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The Pupil in Neurologic Diagnosis
The Pupil in Neurologic Diagnosis ROBERT W. HOLLENHORST, M.D.
The complexity of the neurophysiologic pathways is nowhere better exemplified than by the processes concerned in regulating the pupil. In addition to the neurochemical effects of epinephrine and acetylcholine on the synapses within the system, there are four major innervational factors which regulate the pupillary structures by their continuous interaction-that is, the parasympathetic and sympathetic systems are regulated by both stimulating and inhibiting forces. When to the above considerations are added the numerous and ever-changing environmental stimulatory and inhibitory influences of light, sound, visual factors and other sensory phenomena, it is indeed amazing that we have succeeded in learning so much about this intricate system. The movements of the pupils must have challenged the curiosity of man from the very earliest times. Pliny (A.D. 23-79)27 and Galen (A.D. 131-201)9 wrote of the effects of drugs upon them. The Arabian Rhazes (A.D. 850-923)1 observed pupillary movements and recognized certain pathologic states. In 1619 Scheiner of Vienna, in his book Oculus, first reported the changes in lens curvature and narrowing of the pupil during accommodation. Robert Whytt of Edinburgh in 1765 described the consensual reaction and the near reflex. Magendie in 1841 and Claude Bemard in 1851 and 1852 wrote on the physiology of the pupil. Although Argyll Robertson 4, 5 of Edinburgh gets credit for describing the luetic pupil in 1869, he himself mentioned that Remak in Berlin had shown him several such cases; and Romberg had described such pupils in 1839. Homer, a Swiss, published in 1869 the first full description of a case of cervical sympathetic paralysis in man and deserves to have his name attached to the syndrome as it is, even though there were previous reports on this phenomenon by Petit in 1727, John Reid in 1839, and Bernard 8 in the 1850's. Five years prior to Horner's paper, Weir Mitchell, Morehouse, and Keen 22 ,23 in Philadelphia described an instance of what we call Horner's syndrome which followed a gunshot wound in the neck. Mitchell had studied under Bemard in Paris in 1850-1851 and must have known of his work. Similarly, Adie's paper and Gordon Holmes's paper on the tonic pupil both appeared in 1931, although Foster Moore 24 , 25 had written about it Medical Clinics of North America- VD!. 52, No. 4, July, 1968
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7 years earlier, and Strasburger35 ,36 and Saenger30,31 wrote of it in 1902 (30 years before Adie); James Ware described it in 1813, 118 years before Adie. The history of drugs that affect the pupil is likewise a fascinating story, but beyond the scope of this paper. A comprehensive bibliography on the pupil was offered by Loewenfeld in 1958.
EXAMINATION INSTRUMENTS. Testing of the pupillary reflexes by simple means is difficult, requiring meticulous care; and the results are generally inaccurate, though exceedingly useful in spite of this limitation. A good flashlight and a loupe or slit lamp are essential. A handy accessory device is a small ruler with holes drilled into it, ranging from 1 to 7 mm in diameter, to measure the size of the pupil (Fig. 1). For accurate measurement it is necessary to use Lowenstein's ingenious electronic pupillometer 20 (Fig. 2). This instrument enables the examiner to measure the pupillary responses to light, dark, accommodation, and other stimuli essentially without interference from extraneous factors, for measurements are made in the dark and the pupillary scan is done with infrared light which does not affect the pupil itself. With this instrument, which measures to an accuracy in the range of milliseconds and records on light-sensitized paper, the examiner can study and analyze the findings at leisure, whereas the smallness and darkness of the pupils, their rapid movements, and their variation in size from moment to moment make any other observation most difficult, and one cannot observe both pupils at once directly as he can the records of both from the electronic pupillometer. By this means one can measure accurately the excursions of the pupil and compare its action with that of its neighbor or with the normal values for latency, rapidity, extent of excursion or length of recovery time following a specific stimulus. Thus, by using standardized stimuli and accurate recording in milliseconds, one can record the action of both pupils simultaneously under conditions not possible clinically.
Figure 1. Ruler with graded punch-holes for clinical measurement of pupil size.
THE PUPIL IN NEUROLOGIC DIAGNOSIS
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NEUROANATOMIC PATHWAYS. Because of the complexity of the neural arcs involved, a short review of the neuroanatomic pathways seems in order. 16. 17. 19 Pupillary Light Reflex (Fig. 3). The arc of the pupillary light reflex starts with stimulation of the rods and cones within the retina; these impulses pass through the optic nerves, with partial decussation at the chiasm, and into the optic tract. The afferent pupillary fibers leave the optic tract just before it reaches the lateral geniculate body, and they pass through the brachium of the superior colliculus to reach the pretectum. There the fibers synapse. Half of the postsynaptic fibers go to the homolateral Edinger-Westphal (EW) nucleus and the other half pass through the posterior commissure and enter the opposite EW nucleus. From each EW nucleus, efferent fibers to the sphincter muscle of the iris pass with other third-nerve fibers through the midbrain and cerebral peduncles into the interpeduncular space and along the base of the brain into the orbit. These parasympathetic fibers go with the nerve bundle to the inferior oblique muscle, but leave it to form a short motor root to the ciliary ganglion. Beyond a synapse in the ganglion, the postsynaptic fibers enter the short ciliary nerves near the posterior pole of the eye, and run in the junction zone of the sclera and choroid anteriorly to the sphincter muscle by way of the ciliary plexus. The innervation of the dilator muscle is from the sympathetic nervous system (Fig. 4). The sympathetic pupillary fibers originate in the sympathetic centers in the ventral hypo thalamus and descend along the
Figure 2.
Electronic pupillograph of Lowenstein.
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Short ciliary nn
jJ-----Short motor root Inferior division oculomotor n.
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::---Hr-Cefebrol peduncle
Figure 3. Pupillary light-reflex pathway (schematic).
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Figure 4. Sympathetic innervation of the pupil.
