Chapter 06: Reflex Dilation

\ CHAPTER 6 Reflex Dilation CONTENTS A. Summary .......................... 1. The Afferent Path .................. 2. The Sympathetic Efferent Path ......... 3. Parasympathetic Inhibition ........... 4. The Reflex Center .................. 5. Dual Innervation of the Intraocular Muscles . . . . . . . . . . . . . . . . . . . . . . . . . 6. Humoral Mechanisms ............... B. Discovery of Pupillary Reflex Dilation ...... C. Appearance ........................ 1. The Normal Reaction ............... 2. Responses to Moderate and Very Intense Stimuli . . . . . . . . . . . . . . . . . . . . . . . . . D. Afferent Pathways .................... E. Sympathetic Innervation of the Dilator Muscle ........................... 1. Historical Background . . . . . . . . . . . . . . . (a) Discovery of the Effects of Sympathetic Paralysis . . . . . . . . . . . . . . . . . . . . . (b) Discovery of the Effects of Sympathetic Stimulation ................... 2. Nerve Paths Connecting the Dilator Muscle with the Central Nervous System .. (a) Preganglionic Fibers from the Cervical Cord to the Superior Cervical Ganglion ..................... (b) The Superior Cervical Ganglion ..... (c) Postganglionic Fibers from the Superior Cervical Ganglion to the Carotid Canal . . . . . . . . . . . . . . . . . . (d) Relations of Oculopupillary Fibers to the Middle Ear . . . . . . . . . . . . . . . . . (e) Relations of Oculopupillary Fibers to the Gasserian Ganglion and the Trigeminal Nerve ............... (f) Sympathetic Fibers in the Orbit ..... (g) Assumed Sensory Fibers in the Cervical Sympathetic Nerve ........ (h) Structural Changes after Interruption of the Sympathetic Nerve Supply ..... F. Mechanism of the Residual Reflex Dilation after Destruction of the Sympathetic Path ... 318 319 319 320 320 320 320 321 321 321 324 324 G. 325 325 325 327 H. 327 327 328 I. 329 332 334 338 J. 342 342 343 K. 1. Assumed Secondary Sympathetic Pathways . . . . . . . . . . . . . . . . . . . . . . . . (a) Assumed Sympathetic Fibers via the Trigeminal Nerve Root ............ (b) The Mystery about the Miosis upon Trigeminal Stimulation: Prostaglandins, Substance P, and Ocular Inflammation . . . . . . . . . . . . . (c) Other Assumed Sympathetic Pathways. 2. Evidence Disproving the Existence of Secondary Sympathetic Pupillodilator Pathways . . . . . . . . . . . . . . . . . . . . . . . . 3. Inhibition of the Pupillary Sphincter Muscle ......................... The Efferent Mechanism: Sympathetic Activation versus Parasympathetic Inhibition .... 1. Historical Background ............... 2. Passive Pupillary Dilation . . . . . . . . . . . . 3. "Active Sympathetic Sphincter Inhibition" . 4. The Role of Anesthesia . . . . . . . . . . . . . . 5. Experimental Errors . . . . . . . . . . . . . . . . Location of the Reflex Center ............ 1. Budge's Center .................... 2. The Diencephalon . . . . . . . . . . . . . . . . . . 3. The Role of the Cortex . . . . . . . . . . . . . . Descending Sympathetic Connections to the Cervical Spinal Cord . . . . . . . . . . . . . . . . . . 1. Historical Background ............... 2. The Main Descending Sympathetic Tract .. 3. Location of Commissural Fibers ........ 4. Additional Pupillary Dilator Pathways in the Brainstem ..................... {a) Lateral Elements ................ (b) Medial Elements ................ Humoral Mechanisms for Pupillary Dilation . 1. Discovery of "Paradoxical" Pupillary Dilation . . . . . . . . . . . . . . . . . . . . . . . . . 2. The Concept of Denervation Supersensitivity .................... 3. Appearance of "Paradoxical" Pupillary Dilation ......................... 4. Noradrenaline versus Adrenaline in "Paradoxical" Pupillary Dilation ....... Conclusions: Integration of Pupillary Dilation Movements . . . . . . . . . . . . . . . . . . . . . . . . . 343 343 343 347 348 349 349 349 349 349 361 364 368 368 369 372 373 376 377 379 381 381 382 383 383 384 387 391 394 A. Summary Pupillary reflex dilation has been embroiled in more controversies than any other pupillary movement. These repetitive and often virulent disputes dragged on for more than two hundred years. They were based chiefly 318 on the protracted quarrel about the anatomic that unusual structure, the pupillary dilator described in Chapters 1 and 3, its existence nately postulated and rejected over and over identity of musde. As was alteragain until 6. Reflex Dilation finally, around the mid-1950s, the electron microscope settled the question. Because of this turbulent history, different descriptions of the mechanism of pupillary reflex dilation have survived to the present; and the reader may even find two different versions in the very same text. This is not as insane as it sounds, since the reflex is indeed composed of more than one mechanism, as will be shown in this chapter; and the only error in various descriptions was to consider one or the other of these the true, essential mechanism, dismissing the others. Just like the light reflex, pupillary reflex dilation is an integrated movement (see conclusions to this chapter and Figure 6-39). The agonistic dilator muscle is activated, and simultaneously the antagonistic sphincter muscle is inhibited. The resulting movement is swift and extensive. But when the nerve path to the dilator muscle is interrupted, the residual passive-inhibitory dilation is slow and incomplete (see Chapter 9). The neural pathways that serve the reaction are long and complex, and still controversial in some details. 1. The Afferent Path Any sensory stimulus (with the exception of light) can elicit pupillary dilation; and spontaneous thoughts and emotions have the same effect as sensory stimuli. In other words, any somatic or visceral afferent nerve as well as all central connections involved in sensation or in general arousal responses can serve as afferent path for pupillary reflex dilation. There is no single, specialized afferent path for this reaction, as has been claimed. 2. The Sympathetic Efferent Path The hypothalamus is the motor center for the activesympathetic component of pupillary reflex dilation. From this diencephalic area arises the great efferent sympathetic fiber system that innervates all visceral organs of the body. The sympathetic pathway to the eye is but a small part of this system. In its lengthy course it descends through the entire brainstem and cervical spinal cord, and then again ascends in the neck, in the cervical sympathetic chain. It re-enters the skull and, now associated with the ophthalmic fifth nerve, passes quite close to its hypothalamic origin toward the orbit and so to the eye. Three segments make up this path, namely, the "central (first) neuron" from the hypothalamus to the cervicothoracic cord; the "preganglionic (second) neuron" from the cord to the superior cervical ganglion below the angle of the jaw; and the "postganglionic (third) neuron" from there to the iris. Damage at different sites of this pathway results in somewhat different clinical syndromes, mostly due to neighborhood signs, caused by injury to adjacent nerve centers or pathways, and partly because injury and regeneration affect the central, the preganglionic, and the postganglionic neurons differently (see Chapters 9 and 25). From the hypothalamus, the central pupillodilator tract runs caudally via the subthalamic-prerubral area, / 319 then turns laterally, and