The Pupil and Headaches

Peter Herman, M.D.

From the Pupillography Lab and the Headache Clinic, Neurology Department, Mount Sinai School ofMedicine, New York, N.Y.

Reprint requests to: Peter Herman, M.D., Pupillography Lab, Annenberg Building 2-12, Mount Sinai MedicalCenter, One Gustave L. Levy Place, New York, N.Y. 10029.

Accepted for Publication: July 6, 1982

SYNOPSIS

Pupillography before and after Cocaine eye drops was performed in twenty patients subject to vascularheadaches. 65% had anisocoria which after Cocaine eye drops increased to 90%. The smaller pupil was notnecessarily on the hemicrania side. Lid droop was observed in nine patients. In ten, the eyelid drooppersisted after Cocaine eye drops. The pupil size was not significantly smaller than in a normal group and itwas round in all but two cases. These findings suggest that patients with cluster and migraine headachehave a subtle chronic sympathetic deficiency which affects both the pupil and eyelid. This deficiency mayincrease during the acute phase, at times causing a prominent Horner Syndrome. Adrenaline deficiency islocally responsible for these changes. No significant changes were found between cluster and vascularheadache patients in this small sample. Pupillography and sympathomimetic eye drops are objective testsin the diagnosis of vascular headache in clinically difficult cases; they are a painless expedient procedure.

(Headache 23:102-105, 1983)

Among ocular abnormalities occurring in vascular headaches, the Horner Syndrome is the most common beingreported with a frequency varying between 5% to 20%.1,2,3,4

The incidence of Horner Syndrome and other pupillary abnormalities are reportedly higher in the cluster varietythan in common migraine.5,6

Further distinction based on clinical aspects, medication response and cerebral circulation sets clusters apartfrom common migraine.7,8 This study reviews the incidence of ocular and pupillary abnormalities in both varieties ofvascular headaches and describes some new findings in combining the use of pupillography and eye drops.

METHOD AND MATERIAL

Twenty patients with vascular headaches referred from the Mount Sinai Headache Clinic were examined. Thegroup included three males and seventeen females. Their age distribution ranged between 17 to 68 (mean 39). Allpatients were chronic headache sufferers and six had mild headaches during the examination. Most were takingmedications for headaches; none of the analgesics used, except for Imipramine, are known to significantly affectpupillary reactions.9,10

Sixteen patients had classic or common migraine and four patients had cluster headaches by accepted criteria.6

Patients were seated for a ten-minute period dark adaptation in the pupillography room. Measurement of eachpupil size and its reaction to light, while the other eye was shielded, was performed with the S1001 GWpupillograph. The light stimulus was a foveally fixated lamp that flashed for 300 msc every four seconds. Pupildiameter and stimulus occurrence were recorded on a 4-channel oscillograph. A detailed description of ourpupillography procedure is given elsewhere.11 After the first recording, 1 gtt. 5% Cocaine was instilled in each eyeand the pupils were measured again after a waiting period of 30 to 35 minutes. The measurement and comparisonof the pupil size, latency to light response and pupillary constriction to light was made directly from the papertracing of the pupillogram which is operated at a sensitivity of ±0.1 mm. The significance of results was calculatedby the student t test. The shape of the pupil was appreciated from the TV screen and the eyelid position wasjudged clinically; it was called significantly prosed if it bordered or covered the pupil proper.

RESULTS

Pupillography demonstrated anisocoria, (mean 0.34 mm.), in 65% of patients before eye drops and in 90%(mean 0.8 mm.) after Cocaine 5%, In 28%, the smaller pupil was on the headache side and in 23%, on theopposite side. The remainder had diffuse headaches.

Fifteen patients out of twenty had an intermediate response, i.e., less than 30% dilation to eye drops (See Table1).

Three patients had dilation over 30% which was arbitrarily called a normal reaction. Three out of the four clusterpatients had a poor response consistent with partial sympathetic deficiency.

