Brit. J. Ophthal. (I975) 59, 387

Ross' syndrome (tonic pupil plus)

THOM:AS R. HEDGES AND EDWARD W. GERNERFrom the Pennsylvania Hospital and the Department of Ophthalmology, University of Pennsylvania, Philadelphia

The tonic pupil is generally defined as a pupil thatis:

(a) found usually in 20 to 40-year-old women,(b) unilateral in go per cent of cases,(c) larger than the uninvolved pupil in lighted sur-

roundings and smaller in unlighted surroundings,(d) essentially unresponsive or sluggish to light and

with a stronger reaction to near,(e) often associated with altered deep tendon re-

flexes (Hedges, I968).It has often been emphasized that the tonic pupil is

a benign condition without systemic implications(Holmes, I93I; Scheie and Albert, 1969). Recentdescriptions of segmental anhidrosis or hypohidrosisin patients with tonic pupils and altered deep tendonreflexes (Ross' syndrome) (Ross, 1958) and the exami-nation of two patients with these findings haveprompted this report and a consideration of the placeof Ross' syndrome with the other dysautonomiasranging from the isolated and uncomplicated tonicpupil through the Shy-Drager syndrome and thesyndrome of pan-dysautonomia.

Report of cases

PATIENT I

A 35-year-old woman was referred to one of us (TRH)by Dr Albert Wagman of Abington Hospital, Abington,Pennsylvania in May 1972 for anisocoria with an un-reactive pupil on the right, first noted in April I97I. Thepatient had been aware of excessive sweating, particularlywhen upset, over the right brow. When aged 3I years,after the birth of a child by Caesarean section, she becameaware of the absence of sweating on the upper part of thetrunk on the right, including the right arm. There was nohistory of bladder or bowel dysfunction, heat intolerance,or orthostatic hypotensive symptoms. At the time of theonset of the anhidrosis the patient was 'depressed' andsought psychiatric consultation. The family history wasnon-contributory. Physical examination revealed thatthere was no sweating on the right side of the face (exceptfor the right brow) and none on the upper trunk on theright to T-7 level and the right arm. The knee and anklejerks were absent bilaterally even with reinforcement.The remainder of the general physical and neurological

Address for reprints: Dr Hedges, the Pennsylvania Hospital, 8thand Spruce Streets, Philadelphia, Pennsylvania 19107, USA

examination was normal. When seen in May 1972, theright pupil was smaller than the left in dim illuminationand larger in a well-lighted room, and did not respond tolight either directly or consensually (Fig. i). The left pupilwas also very sluggish in response to light. Both pupilsresponded to near (Fig. 2) but the reaction on the rightwas sluggish. Near points of accommodation were equal.A 2-5 per cent solution of methacholine chloride causedmarked miosis bilaterally and pilocarpine 0o25 per centalso showed a very positive response bilaterally (Fig. 3).Neosynephrine Ioper cent resulted in dilatation bilaterally.The serology, blood sugar, protein-bound iodine, spinaltap, skull and cervical spine x rays, and electroencephalo-gram were all normal. There has been no change in thepatient's status during the past 2 years. She was last seenin April 1974.

PATIENT 2

This 6o-year-old woman was seen in consultation by oneof us (TRH) on I I November 1973 for anisocoria. Shehad been aware of the left pupil being larger and notresponsive to light ever since childhood. At the age of 46years, after severe emotional trauma (mother's suicide),she noted decreased sweating on the right side of the bodyand excessive sweating on the left. There were no symptomsof heat intolerance, bladder or bowel dysfunction, ororthostatic hypotension. She has two children and noother members of the family have similar difficulties. Onexamination, blood pressure was normal without ortho-static changes. She had decreased sweating over the entireright side of the body. The knee jerks were hypoactivebilaterally and the ankle jerks were absent bilaterallyeven with reinforcement. The left pupil was smaller thanthe right in room light but larger in dim light and did notreact to light either directly or consensually (Fig. 4). Theleft pupil was sluggishly reactive to near and re-dilatedvery slowly. Near points of accommodation were equal.The methacholine chloride (2-5 per cent) test and the025 per cent pilocarpine test showed a positive reactionon the left (Fig. 5). The serology, blood sugar, and skullx rays were normal. This patient' ssigns have not 'pro-gressed' or altered in any way in the I5 years since theanhidrosis was superimposed upon the pupillary anomalynoted since childhood.