descends in the lateral tegmentum of the midbrain, pons, and medulla (further ventraJly in cat than in human brains). In the cord, the fibers travel superficially in the lateral funiculus until, at the C8 to T2 level, they turn mesially and synapse with the preganglionic sympathetic neurons in the intermediolateral cell column ("Budge's center"). This descending brainstem path used to be considered diffuse, and composed of a chain of small interneurons, but lately it has been found to be quite discrete. Unilateral stimulation of the brainstem or the spinal cord rostral to Budge's center yields bilateral pupillary dilation, even when the brainstem is transected above the stimulated point. Some of the pupillary dilator fibers must hence cross to the other side at the level of Budge's center or close to it. But the ipsilateral reactions are much more extensive than the contralateral ones; and lateral brainstem lesions located as far rostrally as the subthalamus produce the clinical appearance of ipsilateral sympathetic paralysis. The crossed fiber contingent thus cannot be large. Central vasomotor, sudomotor, and pilomotor fibers to the ipsilateral head, neck, and body, and fibers to the smooth muscles of the orbit, must run close to the pupillary pathway, since lesions at different brainstem levels usually involve these functions also. The preganglionic sympathetic fibers arise from the lateral horn cells of the cervicothoracic spinal cord. They leave the cord by its ventral roots, with some rostrocaudal dissociation of functions, whereby the pupillary fibers, chiefly from C8 to T2, are the most rostral, and the pilomotor fibers, chiefly from TS to T6, the most caudal group. After joining the sympathetic chain, the pupillary fibers tum upward toward the head. They traverse the first thoracic and inferior cervical ganglia and then pass (without interruption) via the ansa of Vieussens, the middle cervical ganglion, and the cervical sympathetic nerve to the superior cervical ganglion, where they synapse with the postganglionic neurons. Postganglionic fibers for the pupil leave the superior cervical ganglion at its rostral pole and accompany the carotid artery into its canal in the temporal bone. In cats and monkeys they then leave the artery and enter the tympanic cavity, cross the anterior part of the promontory, and leave the mjddle ear to enter the cranial vault, emerging from between the surfaces of the petrous and the alisphenoid bones, just lateral to the Vidian nerve. They approach the Gasserian ganglion and enter the ophthalmic branch of the trigeminal nerve just distal to its origin from that ganglion. It is still uncertain whether the path through the middle ear is the same in man as in monkeys and cats. The fibers for the nictitating membrane and the orbital smooth muscles appear to accompany the pupillary fibers along their path through the middle ear, while the vasomotor fibers are said to continue along the carotid artery and its branches in the periarterial plexj. The further path for these fibers is not clear. There are 320 / I. Anatomy and Physiology species differences and individual variations in anatomic details of this small area, and this may be the reason for the many different descriptions given in different texts. Within the skull, the pupillary fibers run in the middle fossa with the ophthalmic fifth nerve, and injury at this site gives rise to "Raeder's paratrigeminal syndrome." The pupillary dilator fibers then pass into the nasociliary branch of the fifth netve and reach the eye by way of the long ciliary fibers. All of these fibers bypass the ciliary ganglion in cats, dogs, and rabbits, and many do in monkeys and man. Again, there are individual differences. Sometimes the long ciliary fibers run very close to the ganglion and can be involved in lesions there. But no pupillary dilator fibers synapse with neurons of the ciliary ganglion. Distal to the ganglion, the long and short ciliary fibers often intermingle. In man, the ciliary ganglion has a "long (or sensory) root," composed of sensory fibers from the eye that travel to the Gasserian ganglion, and a "sympathetic root," made up of vasomotor fibers from the intracranial vascular plexus that run to the eye. These fibers also merely run along or through the ganglion without synapse, and in cats, dogs, rabbits, and many other animals there are no such roots. 3. Parasympathetic Inhibition When the sympathetic efferent path to the eye is cut, the pupil still is able to dilate in response to psychosensory stimuli, though the reactions are much reduced in extent and speed. These residual responses often were said to be due to impulses running by way of auxiliary sympathetic fibers not contained in the cervical chain. These would remain intact after cetvical sympathectomy. But none of the nerves said to conduct these extra sympathetic fibers ever were proven actually to contain them; and further, the residual dilation movement still present after cervical sympathectomy is not affected by syrnpathicolytic drugs, and thus cannot be adrenergic in nature. In contrast, the reactions are missing when the parasympathetic supply of the sphincter muscle is abolished beforehand by cutting the third netve, or by treating the eye with atropine. Thus the residual dilation must be due to inhibition of parasympathetic outflow. A great many experiments have proven this conclusion to be correct. An important point is that parasympathetic inhibition is a central netvous event. Under the influence of psychosensory or of some brain stimuli the pupillary sphincter muscle relaxes because the postganglionic short ciliary nerves cease to fire; and these fibers fall silent because central inhibitory neurons suppress the activity of the pupillo-constrictor neurons of the Edinger-Westphal nucleus. 4. The Reflex Center For the parasympathetic-inhibitory component of pupillary reflex dilation, the Edinger-Westphal nucleus thus is the central site. For the active-sympathetic component, the spinal cord at first was thought to be the site of central transmission. Afferent impulses from the body were said to reach Budge's center, and to be conveyed to the eye directly by its (preganglionic) sympathetic neurons. But lesions rostral to Budge's center were found to block the reaction, so that afferent stimuli must ascend to some higher center which then sends efferent connections down to the cord. Budge's center thus is only a cell station of the efferent sympathetic path, not the center for afferent-efferent reflex transmission. The hypothalamus seems to be the most caudal site at which this transmission can take place, since the sympathetic part of reflex dilation can still occur in animals deprived of their forebrain but not when the hypothalamus is disconnected from the lower brainstem. There are, however, reasons to believe that in normal, conscious mammals, the cerebral hemispheres play a role in the elaboration of the reaction, so that the hypothalamus is only a motor center, normally brought into play by higher neuronal networks (see also Chapter 9). 