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Show STATE OF THE ART Pupil Abnormalities in Selected Autonomic Neuropathies Fion D. Bremner, PhD and Stephen E. Smith, PhD Abstract: Examination of the pupil provides an opportunity to detect disturbances in the autonomic innervation of the eye. The pupil is frequently affected in patients with generalized autonomic neuropathies. This literature review confirms a high prevalence of sympathetic deficits and parasympathetic deficits in acute or subacute dysautonomia, diabetes, amyloidosis, pure autonomic failure, paraneoplastic syndromes, Sjogren syndrome, familial dysautonomia, and dopamine ^- hydroxylase deficiency. It confirms the relative scarcity of a pupil abnormality in patients with multiple system atrophy. There are difficulties in clinical diagnosis of pupil abnormalities and interpretation of pupil pharmacologic tests, particularly when combined sympathetic and parasympathetic deficits are present. (/ Neuro- Ophthalmol 2006; 26: 209- 219) Autonomic neuropathy is characterized by cardiovascular, gastrointestinal, genitourinary, and sweat gland dysfunction. In most cases, sympathetic and parasympathetic branches of the autonomic nervous system are involved, although in a few instances, there is selective hypofunction in one or another branch. Pupil abnormalities have been widely reported in association with generalized autonomic failure but, except in diabetes, rarely investigated in detail. In this review, we have used electronic ( Medline, PubMed) and manual techniques to search the literature for published reports of pupil abnormalities in selected autonomic neuropathies. Most reports are anecdotal- based on clinical observations and only sometimes supported by confirmatory tests. With the exception of diabetes mellitus, there are no systematic studies of pupil involvement in these Department of Neuro- ophthalmology, National Hospital for Neurology and Neurosurgery, London, United Kingdom. Address correspondence to Stephen E. Smith, PhD, Department of Neuro- ophthalmology ( Box 142), National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom; E- mail: sesmith@ doctors. org. uk conditions. The findings have been grouped according to etiology, and we have assessed the evidence for the pupil signs before attempting to draw sweeping conclusions. Because the pupil constrictor muscle is supplied by parasympathetic fibers and the dilator by sympathetic fibers, complete failure of iris innervation should result in a pupil of medium diameter that is unresponsive to light, near, and alarm stimuli, although persistence of adrenal medullary function might allow slow dilator responses to stress from circulating catecholamines. Very few such instances of " pupilloplegia" are reported except in cases of acute or subacute pandysautonomia. Selective parasympathetic denervation should result in relative mydriasis in light and diminution in constrictor reflexes with or without pupillotonia ( which is thought to result from aberrant reinnervation [ 1]). Selective sympathetic denervation should result in relative miosis in darkness with dilatation lag ( 2) and diminution of the startle reflex as seen in Horner syndrome ( 3,4). In all such instances, the pupil would be expected to show supersensitivity to topical administration of receptor agonists ( 2% or 2.5% methacholine and 0.1% or 0.125% pilocarpine at the sphincter muscle, 1% phenylephrine or 1% epinephrine at the dilator muscle). ACUTE AND SUBACUTE DYSAUTONOMIA This acute or subacute condition is characterized by widespread dysfunction of one, or more usually both, branches of the autonomic nervous system coupled occasionally with somatic sensory or sensorimotor impairment. In some cases, it follows an episode of influenza- like illness and recovery is variable. Acute and subacute dysautonomia commonly involve the pupil. Published cases ( Table 1) can be divided into several forms: a predominantly cholinergic type affecting the parasympathetic nervous system ( 5- 19), an adrenergic type affecting the sympathetic nervous system ( 20,21), a mixed type ( 22- 51,202), and forms with additional involvement of sensory ( 52- 63) or sensorimotor peripheral nerves ( 64). Despite differences in clinical presentations, the pupil findings in cases within the different groups