Table 1

Constriction Constrictionto Light % to Light %

Intermediate* Pupil Size (mm) Reverse Before Cocaine After CocaineCocaine Response Right Left Ptosis Ptosis Right Left Right Left

ALL VASCULAR In 9 out of 11 None in HEADACHE 15 6.1 6.0 cases seen 11 25.0 25.5 20.0 20.0 MIGRAINE(Classic and common) 11 6.0 5.9 6 - 26.0 25.0 24.0 24.0 CLUSTER 4 6.2 6.1 3 - 24.3 24.7 16.7 16.5

*Intermediate response is dilation, but less than 30%

Complete lack of response to Cocaine was recorded only in three cases. In two patients, the pupil becamesmaller after Cocaine use.

There was a significant lid droop in six, including two cluster patients. Bilateral lid retraction was noted in tenpatients after drops, in six occurring in the lower lid. In ten headache patients, three with cluster, the lid position didnot appear to change after eye drops.

The pupillary constriction to light after eye drops decreased in 15 out of 20 patients, increased in 4, and wasunchanged in 2. The mean pupillary constriction was significantly decreased after eye drops (r <0.5) more so incluster patients (r < 0.1). The delay to light increased in 2, decreased in 6, and was unchanged in 13. Only in twocases was the delay to light longer than what we consider normal,11 i.e., 400 msc.

In three patients, there was a dissociate response i.e., the pupil reacted to drops and the eyelid did not or viceversa (See Table 2). (Redilation lag was noted in 2 patients.)

Comment

The present study shows that subtle anisocoria is present in about 65% of migraineurs. The percentage

Table 2Pupil Response to Cocaine 5%, 1 gtt. O.U.

Unilateral BilateralNone 3 0Intermediate 3 12Good (normal) 0 3Decrease 0 2

Eyelid Response to Cocaine 5%, 1 gtt. O.U.Unilateral Bilateral

None 0 10Retraction 0 10 4 upper

6 lower*Dissociated response 3 0

*Implies that only the eyelid but not the pupil reacted or vice-versa.

of pupillary inequality increases significantly after Cocaine up to 90%, and the anisocoria more than doubles.Before eye drops, only three patients had anisocoria greater than 0.5 mm. Conceivably however; any degree ofanisocoria with lid droop may indicate sympathetic dysfunction.

Such a high percentage and magnitude of anisocoria is not explained by the natural occurrence of unequalpupils in the normal population (about 17%).12 Nor was this a phenomena of simple central anisocoria12 since thepupillary inequality increased with eye drops.

In 75% of our cases, the pupil responded bilaterally but less than 30% to 5% Cocaine which we chose to call anintermediate response; in other words, dilated very slightly. The use of Cocaine eye drops may make the diagnosisof sympathetic deficiency but doesn't allow to differentiate between pre or post ganglionic Horner.3,13,14,15 However,the pharmacologic studies at the Headache Center in Florence have shown, by immunohistologic techniques,decrease of Adrenaline receptors in the iris, along with a "paradoxical" reaction to Noradrenaline in headachepatients.16 There is therefore a body of evidence for corroborating a diagnosis of "post ganglionic Horner" invascular headache.

The site of the sympathetic deficit is of more than theoretical interest since authors with large series of Hornerpatients agree13,14 that a preganglionic Horner may be an ominous finding; about 50% harboring metastatic orprimary neoplasms.

In about 28% of patients, the smaller pupil was on the headache side while in 23%, it was on the opposite side.A Horner Syndrome is thought to occur usually on the headache side and this may be true in complete sympatheticparalysis with obvious lid droop and markedly smaller pupil.2,3,4

The presence of mild bilateral ptosis and bilateral poor pupil reaction even in cases of patients with consistentunilateral headaches suggests that the sympathetic deficiency in vascular headaches involves both eyes. This is ingood accord with well known systemic manifestations of vascular headaches such as temperature imbalance,cardiac rhythm modifica-

tions, mood changes, all of which indicate widespread autonomic dysfunction.6

Moderate lid retraction occurred in ten patients after use of Cocaine with the lower lid retracting more than upper lid (See Table 2).The very technique of instilling eyedrops favors more chemicals in the lower eyelid affecting the inferior Müller muscle. In fresh orcomplete cases of Horner, the eyelids will usually not change position after Cocaine is instilled in the conjunctival sac. The moderateretraction of eyelid in these cases may be similar to the partial response of the pupil to Cocaine.17