5. Dual Innervation of the Intraocular Muscles As described in Chapter 1, there is ample evidence that both the sphincter and the dilator muscle are supplied with a double set of cholinergic and adrenergic netve endings. For this reason, and because sphincter tissues in vitro lengthen under the influence of catecholamines in physiologic concentrations, it was said that pupillary reflex dilation "did not require" an agonistic dilator muscle and was brought about solely by "active relaxation" of the sphincter, under the influence of sympathetic netves. There are good reasons, however, to believe that this inhibitory mechanism plays only a minor role in sympathetic pupillary reflex dilation. It does not initiate the movement, but may facilitate it by reducing the sphincter muscle's tone. 6. Humoral Mechanisms Two "humoral" influences take part in pupillary reflex dilation. Normally their influence is weak and is masked by the extensive dilation movements brought forth by the neurologic mechanisms. But after damage to its sympathetic netve supply, the pupillary dilator muscle becomes abnormally sensitive to circulating catecholamines; consequently, extensive pupillary dilation can occur when these enter the bloodstream upon psychosensory or other stressful stimulation. The adrenergic humoral substance first discovered was adrenaline, discharged from the medulla of the adrenal glands. Later it was found that stimulation of postganglionic sympathetic neurons releases noradrenaline from the netve endings, and some of this material can spill over into the general circulation and thus elicit responses at distant sites. Pupillary reactions described in this chapter indicate this latter mechanism to be the most important one for "paradox" pupillary dilation in everyday life, since it is evoked by mild to moderate stimuli, while adrenal discharges are called into action only in response to very severe stress. 6. Reflex Dilation / 321 B. Discovery of Pupillary Reflex Dilation Although one may be expo ed to a strong light, one does not alway clo e the pupil when one looks intently at an object who e image ha to pa_int itself trongly on the fundu of the eye; and thts can be een in tho e animals who can clo e and dilate the pupil extraordinarily such a cat ; for when they are in daylight and in a state of tranquility, they have the pupil almost completely closed, but if some unu ual object appears suddenly to which they pay attention, one ee them open it as much as they can all at once. 1 (de La Hire, 1700) In Galen' time and for many centuries later, dilation of the pupils wa related to defective vision. The first mention of a different kind of pupillary dilation we were able to find came almost eight hundred years after Galen, when Ammar (1000) described extreme pupillary enlargement in a woman who, under the stress of bilateral cataract operation, had succumbed to convulsions. But Ammar appears to have drawn no general conclusions from this observation. Another seven hundred years elapsed until the mechanism of this movement attracted attention in connection with discussions about the existence of iris muscles, as described in Chapter 1. In 1704 Mery, while studying the ocular fund us of cats by observing the eye underwater, noticed a new and strange phenomenon: "If one dips the head of a living cat under water, and exposes its eyes to the rays of the sun, the pupil dilates instead of contracting; however, when exposed in the air to the same rays of the sun, the pupil constricts instead of dilating." 2 Mery thought that the cat, unable to breathe under water, lost its "vital spirits"; and since these normally filled and expanded the iris under the influence of light, their loss resulted in shrinkage of the iris and contraction of its radial fibers, so that the pupil enlarged. La Hire (1709) objected to this explanation. He said that the animal, "being in a violent state, paid attention to all that surrounded it, which obliged it to keep its pupil wide open." 3 La Hire's recognition of a relation between pupil size and the individual's emotional state thus preceded Zinn's and Fontana's descriptions by a half-century. Zinn (1757) observed that the normal pupil of man and animals was small in sleep. Fontana (1765) saw this also; and further, when the subject was suddenly awakened, the pupils dilated widely. This movement occurred even in bright light. Indeed, when Fontana exposed a cats eye to an intense beam of light but at the same moment frightened the animal, its pupil dilated and remained large until it again calmed down. Further, in man and animals the pupils were smaller after death than they had been in the living individual in dim light (Morgagni, 1719; Winslow, 1732; Whytt, 1751; Fontana, 1765). Fontana concluded that miosis was the resting state of the pupil: the natural contractile force of the iris revealed itself in the absence of brain activity so that the pupil contracted; and the dilation upon awakening or upon sensory stimulation and emotional excitement was an active movement. The mechanism of this movement was debated for an additional two centuries, and forty thousand animals have been killed, by rough guess, dudng this time, most of them in repetitions of experiments done many times before. This surely seems excessive, especially since the true explanation was given many times along the way. But these reports were simply forgotten or discarded on inadequate grounds. C. Appearance 1. The Normal Reaction In conscious individuals, any sensory, emotional, or mental stimulus elicits pupillary reflex dilation. 4 In the past, reaction to sensory stimuli were often said to differ from those due to psychic stimuli. But this is not true. The same cerebral centers and the same motor system are responsible for the pupillary movement in either case; and therefore the quality of the stimulus does not alter the response: sound, touch, or pain; fear, 1. "Mais quoiqu'on soit expose a une asses grande lumiere, on ne ferme pas toujours la prunelle quand on est attentif a regarder quelqu'objet dont !'image doit se peindre vivement sur le fond de l'ceil, ce qu'on remarque dans les animaux qui peuvent fermer & dilater extraordinairement la prunelle comme les chats; car lorsqu'ils sont au grand jour & dans un etat tra~quille, ils ont la prunelle presque toute fermee, & s'il arrive sub1tement quequ'objet extraordinaire auquel ils font attention, on les voit alors l'ouvrir autant qu'ils peuvent & toute d'un coup" (quoted in Mazzolini 1980). joy, or anger; spontaneous thoughts and intentional efforts-all can dilate the pupils. The amplitude of the reacti?n depends upon the degree of arousal caused by the stimulus, and upon the subject's physical and mental state at the time it is applied. , 2. ''Quand l'on plonge dans l'eau 1~ tete d'un chat vivant, si I_on expose ~es ?'~ux aux rayons du Soe1l, la prunelle se dilate au lieu de ce retrec1r; au contraire exposes dans )'air aux memes r~yons de cet Astre, la prunelle se retrecit au lieu de se d1later." , 3._"Etant dans_ un. etat viole~t, !ait ~ttention a tout ce qui 1 env1ronne'. ce qm dmt encore I obhger a tenir sa prunelle fort ouverte" (cited by Mazzolini, 1980). ~- This excl_udes light and near-vision stimuli, whose specific pup11lo-constnctor effect almost always overrides their general sensory effect. 