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THE PUPIL IN NEUROLOGIC DIAGNOSIS
875
ventrolateral part of the stem and spinal cord to enter the center of Budge in the cervicothoracic region, where they synapse. The preganglionic fibers leave the cord through the ventral roots of the first and second thoracic segments, enter the first thoracic sympathetic ganglion, and then go up the sympathetic chain to synapse in the superior cervical ganglion. The postganglionic fibers accompany the carotid artery and its branches, traverse the tympanic cavity, re-enter the cranial cavity, and join the Gasserian ganglion. The fibers run via the ophthalmic branch of the fifth cranial nerve into the orbit. Some fibers go directly to the long ciliary nerves and some go first through the ciliary ganglion and thence to the long ciliary nerves. Since the hypo thalamic sympathetic centers are controlled by cortical and thalamic centers, pupillary dilatation may be produced by sensory stimuli, emotions and spontaneous thoughts. The sympathetic system can dilate the pupil actively; but the pupil can dilate passively also, for doubtless there are inhibiting influences on the third-nerve nucleus which arise (1) in cortical area 8 and connect directly to the EW nucleus; (2) in the cortex, from which they traverse the thalamus and hypothalamus first and then go to the EW nucleus; and (3) from every sensory nerve except the optic nerve, these impulses reaching the EW nucleus over a diffuse afferent system in the reticular formation. If the dilator muscle is denervated by a break in the sympathetic pathways, it may become hypersensitive to adrenalin and noradrenalin, especially if the fibers interrupted are postganglionic; and hence, although the pupil usually becomes a little smaller, it may become larger than the other pupil during psychosensory or other stress (so-called paradoxical pupillary dilatation) by reason of release of circulating adrenalin. Similarly, if the sphincter muscle is denervated, it may become hypersensitive to cholinergic substances (as in the Adie pupil when methacholine [Mecholyll chloride is instilled). Constriction of the pupil therefore may be produced (1) by active contraction of the sphincter muscle through parasympathetic thirdnerve fibers; (2) by lessening of the inhibitory influences on the EW nucleus, because of sleep, fatigue, or narcosis, or because of an organic midbrain lesion cephalad to the EW nucleus; (3) by the effect of cholinergic substances after parasympathetic denervation; and (4) by paralysis of the dilator muscle caused by a break in the sympathetic pathways. Dilation of the pupil may be brought about (1) by active contraction of the dilator muscle through sympathetic stimulation; (2) by increased inhibition of the EW nucleus by impulses arising from the cerebral cortex, thalamus, hypothalamus or peripheral sensory pathways; and (3) by the effect of adrenergic substances after sympathetic denervation. Near Reflex. The pathways of the near reflex are less well defined. The afferent arc of the convergence reflex probably arises in the rectus medialis, travels up the third nerve or up the ophthalmic division of the fifth nerve and reaches· the mesencephalic root of the fifth nerve, and from there relays to the convergence center and thence to the EW nucleus. The afferent arc of the accommodative reflex originates in the retina as a response to a blurring of an image, goes to the calcarine
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cortex (area 17), then to the peristriate cortex (area 19), and down the occipito-mesencephalic tract to the midbrain, convergence center and EW nucleus. The efferent arc of both components of the near reflex travels down the third cranial nerve, departs from it proximal to the ciliary ganglion, and relays in an accessory ganglion from which postganglionic fibers reach the sphincter muscle. METHODS OF ELECTRONIC PUPILLOGRAPHY. In preparation for electronic pupillography, the eyes of the subject are dark-adapted, for the testing is done in the dark and the pupils are scanned with infrared light. 1. To test the motor system and the motor pathways in the iris, a series of short flashes are cycled at 1 pulse per second, then 2 per second, and then 3. 2. To test for alternating contraction anisocoria (in which the pupil of the stimulated eye becomes smaller than the consensual pupil, because of an anterior dorsal midbrain lesion damaging the pretectal fibers to the EW nucleus), each eye is alternately stimulated with 1 second of steady light and 3 seconds of darkness. 3. To test for afferent-arc lesions, a light of 0.2 foot-candle (ft-c) is directed, 1 second on and 3 seconds off, into each eye alternately. 4. To test for efferent-arc lesions, a light of 15 ft-c is directed into each eye alternately, with a sensory sound stimulus accompanying. 5. To test for supranuclear inhibitory influences leading to fatiguetype constriction of pupils, a light of 15 ft-c is used with background light. 6. To test for pupillary unrest or spastic pupil, a steady light is directed to the light-adapted eye for 30 seconds and then for cycles of 3 seconds with 1 second of dark. 7. To test for fatigue or narcolepsy, having the patient sit in the dark with no stimulus for 2 to 5 minutes, recording continuously by means of infrared illumination of the pupil. 8. To test the near reflex, using a suitable target to stimulate convergence and accommodation.
NORMAL FINDINGS The components of the pupillary reaction (Fig. 5) are easily tested with the electronic pupillometer. In the contraction period, there is a latent interval of 0.2 to 0.3 second, followed by three distinct phases: (1) a rapid parasympathetic component mediated through the optic nerve, optic tract, pretectal area, third-nerve nucleus, third-nerve fibers, ciliary ganglion and short ciliary nerves to the iris sphincter; (2) a slow inhibitory action exerted on the third-nerve nucleus by the sympathetics from the posterior hypothalamus; and (3) a variable and slower inhibition by the sympathetic system. The peak speed of contraction measures 5.5 to 7.0 mm per sec, and the duration of the contracting movement is 1.0 to 1.3 seconds. Darkadapted pupils normally have a diameter of 6.5 to 8.5 mm, whereas lightadapted pupils measure about 2.5 to 6 mm; hence the extent of contraction ranges from 2.5 to 4.0 mm.
877
THE PUPIL IN NEUROLOGIC DIAGNOSIS
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Components of pupillary reaction.
The stimulating light is removed after 1 second, and after a short latent period of 0.2 to 0.3 second the three phases of dilation begin: (1) a preliminary small dilation and then (2) a faster secondary phaseboth due to relaxation of the parasympathetic influences; then (3) a slow final dilation due to sympathetic action on the dilator muscle. The peak speed of re dilation ranges from 3.0 to 4.5 mm per sec. Necessarily, if the parasympathetic system is damaged, the pupil will contract poorly. If the sympathetic system is damaged, the first phase of contraction will be accomplished but the second will be diminished and the third absent, resulting in the so-called tonohaptic or square pattern on the graph. If the sympathetic system is hyperactive, the first phase of contraction will be normal but the second and third phases will be prolonged.