The average pupil diameter in migraineurs, ± 6 mm., is not smaller when compared to the age-matched pupil diameter among 1,789normal subjects.12

Most pupil testing were done during headache-free period or only when light headaches were present. Obvious anisocoria and muchless, a full blown Horner were not seen. The presence of a sympathetic deficiency (poorly reacting pupils to Cocaine) at such timessuggest therefore that this sympathetic deficiency is a "chronic" phenomena in migraineurs or at least present in cycles. Thus,Noradrenaline deficiency itself or hormonal changes decreasing or blocking Noradrenaline (Prostaglandin?)6 should be seriouslyconsidered among the neurotransmitters implicated in vascular headache syndromes.

The cluster patients showed no significant difference in percentage and extent of anisocoria when compared with migraine patients;however, lid ptosis was found in three out of four cluster patients and was permanent in one (See Table 1 ). The number of clusterpatients is too small for any significant conclusions.

In migraine headaches, spasms of small cerebral vessels18 and initial slowing of rCBF frequently causes scotoma and rarely ahemispheric syndrome.7,19 In cluster headaches, the spasm occurs in the large vessels (carotid and basilar arteries) and scalp arteriesas shown by angiography - with high rCBF during the attack.20,21,22

The differences between cluster and vascular headaches may be viewed then as differences in the size and location of the affectedvessel rather than a different disease since they are bound and possibly caused by deficiency in similar chemical mediators.

Whether the fluctuations in size and subsequent flow disturbances seen in the carotid arteries and the ophthalmic artery18,19,21,22

spreads to the vessels of the iris is questionable.23 But the full Horner Syndrome occasionally seen during the acute headache attackmay be secondary to the dilatation and edema of the carotid, angiographically proven, affecting the sympathetic fibers coursing alongthe carotid artery.2,18

The Horner Syndrome associated with hemicrania and contralateral long tract signs can be a forebearer of catastrophic carotidartery lesions such as spontaneous dissection or carotid thrombosis.24,25,26

The decrease in pupil size in some patients with sympathetic deficiency after Cocaine was described previously. No goodexplanation is at hand.13

A case report of a patient with headaches describes increased intraocular pressure.27 In a recent study, we have shown that thelight delay is a sensitive indicator of increased ocular pressure.11 In the present series, all patients save two had normal light latency.Therefore, at least when measured during headache free period, there is indirect evidence that the intraocular pressure is probablynormal.11

Although not systematically studied, the redilation of the pupil did not appear affected. This rules out a role for the parasympathetic inthe miosis of headaches.

The coefficient of constriction was decreased significantly after Cocaine drops (See Table 1). This happens because in anincomplete sympathetic lesion, the mild tonic increased in the dilator muscle after Cocaine use, partially opposes the constrictor. In acomplete Homer lesion, pupillary constriction would not be expected to change after Cocaine or Paredrine.

Redilation lag28 was present only in two patients. The redilation lag is probably seen when a large number of fibers are affected.Since in most cases we dealt with only a subtle sympathetic deficiency, its absence is not surprising.

Recent29 and previous reports30 have mentioned abnormal pupil shapes, mostly oval pupils, in strokes syndrome particularly theones affecting the posterior circulation as well as in encephalitis.

The pupil shape was round in all but two of our cases. Therefore, in the presence of a headache syndrome and abnormal pupillaryshape, vascular headache should be at the bottom of the differential diagnosis list.

Dilatation of the pupil with headaches is occasionally mentioned and considered by some a benign condition.5,31 This is a rarephenomena and should keep the neurologist on the alert. Eye drops on such cases should probably not be used and the counsel of aknowledgeable ophthalmologist may be important.

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