322 / I. Anatomy and Physiology For example, when a person is just about to drift off to sleep, a loud crash nearby that awakens and alarms him will bring about an energetic enlargement of the pupils. In contrast, a sound at least as loud may have virtually no effect when it is familiar, harmless, and expected, and when the subject is already wide awake before the stimulus is presented. Among the animals we have tested, cats have by far the most dramatic reactions, followed, in order of relative extensiveness of the reactions, by monkeys, rats, dogs, human adults, rabbits and guinea pigs, birds, and frogs (Figure 6-1). In birds, the dilation is slight, slow, and often blocked by a coinciding contraction of the striated sphincter muscle that occurs when the animal 9 I~ MAN ------1 13-DOG 71---------1 :~ ., ~-~io- Jt---------t 8 - 9 7 ll>-CAT 12-RABBIT-----1 /'--._ n / - ,-J.// 91----,''-------t I I ,1---11----------1 J-RAT llt-----------1 8...,.,,"""'::...._-----1 21:1--===_ 71----------t 61------------1 I 51------------1 t~J:1------t 4l---------f 3 ,_l ..~ ,. I PIG t 31------------1 0 FROG -i-- PIGEON 31----------t "i 3 E 2 £:1!"1:imiJlllllllllllllllllllllllllllIIIlmwl !i'~lw:wlllllllllllllllllllllIWIIlIIIIIIIJ 0.1 Ste'.-+ Figure 6-1. Reflex dilation in mammals, bird and frog. Only one pupil is shown in each pupillogram. Pupillary diameter (in mm) is plotted against time (in 0.1-second units). The arrows indicate the moment of a sudden, loud noise. For animals with a smaller iris than the human one, the ordinate was enlarged, taking the horizontal corneal diameter from limbus to limbus as multiplying factor. In this way the relative force of the dilation movement is presented more accurately than by drawing all reactions to the same scale. The experiments were done in a darkened room. The animal's pupils were contracted by a series of short light stimuli. In this condition the pupils have a good mechanical range for dilation movements, and the reflexes are especially extensive. Before the sound stimulus the animals were calm and comfortable, but the sudden noise startled and frightened them. The reactions shown here are extensive for each species, that is, the differences shown are species differences, not individual variations. (From I.E. Loewenfeld, Documenta ophthal., 12 [1958]:l 85) answers the stimulus with a blink. After the sphincter has been paralyzed with a curarizing drug, the dilation becomes more reliable (Figure 6-2). The latent period for pupillary reflex dilation i shortest in cats and monkeys (somewhat longer than 0.2 second) and longest in rats and man (0.3 to 0.5 sccond). 5 It is as long in birds as it is in mammals, in contrast to the short latent period for the light reflex in birds. Together with the persistence of the dilation after curare, this long latent period demonstrates that a feeble smooth muscle dilator must be responsible for the movement. In frogs the latent period is long, which is not surprising in this rudimentary response. Besides the pre-existing state of arousal of the individual and the emotional impact of the stimulus already mentioned, the illumination at the time of stimulation influences the amplitude of the resulting reflex, since it sets the mechanical range for pupillary dilation. In darkness, the pupil is already large before the stimulus, and further enlargement is more limited than when the pupil is smaller (Figure 6-3); in bright light, on the other hand, the powerful constriction of the sphincter muscle opposes the dilation movement. Similarly, both the atropinizcd and the eserinized pupil have only inextensive reflex dilation; and under pathologic conditions, paralysis of the pupillary sphincter as well as sphincter spasms can limit the amplitude of pupillary reflex dilation (Figures 6-4 and 6-5). The residual reactions may be so small that they are hard to see with the unaided eye. Records show, however, that they follow the same time-amplitude pattern as the reactions of the normal fellow pupil. This pattern is characteristic of all normal reflex movements. After the latent period, the dilation accelerates and reaches peak speed within less than a second; thereafter, it slows down progressively (Figure 6-5,A). When the reaction is extensive, this peak speed can be as fast as that of the light reflex in some animals. It is especially interesting that both the light reflex and reflex dilation reach higher peak speeds than can be obtained by supramaximal stimulation of their respective agonistic nerve supply (see Chapter 9). When a sensory stimulus such as a sound is repeated at monotonous intervals, it gradually loses its effectiveness: when well known and not threatening, it arouses the subject less and less. Psychologists refer to this fading of the reaction with repetition as "habituation of the orienting reflex" (see Chapter 13). It is said to be due to the fact that the stimulus is no longer new. We prefer to say that the individual becomes accustomed to 5. Most of our animal experiments were done with motion picture recording at film speed of ten frames per second. We therefore do not give second decimals for these records, except when the reactions were averaged. The reactions of birds (pigeons and chickens) were recorded photoelectrically at sixty cycles per second because of the fast striated muscle responses. 6. Reflex Dilation the stimulus and consider this a complex event, involving memory, recognition, and judgment. Not all stimuli lose their effectiveness upon repetition. To the contrary, if a stimulus has some annoying feature, the emotional impact of monotonous repetition can be very great indeed. Everyone knows how infuriating the constant banging of a poorly closed door can become (or, if you live in a city, the rattling of an empty beer can up and down the alley). True torture can be evoked by mild stimuli given over and over again, as demonstrated by the "Chinese torture" of an endlessly repeated falling waterdrop. Psychosensory reflex dilation of the pupil has been mistaken at various times for a whole array of supposedly separate phenomena. For example, the "ciliospinal reflex," a staple of ophthalmologic and neurologic texts, is said to result from irritation of the cervical sympathetic nerve when the side of the patient's neck is scratched. Considering that the anatomic course of the nerve in this region is a good 2 centimeters or so below the examiner's finger, this is clearly impossible. While the nerve itself therefore is not stimulated, the patient is: when the stimulus is felt, both pupils dilate as a reflex movement. But the examiner is too busy watching the patient's pupil on the stimulated side to notice that the contra lateral pupil dilates as well. Further misinterpretations and inventions are listed in Table 6-1 and defined in Chapter 30. 5 ..,. 3 2 t 6 5 E Cf. E3 +: ' •-B 13 12 II 10 9 ~F ~i - ,--- I 7 6 5 ,,. 323 ------ I 8 t / Ill 111111111111111111111111111111111 B 1111111111 II I Ill o.,set.