Journal of Neuro-Ophthalmology, September 1998, Volume 18, Issue 3

Comparison of Cholinergic Supersensitivity in Third Nerve Palsy and Adies Syndrome

OBJECTIVE: To determine whether the degree of cholinergic supersensitivity of the pupil differs in patients with preganglionic injury of the oculomotor nerve (third nerve palsy) compared with patients with postganglionic injury (Adie's pupil). METHODS: In this retrospective study, the authors first identified 11 patients with oculomotor nerve palsy and 11 patients with unilateral Adie's pupil who demonstrated supersensitive pupillary responses using dilute pilocarpine. The same methods for testing supersensitivity of the iris sphincter, and for defining its presence, had been used in both groups of patients. Pupil diameters of the affected and unaffected fellow eye were measured directly from self-developing photographs obtained before and 30 minutes after pilocarpine 0.1% was applied to both eyes. The amount of absolute constriction of the affected pupil, as well as the net constriction of the affected pupil (i.e., the amount of pilocarpine-induced constriction of the unaffected pupil subtracted from the amount of pilocarpine-induced constriction of the affected pupil), was compared between the two groups of patients using the Mann-Whitney test. RESULTS: No significant differences were identified in any of the comparisons. CONCLUSIONS: The degree of cholinergic supersensitivity of the iris sphincter appears to be similar regardless of whether the site of injury along the parasympathetic pathway of the oculomotor nerve is preganglionic or postganglionic.

Journal of Neuio- Ophllmlmology IH( J): 171- 175, 19V8. © 1998 Lippincoll Williams & Wilkins, Philadelphia Comparison of Cholinergic Supersensitivity in Third Nerve Palsy and Adie's Syndrome Daniel M. Jacobson, M. D., and Robert A. Vierkant, M. A. S. Objective: To determine whether the degree of cholinergic supersensitivity of the pupil differs in patients with pregangli­onic injury of the oculomotor nerve ( third nerve palsy) com­pared with patients with postganglionic injury ( Adie's pupil). Methods: In this retrospective study, the authors first identified 1 1 patients with oculomotor nerve palsy and 1 1 patients with unilateral Adie's pupil who demonstrated supersensitive pupil­lary responses using dilute pilocarpine. The same methods for testing supersensitivity of the iris sphincter, and for defining its presence, had been used in both groups of patients. Pupil di­ameters of the affected and unaffected fellow eye were mea­sured directly from self- developing photographs obtained be­fore and 30 minutes after pilocarpine 0.1% was applied to both eyes. The amount of absolute constriction of the affected pupil, as well as the net constriction of the affected pupil ( i. e., the amount of pilocarpine- induced constriction of the unaffected pupil subtracted from the amount of pilocarpine- induced con­striction of the affected pupil), was compared between the two groups of patients using the Mann- Whitney test. Results: No significant differences were identified in any of the comparisons. Conclusions: The degree of cholinergic supersensitivity of the iris sphincter appears to be similar regardless of whether the site of injury along the parasympathetic pathway of the oculo­motor nerve is preganglionic or postganglionic. Key Words: Supersensitivity- Third nerve palsy- Oculo­motor nerve palsy- Adie's pupil- Pilocarpine- Pupil- Cholinergic. Cholinergic supersensitivity of the iris sphincter can be demonstrated in many patients with congenital, com­pressive, and traumatic injuries of the oculomotor nerve, similar to the supersensitivity characteristic of postgan­glionic parasympathetic oculomotor disorders, such as Adie's tonic pupil ( 1- 7). Some authorities have sug- Manuscript received October 1997; accepted February 1998. From the Departments of Neurology and Ophthalmology ( D. M. J.), Marshfiekl Clinic, and the Department of Epidemiology and Biostatis-tics ( R. A. V.), Marshfiekl Medical Research Foundation, Marshfiekl, Wisconsin, U. S. A. Address correspondence and reprint requests to Daniel M. Jacobson, M. D., Marshfiekl Clinic, 1000 N. Oak Avenue, Marshfiekl, WI 54449. U. S. A. Preliminary results of the this study were presented, in part, as a poster presentation at the