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Show Journal of Neuro- Ophtlialmology 18( 2): 143- 147, 1998. €> 1998 LippincoU- Raven Publishers, Philadelphia Asymptomatic Autonomic and Sweat Dysfunction in Patients With Adie's Syndrome Daniel M. Jacobson, M. D., and Bradley C. Hiner, M. D. A study was conducted to determine by using noninvasive tests whether autonomic dysfunction occurs in patients with Adie's syndrome. Eighteen consecutive patients with Adie's syndrome prospectively underwent a standardized battery of five noninvasive tests of autonomic function, including three that predominantly reflected parasympathetic function and two that predominantly reflected sympathetic function. Eight of these patients additionally underwent thermoregulatory sweat testing. Of the 18 patients 10 ( 56%) had no abnormal autonomic test results, 5 ( 28%) had one abnormal result, 2( 11%) had two abnormal results, and 1 ( 6%) had three abnormal results. None of the patients had more than three abnormal results. Tests that predominantly reflected parasympathetic function produced abnormal results more frequently than those that predominantly reflected sympathetic function. Three of eight ( 38%) patients who underwent thermoregulatory sweat testing showed abnormal patterns of sweating. Although abnormal autonomic and sweat functions are not uncommon in patients with Adie's syndrome, the abnormalities are mild and are generally unassoci-ated with symptoms of dysautonomia. Such abnormalities have little clinical significance but may be important from a nosologic point of view. Key Words: Adie's pupil- Adie's syndrome- Autonomic- Parasympathetic- Sweat- Sympathetic. Adie's tonic pupil represents an idiopathic, chronic, progressive autonomic neuropathy restricted to the postganglionic parasympathetic neurons of the oculomotor nerve. Adie's syndrome, or the Holmes- Adie's syndrome, refers to the condition in which tonic pupils exist in a patient with impairment of muscle- stretch reflexes ( 1). Unless otherwise specified, we will use the term Adie's syndrome throughout the remainder of this discussion to refer to patients with either Adie's tonic pupil or the Holmes- Adie's syndrome. Patients with Adie's syndrome generally do not expe- Manuscript received June 19, 1997; accepted March 6, 1998. From the Departments of Neurology ( D. M. J., B. C. H.) and Ophthalmology ( D. M. J.), Marshfield Clinic, Marshfield, Wisconsin, U. S. A. Presented in part at the Fifth International Symposium on the Autonomic Nervous System, sponsored by the American Autonomic Society, Rochester, Minnesota, October 21- 23, 1994. Address correspondence and reprint requests to Daniel M. Jacobson, MD, Marshfield Clinic, 1000 N. Oak Ave., Marshfield, WI 54449, U. S. A. rience more widespread symptoms of dysautonomia. However, tonic pupils may coexist in patients who have generalized manifestations of autonomic insufficiency caused by certain systemic neuropathies, such as Sjogren's syndrome ( 2,3), paraneoplastic sensory neu-ronopathy, and dysautonomia ( 4,5), and in some, disorders of primary autonomic failure ( 6). In these conditions, however, symptoms and signs of autonomic failure or peripheral neuropathy dominate the clinical manifestations so that affected patients would not be assigned a diagnosis of Adie's syndrome. The nosologic distinction between Adie's syndrome and some idiopathic conditions associated with tonic pupils and other features of dysautonomia ( Adie's- plus or tonic pupil- plus syndromes) may not always be clear, however. For example, Ross syndrome is an unusual disorder associated with tonic pupils, hyporeflexia, and progressive segmental impairment of sweat function ( 7- 9). Because affected patients experience symptomatic anhidrosis and, at times, other symptoms of dysautonomia, Ross syndrome, not Adie's syndrome, would generally be the correctly assigned diagnosis in that setting. The clinical distinction between Adie's syndrome and other tonic pupil- plus syndromes becomes even more blurred considering that some investigators have identified abnormalities of autonomic cardiovascular and sweat function in patients with idiopathic tonic pupils ( 10- 13). The purpose of this study was to explore further whether evidence of dysautonomia can be identified in patients with Adie's syndrome. Identification of such abnormalities would require reconciliation of the nosologic distinction between Adie's and Ross syndrome. METHODS The thermoregulatory sweat testing portion of this protocol was reviewed and approved by the Institutional Review Board of the Marshfield Clinic. The participating neuro- ophthalmologist ( D. M. J.) recruited consecutive patients who had newly diagnosed Adie's syndrome regardless of duration of disorder, gender, or age; whether one or both eyes were affected, or whether muscle-stretch reflexes were impaired. The diagnosis of Adie's pupil was established by identifying the typical 143 144 D. M. JACOB SON AND B. C. MINER defining pupil characteristics in all patients, including impaired direct- light reaction, light- near dissociation, tonic redilation after miosis induced by prolonged accommodation, and sector palsy of the iris sphincter identified by slit lamp biomicroscopy. No clinically apparent cause was identified in any of the patients. None of the patients reported symptoms of sweat impairment. Although most of the included patients underwent dilute pilocarpine testing, we did not require the