+ Figure 6-3. Pupillary reflex dilation of a cat with large and with small pupil before the stimulus was applied. The arrows mark the time of presentation of sudden sensory stimuli (loud barking and blowing into the animal's face). The pupillary dilation movement was less extensive in darkness (A) than in room light (B), because the large initial diameter limited the mechanical range for dilation. The time-amplitude pattern of the reaction, however, was similar in the two reactions. (From 0. Lowenstein and I.E. Loewenfeld. Annis. N. Y Acad. Sci., 117 [J 964]: 142) ., 1---------,:------------------------1 " 1-----t-__;,l_ -------------l ' I I 11111111 I I 1111111111I111111111111111111111I1111111111111 0.1.sec . ..Figure 6-2. Pupillary reflex dilation in the pigeon. Pupillary diameter is recorded as the ordinate against time as the abscissa. The arrows indicate time of presentation of sensory stimuli (loud noise, produced by a cap pistol). A: Normal reaction. The dilation was slow and shallow compared to the fast light reflexes of these animals. B: Reaction after the striated sphincter muscle was paralyzed by local application of a solution of tubocurarine chloride. Under the influence of the drug, the pupil had dilated to 5.5-mm diameter and failed to react to light. The reactions to sound stimuli, however, were not disturbed. To the contrary, considering the already large initial pupil size before the sensory stimuli, they were good, and they occurred regularly, while before administration of the drug they often had been blocked by energetic contractions of the pupil associated with eyeblinks. (From I.E. Loewenfeld Documenta ophthal., 12 (1958]:185) 0.1 sec.-+ Figure 6-4. Effect of instillation of physostigmine on pupillary reflex dilation. Pupillograms of a normal cat. At the times marked by the arrows, sudden, loud sound stimuli were presented. A: Normal, extensive reflex dilation, equal in the two eyes; B, 18 minutes, and C, 30 minutes after several drops of 2% physostigmine hydrochloride had been instilled into the conjunctiva! sac of both eyes. As the pupils became small, the reflex dilation became inextensive, and at peak miosis it was almost entirely blocked. (From O. Lowenstein and I.E. Loewenfeld, Arch. Neural. Psychiat., 64 [1950]:313; c 1950, American Medical Association) 324 / I. Anatomy and Physiology Table 6-1. - - - - Supposed pupillary signs partly or entirely due to pupillary reflex dilation Attention ( or cortical) reflex { Haab' s or Piltz' s reaction) Bumke' s {anxiety} :eu:eils Catatonic pupillary immobility {s:easmus mobilis 1 or mobile spasm) Cilio-s2inal reflex Claude Bernard's triad Cochlea -:eu:eillary reflex Cutaneous pupillary reflex Flatau's neck response (neck mydriasis, or nucho-mydriatic sign} Goe:e:eert' s sisn Ins:eiration mydriasis Juxta-occipito-trapezoid phenomenon See Chapter - Moskowskij 's sign Pleura -pupillari reflex Poudour du Petit's syndrome Redlich's :ehenomenon Skin pupillary reflex - S:eastic mydriasis - Trigeminus reflex ( oculo -pupillary oculo-sensory reflex, Trigemino -facial reflex, or Varaday' s reaction) - Vagotonic :eu,eillari reflex Vestibular pupillari reilex - Wiener and Wolin.er' s sign - Wittendorfer' s clonic mydriasis - or - 30 for definitions. 13 - 7 ,,,~----~--------- ............. ~~~ 2. Responses to Moderate and Very Intense Stimuli The reactions described so far result from moderate, short-lasting psychosensory stimulation such as a sudden loud sound, a pinprick, or a verbal suggestion that arouses the individual. In anesthetized animals a shortlasting, weak electric stimulus in some areas of the brain will bring about a similar response. After an initial, vigorous dilation, the pupils recontract fairly promptly. This contraction is more gradual than the dilation movement; but within about 5 to 10 seconds the response comes to an end. In answer to longer-lasting or severe stress, in contrast, the pupils fail to recontract as soon and may remain mydriatic for a protracted period. The difference between the responses to moderate and to strong stimulation is not merely quantitative. Reactions to moderate stimulation are predominantly neurologic events, while powerful stimuli evoke additional, humoral mechanisms, as will be discussed below. 12 II /.. I I A I I I ----..·"" ~ i I 7 I I 6 5 ,\ ... 'I 1-\ :-i I :-,-', 3 2 B :-~•-\ f - . I f!,j 0 0.1 ,,_ sec.-- Figure 6-5. Effect of parasympathetic deneivation on pupillary reflex dilation. Pupillogram (A) and speed cuive (B) of reflex dilation in a cat whose right ciliary ganglion had been removed. The right pupil (solid line) was larger than the left, and the reflex dilation was less extensive than on the normal side. But the movement showed the same time-amplitude pattern on the two sides. (From I.E. Loewenfeld, Documenta ophthal., 12 [1958): 185) D. Afferent Pathways From time to time, publications have appeared about the "afferent path of the pupillodilator fibers" (Bain, lrving, and McSwiney, 1935; Harper, McSwiney and Suffolk, 1935; Harper and McSwiney, 1937; Harris, Hodes, and Magoun, 1944; Evans, 1961; Loewy, Araujo, and Kerr, 1973). This term suggests that there are special afferent pupillary fibers from various stimulated areas of the body to the eye. But this is not true. Reflex dilation is elicited by any vivid sensory stimulus anywhere in the body. The sensory messages are conveyed directly to the cerebral sites involved in sensation and in elaboration of arousal and affective behavior by way of the established visceral and somatic afferent paths, and indirectly via collateral branches in the brainstem reticular formation. Efferent impulses are then transmitted to many somatic and autonomic motor nuclei, and thence via descending paths to the respective effectors. The pupillary movement is merely a small part of the total event; and it makes no more sense to imagine special afferent connections for pupillary dilation than for any other of the motor systems that act together in these mass responses. The sensitivity of the pupil to all afferent stimuli that cause pain became important when the pupil began to be used to monitor the levels of anesthesia. Schiff (1874, 1875) referred to the pupil in this connection as the most sensitive and reliable "esthesiometer" of the body. At a time when death frequently occurred due to anesthesia with ether or chloroform, this catchy term took hold of people's imagination, so that it has survived to the present. 6. Reflex Dilation / 325 E. Sympathetic Innervation of the Dilator Muscle 1. Historical Background Pupillary reflex dilation and pupillary enlargement due to electric stimulation of the cervical sympathetic nerve resemble each other closely; further, pupillary reflex dilation is greatly diminished when the cervical sympathetic nerve is cut. It is therefore natural to assume that the reflex movement is brought about by sympathetic innervation of the pupillary dilator muscle, as many authors did during the last two centuries. (a) Discovery of the Effects of Sympathetic Paralysis The effects of sympathetic paralysis were established long before those of sympathetic stimulation, and before it was realized that normal pupmary reflex dilation exists. In 1712 in Namur, France, Fran~ois Pourfour du Petit experimented on the vagosympathetic nerve of living dogs. He continued this work in Paris after he had settled there in 1713 6 and made the following discoveries. When he cut the animals' vagosympathetic trunk in the neck, the eye receded in its socket and seemed to become smaller; the nictitating membrane protruded, and the pupil became smaller than that on the normal side. Sometimes there were exudates in the nasal angle of the eye, and the conjunctiva reddened as if the eye were inflamed. These findings were surprising because until then it had been thought that the sympathetic or "intercostal" nerve arose in the brain; and its roots emerged from the anastomoses with various cranial nerves ( especially the fifth) and then descended in the neck and ganglionic chain to the rest of the body (Galen,7 Vesalius, 1543· Etienne, 1545; Eustachio, 1552; Fallopius, 1561; Willis, 1664; Vieussens, 1684). But here the opposite was true: since a lesion in the neck caused changes in the eye, the intercostal nerve must send "vital spirits" up the neck toward the head. Petit repeated his experiments in the presence of Winslow, Senac, Hunaut, and others in Paris (1720, 1725). He also traced the peripheral course of the cervical sympathetic nerve and published his findings in the Memoires of the Academie de Science in 1727. In time, the effects of interruption of the cervical sympathetic chain became better known. The eye looked smaJl because the upper lid drooped slightly while the lower lid was elevated and in animals enophthalmos developed also. The eye looked red, and the animal's face and ear on the side of the lesion became warmer than on the other side because the sympathetic lesion paralyzed vasomotor nerves. In human patients the skin became dry on the denervated side because the sudomotor fibers were impaired; in frogs the skin became dark 6. For a good biographical sketch, see Mazzolini, 1980. 