American Neurological Association Annual Meeting, Washington, DC, April 8- 9, 1995. gested that the degree of supersensitivity observed in patients with lesions affecting the preganglionic third nerve segment is less than that observed in patients with lesions affecting the postganglionic segment ( 8- 10). The purpose of this retrospective investigation was to test the validity of this observation. PATIENTS AND METHODS We compared the amount of constriction of the super­sensitive pupil in response to dilute pilocarpine in two populations: patients with unilateral oculomotor nerve palsy and patients with unilateral Adie's tonic pupil. The patients with oculomotor nerve palsy comprised a group of 11 people who were identified during a previous pro­spective investigation to determine the frequency of pre­ganglionic cholinergic supersensitivity ( 7). This group included five patients with parasellar lesions compress­ing the third nerve, four patients with trauma- induced ophthalmoplegia, and two patients with congenital third nerve palsy. Six of these patients had additional pupillary signs consistent with aberrant reinncrvation of the iris sphincter, including light- near dissociation, segmental palsies of the iris in response to light, or segmental con­traction of the iris in response to ocular duction. The patients in the Adie's pupil group represented the first 11 consecutive patients with this condition who were evaluated during the same period and were found to have supersensitive pupils. All patients in the Adie's group had an affected pupil that demonstrated impair­ment of the direct light reaction, light- near dissociation, segmental palsies of the iris sphincter observed during slit- lamp biomicroscopy, and tonic redilation after a near response. The fellow eye did not demonstrate any of these pupillary signs. We used the same protocol for testing cholinergic su­persensitivity, and the same criteria for defining its pres­ence, in both groups of patients, as described in greater detail elsewhere ( 11). All patients were first instructed to gaze in the distance for at least 1 minute to relax any tonic near miotic response and, in the case of patients with oculomotor nerve palsy, to control for ga/. e- evoked changes in pupil size resulting from aberrant regenera- 171 172 D. M. JACOBSON AND R. A. VIERKANT TABLE 1. Clinical and demographic features of II patients with oculomotor nerve palsy and 11 patients with Adie's tonic pupil Oculomotor nerve palsy Adie's syndrome Age median ( range), years 39 ( 3.5- 87) 33 ( 27- 53) No. women, men 6,5 6,5 Duration median ( range), years" 2.5 ( 0.02- 39) 1.4 ( 0.08- 21) Iris color light 8, dark 3 light 7, dark 4 Involved eye right 3, left 8 right 7, left 4 " Estimated by inspecting old photographs, reviewing documents of prior examinations, and considering reported symptoms. The duration abstracted represented the minimum interval time from estimated onset to current evaluation in all patients with oculomotor nerve palsy and in 10 of the 1 I patients with Adie's tonic pupil. No information was available in one of the patients with Adie's pupil that would allow us to estimate its duration. tion of the iris sphincter. Baseline pupil sizes were then documented in darkness ( 15 seconds after extinguishing ambient light) using self- developing photographs ob­tained from a Polaroid CU- 5 camera ( Cambridge, MA) with I : 1 magnification. We then applied two drops of freshly prepared pilocarpine 0.1% 5 minutes apart to both eyes. Pupil sizes were again documented using the same photographic technique in darkness 30 minutes later. We used a hand- held magnifying reticle to measure pupil diameters directly from the photographs with an accuracy of within 0.1 mm. We recorded the pupil sizes in darkness for two rea­sons. First, this ambient light condition minimizes the additional miotic influence of the pupillary light reflex. Second, the starting sizes of the pupils are maximized in darkness so that mechanical resistance of the iris tissue during pilocarpine- induccd miosis is minimized. Pupil responses to pilocarpine in darkness, therefore, are rela­tively free of physiologic influences other than the phar­macologic effect of the dilute cholinergic agonist. We determined the amount of constriction of the af­fected pupil in response to dilute pilocarpine