of sweating.
- Other signs may include hyperopia due to accommodative paresis,
- difficulty reading.
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.
A 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.
Prognosis of The Tonic Pupil/Holmes-Adie or Adie Syndrome
Holmes-Adie syndrome is not life-threatening or disabling. The loss of deep tendon reflexes is permanent. Some symptoms of the disorder may progress. For most individuals, pilocarpine drops and glasses will improve vision.
What are other names of The Tonic Pupil/Holmes-Adie or Adie Syndrome
- Adie’s Pupil
- Adie’s Syndrome
- Adie’s Tonic Pupil
- Holmes-Adie Syndrome
- Tonic Pupil Syndrome
Causes of The Tonic Pupil/Holmes-Adie or Adie Syndrome
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.
In most instances, the exact cause of Adie syndrome is unknown (idiopathic).
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.
Treatment of The Tonic Pupil/Holmes-Adie or Adie Syndrome
Doctors may prescribe reading glasses to compensate for impaired vision in the affected eye, and pilocarpine drops to be applied 3 times daily to constrict the dilated pupil. Thoracic sympathectomy, which severs the involved sympathetic nerve, is the definitive treatment for excessive sweating.
Research on Adie syndrome is ongoing. Scientists are trying to identify the underlying cause of the disorder so that better treatments may be developed.
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.
The usual treatment of a standardized Adie syndrome is to prescribe reading glasses to correct for impairment of the eyes. Pilocarpine drops may be administered as a treatment as well as a diagnostic measure. Thoracic sympathectomy is the definitive treatment of diaphoresis if the condition is not treatable by drug therapy.