7. Galen lived between 131 and 201; I do not know the date of this particular description. and smooth and no longer showed normal chr<:>matophore contractions. Molinelli (1775). first noticed _a change in iris coloration after cefVlcal sympathet_ic damage, and similar changes were observed la~e~ m human patients as well as in animals whe~ the m~ury occurred in infancy. The pupillary contraction to hght remained brisk after interruption of the ocular sympathetic nerve supply. In animals and in small children with large pupils, the sympathetic palsy even enhanced the light reflex (Claude Bernard, 1852). In contrast, reflex dilation of the pupil in response to sensory, emotional, or mental stimuli was reduced and slow. In human pathology all these signs later were referred to as "Horner's syndrome" or (in France) under the name of Claude Bernard (see Chapter 25). For the physiologic discovery of the effects of sympathetic paralysis Claude Bernard's name was substituted for Pourfour du Petit's mainly because of Bernard's strenuous claims that it had been he and he alone who had first noted all the signs produced by sympathetic lesions. He arrogated to himself especially the discovery of the vasomotor role of sympathetic nerves that is univers_al~y credited to him today. Table 6-2 shows that th1s 1s unjust: all the effects of cervical sympathetic lesions had been known earlier. As to the vasomotor effects, Pourfour du Petit and most investigators after him had seen the red conjunctiva brought on by sympathectomy. A rise in skin temperature had been described by Dupuy (1816). Henle (1840) saw muscle cells in the vascular walls and knew that they could be contracted by direct stimulation or indirectly by stimulation of sensory nerves; and that they governed the distribution of blood in the body. Ruete {1846) summarized the state of knowledge at the time as follows: "It is now an established fact that the vasomotor tonus depends on the sympathetic nerve. An increase in sympathetic excitation can therefore be deduced from increased vascular tonus. Increased vascular tonus is revealed by greater hardness and tension and lesser filling, decreased tonus by greater filling, enlargement and softness of the vessel. 8 It must be added that Claude Bernard's observations of the effects of sympathectomy and his interpretation of the vascular effects contained flaws (1852, 1853). He said that removal of the sympathetic caused simultaneous contractions of all muscles of the ipsilateral face: the globe was retracted into the orbit by contraction of the extraocular muscles while it was partly covered by forward movement of the third lid; the eye seemed much 8. "Es ist jetzt eine ausgemachte Thatsache, dass der Ton us der Gefasse vom nervus sympathicus abhangt. Die hohere Erregung desselben ist daher zu entnehmen aus der Zunahme des Tonus. Die Zunahme des Tonus wird erschlossen aus der grosseren Harte, Spannung und der geringeren Anfiillung, dagegen die Abnahme desselben aus der grosseren Anfiillung, Ausdehnung und Weichheit der Ader." I 326 Table 6-2. I. Anatomy and Physiology The discovery of sympathetic paralysis POSTOPERATIVE DEFICITS Cll ....... Q) Q) Cll Cll H ~ ;::1 Q) > f/l Q) ~ Cll Q) ...... 1727 1755 1787 1795 1816 1827 1837 1838 1839 1839 1839 1840 1840 1842 1845 1846 1846 1847 1851) 1852 1 52 1 52 1 53 1853 1852 1852 AUTHOR du Petit Molinelli Arnemann Cruickshank Dupuy Mayer Brachet Arnold Hannover Reid Valentin Henle Stilling Longet Guarini Ruete Volkmann Valentin Budge & Waller Budge Budge & Waller Waller Budge Waller Hannover Claude Bernard Cl:! Cl! H ,.q Cll s 0 H 0. 0 ..... YEAR "O ..a ~ (I) H ...., ...... Cll ;::1 C) s 0. ·2 0. ...... 0 Cl! 0. i=: Q) 0 C) H '1:1 z <+-< ..... 0 ~ ~ cD s ...., ....... ....... > '1:1 i=: ..... C/l Cll Q) § ...... (I) Cll C/l C/l Q) > Cll H (I) H Cl! ,.q ECl! H ~ ..... ...., cu Q) ;!: Cll (I) s::: s ..... ...., 0. (I) 0 ~ .::; .§ ....... ...., ...., 0 C/l C/lcu (I) - - - - - -- SPECIES OPERATION dog dog dog dog horse aonkey, rabbit dog dog, chicken cat cat, dog dog, rabbit general st. dog dog animals dog man cat dog, cat, frog, rabbit cut vago-sympathetic tie vago-sympathetic * cut vago-sympathetic cut vago-sympathetic SC ganglionectomy cut sympatnetic SC gangiionectomy cut vago -sympaHieHc SC ganglionectomy cut vago -sympathetic tie :12ostgangl. tibers cut vascular nerves sympathetic lesions cut vago-sympathetic cut symp. or ganglionectomy cut vago-sympatlietic cut sympatliefac cut cervical sympathetic cut vago -sympathetic cut dorsal or ventral roots Tl - T3; cut postganglionic fibers in 5th nerve, or spinal cord lesions -+ + + -+ -++ -+ - -- -- - ++ - ++ -+ - + -+ cat dog cut cervical sympathetic cut vago-sympathetic - - -+ - - - - - - ++ ..:t. - - - - -+ -+ -+ + + + -+ + + + + ...±..+ -+- -+ -- - --++ -+ - - -+ + -+ -+ -++ - ~ + + -+ -++ - -+ -+ - + - - -+ + - + '+ -+ -+ --- -+ - -+ - - -+ - -+ - - + + + -+ -- - - + + - -+ + - - -- -- -- --+ --+ - -- -- -- --- -- -- - - ---- - - -- -+ SC ganglion= superior cervical ganglion; Tl - T3 = spinal segments (first to third thoracic); NM= nictitating membrane; +=effect observed; - = effect denied. After 1852, these operations have been repeated innumerable times; for clinical cases described before 1852, see Table 25-1. * = pale iris. smaller and the palpebral fissure was distorted because of closing of the lids, especially the lower; the nostril and mouth on the affected side were retracted, and the entire face seemed "drawn" by the contraction of the muscles. Conversely, stimulation of the stump of the divided sympathetic caused relaxation of all muscles: the eye returned to its normal place, the lids opened, and the pupil dilated. During the 1850s Claude Bernard said that these many signs that he had found (but which, in fact, do not exist) could not be explained by the theory of an antagonistic double innervation which Budge and Waller and others had assumed for iris movements (with sympathetic innervation for the dilator muscle and third nerve innervation for the sphincter). He also could not accept the general opinion that the increased temperature in the face and ear of the affected side was the secondary consequence of greater blood filling of the denervated vascular bed (Ruete, 1846; Budge and Waller, both 1853; BrownSequard, 1854, and 1856, and others). This rise in temperature was rapid; it was a "quite