DISORDERS AND ABNORMAL FINDINGS LESION IN AFFERENT ARC OF LIGHT REFLEX:17 (FIG. 6). Lesions of the retina, optic nerve, chiasm, and optic tract interfere with the transmission of the requisite amount of light stimulus. The pupils remain of equal size, both in light and in darkness. There are normal reactions in both pupils when the good eye receives the stimulus, but the following abnormal reactions in both pupils when the affected eye is stimulated: (1) lengthened latent period; (2) diminished extent of contraction; (3) shortened contraction time; (4) low-intensity reaction (little or no contraction in response to low-intensity stimuli) and frequent V and W shapes on the pupillogram; and (5) pupillary escape phenomenon (the
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Pattern of pupillary responses in lesion of the afferent arc, right eye.
pupil contracts with a bright stimulus and stays small if it continues, but re dilates if the light intensity is reduced). The clinician can easily test for this condition by stimulating the eyes alternately with a flashlight and comparing the responses of the directly and consensually stimulated eyes. ALTERNATING CONTRACTION ANISOCORIA 15 (FIG. 7). A dysfunction that may be unilateral or bilateral, alternating contraction anisocoria is characterized by greater pupillary reactivity in the directly stimulated eye than in the consensually reacting pupil. It is caused by damage in the anterior dorsal midbrain, involving the pathway from the pretectal area to the EW nucleus. In light, the affected pupil is usually smaller than the other; but the two have equal size in the dark. This condition is rare, and practically impossible to diagnose without the pupillometer. Dark
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Alternating contraction anisocoria, bilateral.
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THE PUPIL IN NEUROLOGIC DIAGNOSIS
ARGYLL ROBERTSON PUPILS. 18 Also either unilateral or bilateral, the condition known as Argyll Robertson pupil is nearly always due to syphilis. It is thought to be due to lesions in the afferent pupillary pathways from the pretectal synapses to the EW nucleus. Such pupils are spastic and hence markedly miotic in both light and darkness, and irregular and unequal. Stimulation with light is followed by a prolonged latent period, then sluggish and inextensive reflexes, or none; but their response to near stimuli is normal or almost so. Clinically, the fully developed Argyll Robertson pupil is easily diagnosed without pupillography and is pathognomonic of syphilis of the central nervous system. An incomplete pattern, however, though often luetic in origin, may be confused with other pupillary defects. PERIPHERAL SYMPATHETIC LESION (HORNER'S PUPIL) (FIG. 8). A lesion affecting the peripheral sympathetic innervation of the eye (producing Horner's pupil) usually is unilateral, and the affected pupil is smaller both in light and in darkness. It contracts faster than normal in reaction to light, producing a tonohaptic shape on the graph of the pupillary reflex. The final re dilation wave is absent. Psychosensory dilation is reduced or absent. Since postganglionic sympathetic fibers are hypersensitive to epinephrine and refractive to cocaine when interrupted, Jaffe's pharmacologic tests are often helpful in localizing the site of the lesion. After the initial pupillographic measurement, 4 per cent cocaine solution is instilled into each eye; and 30 minutes later a pupillographic tracing is made. Then 0.1 per cent epinephrine solution is instilled into each eye, and after 20 minutes the pupillography is repeated. Finally 1 per cent homatropine hydro bromide is instilled and a third pupillogram is made. The results in cases of Horner's pupil are as shown in Table 1. Clinically, Horner's pupil is fairly easy to diagnose, for in addition to
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Reactions to Jaffe's Tests in Cases of Horner's Pupil PUPILLARY REACTION TO
NEURON HAVING LESION
COCAINE
EPINEPHRINE
HOMATROPINE
First Second Third
Good None None
None Mild dilatation Strong 'dilatation
Poor Poor Poor
the pupillary signs listed above, the homolateral palpebral fissure is narrowed by slight ptosis of the upper lid and slight elevation of the lower lid, both caused by paresis of Muller's muscles. ANISOCORIA DUE TO THIRD-NERVE PARESIS (FIG. 9). If anisocoria is due to paresis of the third nerve, the homolateral pupil becomes dilated; but in darkness the anisocoria is lessened by the dilation of the normal pupil. Reactions of the affected pupil are sluggish and inextensive, perhaps nonexistent; but psychosensory reactions are unimpaired. Clinically, the pupil appears moderately dilated and poorly reactive, often with associated signs of paresis in extraocular muscles. It does not have the slow tonic reaction of the Adie pupil. ANISOCORIA DUE TO ADIE'S (TONIC) PUPIL (FIG. 10). Unilaterality is a preponderant characteristic of Adie's (tonic) pupil, which is another cause of anisocoria. The moderately enlarged pupil usually tends to equalize with the opposite pupil in the dark. Contraction in response to light is very slow and almost imperceptible; and the contraction with
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881
THE PUPIL IN NEUROLOGIC DIAGNOSIS
near focus is similar, though more extensive. Redilation is also very sluggish and delayed. The causative lesion is in the ciliary ganglion. Clinically, the tonic pupil is relatively simple to diagnose. When the accommodative function is affected, as not infrequently it is, the condition may be confused with paresis of the third nerve; but the characteristic slow tonic contraction and re dilation of the tonic pupil is not seen in oculomotor-nerve paresis. Also, the frequent absence of tendon reflexes and the hypersensitivity of the tonic pupil to 21/2 per cent methacholine chloride are helpful in corroboration.: l • 14. :12, :J3 MISCELLANEOUS. In addition to the more common lesions discussed above, irritative lesions in the diencephalon, like states of excitement or schizophrenia, may cause the pupils to exhibit very wide dilatation and to have either no light reflex or sluggish inextensive reflexes of short duration that make V and W shapes in the pupillogram. Such pupils dilate even further under psychosensory stimulation. That the parasympathetic arc is intact is demonstrable in the differential curves, for the light reflexes show a normal peak speed of contraction which increases on repeated stimuli as the hyperirritable sympathetic system becomes fatigued. Miosis likewise may result from diencephalic lesions if they paralyze the supranuclear inhibiting sympathetic fibers which pass from the diencephalon to the EW nucleus. Such lesions may be of postencephalitic origin, or may result from multiple sclerosis or arteriosclerosis. The pupillogram indicates miosis with a shortened latent period and fast, abrupt, though less than normally extensive light reflexes, which produce tonohaptic shapes and are always bilateral. Narcolepsy typically Li ght
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Adie's tonic pupil.
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causes pupils to be small during the somnolent periods and large during the alert periods, so that pupillographic tracings are characteristically composed of alternating periods of mydriasis and miosis. All of these pupillary symptoms and their neurologic significances are presented concisely in Table 2.
Table 2. Neurologic Significance of Pupillary Abnormalities (Assuming No Influence of Systemic or Local Drugs or of Ocular Disease) 1. Pupils of Normal Size
II.