using two different formulas. The first involved a simple subtrac­tion of the postpilocarpine pupil diameter from the base­line pupil diameter. Henceforth, we will refer to this variable as the absolute constriction of the affected pupil. Because the size of the pupils is constantly changing, we also determined the amount of constriction of the af­fected pupil using the unaffected pupil as an internal control to account for changes in pupil size that occurred during the 30- minute interval between baseline and post­pilocarpine assessment of pupillary diameters ( 12). Gen­era] factors, such as fatigue and accommodation, affect the size of both pupils in any one person to the same degree. The excess amount of constriction of the affected pupil, after accounting for general changes that influ­enced the size of both pupils, was determined by sub­tracting the amount of pilocarpine- induced constriction of the uninvolved ( internal control) pupil from the amount of pilocarpine- induced constriction of the af­fected pupil. We refer to this variable as the net constric­tion of the affected pupil. All patients included in this study demonstrated su­persensitivity of their affected pupil, defined as present if one of two conditions were fulfilled. In the first criterion, the affected pupil was supersensitive if it constricted at least 0.5 mm more than the uninvolved pupil in response to dilute pilocarpine. This degree of net constriction ex­ceeds the normal interocular variability of pupillary con­striction to dilute pilocarpine in healthy subjects under the same testing protocol used in this study ( 5). In the second criterion, the affected pupil was supersensitive if it started out larger than the uninvolved pupil but then became smaller than the unaffected pupil after pilo­carpine was applied to both eyes. For such a change to occur, the involved pupil had to overcome mechanical resistance of the iris, and could do so only if its cholin­ergic activity exceeded that of the uninvolved pupil's activity ( 11). We used the Mann- Whitney test ( 13) ( two- sided) to compare the absolute constriction and net constriction of the affected pupil between the two groups. We chose this test because the number of patients in the two compari­son groups was small and because the data did not appear to be normally distributed. To determine whether a dif­ference in baseline pupil size between the two groups influenced the degree of pilocarpine- induced constric­tion, we also compared the baseline pupil diameter and anisocoria in the two groups. Finally, we performed a TABLE 2. Results of pupil measurements in II patients with oculomotor nerve palsy and II patients with Adie's tonic pupil Measure Baseline diameter of affected pupil Median ( range), mm Baseline anisocoria'' Median ( range), mm Absolute constriction of affected pupil Median ( range), mm Net constriction of affected pupil Median ( range), mm Oculomotor nerve palsy 6.0 ( 4.0- 8.3) 0.2(- 1.1^+. 0) 2.5 ( 1.5- 6.1) 1.0 ( 0.6- 4.6) Adie's syndrome 6.5 ( 3.2- 9.5) 0.1 (- 1.4- 1.9) 3.7( 0.6- 6.1) 0.6 ( 0.2- 4.0) P- value" 0.57 0.26 0.20 0.45 " Determined by the Mann- Whitney test ( two- sided). '' Determined by subtracting the diameter of the unaffected pupil from the diameter of the affected pupil. A negative value indicates that the affected pupil was smaller than the unaffected fellow pupil. J Newv- Ophlhulmol, Vol. IH, No. J, 1998 CHOLINERGIC SUPERSENSITIVITY 173 similar analysis comparing the amount of net constric­tion of the affected pupil between the group of patients with third nerve palsy who had signs of aberrant regen­eration and the group who did not. RESULTS Clinical and demographic characteristics of the two groups are summarized in Table 1. The patients were similar with regard to age, gender, duration of involve­ment of the affected pupil, and iris color. As summarized in Table 2, there were no significant differences between the two groups with regard to the baseline diameter of the affected pupil, baseline anisocoria, amount of abso­lute constriction of the affected pupil ( Fig. 1), or amount of net constriction of the affected pupil ( Fig. 2). The amount of net constriction of the affected pupil in the group of patients with third nerve palsy who had signs of aberrant reinnervation was smaller than that value found in the group