DiscussionStrasburger (I 902) described a non-syphilitic youngman with a unilateral dilated pupil which constrictedslowly to both light and near, and dilated slowly

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388 British journal of Ophthalmology

FIG. I Patient r. Dim illumination-right pupil smaller than left. Stippled area shows area ofhyperhydrosis infacial area ofanhydrosison the right

F I G . 2 Patient I. Light-near dissociation showing good reaction to near

when the stimuli were removed. Nonne (I902) andthen Markus (I906) described this peculiar pupillarymovement and noted its association with absentankle and knee jerks. This association of absent deeptendon reflexes with a myotonic pupil is most widelyknown by the eponym of Adie's syndrome after the

man who emphasized the relationship between thesetwo findings. Adie (1932) in his original paper, alsoemphasized the benign, non-progressive nature of thiscondition-an idea which has persisted to the presentday.

After Adie's report, additional cases were added to

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Ross' syndrome (tonic pupil plus) 389

F I G. 3 Patient I. Positive reaction (moisis) to 25 per cent mecholyl and i per cent pilocarpine bilaterally

F I G . 4 Patient 2. Left pupil in dim light larger than left (reverse in bright light) did not react to light directly or consensually

IN~~~~~~~~~~~~~~~~~~~~~~~IIG. 5 Patient 2. Positive miotic reaction on the left to..mecho.yl _ per cent and pilocarpine per cent

F IG . 5 Patient 2. Positive miotic reaction on the left to mecholyl f per cent andpilocarpine iper cent

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390 British Journal of Ophthalmology

the literature but of particular interest were theoccasional findings, as noted by Kennedy, Wortis,Reichard, and Fair (1938) of vasomotor instability,absent oculo-cardiac reflex, and emotional instabilityin some of these patients. Indeed, these findings wereso prominent in some of his patients that Kennedypostulated a lesion in the hypothalamus.

Starting from a solid understanding of pharma-cology and the classic work in denervation hyper-sensitivity, Scheie (I940) described the use of a

2-5 per cent solution of methacholine chloride todemonstrate denervation hypersensitivity in tonicpupils. The positive response of tonic pupils to thisweak solution led the author to postulate that thelesion in Adie's syndrome was situated either in theciliary ganglion or in the post-ganglionic fibres.Subsequent pathological studies demonstrated neuron-al dfgeneration in the ciliary ganglion in Adie'ssyndrome and thus supported his postulate (Harrimanand Garland, I968). The lesion responsible for theabsence of deep tendon reflexes in Adie's syndromehas never been clearly delineated. However, physio-logical studies (Walsh and Hoyt, I969) point to a

segmental spinal cord lesion. Itwas curious, therefore,that more extensive symptoms were not associated withthe syndrome.When Ross (1958) first noted segmental anhidrosis

in a patient with a tonic pupil and hyporeflexia, hebelieved it to be only a chance association, particularlysince the patient had had the tonic pupil for 2 I years

before developing the anhidrosis. Petajan, Danforth,D'Allesio, and Lucas (I965), in a subsequent case

report of Ross' syndrome, suggested that the relation-ship of progressive segmental loss of sweating withAdie's syndrome was, in fact, not fortuitous. Thisopinion has been supported by additional case

reports (Bonnin, Skinner, and Whelan, I96I;Hardin and Gay, I965; Lucy, Van Allen, andThompson, I967; Esterly, Cantolino, Alter, andBrusilow, I968). Moreover, the fact that sweatglands are cholinergically innervated (although partof the sympathetic nervous system) would point toan, as yet, undefined degenerative process of theautonomic nervous system (Petajan and others,I965). This is not to suggest, however, that thesymptoms need be serious or that the process isinvariably progressive. Long-term reports of patients

with Adie's syndrome suggest that longevity is notincompatible with the condition nor is it necessarilyprogressive (Weber, 1933; Laties and Scheie, I965).However, it would now appear that the conditionmay not be benign in all individuals and long-termfollow-ups may be necessary to determine the eventualoutcome.