Ill.
IV.
V.
A. One pupil reacts less well to both light and accommodation, but may contract slowly in response to such stimuli Adie's pupil B. Both pupils react better when one eye is stimulated than when the other eye is stimulated Lesion in afferent arc C. One pupil reacts poorly to light but well to accommodation Lesion in vicinity of EW nucleus D. Both pupils react poorly or do not react to light and accommodation Bilateral Adie's pupil Lesions of afferent arcs for both eyes Lesion of midbrain E. Both pupils react poorly to light but well to accommodation Lesion of midbrain in vicinity of EW nucleus Pupils Miotic A. Both pupils react poorly to light but well to accommodation Lesion in afferent arc at pretectum. probably from syphilis B. Both pupils react poorly to accommodation but well to light Lesion in pathway between convergence center and EW nucleus, ventral to aqueduct of Sylvius C. Both pupils react well Normal May be bilateral intramedullary lesion; or lesion of medulla, pons, or midbrain Both Pupils Dilated A. Dilatation is only moderate; both pupils react well Probably no lesion; often accompanies myopia B. Both pupils are widely dilated, and reflexes are sluggish or absent Anxiety or psychosis Diencephalic irritative lesion C. Both pupils react poorly to light or accommodation, or both Lesion in afferent arc, both eyes Lesion in midbrain or interpeduncular space Bilateral peripheral third-nerve lesions Adie's pupils, bilateral One Pupil Normal Size, the Other Small A. Reactions are normal Physiologic anisocoria Smaller pupil Horner's pupil (persists in darkness; use cocaine-epinephrine test) B. Smaller pupil reacts poorly to light and accommodation Adie's pupil (if recently in light) Pretectallesion, probably from syphilis (if not associated with loss of light reflex) Combined lesion of sympathetic and third cranial nerve, as in Raeder's paratrigeminal syndrome One Pupil of Normal Size, the Other Dilated A. Reactions are normal Physiologic anisocoria B. Reactions of larger pupil are diminished or absent Adie's pupil (test with 2.5 % methacholine or 0.25% physostigmine) Lesion in course of homolateral third nerve C. Light reflexes of larger pupil are diminished or absent, but accommodation is normalor vice versa Adie's pupil Lesion in midbrain near EW nucleus
THE PUPIL IN NEUROLOGIC DIAGNOSIS
883
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HOLLENHORST
35. Strasburger, J.: Pupillentriigheit bei Accommodation und Convergenz. Neurol Zbl 21:738-740 (Aug. 16) 1902. 36. Strasburger, J.: Pupillentriigheit bei Accommodation und Convergenz od er myotonische Pupillenbewegung? Neurol Zbl 21: 1052-1054 (Nov. 16) 1902. 37. Thompson, H. S.: Afferent pupillary defects: Pupillary findings associated with defects of the afferent arm of the pupillary light reflex arc. Amer J Ophthal 62:860-87:3 (Nov.) 1966. 38. Ware, J.: Observations relative to the near and distant sight of different persons. Phi! Trans RoySoc London, 1813, pp. 31-50. 39. Why tt, R.: Observations of the Nature, Causes and Cure of Those Disorders Which Have Been Commonly Called Nervous Hypochondriac, or Hysteric. Ed. 2, Edinburgh, T. Becket, 1765, pp. 16-17.
The complexity of the neurophysiologic pathways is nowhere better exemplified than by the processes concerned in regulating the pupil. In addition to the neurochemical effects of epinephrine and acetylcholine on the synapses within the system, there are four major innervational factors which regulate the pupillary structures by their continuous interaction-that is, the parasympathetic and sympathetic systems are regulated by both stimulating and inhibiting forces. When to the above considerations are added the numerous and ever-changing environmental stimulatory and inhibitory influences of light, sound, visual factors and other sensory phenomena, it is indeed amazing that we have succeeded in learning so much about this intricate system. The movements of the pupils must have challenged the curiosity of man from the very earliest times. Pliny (A.D. 23-79)27 and Galen (A.D. 131-201)9 wrote of the effects of drugs upon them. The Arabian Rhazes (A.D. 850-923)1 observed pupillary movements and recognized certain pathologic states. In 1619 Scheiner of Vienna, in his book Oculus, first reported the changes in lens curvature and narrowing of the pupil during accommodation. Robert Whytt of Edinburgh in 1765 described the consensual reaction and the near reflex. Magendie in 1841 and Claude Bemard in 1851 and 1852 wrote on the physiology of the pupil. Although Argyll Robertson 4, 5 of Edinburgh gets credit for describing the luetic pupil in 1869, he himself mentioned that Remak in Berlin had shown him several such cases; and Romberg had described such pupils in 1839. Homer, a Swiss, published in 1869 the first full description of a case of cervical sympathetic paralysis in man and deserves to have his name attached to the syndrome as it is, even though there were previous reports on this phenomenon by Petit in 1727, John Reid in 1839, and Bernard 8 in the 1850's. Five years prior to Horner's paper, Weir Mitchell, Morehouse, and Keen 22 ,23 in Philadelphia described an instance of what we call Horner's syndrome which followed a gunshot wound in the neck. Mitchell had studied under Bemard in Paris in 1850-1851 and must have known of his work. Similarly, Adie's paper and Gordon Holmes's paper on the tonic pupil both appeared in 1931, although Foster Moore 24 , 25 had written about it Medical Clinics of North America- VD!. 52, No. 4, July, 1968
871
872
ROBERT
W.
HOLLENHORST
7 years earlier, and Strasburger35 ,36 and Saenger30,31 wrote of it in 1902 (30 years before Adie); James Ware described it in 1813, 118 years before Adie. The history of drugs that affect the pupil is likewise a fascinating story, but beyond the scope of this paper. A comprehensive bibliography on the pupil was offered by Loewenfeld in 1958.