special modification of circulation," associated with marked increase of sensation in the affected area. Despite much opposition (see especially BrownSequard) Claude Bernard therefore continued to speak during the following decade of a special "calorific" function of the sympathetic, or a special contingent of "nerfs calori:fiques" in this path. 6. Reflex Dilation The immediate paralytic effects of preganglionic sympathectomy were found to be le pronounced than those after removal of the uperior cervical ganglion (Budge, 1852); and pharmacologic reaction al o differed after pre- and postganglionic lesions. It thus appeared that the ganglion, separated from its central connections, continued to exert an influence on the eye. This agreed well with the fact that the sympathetic nerve was able to regenerate after it had been cut in the neck, but no regeneration could take place when the superior cervical ganglion had been removed (Langley, 1897). Nevertheless, the paralytic signs tended to fade after postganglionic lesions at least as much as after preganglionic ones. Some days or weeks after the operation, the eye seemed almost normal (Pourfour du Petit, 1727); and upon physical or emotional stress, the operated side would even show signs of sympathetic excitation (Budge, 1852 and 1855). These apparently paradoxical effects were the source of lively discussions over many decades. (b) Discovery of the Effects of Sympathetic Stimulation It was not until almost 120 years after Petit's discovery that experiments were done in which sympathetic nerves were stimulated. This is surprising, since the nerve is sensitive to mechanical stimulation: even a slight pull, exerted inadvertently during an operation, sometimes results in extensive pupillary dilation. Mechanical and electric stimulation had come into general use in physiologic research toward the end of the eighteenth century; and pupillary contraction had been obtained by electric stimulation of the eye (Fowler, 1793; Maunoir, 1812). Several authors had said that the sympathetic neive must move the iris by causing its radial fibers to contract. But-aside from a generally overlooked publication by Guarini (1844) describing the effects of mechanical stimulation of the superior ceivical ganglion-there appears to have been no direct experimental proof of this opinion until Bi:ffi's thesis in 1846. Biffi showed that cervical sympathetic stimulation caused reactions in the eye and head exactly opposite to the effects of sympathetic paralysis, namely, pupillary dilation, widening of the palpebral fissure, retraction of the nictitating membrane, contraction of the blood vessels in the eye and face, and (in animals) exophthalmos. In all these features the results of artificial stimulation of the ceivical sympathetic nerve closely resembled those shown in response to sensory stimulation or to emotional stress, as will be described below. 2. Nerve Paths Connecting the Dilator Muscle with the Central Nervous System / 327 animaux ' that reach the eye ascend in the cervical sympathetic nerve. During the following century these impul es were generally thought to come from the "great ganglionated sympathetic chain" that runs para!lel to the cord; but apparently the question of theu specific origin did not stimulate particular interest. . Around 1850 Waller had observed that degeneration of severed peripheral neives proceeds from the point of section to the nerve endings but not toward the celJ bodies· and he had realized the usefulness of this fact in tracing a nerve to its cells of origin. He demonstrated to Budge that after vagosympathetic transection in the neck, the ascending sympathetic fibers and the descending vagal fibers degenerate. By combining nerve stimulation and sections at different levels with fiber degeneration studies, these two great investigators traced the cervical sympathetic nerve into the spinal cord at the base of the neck. When the cord was transected rostral and caudal to the segments of entry, or when the sympathetic chain was divided below the first thoracic ganglion, no nerve degeneration could be found in the cervical sympathetic chain. This was an important physiologic discovery because it proved that the autonomic nervous system, considered independent of the central neivous system for many decades, as its name implies,9 actually took its origin from the spinal cord. In following years the peripheral sympathetic pathways were traced. The pupillary dilator fibers leave the spinal cord and traverse the first thoracic and the inferior cervical ganglia of the peripheral sympathetic chain. They then continue by way of the ansa of Vieussens and the middle cervical ganglion to the superior cervical ganglion, where they synapse with the cells of the postganglionic neurons (Figure 6-6). Most of the fibers for the pupil leave the cord at its first and second thoracic segments. While the upper and lower margins of this area vary to a degree between species and among individuals ( as shown in Tables 6-3 and 6-4) reports of pupillary dilation due to stimulation of spinal segments above C8 or below T3 were certainly based on experimental errors, such as intensive stimulation with stray currents or inadvertent stimulation of sensory pathways. It is of clinical interest that th(? sympathetic fibers for_ the pupil leave the cord at a slightly more rostral level tfian do tbase for the eyehds aad far the ocular and tacial blood vessels, as demonstrated by Langley (1897; see Figure 6-7 and Table 6-4). This explains why, in rare cases with sympathetic deficit, the pupil can be spared. In this area the oculopupillary sympathetic fibers can be caught by abnormal cervical ribs (Sargent, 1921; we also have seen such a case). The efferent path of the sympathetic fibers that innervate the iris is fairly complex, and various details were discovered at different times. (a) Pregangliooic Fibers from the Cervical Cord to the Superior Cervical Ganglion As already mentioned, Petit established in 1712 that the "esprits 9. From the Greek autonomos, "self-governing" "without outside control." 328 / I. Anatomy and Physiology Cervical ribs probably are responsible for exceptional instances of "hereditary sympathetic heterochromia." Whether the iris is involved in lesions of this kind or whether it is spared depends upon individually variable factors such as the level of exit of the sympathetic fibers for the iris from the cord, and the size and direction of the cervical rib. In the ophthalmologic literature, sympathetic heterochromia as such has sometimes been considered a genetic trait. It is, however, only the consequence of early interruption of the oculosympathetic path, as in any other kind of congenital Homer's syndrome. Cervical ribs, on the other hand, do run in famiJies. Langley further demonstrated (1900) that none of the sympathetic fibers that reach the superior cervical ganglion have their cell bodies in lower cervical ganglia; all or cervical ganglion CCA C .-~~!--",- C6 ~ )~---:=!l:~--.t--"l C8 sen men C7 slbcl~ middle cervical ganglion • 4"1.---~;;,,;;;..., • I ganglion] ngtlon T1 stellate ganglion ._,-:_ ..:·.