are essentially J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 209 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Bremner and Smith TABLE 1. Pupil abnormalities in Demographics Number of cases Male/ Female ( where stated) Median age Age range Pupil Shape Irregular/ Oval Normal Not stated Pupil Diameter Larger than normal Smaller than normal Notable anisocoria Normal Not stated Pupillary Light Reflex Absent Reduced Redilatation lag Normal Not stated Pupillary Near Reflex Absent Reduced Normal Not stated Pupillary Cholinergic Supersensitivity Present Absent Not stated Pupillary Adrenergic Supersensitivity Present Absent Uncertain Not stated Pupil Response to Cocaine Absent Reduced Normal Not stated Pupil Diagnoses Horner ( Unilateral) various forms Cholinergic ( 5- 19) 14 7/ 7 24 6^ 19 0 1 13 11 0 1 1 1 10 2 0 0 2 8 1 0 5 6 0 8 0 2 0 12 1 1 1 11 0 of acute and subacute dysautonomia Predominant pattern of peripheral nerve involvement Adrenergic ( 20- 21) 2 2/ 0 32 19- 46 0 0 2 0 1 0 0 1 0 0 0 0 2 0 0 0 2 0 0 2 0 0 0 2 0 0 0 2 1 Mixed ( 12,18,22- 51,202) 45 20/ 24 29 3- 74 8 6 31 12 3 5 9 16 19 13 2 2 9 14 3 5 23 19 2 24 10 2 1 32 5 0 1 39 0 Sensory and autonomic ( 18,52- 63) 14 5/ 9 27 4- 65 3 1 10 3 0 2 3 6 8 4 0 1 1 5 1 1 7 2 1 11 3 0 0 11 2 1 0 11 0 Sensorimotor and autonomic ( 64) 1 0/ 1 26 26 0 0 1 0 0 0 0 1 0 1 0 0 0 0 0 0 1 0 0 1 0 0 0 1 0 0 0 1 0 All cases 76 34/ 41 28 3- 74 11 8 57 26 4 8 13 25 37 20 2 3 14 27 5 6 38 27 3 46 13 4 1 58 8 2 2 64 1 210 © 2006 Lippincott Williams & Wilkins The Pupil in Autonomic Neuropathies J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 similar. The shape of the pupil is often oval or irregular in outline. Mydriatic pupils are described as having a poor reaction to a light stimulus or a target viewed at reading distance (" near target"). The only exception is one reported case of the acute adrenergic type whose pupils were small and who appeared to have bilateral Horner syndrome ( 20). The majority of patients have not undergone formal pharmacologic testing, but among patients who were tested, 75% showed evidence of sympathetic deficit ( 7,14,17,19,24- 27,31,32,34,36,42,43,46,49,50,53,58- 60) and 90% demonstrated parasympathetic deficit ( 7,8,10- 12,14,17- 19,22,25- 28,31- 37,40,42,43,46,53,58- 60). Overall, the findings indicate that a high proportion of these cases involve both parasympathetic and sympathetic denervation of the pupil. Recent observations suggest that these pupil abnormalities may result from widespread autonomic ganglion-opathy and they are strongly linked to the presence of autoantibodies to ganglionic cholinergic receptors ( 65- 67). Acute dysautonomia in cats and dogs also causes mydriasis, reduced or absent light reflexes, and supersensitivity to both pilocarpine and epinephrine ( 68- 70). DIABETES MELLITUS The pupil is frequently abnormal in both types of diabetes mellitus: type 1 or insulin- dependent diabetes, which is commonly of early onset; and type 2 or noninsulin-dependent diabetes, which is usually of later onset. The most common observation is that the pupil is miotic ( 71- 77), particularly in darkness. A screening study of 359 unselected diabetic patients found that 21.7% had abnormally small pupils for age ( 78). Significant associations between small pupils and a wide range of diabetic complications have been recorded: cardiovascular autonomic dysfunction ( 79), peripheral sensory loss ( 73,77), retinopathy ( 80), nephropathy ( 73), and unduly prolonged and severe hyperglycemia ( 73,77). Acute hyperglycemia may cause miosis that reverses when normoglycemia is established ( 81,82). The common occurrence of a small pupil with intact light reflexes, in contrast to the rarity of a large pupil with poor light reflexes, suggests that the sympathetic iris innervation is more susceptible to damage than the parasympathetic innervation. Histologic studies of hides removed from patients with diabetes during cataract surgery have confirmed that loss of nerve terminals occurs preferentially from the dilator pupillae ( 83,84). The reason for the greater susceptibility of the sympathetic nerves is unknown; it may be related to the greater length of the nerve pathway ( 90). The mydriatic response to direct- acting sympathomimetic agents is exaggerated in patients with diabetic autonomic