EXAMINATION INSTRUMENTS. Testing of the pupillary reflexes by simple means is difficult, requiring meticulous care; and the results are generally inaccurate, though exceedingly useful in spite of this limitation. A good flashlight and a loupe or slit lamp are essential. A handy accessory device is a small ruler with holes drilled into it, ranging from 1 to 7 mm in diameter, to measure the size of the pupil (Fig. 1). For accurate measurement it is necessary to use Lowenstein's ingenious electronic pupillometer 20 (Fig. 2). This instrument enables the examiner to measure the pupillary responses to light, dark, accommodation, and other stimuli essentially without interference from extraneous factors, for measurements are made in the dark and the pupillary scan is done with infrared light which does not affect the pupil itself. With this instrument, which measures to an accuracy in the range of milliseconds and records on light-sensitized paper, the examiner can study and analyze the findings at leisure, whereas the smallness and darkness of the pupils, their rapid movements, and their variation in size from moment to moment make any other observation most difficult, and one cannot observe both pupils at once directly as he can the records of both from the electronic pupillometer. By this means one can measure accurately the excursions of the pupil and compare its action with that of its neighbor or with the normal values for latency, rapidity, extent of excursion or length of recovery time following a specific stimulus. Thus, by using standardized stimuli and accurate recording in milliseconds, one can record the action of both pupils simultaneously under conditions not possible clinically.
Figure 1. Ruler with graded punch-holes for clinical measurement of pupil size.
THE PUPIL IN NEUROLOGIC DIAGNOSIS
873
NEUROANATOMIC PATHWAYS. Because of the complexity of the neural arcs involved, a short review of the neuroanatomic pathways seems in order. 16. 17. 19 Pupillary Light Reflex (Fig. 3). The arc of the pupillary light reflex starts with stimulation of the rods and cones within the retina; these impulses pass through the optic nerves, with partial decussation at the chiasm, and into the optic tract. The afferent pupillary fibers leave the optic tract just before it reaches the lateral geniculate body, and they pass through the brachium of the superior colliculus to reach the pretectum. There the fibers synapse. Half of the postsynaptic fibers go to the homolateral Edinger-Westphal (EW) nucleus and the other half pass through the posterior commissure and enter the opposite EW nucleus. From each EW nucleus, efferent fibers to the sphincter muscle of the iris pass with other third-nerve fibers through the midbrain and cerebral peduncles into the interpeduncular space and along the base of the brain into the orbit. These parasympathetic fibers go with the nerve bundle to the inferior oblique muscle, but leave it to form a short motor root to the ciliary ganglion. Beyond a synapse in the ganglion, the postsynaptic fibers enter the short ciliary nerves near the posterior pole of the eye, and run in the junction zone of the sclera and choroid anteriorly to the sphincter muscle by way of the ciliary plexus. The innervation of the dilator muscle is from the sympathetic nervous system (Fig. 4). The sympathetic pupillary fibers originate in the sympathetic centers in the ventral hypo thalamus and descend along the
Figure 2.
Electronic pupillograph of Lowenstein.
874
ROBERT
W.
HOLLENHORST
Short ciliary nn
jJ-----Short motor root Inferior division oculomotor n.
I - - - - - - of
::---Hr-Cefebrol peduncle
Figure 3. Pupillary light-reflex pathway (schematic).
HYPOTHAlAMUS;~::~==~~~~r'~
CIL..IARY
GANGLION
SUPERIOR
--- - ------------
SYMPA T HE TI C INH I BITING
CERVICAL
GANGLION
PATHWAYS
PATHWAYS
••• • • • ____ • _ __ _ ••• •• • •• • PARASVMPATHETIC
P ATHWAYS
Figure 4. Sympathetic innervation of the pupil.
I\J)\,<:---
CILl OS PINAL CENTER OF
BUDGE
THE PUPIL IN NEUROLOGIC DIAGNOSIS
875
ventrolateral part of the stem and spinal cord to enter the center of Budge in the cervicothoracic region, where they synapse. The preganglionic fibers leave the cord through the ventral roots of the first and second thoracic segments, enter the first thoracic sympathetic ganglion, and then go up the sympathetic chain to synapse in the superior cervical ganglion. The postganglionic fibers accompany the carotid artery and its branches, traverse the tympanic cavity, re-enter the cranial cavity, and join the Gasserian ganglion. The fibers run via the ophthalmic branch of the fifth cranial nerve into the orbit. Some fibers go directly to the long ciliary nerves and some go first through the ciliary ganglion and thence to the long ciliary nerves. Since the hypo thalamic sympathetic centers are controlled by cortical and thalamic centers, pupillary dilatation may be produced by sensory stimuli, emotions and spontaneous thoughts. The sympathetic system can dilate the pupil actively; but the pupil can dilate passively also, for doubtless there are inhibiting influences on the third-nerve nucleus which arise (1) in cortical area 8 and connect directly to the EW nucleus; (2) in the cortex, from which they traverse the thalamus and hypothalamus first and then go to the EW nucleus; and (3) from every sensory nerve except the optic nerve, these impulses reaching the EW nucleus over a diffuse afferent system in the reticular formation. If the dilator muscle is denervated by a break in the sympathetic pathways, it may become hypersensitive to adrenalin and noradrenalin, especially if the fibers interrupted are postganglionic; and hence, although the pupil usually becomes a little smaller, it may become larger than the other pupil during psychosensory or other stress (so-called paradoxical pupillary dilatation) by reason of release of circulating adrenalin. Similarly, if the sphincter muscle is denervated, it may become hypersensitive to cholinergic substances (as in the Adie pupil when methacholine [Mecholyll chloride is instilled). Constriction of the pupil therefore may be produced (1) by active contraction of the sphincter muscle through parasympathetic thirdnerve fibers; (2) by lessening of the inhibitory influences on the EW nucleus, because of sleep, fatigue, or narcosis, or because of an organic midbrain lesion cephalad to the EW nucleus; (3) by the effect of cholinergic substances after parasympathetic denervation; and (4) by paralysis of the dilator muscle caused by a break in the sympathetic pathways. Dilation of the pupil may be brought about (1) by active contraction of the dilator muscle through sympathetic stimulation; (2) by increased inhibition of the EW nucleus by impulses arising from the cerebral cortex, thalamus, hypothalamus or peripheral sensory pathways; and (3) by the effect of adrenergic substances after sympathetic denervation. Near Reflex. The pathways of the near reflex are less well defined. The afferent arc of the convergence reflex probably arises in the rectus medialis, travels up the third nerve or up the ophthalmic division of the fifth nerve and reaches· the mesencephalic root of the fifth nerve, and from there relays to the convergence center and thence to the EW nucleus. The afferent arc of the accommodative reflex originates in the retina as a response to a blurring of an image, goes to the calcarine
876
ROBERT
W.