presence of cholinergic supersensitivity of the iris sphincter to diagnose Adie's pupil. All 9 of the 18 patients who underwent serologic testing for Treponema pallidum had non-reactive results. Patients were not included if they had diabetes or Parkinson's disease, were receiving a neurotoxic medication, admitted to excessive alcohol use, or had some other disorder known to be associated with central or peripheral autonomic dysfunction. Patients were instructed to discontinue all medications for 12 hours before they underwent autonomic testing, unless medically contraindicated. The following patient characteristics were abstracted from the medical record and recorded in a database: age; gender; whether one or both pupils were affected; estimated duration of anisocoria using information from patient observations, prior examinations, and inspection of photographs; and, whether muscle- stretch reflexes were impaired. Examination of muscle- stretch reflexes was performed by the same examiner ( D. M. J.) under the same test conditions: Patients were seated upright, their extremities were fully relaxed, and the Jendrassik maneuver was not used. For the purposes of this investigation, we considered a patient to have impaired muscle-stretch reflexes if more than one ankle or knee jerk was graded as trace or absent. All patients underwent a standardized battery of five noninvasive tests of autonomic function, as suggested by the American Academy of Neurology and the American Diabetes Association ( 14,15). Three of the tests reflected predominantly parasympathetic cardiovagal function: heart rate response to deep breathing ( E: I ratio), standing ( 30: 15 ratio), and the Valsalva maneuver ( Valsalva ratio). Two of the tests reflected predominantly peripheral sympathetic vasomotor tone function: blood pressure response to standing ( orthostatic blood pressure change) and to sustained hand grip ( handgrip test). We used published cutoff values to define an abnormal result for the tests of autonomic function ( 16,17). Our testing protocol was identical to those used by the laboratories from which we obtained these values. We considered a result to be abnormal only if it was in the abnormal, not the borderline, range ( that is, beyond the 95th percentile confidence interval). In addition, we verified that these published results were reproducible in our laboratory by testing 14 healthy women and 14 healthy men whose ages ranged from 21 to 48 years ( mean and median age, 31 years). Five of 28 ( 18%) of our normal subjects had one abnormal test result. The E: I ratio was abnormal in 1 of 28 ( 4%) subjects, the 30: 15 ratio was abnormal in 1 of 28 ( 4%) subjects, and the Valsalva ratio was abnormal in 3 of 28 ( 11%) subjects. None of these subjects showed abnormalities on more than one test. Thermoregulatory sweat testing became available at our institution after our investigation was initiated; therefore, we were unable to test all patients who underwent the noninvasive autonomic battery with this method. Patients were paid $ 25.00 for participating in this phase of the investigation. Our test equipment and protocol were identical to that described by Fealey ( 18). Briefly, unclothed patients lie supine on a cart. Genitals in men and women, and breasts in women, are covered. A mixture of Alizarin red dye, corn starch, and sodium carbonate is applied to their exposed skin. A temperature probe is placed in their mouth, and two probes are applied to their skin. The cart is then rolled into the test chamber, which has large windows so that the subject can be viewed by the technician. The chamber is heated to 109° C with 45% humidity. The test is continued until the patient's core temperature is raised to 38° C, which usually takes between 30 and 45 minutes. The test is then terminated. The indicator powder turns purple when exposed to body moisture. We document the pattern of sweating by drawing a picture of it on a standard diagram and by analyzing a video recording made at the time the test is completed. We considered a subject to have an abnormal test result if the pattern of sweating conformed to one of the seven abnormal patterns described by Fealey ( 18). RESULTS Demographic and clinical characteristics of the 18 patients included in this investigation are summarized in Table 1. Thirteen of the patients underwent testing for cholinergic supersensitivity using dilute pilocarpine. Eight of 12 ( 67%) patients with unilateral tonic pupils showed supersensitivity in their affected pupil. The frequency of abnormal autonomic function in our population was low. Of 18 patients tested, 10 ( 56%) had no abnormal results, 5 ( 28%) had only one abnormal TABLE 1. Demographic and clinical characteristics of 18 patients with Adie ' s syndrome Median Range Age, years Duration," years Gender Women Men Laterality of involvement Unilateral Bilateral Impaired muscle stretch reflexes 48.5 2 No. patients II 7 17 1 12 21- 75 0.08- 25 Percent (%) 61 39 94 6 67 " The listed duration was derived by considering information available for 13 of the patients who had clinical or photographic evidence that supported this estimate. In the remaining five patients, the abnormal pupil was discovered during a routine examination at or around the time of initial neuro- ophthalmologic referral to evaluate this sign. J Nenm- Ophllwlniol, Vol. 18, No. 2, 1998 AUTONOMIC AND SWEAT DYSFUNCTION IN ADIE'S SYNDROME 145 result, 2 ( 11%) had two abnormal