neuropathy ( 79,80), implying denervation supersensitivity ( 85,86). In one study ( 79), severe miosis was found to be associated with supersensitivity to phenylephrine but normal responses to the indirect- acting sympathomimetic hydroxy amphetamine. These findings indicate that diabetic miosis is at least partly neuropathic in origin but that the postganglionic neuron remains functionally intact. It seems unlikely that diabetes blocks transmission of sympathetic impulses at any one point along the sympathetic pathway; more probably the deficit results from a composite of mildly reduced function throughout. The anticholinergic drug tropicamide produces less mydriasis in diabetic pupils than in nondiabetic pupils, presumably because of the loss of effective pupil dilator function. Some observers have used measurement of the pupil response to a large dose of an anticholinergic to assess dilator muscle function and thus, indirectly, the percent of diabetic neuropathy ( 75,87). Full mydriasis in practice requires combined instillation of tropicamide and phenylephrine ( 88). The amplitude of the pupillary constriction to light is reduced in diabetic pupils ( 89,90). Light reflexes, if present, are slow in onset and time course, giving prolonged latency times and reduced maximum velocities of constriction and redilatation ( 77). This reduction is usually found only in pupils that are already small from sympathetic dysfunction. In severely affected patients, therefore, pupil size remains almost constant despite wide changes in illumination. There are a number of possible explanations for this. First, neovascularization of the iris ( rubeosis) may have stiffened the iris and immobilized the pupil. Recent evidence also shows that patients with type 2 diabetes can develop iris transillumination defects, particularly if there is severe retinopathy, suggesting hypoxic damage to the iris ( 91). Second, retinopathy and laser photocoagulation treatment attenuate the afferent limb of the pupil light reflex. Third, it is likely that damage to the parasympathetic supply underlies at least some of the observed reduction in pupil light responses. The pupil will constrict after topical administration of pilocarpine ( 80), and light reflexes are attenuated even after adjustments are made to the stimulus intensity to take into account differences in retinal sensitivity ( 90). Presumably, the iris in such patients is essentially denervated in both autonomic branches. The enhanced response of the diabetic pupil to cholinomimetic agents such as pilocarpine ( 80) supports this hypothesis. Random variation in the pupil diameter when the eye is exposed to constant illumination, known as hippus, is always symmetric in the two eyes and thought to be central in origin ( 92). Patients with diabetes with neuropathy show reduced hippus compared with healthy subjects ( 77,93). It is not clear whether this phenomenon is the result of peripheral damage to the autonomic nerves and iris muscles or whether the central control centers for pupil size are affected. 211 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Bremner and Smith AMYLOIDOSIS Systemic amyloidosis consists of a heterogenous group of conditions characterized histologically by deposition of abnormal birefringent protein in tissues. The protein responsible for most cases of familial amyloid ( AF) polyneuropathy is transthyretin, whereas the most common form of acquired amyloidosis ( AL) involves deposition of light- chain paraproteins. Clinical features suggestive of widespread damage to the autonomic nervous system are well recognized, although uncommon, in both AF and AL. In their survey of 229 cases of AL seen at the Mayo Clinic, Kyle and Greipp ( 94) reported 31 ( 14%) patients who had orthostatic hypotension. Among the subset of patients with AL who develop polyneuropathy, however, autonomic dysfunction appears to be common. Thus, Trotter et al ( 95) found orthostatic hypotension in 8, bowel upset in 9, and impotence in 8 of 10 patients. There is histopathologic evidence of amyloid deposition in the sympathetic ganglia and sympathetic chain ( 96- 99). The most apparent ophthalmic manifestation of amyloidosis is amyloid deposition in the lids, extraocular muscles, ocular adnexae ( 100- 104), and the eye, especially the vitreous gel ( 