HOLLENHORST
cortex (area 17), then to the peristriate cortex (area 19), and down the occipito-mesencephalic tract to the midbrain, convergence center and EW nucleus. The efferent arc of both components of the near reflex travels down the third cranial nerve, departs from it proximal to the ciliary ganglion, and relays in an accessory ganglion from which postganglionic fibers reach the sphincter muscle. METHODS OF ELECTRONIC PUPILLOGRAPHY. In preparation for electronic pupillography, the eyes of the subject are dark-adapted, for the testing is done in the dark and the pupils are scanned with infrared light. 1. To test the motor system and the motor pathways in the iris, a series of short flashes are cycled at 1 pulse per second, then 2 per second, and then 3. 2. To test for alternating contraction anisocoria (in which the pupil of the stimulated eye becomes smaller than the consensual pupil, because of an anterior dorsal midbrain lesion damaging the pretectal fibers to the EW nucleus), each eye is alternately stimulated with 1 second of steady light and 3 seconds of darkness. 3. To test for afferent-arc lesions, a light of 0.2 foot-candle (ft-c) is directed, 1 second on and 3 seconds off, into each eye alternately. 4. To test for efferent-arc lesions, a light of 15 ft-c is directed into each eye alternately, with a sensory sound stimulus accompanying. 5. To test for supranuclear inhibitory influences leading to fatiguetype constriction of pupils, a light of 15 ft-c is used with background light. 6. To test for pupillary unrest or spastic pupil, a steady light is directed to the light-adapted eye for 30 seconds and then for cycles of 3 seconds with 1 second of dark. 7. To test for fatigue or narcolepsy, having the patient sit in the dark with no stimulus for 2 to 5 minutes, recording continuously by means of infrared illumination of the pupil. 8. To test the near reflex, using a suitable target to stimulate convergence and accommodation.
NORMAL FINDINGS The components of the pupillary reaction (Fig. 5) are easily tested with the electronic pupillometer. In the contraction period, there is a latent interval of 0.2 to 0.3 second, followed by three distinct phases: (1) a rapid parasympathetic component mediated through the optic nerve, optic tract, pretectal area, third-nerve nucleus, third-nerve fibers, ciliary ganglion and short ciliary nerves to the iris sphincter; (2) a slow inhibitory action exerted on the third-nerve nucleus by the sympathetics from the posterior hypothalamus; and (3) a variable and slower inhibition by the sympathetic system. The peak speed of contraction measures 5.5 to 7.0 mm per sec, and the duration of the contracting movement is 1.0 to 1.3 seconds. Darkadapted pupils normally have a diameter of 6.5 to 8.5 mm, whereas lightadapted pupils measure about 2.5 to 6 mm; hence the extent of contraction ranges from 2.5 to 4.0 mm.
877
THE PUPIL IN NEUROLOGIC DIAGNOSIS
6
E: E:
Da rk
,-
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Redilation
Li ght
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Figure 5.
Components of pupillary reaction.
The stimulating light is removed after 1 second, and after a short latent period of 0.2 to 0.3 second the three phases of dilation begin: (1) a preliminary small dilation and then (2) a faster secondary phaseboth due to relaxation of the parasympathetic influences; then (3) a slow final dilation due to sympathetic action on the dilator muscle. The peak speed of re dilation ranges from 3.0 to 4.5 mm per sec. Necessarily, if the parasympathetic system is damaged, the pupil will contract poorly. If the sympathetic system is damaged, the first phase of contraction will be accomplished but the second will be diminished and the third absent, resulting in the so-called tonohaptic or square pattern on the graph. If the sympathetic system is hyperactive, the first phase of contraction will be normal but the second and third phases will be prolonged.
DISORDERS AND ABNORMAL FINDINGS LESION IN AFFERENT ARC OF LIGHT REFLEX:17 (FIG. 6). Lesions of the retina, optic nerve, chiasm, and optic tract interfere with the transmission of the requisite amount of light stimulus. The pupils remain of equal size, both in light and in darkness. There are normal reactions in both pupils when the good eye receives the stimulus, but the following abnormal reactions in both pupils when the affected eye is stimulated: (1) lengthened latent period; (2) diminished extent of contraction; (3) shortened contraction time; (4) low-intensity reaction (little or no contraction in response to low-intensity stimuli) and frequent V and W shapes on the pupillogram; and (5) pupillary escape phenomenon (the
878 e: e:
ROBERT
Dark 15 It . c right eye
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I
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HOLLENHORST
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6
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Figure 6.
Pattern of pupillary responses in lesion of the afferent arc, right eye.
pupil contracts with a bright stimulus and stays small if it continues, but re dilates if the light intensity is reduced). The clinician can easily test for this condition by stimulating the eyes alternately with a flashlight and comparing the responses of the directly and consensually stimulated eyes. ALTERNATING CONTRACTION ANISOCORIA 15 (FIG. 7). A dysfunction that may be unilateral or bilateral, alternating contraction anisocoria is characterized by greater pupillary reactivity in the directly stimulated eye than in the consensually reacting pupil. It is caused by damage in the anterior dorsal midbrain, involving the pathway from the pretectal area to the EW nucleus. In light, the affected pupil is usually smaller than the other; but the two have equal size in the dark. This condition is rare, and practically impossible to diagnose without the pupillometer. Dark
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Figure 7.
Alternating contraction anisocoria, bilateral.
5
879
THE PUPIL IN NEUROLOGIC DIAGNOSIS
ARGYLL ROBERTSON PUPILS. 18 Also either unilateral or bilateral, the condition known as Argyll Robertson pupil is nearly always due to syphilis. It is thought to be due to lesions in the afferent pupillary pathways from the pretectal synapses to the EW nucleus. Such pupils are spastic and hence markedly miotic in both light and darkness, and irregular and unequal. Stimulation with light is followed by a prolonged latent period, then sluggish and inextensive reflexes, or none; but their response to near stimuli is normal or almost so. Clinically, the fully developed Argyll Robertson pupil is easily diagnosed without pupillography and is pathognomonic of syphilis of the central nervous system. An incomplete pattern, however, though often luetic in origin, may be confused with other pupillary defects. PERIPHERAL SYMPATHETIC LESION (HORNER'S PUPIL) (FIG. 8). A lesion affecting the peripheral sympathetic innervation of the eye (producing Horner's pupil) usually is unilateral, and the affected pupil is smaller both in light and in darkness. It contracts faster than normal in reaction to light, producing a tonohaptic shape on the graph of the pupillary reflex. The final re dilation wave is absent. Psychosensory dilation is reduced or absent. Since postganglionic sympathetic fibers are hypersensitive to epinephrine and refractive to cocaine when interrupted, Jaffe's pharmacologic tests are often helpful in localizing the site of the lesion. After the initial pupillographic measurement, 4 per cent cocaine solution is instilled into each eye; and 30 minutes later a pupillographic tracing is made. Then 0.1 per cent epinephrine solution is instilled into each eye, and after 20 minutes the pupillography is repeated. Finally 1 per cent homatropine hydro bromide is instilled and a third pupillogram is made. The results in cases of Horner's pupil are as shown in Table 1. Clinically, Horner's pupil is fairly easy to diagnose, for in addition to
Dark
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Figure 8.