results, and only 1 ( 6%) had three abnormal results. None of the patients had more than three abnormal test results. The most common abnormal test result in those 8 patients with abnormal autonomic function was the E: I ratio, followed by the Valsalva ratio and the 30: 15 ratio and handgrip test ( Table 2). With the exception of the handgrip test, the tests that produced abnormal results predominantly reflected parasympathetic dysfunction. Fisher's exact test was used to determine whether patients with abnormal test results differed from those with normal test results in age ( more or less than the median age of the patient population, 48.5 years), in duration of tonic pupil ( more or less than the median estimated duration, 2 years), or presence or absence of impaired muscle- stretch reflexes. No significant differences were identified from any of these contingency tables, although the power to detect a difference was limited by the small number of patients in each group. In three of the eight ( 38%) patients who underwent thermoregulatory sweat testing, abnormal patterns of hy-pohidrosis were observed. The first patient was a 52- year- old women with a left- side tonic pupil documented for 2 years, with normal muscle- stretch reflexes. She had diffuse hypohidrosis from her upper chest caudally, and regional absence of sweating over her left cheek ( Fig. 1). During autonomic testing, she had an abnormal E: I ratio. The second patient was a 32- year- old man with a right-side tonic pupil documented for 6 months with abnormal muscle- stretch reflexes who showed mild distal gradient diminution of sweat activity in his legs ( Fig. 1). His battery of autonomic testing was otherwise normal. The third patient was a 39- year- old women with a right- side tonic pupil documented for 2 years and normal muscle-stretch reflexes who exhibited patchy, focal regions of relative hypohidrosis, particularly in both of her arms and across her abdomen. These regions were asymmetric and irregular in shape. In addition, she had distal loss of sweat function in the legs, involving the left side more than the right ( Fig. 1). Her only abnormal result during autonomic testing was produced by the handgrip test. DISCUSSION The results of our study show that abnormalities of autonomic function, assessed using standardized nonin- TABLE 2. Abnormal test results of autonomic function in 18 patients with Adie's syndrome Test E: l ratio" 30: 15 ratio Valsalva ratio Orthostatic BP change Handgrip test < or < or > or < or Abnormal cut- off = 1.00 = 1.20 = 30 mm Hg systolic = 10 mm Hg diastolic No. patients abnormal (%) 5( 28) 2( 11) 3( 17) 0( 0) 2( 11) " Cut- off is age- dependent, ranging from greater than or equal to 1.23 in patients between the ages of 16 and 20 years, to greater than or equal to 1.05 in patients between the ages of 76 to 80 years. FIG 1. Patterns of sweating made from drawings taken from three patients with Adie's syndrome at the time they underwent thermoregulatory sweat testing. The shaded areas indicate areas of sweating: a 52- year- old woman ( left) with diffuse hypohidrosis below the neck and absent sweating over her left cheek, the side of her tonic pupil; a 32- year- old man ( middle) with distal gradient asymmetric hypohidrosis of his legs; a 39- year- old woman ( right) with regional absence of sweating in an asymmetric pattern across portions of her arms and abdomen, with asymmetric distal loss of sweating in her legs. vasive methods, are not uncommon in patients with Adie's syndrome. In patients with autonomic neuropathies, the degree of clinically relevant dysautonomia is generally proportional to the number of abnormal results in tests of autonomic function ( 19). Accordingly, we also conclude that the dysautonomia associated with Adie's syndrome is mild, consistent with the general clinical impression that patients with Adie's syndrome usually do not report symptoms of widespread autonomic dysfunction. We routinely administer an autonomic screening questionnaire to patients who undergo testing in our laboratory. Review of the responses of those patients who participated in this investigation showed that a minority answered some of the questions affirmatively, but there was no correlation between those who answered affirmatively and those who exhibited abnormalities of autonomic function. This further minimizes the clinical significance of identifying features of dysautonomia by using noninvasive techniques in patients with Adie's syndrome. It is interesting to note that the most common abnormalities of autonomic function in these patients were displayed in tests that are thought to reflect parasympathetic integrity. Because the neurons affected in Adie's tonic pupil are also parasympathetic, perhaps whatever insult is responsible for Adie's syndrome similarly injures neurons of the parasympathetic system elsewhere, albeit largely subclinically. In the only clinical-pathologic report of changes that occur in autonomic neurons other than the ciliary ganglion, Harriman and Garland ( 20) described residual nodules and loss of neurons in the superior cervical ganglion, suggesting that injury to the sympathetic system additionally occurs in Adie's syndrome. .1 Neuw- Ophthalmol, Vol. 18, No. 2. 