In this issue of Journal of Neuro-Ophthalmology, Kalapesi et al (1) describe a young woman with Harlequin syndrome and bilateral tonic pupils. Harlequin syndrome is caused by sympathetic denervation of the face without sympathetic denervation of the eye. The combination of Harlequin syndrome and tonic pupils overlaps with Ross syndrome, which combines segmental anhidrosis, tonic pupils, and areflexia (2). Case reports of Ross syndrome have included patients with hemifacial anhidrosis (3). What other causes of autonomic dysfunction should be considered in the differential diagnosis of autonomic disturbances of the eye or face?
IMMUNE-MEDIATED AUTONOMIC NEUROPATHIES
Guillain-Barré syndrome may be associated with bilateral tonic pupils and may involve both parasympathetic and sympathetic post-ganglionic neurons (4). Patients with Miller Fisher syndrome (MFS) may also have bilateral tonic pupils (5,6); nearly half of patients with MFS demonstrate sluggish pupils and mydriasis (7). Rarely, acute mydriasis is the sentinel sign of MFS (8). Pupillary dysfunction and decreased tear production each occur in approximately 70% of patients with Lambert-Eaton myasthenic syndrome (9). The pupillary findings include abnormal light reflexes and denervation hypersensitivity affecting both the iris sphincter and dilator. In one case report, a patient with Lambert-Eaton myasthenic syndrome presented with photophobia and was found to have dilated tonic pupils and cholinergic hypersensitivity (10). Similarly, acute pandysautonomia may cause tonic pupils and abnormalities of lacrimation (11,12). Patients with paraneoplastic autonomic neuropathy have demonstrated tonic pupils in association with anhidrosis (13,14).
SYSTEMIC AUTOIMMUNE DISORDERS
Patients with Sjögren syndrome may have unilateral or bilateral tonic pupils, often associated with anhidrosis and sensory ataxia (15,16). Adie syndrome also has been reported as the initial sign of Sjö gren syndrome (17,18). Systemic lupus erythematosus rarely may cause tonic pupils as part of a generalized autonomic neuropathy (19,20). Both systemic lupus erythematosus and progressive systemic sclerosis are associated with pupillometric abnormalities in approximately 25% of patients (21). Pupillometry also shows abnormalities in 20% of patients with inflammatory bowel disease (22). Acquired myasthenia gravis is not associated with clinical pupillary dysfunction, but mild slowing of the light reflex is reported with a congenital form of myasthenia caused by endplate acetylcholinesterase deficiency (23).
The prototypical infection causing pupillary abnormalities is syphilis. Although Argyll Robertson pupils are the ophthalmological hallmark of syphilis, tonic pupils also may occur (24). Thompson (5) reported positive syphilitic serology in seven of 46 patients with bilateral tonic pupils. Argyll Robertson pupils have also been reported in a patient with Lyme disease (25). Human immunodeficiency virus infection leads to a variety of pupillary abnormalities, including miosis and mydriasis, in up to 66% of patients (26). Botulism causes acute neuromuscular paralysis as well as xerophthalmia and mydriasis. The rare development of tonic pupils after botulism suggests that the site of action of the toxin may be the ciliary ganglion or the cholinergic terminals of the iris (27-29). In cases of leprosy, autonomic defects have included abnormal pupillary reactivity and chronic iridocyclitis, leading to smooth muscle destruction and miosis (30,31). Finally, rabies may be associated with transient or asymmetric mydriasis and poorly reactive pupils (32).