Horner's pupil.
%............... .
880
ROBERT
Table 1.
W.
HOLLENHORST
Reactions to Jaffe's Tests in Cases of Horner's Pupil PUPILLARY REACTION TO
NEURON HAVING LESION
COCAINE
EPINEPHRINE
HOMATROPINE
First Second Third
Good None None
None Mild dilatation Strong 'dilatation
Poor Poor Poor
the pupillary signs listed above, the homolateral palpebral fissure is narrowed by slight ptosis of the upper lid and slight elevation of the lower lid, both caused by paresis of Muller's muscles. ANISOCORIA DUE TO THIRD-NERVE PARESIS (FIG. 9). If anisocoria is due to paresis of the third nerve, the homolateral pupil becomes dilated; but in darkness the anisocoria is lessened by the dilation of the normal pupil. Reactions of the affected pupil are sluggish and inextensive, perhaps nonexistent; but psychosensory reactions are unimpaired. Clinically, the pupil appears moderately dilated and poorly reactive, often with associated signs of paresis in extraocular muscles. It does not have the slow tonic reaction of the Adie pupil. ANISOCORIA DUE TO ADIE'S (TONIC) PUPIL (FIG. 10). Unilaterality is a preponderant characteristic of Adie's (tonic) pupil, which is another cause of anisocoria. The moderately enlarged pupil usually tends to equalize with the opposite pupil in the dark. Contraction in response to light is very slow and almost imperceptible; and the contraction with
Li 9 ht
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....
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......
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~ ::...,
....
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R or L
7
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,
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4
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Seconds Figure 9. Anisocoria due to paresis of third nerve on right. Note preservation of sympathetic psychosensory dilatation. Right pupil is dilated in light, but pupils are of equal size in dark or under infrared illumination.
881
THE PUPIL IN NEUROLOGIC DIAGNOSIS
near focus is similar, though more extensive. Redilation is also very sluggish and delayed. The causative lesion is in the ciliary ganglion. Clinically, the tonic pupil is relatively simple to diagnose. When the accommodative function is affected, as not infrequently it is, the condition may be confused with paresis of the third nerve; but the characteristic slow tonic contraction and re dilation of the tonic pupil is not seen in oculomotor-nerve paresis. Also, the frequent absence of tendon reflexes and the hypersensitivity of the tonic pupil to 21/2 per cent methacholine chloride are helpful in corroboration.: l • 14. :12, :J3 MISCELLANEOUS. In addition to the more common lesions discussed above, irritative lesions in the diencephalon, like states of excitement or schizophrenia, may cause the pupils to exhibit very wide dilatation and to have either no light reflex or sluggish inextensive reflexes of short duration that make V and W shapes in the pupillogram. Such pupils dilate even further under psychosensory stimulation. That the parasympathetic arc is intact is demonstrable in the differential curves, for the light reflexes show a normal peak speed of contraction which increases on repeated stimuli as the hyperirritable sympathetic system becomes fatigued. Miosis likewise may result from diencephalic lesions if they paralyze the supranuclear inhibiting sympathetic fibers which pass from the diencephalon to the EW nucleus. Such lesions may be of postencephalitic origin, or may result from multiple sclerosis or arteriosclerosis. The pupillogram indicates miosis with a shortened latent period and fast, abrupt, though less than normally extensive light reflexes, which produce tonohaptic shapes and are always bilateral. Narcolepsy typically Li ght
DarK
L. eye
8
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7
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....
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............................... .
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..............
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Figure 10.
Adie's tonic pupil.
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'"
'.
.....
....
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::::
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~
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.'"
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-
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3
882
ROBERT
W.
HOLLENHORST
causes pupils to be small during the somnolent periods and large during the alert periods, so that pupillographic tracings are characteristically composed of alternating periods of mydriasis and miosis. All of these pupillary symptoms and their neurologic significances are presented concisely in Table 2.
Table 2. Neurologic Significance of Pupillary Abnormalities (Assuming No Influence of Systemic or Local Drugs or of Ocular Disease) 1. Pupils of Normal Size
II.
Ill.
IV.
V.