1998 146 D. M. JACOB SON AND B. C. HINER The frequency of detecting abnormalities of autonomic function using noninvasive tests is dependent on several variables, including the sensitivity of the test and the cutoff value used to define an abnormal result. Hope- Ross et al. ( 10) tested eight women and three men with Adie's syndrome, using four of the same noninvasive tests of autonomic function used in our study. The characteristics of their group were similar to those of our group, including a median age of 49 years, median duration of 6 months, and frequency of unilateral involvement and abnormal muscle- stretch reflexes of 82%. They used the same cutoff values derived from Ewing and Clarke ( 16) that we used in our investigation. When considering patients who had abnormal, not borderline, results they also found a low frequency of autonomic dysfunction: Seventy- three percent of their patients had no abnormal results, 18% had one abnormal result, 9% had two abnormal results, and none had more than two abnormal results ( 10). Bacon and Smith ( 11) also investigated patients with Adie's syndrome, by using a battery of six noninvasive tests of autonomic function, including four used in our investigation ( E: I ratio, Valsalva ratio, handgrip test, and assessment of blood pressure response to orthostatic changes) and three tests of sweat function. They compared the responses of 53 patients with those from 71 healthy control subjects, and found that 83% of patients had at least one abnormal test result, 57% had at least two abnormal results, and 40% had at least three abnormal results. Some of the reasons their prevalence rates may have been higher than those identified by us and by Hope- Ross et al. ( 10) were that they included the results of all three sweat tests in their frequency determinations, and because some of their tests incorporated measuring systems with relatively greater sensitivity, such as determining digital blood flow in response to hand immersion in ice water using plethysmography. Also, they incorporated more individual tests in their autonomic function battery, compared with the number used in our study or that used by Hope- Ross et al. ( 10). The probability of identifying results that are outside of population- defined confidence intervals increases as the number of tests performed increases. We found that 38% of our patients with Adie's syndrome who underwent testing for sweat impairment exhibited abnormal patterns identified using a topically applied indicator dye powder. This frequency compares favorably with the 29% rate of abnormal sweat function detected by Bacon and Smith ( 11) but is lower than the 57% rate detected by Hallermann ( 12), both of whom also used an indicator dye method. Although nonspecific, abnormal patterns of sweat function in patients with Adie's syndrome suggest the presence of additional impairment of sympathetic function. The segmental nature of the anhidrosis and results of physiologic tests of sudomotor function strongly implicate the sympathetic ganglion or postganglionic neurons as the location of the sweat defect in patients with Ross syndrome ( 21- 23). None of the patients with abnormal patterns of sweating in our study FIG. 2. Graphic representation of the overlap between Adie's and Ross syndromes. Disorders associated with tonic pupils and other features of dysautonomia may represent a continuum, with Adie's syndrome at one end and Ross syndrome at the other, defined primarily by the degree of clinically evident sweat dysfunction. Some patients with Adie's syndrome have subclinical or mild clinical features of dysautonomia, and their disorders lie somewhere between the two ends of the continuum ( Adie's- plus or tonic pupil- plus syndromes). reported symptoms of excessive or reduced sweating. Such abnormalities presumably reflect subclinical injury to the postganglionic cholinergic sudomotor pathway caused by whatever injury is responsible for the initial insult in Adie's syndrome that affects the postganglionic cholinergic pupillomotor neurons. In summary, we confirmed that evidence of generalized autonomic dysfunction exists in some patients with Adie's syndrome. Such abnormalities are probably of little clinical significance, however, because they were identified in approximately half of our patients only, were mild in degree in most patients who had such abnormalities, and were unassociated with symptoms of dysautonomia. These findings may be important from a nosologic point of view. Adie's syndrome and Ross syndrome are both progressive disorders affecting the postganglionic parasympathetic innervation of the pupil along with impairment of muscle stretch reflexes. Perhaps, they represent opposite ends of a continuum, defined clinically by the degree of symptomatic impairment of sweat and autonomic function present in a patient ( Fig. 2). Weller et al. ( 9) have also challenged the classification of Ross syndrome as a separate entity. In patients with no clinical manifestations of autonomic dysfunction, the presence of subclinical abnormalities detected by noninvasive methods indicates that their disorder lies closer to the Adie's end of the continuum than the Ross end. In the unusual patient with Adie's syndrome who has additional, but nondebilitating, symptoms of dysautonomia, their disorder may lie somewhere near the middle of the continuum ( 24). Such patients may have evidence of sudomotor dysfunction that can be detected using physiologic tests of sweat function. Finally, those patients with symptomatic impairment of sweat and autonomic function are classified at the Ross end of the continuum. 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