of patients without such signs by a marginally significant degree ( P = 0.052). As shown in Figure 3, however, the result of this compari­son was highly influenced by a single patient in the group without aberrant reinnervation. DISCUSSION We were unable to find a difference in the amount of absolute or net constriction of the affected pupil in re­sponse to dilute pilocarpine in patients with third nerve palsy and Adie's syndrome who had pupils that demon­strated cholinergic supersensitivity. This may be partially due to small sample sizes in each group. Another reason for the wide range of pupil responses noted in Table 2 is the interocular and intersubject variability inherent in all tests that rely on administration of topical pharmacologic agents. The large range of piloearpine- indueed pupillary con­striction noted in Table 2 suggests that variables that we did not measure, such as the degree of parasympathetic degeneration and regeneration of efferent pupillomotor fibers, also influence the degree of cholinergic supersen­sitivity. The miotic responses to dilute pilocarpine that were measured in our study reflect the global change in pupil size resulting from the combined summation of the state of cholinergic sensitivity of all individual segments of the iris. Although enhanced cholinergic sensitivity of a segment of the iris sphincter may initially be present after acute denervation, this response may diminish or resolve completely as that segment becomes reinner-vated ( 14). In support of this concept was the observation that the amount of net constriction of the pupil was smaller in the group of patients with third nerve palsy who had signs of aberrant reinnervation, compared with the group who did not. However, the significance of this result should be tempered by the fact that the comparison showed a marginal difference, the result was heavily in­fluenced by a single patient, and the number of patients in both comparison groups was small. Although this re- 9- i & 7 \ * i- 0) E 4" b 3 H 1CH E & o E ro b 9- 7- 3- 2- Baseline Post- Pilocarpine Affected III Palsy Pupil Baseline Post- Pilocarpine Affected Adie's Pupil FIG. 1. Column graphs showing the absolute baseline and post-pilocarpine pupil diameters of the affected pupil in each patient with third nerve palsy ( top) and Adie's syndrome ( bottom). As expected, the affected pupil of each patient become smaller in response to dilute pilocarpine. Although a moderate amount of variability is observed, there was no significant difference in the amount of absolute constriction of the affected pupil between the two groups. suit is compelling, it needs to be confirmed using a greater number of patients. On the other hand, many variables that can influence the degree of cholinergic supersensitivity of the iris sphincter were probably not significant factors in this study. For example, the interval time between onset of ./ Neum- Opluhalmol, Vol. IX. No. J, I99X 174 D. M. JACOBSON AND R. A. VIERKANT 5- 1 * J 9- Baseline Anisocoria Net Constriction III Palsy Baseline Anisocoria Net Constriction Adie's Pupil FIG. 2. Column graphs showing the relationship between the amount of baseline anisocoria and the amount of net constriction of the affected pupil in response to pilocarpine applied to both pupils for each patient with third nerve palsy ( top) and Adie's syndrome ( bottom). In some patients, the affected pupil was smaller than the unaffected pupil, resulting in a negative value for anisocoria. As expected, the amount of net constriction was greater than the degree of baseline anisocoria for both groups of patients because the patients were preselected on the basis that they showed cholinergic supersensitivity. Although a large amount of variability is observed, there was no significant differ­ence in the degree of net constriction of the affected pupil be­tween the two groups. 