105- 108). Pupillary abnormalities have been reported, usually in association with other evidence of autonomic dysfunction. In 21 reported cases ( Table 2), the pupil abnormality was reported as hyporeactive ( 109), asymmetric or unreactive ( 95), or showing light- near dissociation ( 110- 112). One case ( 112) was reported as having bilateral " Holmes- Adie" pupils, parasympathetic denervation being confirmed by finding supersensitivity to methacholine ( 96). These pupil abnormalities are consistent with a parasympathetic deficit for which amyloid deposition in the ciliary ganglion may be responsible ( 113,114). Bilateral pupil dilatation lag, which indicates a sympathetic deficit, has also been reported in patients with amyloidosis and autonomic neuropathy. In at least one of these cases, amyloid deposition in the sympathetic chain appeared to be responsible ( 115). MULTIPLE SYSTEM ATROPHY Multiple system atrophy ( MSA; Shy- Drager syndrome) is a progressive condition associated with a variable incidence of extrapyramidal disorder with parkinsonism, cerebellar dysfunction, and dysautonomia. The condition is often accompanied by a sleep disturbance and bladder dysfunction. It is notoriously unresponsive to antiparkinsonian medication. Pupil abnormalities are occasionally found in MSA ( Table 2). In their original description of this condition, Shy and Drager ( 116) described iris atrophy and anisocoria in both of their patients. One of them had ptosis and miosis in one eye and also had reduced pupillary reactions to light and near. Anisocoria has appeared frequently in subsequent reports ( 117- 123), although some patients with MSA may have had unilateral Horner syndrome ( 117,118,124) or alternating Horner syndrome as reported in 6 patients ( 125- 127). The mechanism is obscure. Despite widespread autonomic dysfunction, however, many patients with MSA have been found to have normal pupils. In one series ( 117), 40 ( 70%) of 57 patients had normal pupils, and the pupils have been reported as normal in this condition by many others ( 42,124,126,128- 130). PURE AUTONOMIC FAILURE Pure autonomic failure ( PAF) is a variably progressive idiopathic condition often occurring in later life in which there is widespread autonomic dysfunction without disturbance of the central nervous system or involvement of the peripheral somatic nerves. The pupil has been rarely studied in detail in PAF. In their original study, Bradbury and Eggleston ( 131) observed that the pupils of their two patients were misshapen but that they reacted normally Although many patients have no pupillary abnormality ( 24,132- 135), absent light reflexes with light- near dissociation have been reported once ( 136). Bilateral ptosis has been observed ( 24) and Horner syndrome reported ( 4,133,135) with adrenergic supersensitivity found in 3 cases. Polinsky et al ( 133) reported that tyramine, an indirect- acting sympathomimetic agent similar to hydrox-yamphetamine, was associated with reduced pupillary dilatation in patients with PAF relative to controls. This difference is consistent with the belief that PAF is a disease of peripheral neurons, whereas MSA is a disease of central neurons. PARANEOPLASTIC SYNDROMES Immune responses to tumors may cause remote ( nonmetastatic) effects on specific target organs, including peripheral nerves, giving rise to various paraneoplastic syndromes. Pupil abnormalities have been widely reported in patients with a number of paraneoplastic syndromes, including Lambert- Eaton myasthenic syndrome ( LEMS) ( Table 2). Bilateral tonic pupils, absent or sluggish reactions to light, and prolonged pupil cycle times have been described in 13 LEMS cases ( 137- 143). Unspecified pupil dysfunction has been noted in 4 cases ( 144), and supersensitivity to cholinergic ( 139,141,145- 148) and adrenergic ( 141,149) agents in 8 cases. The aggregate frequency of reported pupil abnormalities in LEMS is 24% ( 21 of 88) ( 150). Pupil abnormalities also occur in other paraneoplastic syndromes. Bilateral tonic pupils with pilocarpine 212 © 2006 Lippincott Williams & Wilkins The Pupil in Autonomic Neuropathies J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 TABLE 2. Pupil abnormalities in acquired amyloidosis ( AL), multiple system atrophy ( MSA), Lambert- Eaton myasthenic syndrome ( LEMS) Demographics Number of cases Male/ Female ( where stated) Age range Pupil Shape Irregular/ Oval Normal Not stated Pupil Diameter Larger than normal Smaller than normal Notable anisocoria Normal Not stated Pupillary Light Reflex Absent Reduced Prolonged cycle time Normal Not stated Pupillary Near Reflex Reduced Normal Not stated Pupillary Cholinergic Supersensitivity Present Absent Not stated Pupillary Adrenergic Supersensitivity Present Absent Not stated Pupil Response to Cocaine Absent Normal Not stated Pupil Diagnoses ' Abnormal' Iris atrophy Horner ( Unilateral) Horner ( Alternating) Horner ( Bilateral) Tonic ( Unilateral) Tonic ( Bilateral) AL Amyloid ( 95- 96,109- 115) 58 20/ 14 33- 72 2 30 26 1 4 3 7 43 5 10 0 7 36 6 4 48 5 0 53 3 0 55 3 1 54 0 0 4 0 4 1 3 MSA ( 42,116- 130) 112 72/ 37 34- 76 0 53 59 14 1 15 53 29 0 17 0 53 42 1 40 71 3 0 109 0 0 112 4 0 108 5 5 9 8 0 0 0 pure autonomic PAF ( 4,24,131- 136) 33 19/ 14 30- 75 2 0 31 0 4 1 21 7 0 1 0 24 8 1 5 27 1 0 32 3 0 30 2 1 30 0 0 4 0 8 0 1 failure ( PAF), and LEMS ( 137- 150) 88 48/ 36 17- 79 0 65 23 2 0 0 63 23 2 8 2 67 9 2 0 86 8 0 80 6 0 82 0 0 88 4 0 0 0 0 0 1 213 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Bremner and Smith supersensitivity have been reported in 3 infants with neuroblastoma ( 147,148) and in adults with presumed anti- Hu-mediated neuronopathies associated with small cell lung carcinoma ( 151- 154), adenocarcinoma of the colon ( 155), and testicular seminoma ( 145). There is one report of bilateral Horner syndrome associated with anti- Hu-mediated demyelinating neuropathy and small cell lung carcinoma ( 156). Unilateral tonic pupils with or without cholinergic supersensitivity have been reported in 4 cases ( 157- 160), but the pupillotonia may be indicative of coincidental Holmes- Adie syndrome ( 3 of the 4 cases had tendon areflexia) and are therefore difficult to interpret. SJOGREN SYNDROME Sjogren syndrome is characterized by keratoconjunctivitis sicca, xerostomia, and numerous extraglandular manifestations that may overlap with rheumatoid arthritis. When these manifestations are part of another connective tissue disorder, Sjogren syndrome is considered secondary. Autonomic neuropathy is a common complication of primary and secondary Sjogren syndromes. Unilateral or bilateral tonic pupils occur, usually with light- near dissociation ( 161- 172). Similar findings have been reported in patients with sicca syndrome in whom a definitive diagnosis of Sjogren syndrome had not yet been made ( 173,174). The recent demonstration of autoantibodies against M3- musca-rinic acetylcholine receptors in patients with Sjogren syndrome suggests that the pupil abnormality may be caused by receptor blockade rather than sphincter muscle denervation in some cases ( 175,176). HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE III ( RILEY DAY SYNDROME, FAMILIAL DYSAUTONOMIA) The familial condition of hereditary sensory and autonomic neuropathy type III ( HSAN III), occurring almost exclusively in Ashkenazi Jews, is characterized by widespread sensory and autonomic disturbance. The hallmark ophthalmic signs of HSAN III are alacrima and corneal hypesthesia ( 177); ulceration and scarring of the corneas are common and blindness may occur. Pupil abnormalities have been widely reported in HSAN III, largely on the basis of pharmacologic evidence. The most common feature, an exaggerated miotic response to 2.5% topical methacholine or 0.1% or 0.125% pilocarpine, is usually attributed to denervation supersensitivity of the iris sphincter muscle ( 178- 189). Such supersensitivity is no longer regarded as pathognomonic of the condition because it is to be expected in any other condition in which there is parasympathetic denervation ( 190). Moreover, not all the evidence supports parasympathetic dysfunction. Three early studies ( 188,191,192) showed that the pupils of these patients react normally to light and a near target, and that there is no pupillotonia or light- near dissociation. The responses to topical anticholinesterases ( physostigmine, neostigmine, and echothiophate) have also been unremarkable in some patients with HSAN III ( or in a single case, slightly exaggerated [ 178]). Such findings would suggest that the parasympathetic innervation in HSAN III is intact. In most patients with HSAN