A. One pupil reacts less well to both light and accommodation, but may contract slowly in response to such stimuli Adie's pupil B. Both pupils react better when one eye is stimulated than when the other eye is stimulated Lesion in afferent arc C. One pupil reacts poorly to light but well to accommodation Lesion in vicinity of EW nucleus D. Both pupils react poorly or do not react to light and accommodation Bilateral Adie's pupil Lesions of afferent arcs for both eyes Lesion of midbrain E. Both pupils react poorly to light but well to accommodation Lesion of midbrain in vicinity of EW nucleus Pupils Miotic A. Both pupils react poorly to light but well to accommodation Lesion in afferent arc at pretectum. probably from syphilis B. Both pupils react poorly to accommodation but well to light Lesion in pathway between convergence center and EW nucleus, ventral to aqueduct of Sylvius C. Both pupils react well Normal May be bilateral intramedullary lesion; or lesion of medulla, pons, or midbrain Both Pupils Dilated A. Dilatation is only moderate; both pupils react well Probably no lesion; often accompanies myopia B. Both pupils are widely dilated, and reflexes are sluggish or absent Anxiety or psychosis Diencephalic irritative lesion C. Both pupils react poorly to light or accommodation, or both Lesion in afferent arc, both eyes Lesion in midbrain or interpeduncular space Bilateral peripheral third-nerve lesions Adie's pupils, bilateral One Pupil Normal Size, the Other Small A. Reactions are normal Physiologic anisocoria Smaller pupil Horner's pupil (persists in darkness; use cocaine-epinephrine test) B. Smaller pupil reacts poorly to light and accommodation Adie's pupil (if recently in light) Pretectallesion, probably from syphilis (if not associated with loss of light reflex) Combined lesion of sympathetic and third cranial nerve, as in Raeder's paratrigeminal syndrome One Pupil of Normal Size, the Other Dilated A. Reactions are normal Physiologic anisocoria B. Reactions of larger pupil are diminished or absent Adie's pupil (test with 2.5 % methacholine or 0.25% physostigmine) Lesion in course of homolateral third nerve C. Light reflexes of larger pupil are diminished or absent, but accommodation is normalor vice versa Adie's pupil Lesion in midbrain near EW nucleus
THE PUPIL IN NEUROLOGIC DIAGNOSIS
883
REFERENCES 1. Abu Bekr (Rhazes), Muhammad ben Zakharia Alrazi, cited by Loewenfeld, 1. E.':I 2. Adie, W. J.: Argyll Robertson pupils true and false. Brit Med J 2:136-138 (July 25) 1931. 3. Adler, F. H., and Scheie, H. G.: The site of the disturbance in tonic pupils. Trans Amer Ophthal Soc 38:183-189,1940. 4. Argyll Robertson, D.: Four cases of spinal myosis: With remarks on the action of light on the pupi!. Edinburgh Med J 15(pt.l):487-493, 1869. 5. Argyll Robertson, D.: On an interesting series of eye-symptoms in a case of spinal disease: With remarks on the action of belladonna in the iris, etc. Edinburgh Med J 14(pt.2): 696-708, 1869. 6. Bernard, M. C.: Influence du grand sympathique sur la sensibilite et sur la calorification. C R Soc BioI (Paris) 3: 163-164 (Dec.) 1851. 7. Bernard, M. C.: Sur les effets de la section de la portion cephalique du grand sympathique. C R Soc BioI (Paris) 4: 168-170 (Nov.) 1852. 8. Bernard, M. C.: Le<;ons sur la physiologie et la pathologie du systeme nerveux. Paris, J. B. Bailliere et fils, 1858, pp. 499; 529-536. 9. Galenus, C., cited by Hirschberg, J.: Geschichte der Augenheilkunde. In Graefe-Saemisch Handbuch der Gesamten Augenheilkunde. Leipzig, Verlag von Wilhelm Engelman, 1899, Vo!. 12, pp. 323-326. 10. Holmes, G.: Partial iridoplegia associated with symptoms of other disease of the nervous system. Trans Ophthal Soc UK 51 :209-224, 1931. 11. Homer, F.: Ober eine Form von Ptosis. Klin Mbl Augenheilk 7: 193-198, 1869. 12. Jaffe, N. S.: Localization of lesions causing Horner's syndrome. Arch Ophthal (Chicago) 44:710-728 (Nov.) 1950. 13. Loewenfeld, I. E.: Mechanisms of reflex dilatation of the pupi!. Docum Ophthal 12:185448,1958. 14. Loewenfeld, I. E., and Thompson, H. S.: The tonic pupil: A re-evaluation. Amer J Ophthal 63:46-87 (Jan.) 1967. 15. Lowenstein, 0.: Alternating contraction anisocoria: A pupillary syndrome of the anterior midbrain. Arch Neurol (Chicago) 72:742-757 (Dec.) 1954. 16. Lowenstein, 0.: Pupillary reflex shapes and topical clinical diagnosis. Neurology (Minneap) 5:631-644, 1955. 17. Lowenstein, 0.: Pupillography: Methods and diagnostic system. Arch Ophthal (Chicago) 55:565-571 (April) 1956. 18. Lowenstein, 0.: The Argyll Robertson pupillary syndrome: Mechanism and localization. Amer J OphthaI42(pt.2):105-121 (Oct.) 1956. 19. Lowenstein, 0.: Electronic pupillography: Why, how and when? Eye Ear Nose Throat Monthly 38:549-558 (July) 1959. 20. Lowenstein, 0., and Loewenfeld, I. E.: Electronic pupillography: A new instrument and some clinical applications. Arch Ophthal (Chicago) 59:352-363 (March) 1958. 21. Magendie, F., cited by Loewenfeld, 1. E. '" 22. Mitchell, S. W.: Injuries of Nerves and Their Consequences. Philadelphia, J. B. Lippincott Company, 1872, pp. 318-321. 23. Mitchell, S. W., Morehouse, G. R., and Keen, W. W., Jr.: Gunshot Wounds and Other Injuries of Nerves. Philadelphia, J. B. Lippincott Company, 1864, Vo\. 6, p. 39. 24. Moore, R. F.: Discussion. Trans Ophthal Soc UK 44:38-43,1924. 25. Moore, R. F.: The non-luetic Argyll-Robertson pupi!. Trans Ophthal Soc UK 51 :203-209, 1931. 26. Petit: Memoire dans lequel il est demontre que les nerfs intercoslaux fournissent des rameaux qui portent des esprits dans les yeux. Histoire Acad Roy Sci (Paris) 1 :9-13, 1727. 27. Pliny Secundus, C., cited by Hirschberg, J.: Geschichte der Augenheilkunde. In GraefeSaemische Handbuch der Gesamten Augenheilkunde. Leipzig, Verlag von Wilhelm Engelman, 1899, Vo!. 12, pp. 308-309. 28. Reid, J.: On the effects of a lesion of the trunk of the ganglionic system of nerves in the neck upon the eyeball and its appendages. Edinburgh Med Surg J 52:36-43, 1839. 29. Romberg, M. H.: A Manual of the Nervous Diseases of Man. (Translated and edited by E. H. Sieveking.) London, Sydenham Society, 1853, Vo!. 2, pp. 397-398. 30. Saenger, A.: Ober myotonische Pupillenbewegung. Neurol Zbl 21 :837-839 (Sept. 16) 1902. 31. Saenger, A.: Ober die Bezeichnung "myotonische Pupillenbewegung." Neurol Zbl 21 :1137-1138 (Dec. 16) 1902. 32. Scheie, H. G.: Site of disturbance in Adie's syndrome. Arch Ophthal (Chicago) 24:225237 (Aug.) 1940. 33. Scheie, H. G., and Adler, F. H.: Site of the disturbance of tonic pupils (Adie's syndrome). (Abstr.) Arch Ophthal (Chicago) 24: 1041-1042 (Nov.) 1940. 34. Scheiner, C., cited by Loewenfeld, I. E.'"
884
ROBERT
W.
HOLLENHORST
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