4- E E c~ o o 3- 2- ( 0 c o O O 1- z + AR - AR Third Nerve Palsy FIG. 3. The median [ horizontal bar) amount of net constriction of the affected pupil in patients with third nerve palsy who had signs of aberrant reinnervation of their affected pupil (+ AR) was smaller than the median amount of this variable in the group of patients with third nerve palsy who did not show such signs (- AR) by a marginally significant degree ( P = 0.052). However, the result of this comparison was heavily influenced by a single pa­tient in the - AR group, a 5- year- old girl with an oculomotor nerve palsy resulting from trauma 2.5 years earlier whose net constric­tion of her affected pupil was 4.6 mm. When this value was re­moved from the comparison, the result was no longer significant ( P= 0.11). the pupil disorder and testing was similar between the two groups. Because our technique of determining the degree of supersensitivity incorporated the fellow eye as an internal control, we eliminated the effects of age, gender, iris color, level of alertness, and state of accom­modation because these variables similarly affect both eyes, not just the involved eye. Larger pupils from many causes other than parasym­pathetic denervation of the iris sphincter constrict more than smaller pupils in response to the same miotic stimu­lus because of mechanical properties of the iris tissue ( 11,15). Because the starting size of the pupils, as well as the baseline anisocoria, was similar in both groups of patients, mechanical resistance of the iris was not a sig­nificant factor influencing the pharmacologic effect of dilute pilocarpine. Ponsford and colleagues ( 2) also investigated whether the degree of supersensitivity differed in patients with preganglionic and postganglionic parasympathetic disor­ders of the oculomotor nerve. They used dilute mefha-choline to test the pupillary responses of 14 patients with third nerve palsy caused by aneurysmal compression and 14 patients with Adie's syndrome, and found similar numbers of patients in both groups whose affected pupil constricted 1.0 mm or more ( 2). However, their results are difficult to interpret in light of the fact that 17% of neurologic control subject pupils, 24% of pupils in pa­tients with subarachnoid hemorrhage without third nerve palsy, and 58% of clinically normal pupils contralateral to the affected pupil in patients with third palsy also constricted 1.0 mm or more ( 2). Methodologic factors ./ Neuro- Ophlhulmol Vol. 18, No. .1 1998 CHOLINERGIC SUPERSENSITIVITY 175 that may have adversely influenced their results included the relatively greater interocular and intrasubject vari­ability of methacholine compared with pilocarpine ( 16), and their technique of testing one eye at a time. In our investigation, we used dilute pilocarpine, a cholinergic agonist with less variability than methacholine, and a pupillometric technique that determined the amount of constriction of the affected pupil while controlling pa­tient factors and interocular variability of drug pen­etrance, the preferred technique advocated by Thompson ( 12). The results of our study contribute new information concerning the development of preganglionic cholinergic supersensitivity. It would appear that the site of injury along the oculomotor parasympathetic pathway in rela­tionship to the ciliary ganglion is not a major factor influencing whether cholinergic supersensitivity of the iris sphincter subsequently develops. It is possible that reduced concentration of acetylcholine or cholinergic stimulation of the iris sphincter resulting from denerva­tion anywhere along the parasympathetic pathway is a satisfactory, although not necessarily sufficient, condi­tion to allow supersensitivity to develop. From a clinical point of view, this study and previous investigations ( 5,11) indicate that evaluating cholinergic supersensitiv­ity, by itself, is not a useful tool to distinguish whether an efferent pupillary defect is due to preganglionic or post­ganglionic damage to the oculomotor nerve. Fortunately, testing for cholinergic supersensitivity is usually not needed to diagnose either an oculomotor nerve palsy or Adie's pupil. Acknowledgment: This study was supported in part by a grant from the Marshfield Medical Research Foundation, Marshfield, Wisconsin. REFERENCES 1. Oono S, Mukuno K. Studies on synkinclic pupillary phenomena resulting from aberrant regeneration of the third nerve. Jptt .1 Clin Ophthalmol 1973; 27: 229- 39. 2. Ponsford JR, Bannister R, Paul EA. Methacholine pupillary re­sponses in third nerve palsy and Adie's syndrome. Brain 1982; 105: 583- 97. 3. Coppeto JR, Monleiro MLR, Young D. Tonic pupils following oculomotor nerve palsies. Ann Ophthalmol 1985; 17: 585- 8. 4. 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