III, the autonomic neuropathy is characterized principally by sympathetic deficits with parasympathetic dysfunction sometimes occurring later. Pupil sympathetic function has rarely been studied in detail. Normal responses to both cocaine and epinephrine were reported in 20 patients ( 178,181) and an exaggerated response to phenylephrine in only one ( 180). A recent study comparing pupil measurements in 14 patients with age- matched healthy controls showed a reduction in pupil diameter in darkness and redilatation velocity, as well as attenuation of the light reflex, possibly indicating mixed sympathetic and parasympathetic failure ( 193). The differences found were surprisingly small but did achieve statistical significance. DOPAMINE p- HYDROXYLASE DEFICIENCY In dopamine ( 3- hydroxylase deficiency, a rare inherited condition, subjects lack the enzyme dopamine ( 3- hydroxylase and therefore cannot synthesize norepinephrine from dopamine, causing a pure sympathetic deficit ( 194- 199). The pupils have been described as small ( 2- 3 mm in diameter) but normally reactive ( 194,195,197) with supersensitivity to topical epinephrine ( 198) and phenylephrine ( 197) but no response to hydroxyamphetamine ( 196), the indirect action of which requires a functional postganglionic sympathetic neuron. Later pupillographic studies of a sibling pair ( 198) revealed severe bilateral redilatation lag ( 4) consistent with these abnormalities. As expected, the pupils showed no supersensitivity to methacholine ( 194,196,198) and did not dilate with the atropinic agent homatropine ( 196). GENERAL COMMENTS A systematic literature review confirms that patients with widespread autonomic dysfunction are often reported as having abnormal pupils. For several reasons, the detection and characterization of these pupil abnormalities can be challenging. The initial clinical examination is often unremarkable because the pupil abnormalities are commonly bilateral and symmetric. The pupils are rarely misshapen even when tonic; anisocoria may not be present under any lighting conditions; and clinical detection of an abnormal response to light or near has a low sensitivity. 214 © 2006 Lippincott Williams & Wilkins The Pupil in Autonomic Neuropathies J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Reports of abnormal pupils associated with generalized dysautonomia are therefore likely to underestimate their actual prevalence if based on clinical observations alone. It should be possible to overcome these difficulties in part by using pharmacologic tests to demonstrate denervation supersensitivity to weak receptor agonists. However, care must be taken in the interpretation of such findings because many patients with autonomic neuropathy have impaired tear formation with or without corneal damage. In such circumstances, transcorneal drug penetration may be enhanced ( 188), thus giving rise to an apparent but false supersensitivity ( 200). This is well illustrated by a recent report of a patient with Sjogren syndrome with dry eyes in whom both pupils were supersensitive to norepinephrine but there was no impairment of the sympathetic supply as demonstrated by a normal mydriatic response to cocaine ( 201). Drug testing may therefore tend to overestimate the prevalence of pupil abnormalities in patients with tear film disturbance. Furthermore, the lack of a " control" eye and the possibility that both parasympathetic and sympathetic supplies are affected make interpretation of pupillary responses to different drugs particularly difficult. In many patients with dysautonomia, iris sphincter and dilator muscles are both likely to be denervated to some percent, but if one deficit predominates, it will mask the other. For example, a patient with bilateral tonic pupils may also have a sympathetic deficit. However, with isocoria and symmetric lids, and without a " control" eye against which to compare redilatation times or responses to topical cocaine, it is impossible to prove any sympathetic deficit. A patient with bilateral Horner syndrome might also have a mild parasympathetic deficit, but the subtle changes in light diameter and responses to light and a near target would be masked by the changes in resting diameter resulting from the sympathetic deficit. 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