In addition to the three primary findings con-stituting Ross' syndrome (tonic pupil, progressivesegmental hypohidrosis, and hyporeflexia), orthostatichypotension has been associated with the condition(Croll and Duthie, 1935; Laufer, 1942; Barnett andWagner, 1958). In reviewing the case reports, it wasof interest to note that several of the patients mayhave had even more extensive evidence of autonomicdysfunction. Indeed, Bradbury and Eggleston (I925)speculated that there might be 'some extensive andpeculiar disturbance in the functional activity of thevegetative nervous system'. These findings shade intoeven more extensive conditions. Diseases of the auto-nomic nervous system such as Shy-Drager syndrome(Shy and Drager, I960) and acute autonomic or

pan-dysautonomic neuropathy (Thomashefsky, Hor-witz, and Feingold, 1972; Young, Asbury, Adams,and Corbett, I969; Wichser, Vijayan, and Dreyfus,1972; Appenzellar and Kornfeld, 1973; McIlwain,I966) cause incapacitating widespread difficulty as

well as being associated with a tonic pupil (Table).Neither of our patients, however, had overt evidenceof more extensive autonomic nervous system dys-function at this time.The association of emotional instability with

Adie's syndrome in some patients has been commentedupon (Kennedy and others, 1938; Laufer, 1942). Inboth our cases there seems to have been a largeemotional component in the history. The secondpatient associated the onset of the hypohidrosis with a

psychiatrically traumatic event. This is not conclusive,however, as the patient may only have become aware

of the hypohidrosis at that time and it may, in fact,have preceded the trauma. The association withemotional instability in the first patient is more

convincing as the onset of the hypohidrosis was notedby the patient's husband and, also at this time, thepatient sought psychiatric help for an apparentlytransient emotional problem. Perhaps the associationofthe peripheral autonomic dysfunction with emotion-

Table Tonic pupil plus

Mecholyl Decreased deep Orthostatic PsychiatricSyndrome Tonic pupil test tendon reflexes hypotension difficultyAdie + + + - +Ross + + + + +Shy-Drager + - +Acute pan-dysautonomia + + - +

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Ross' syndrome (tonic pupil plus) 391

al instability is not as remote as it initially appearswhen it is recalled that acetylcholine is a transmitterwithin the brain as well as in the peripheral nervoussystem (Young and others, I969).The ophthalmologist, when confronted with

patients with a tonic pupil, therefore, should notnecessarily dismiss them all as cases ofAdie's syndromeand assume they are benign. Inquiry into orthostatichypotensive symptoms, emotional states, and sweatingdifficulties should be made. In addition, the findingof bilaterality of tonic pupils should alert the ophthal-mologist to the possibility of more widespreadproblems. Loewenfeld and Thompson (I967), in anextensive review of the tonic pupil, noted that whileonly iI per cent of cases of unilateral tonic pupil were'complex', fully 6o per cent of bilateral cases were'complex'. In the cases of Ross' syndrome reported todate only the original case had a unilateral tonicpupil; the remainder had bilateral involvement

(Esterly and others, I968). In our cases, one patienthad unilateral involvement while the other hadbilateral involvement. Thus it would appear thatbilaterality should further heighten the suspicion of amore extensive disease process.

Summary

Two cases of tonic pupil, hyporeflexia, and segmentalhypohidrosis (Ross' syndrome) are reported. Therelationship of this syndrome to other autonomicdysfunctions is discussed. Those symptoms (emotionalinstability, loss of sweating, orthostatic hypotensivesymptoms, and signs of bilaterality of the tonic pupil)which should alert the clinician to more extensivedisease states are noted. It is suggested that theseconditions may represent a continuum or spectrum ofdisorders with a widespread degree of severity andprogression.

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