HEREDITARY NEUROPATHIC DISORDERS AND NEURODEGENERATIVE DISORDERS
These chronic disorders may present with lacrimal or pupillary dysfunction, usually in association with other evidence of dysautonomia. The familial and acquired forms of amyloidosis may cause parasympathetic dysfunction, including bilateral tonic pupils, or sympathetic dysfunction, including miosis and dilatation lag in darkness (33,34). Pathological studies have shown amyloid deposition in the sympathetic chain and ganglia (33) and in the ciliary ganglion (35,36). "Scalloped pupils" may occur in familial amyloidosis (37) and are likely caused by amyloid deposits in the iris. Patients with Charcot-Marie Tooth disease, including either the predominantly demyelinating (CMT 1B) or axonal (CMT 2J) forms, may exhibit tonic pupils (38-40). Argyll Robertson pupils also have been reported in patients with CMT type 3 (41). More than 25% of patients with Dejerine-Sottas disease, an infantile form of hereditary demyelinating neuropathy, demonstrate pupillary abnormalities, including Argyll Robertson pupils and progressive asymmetric miosis (42). Riley Day syndrome (familial dysautonomia) may be associated with decreased tear formation and corneal hypesthesia and ulceration (43). Defective lacrimation also may occur in congenital insensitivity to pain with anhidrosis (44). Finally, pupil abnormalities may be encountered in inherited or sporadic neurodegenerative conditions. Rarely, patients with spinocerebellar ataxia type 1 present with large light-near dissociated pupils (45). Neurodegenerative disorders involving the autonomic nervous system, such as multiple system atrophy, may produce both parasympathetic and sympathetic pupillary dysfunction (46).
NUTRITIONAL DEFICIENCY AND TOXIC AGENTS
Nutritional deficiency and exposure to toxins are rare causes of pupillary dysfunction. Thiamine deficiency may be associated with an Argyll Robertson pupil in the context of Wernicke encephalopathy (47,48). Trichloroethylene, used in rubber production and dry cleaning, may lead to loss of pupillary reflexes in addition to a trigeminal neuropathy (49). Organophosphate exposure may produce miotic pupils and hyperlacrimation (50). Hemosiderin may be considered an endogenous toxin because superficial siderosis causes hearing loss and cerebellar and pyramidal dysfunction. Pelak et al (51) reported a patient with superficial siderosis who had a unilaterally impaired light reflex and a better near response without other evidence of a tonic pupil. They attributed the findings to selective involvement of the superficially located pupillary fibers in the third nerve.
Diabetes is frequently associated with autonomic pupillary dysfunction. In a recent study (52), 78% of patients with type II diabetes (mean duration of 18 years) showed pupillometric abnormalities and 58% had both sympathetic and parasympathetic dysfunction. When compared as a group to age-matched controls, both type I and type II diabetic patients show slower and less extensive pupillary dilatation in darkness, slower and less extensive constriction to light, and a greater response to dilute pilocarpine eyedrops (53,54,56,57). Loewenfeld (58) described "sticky" (sluggish) pupils in approximately 30% of diabetic patients, all 40 years old or older. In type I diabetes, the prevalence of abnormal pupillary responses increases with the duration of diabetes and correlates with the development of other diabetic complications (54,55,59). Diabetes also may rarely cause bilateral tonic pupils (5), Argyll Robertson pupils (47,48), or Horner syndrome (34,60).
Given the many generalized disorders that give rise to autonomic denervation of the eye, it is surprising how seldom this association is encountered in neuro-ophthalmological practice. In a series of 450 patients with Horner syndrome (60), not one case was reported to be associated with a systemic "neuropathic" process. Similarly, of 150 patients with tonic pupils reported by Thompson (5), only 21 (14%) cases were systemically neuropathic. By far the most common cause of Horner syndrome and tonic pupils is a localized disease process, often idiopathic. However, bilateral pupillary abnormalities often implicate an underlying systemic neuropathic condition. Among Thompson's patients (5), 47% with bilateral tonic pupils had systemic neuropathic disorders (5). In addition to syphilis, common causes included diabetes, alcoholism, and hypertrophic neuropathies. Bilateral Horner syndrome is usually difficult to recognize clinically. Using pupillometry, Smith and Smith (34) identified 20 patients with bilateral Horner syndrome, based mainly on the presence of pupillary dilatation lag. Eighteen of the patients had widespread autonomic dysfunction, most commonly caused by diabetes, amyloidosis, inherited neuropathies, and pure autonomic failure, previously called progressive autonomic failure or Bradbury-Egglestone syndrome. Therefore, generalized disorders of autonomic function should be considered when pupillary dysfunction is bilateral.
Although we have described a large number of autonomic disorders affecting the pupil, the ability to define the pathophysiology of many of these disorders remains elusive. The patient described by Kalapesi et al (1) demonstrates the difficulty of determining pathophysiology, or even cause, in many of these patients. Further description of such cases may assist in the development of greater understanding of these heterogeneous disorders.
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