-: .. \' T1 T4 Figure 6-6. The human cervical sympathetic chain. The abbreviations mean the following: A, aortic artery; CCA, common carotid artery; SA, subclavian artery; Cl through T4, preganglionic sympathetic fibers arising from the respective segments of the spinal cord; icn, inferior cardiac (postganglionic) nerve; men, middle cardiac nerve; sen, superior cardiac nerve; sin, superior laryngeal nerve; phr, pharyngeal rami. (Modified from E.L. House and B. Pansky,A Functional Approach to Neuroanatomy [New York: Blakiston (McGraw-Hill), 1967]: Fig. 15-5) are preganglionic fibers of central nervous origin. Langley found this true of all sympathetic efferent paths. He thereby established the "two-neuron" structure of the autonomic nervous system: all its preganglionic neurons are contained within the brain or spinal cord; and the peripheral paths all undergo a single synapse, no matter how many ganglia they may traverse along the way. The sympathetic nerve fibers emerge from the cord with the ventral roots; and it has always been assumed that they travel for each of the segments C8 to T2 with the rami communicantes to the respective paravertebral ganglion before turning cephalad to assemble in the cervical sympathetic chain. Palumbo, however, on the basis of wide surgical experience, believes that they take a slightly different course. Palumbo (1957, 1976) used a ventral transthoracic approach for surgical sympathectomy of the upper body and extremities. He found that Horner's syndrome did not result in his patients when he excized the sympathetic chain from TS upward to (and including) the first thoracic ganglion just cephalad to the first thoracic ramus communicans. He concluded that the oculosympathetic fibers "apparently leave the roots of the eighth cervical, first, and/or second thoracic nerves, passing via a separate paravertebral pathway to gain entrance to the upper aspect of the stellate ganglion." The cervical sympathetic fibers ascend to the superior cervical ganglion and synapse there with the postganglionic neurons. (b) The Superior Cervical Ganglion This ganglion is a relatively large, spindle-shaped structure that lies near the carotid bifurcation. It is believed to be formed by the coalescence of four ganglia that correspond to the upper four cervical nerves (Gray's Anatomy, 35th ed., 1973). In addition to the fibers ascending to it via the cervical sympathetic trunk, it receives fibers from these nerves; but no pupillary fibers take this path (see below). It sends lateral postganglionic branches to various cranial nerves (vagus, glossopharyngeal, hypoglossal) and to the jugular bulb and the meninges; laryngeopharyngeal and cardiac branches to the carotid body and the larynx, pharynx, and heart; and anterior branches to the external carotid plexus that supplies the vasomotor and sudomotor innervation of the face. A large bundle of rostral fibers travels to the internal carotid plexus (Figure 6-6). The superior cervical ganglion often is tightly apposed to the nodose ganglion of the vagus, with some exchange of fibers between the vagal and sympathetic trunks. There is a degree of topical order within the ganglion in the arrangement of postganglionic neuron groups to the various effectors. The importance of these facts is discussed in connection with injury and repair in the nervous system (Chapter 11). The cervical sympathetic nerve and superior cervical ganglion derive their blood supply from ascending branches of the carotid artery; and interference with 6. Reflex Dilation Nictitating Membrane (c) Postganglionic Fibers from the Superior Cervical Ganglion to the Carotid Canal The pupillary dilator fibers leave the superior cervical ganglion with the internal carotid nerve, the thickest postganglionic branch of the ganglion, emerging from its rostral pole (Figures 6-6 and 6-8). They accompany the artery to the base of the skull. The sympathetic motor fibers for the upper and lower lid (Miiller's muscle), and in animals for the nictitating membrane, accompany the pupillary fibers. While almost all contemporary texts say that the oculopupillary fibers form part of the internal carotid plexus in this segment of their path, earlier authors stated emphatically that they run as an Blood Vessels Secretion of Sub maxi I lary Gland Hairs of Face and Neck 'sup.cervical ganglion - cervical sympathetic spinal nerves / T1 T2 T3 ~T4 ~TS ~T6 ~T7 ~T8 I I I I I I ',,_~ T1 T2 T2 T3 T3 T4 T4 \ __.,~TS ~T6 ~T7 ~T7 Figure 6-7. Origin from the spinal cord of sympathetic fibers to the eye and face ( cat) (Slightly modified from J .N. Langley, Phil. ''2. '-·-~~ ~TS ~T1 T1 ~T2 T2 \, __~T3 T3 T4 T4 TS ~T6 ~T8 329 that small blood vessels are compromised by such procedures than that the surgeon stumbled upon or actually cut the sympathetic trunk as it runs cephalad within the carotid sheath. Further, in the postsurgical cases we have seen, the Horner's syndrome was permanent, as one would expect with postganglionic lesions, while preganglionic nerve fibers regenerate quickly and completely. Whether these suppositions are correct will be shown when such patients are tested for postganglionic pupillary and other defects. these vessels can cause Horner's syndrome. Koplin (1905) and Sears and co-workers (1981) have suggested that some of the many instances of Homer's syndrome of unknown origin may have been caused by underlying vascular disease, with occlusion of nutrient vessels to the sympathetic ganglion. Sears et al. supported this assumption by producing (in rabbits) all the signs of sympathetic paralysis by occluding the small vascular branches from the carotid and the anterior pharyngeal arteries to the superior cervical ganglion. Correspondingly, they found progressive neuronal death and fibrosis in the ganglion on the operated side. It thus is possible that in some patients the sudden, apparently spontaneous development of Homer's syndrome is due to ischemic damage to the sympathetic nerve or ganglion, comparable to the ischemic third nerve palsy found in diabetes. In addition, patients with Homer's syndrome due to neck trauma or surgery (such as thyroidectomy, or removal of tumors or of infected lymph glands) may have-at least partly-postganglionic sympathetic lesions. This possibility had not occurred to anyone because the lesions were known to be located in the neck, so that preganglionic impairment was assumed. However, it actually appears more likely Pupil / TS TS T6 ~T6 T7 ~T7 ~T8 Trans. Roy. Soc. London, 85 [1892]:124) ~TS 330 / I. Anatomy and Physiology Table 6-3. YEAR Spinal roots that carry pupillodilator fibers VE TRAL ROOTS -C5 C5 C6 C7 CB Tl SPECIES AUTHOR 1851 1 52 1853 1 55 1862 Budge & Waller Budge Brown -Se guard Budge Claude Bernard 167 Salkowsky ~ Fran2oiS-Franck ~ Ferrier 1885 Klumpke 1892 Langle_y Langle_y 192 1 93 Nawrocki & Przybylski Braunstein T94 1896 Oppenheim 197 Langle_y 1910 Straub 1933 Cardozo 1938 Dechaume & Morin 1943 Ray & al. rabbit rabbit rabbit ( ?} rabbit dog rabbit do~ monkey dog dOFz1cat, rabbit ape cat - - - - - - - - - -u + 0 + 0 _Q_ + ? 0 0 0 0 + 0 () () - - ~ 0 0 + + + + 0 - + + + - - -- + + + + 0 + + 0 + + + 0 0 0 0 _Q ....Q. + + 0 0 0 + 0 0 0 + - + + + + + - ++ man -+ + 0 - 0 + 0 + 0 + + stimulation stimulation + cord hcmisection & stimulation root section & stimulation 0 - - stimulation root section 0 0 + T6 stimulation _Q_ ~ stimulation - - root section stimulation 0 () 0 ~ stimulation 0 0 0 0 --:j:" + + 7=" - - - - - + 0 + + 0 0 0 0 0 - + -- - -- - - - - -- + ++ -- - - - - - 0 0 0 0 + + -- - - - - - - - + - + - 0 0 0 0 0 + + 0 dog + + 0 cat man cat cat cat + + ...l ..:L -2 ...l -1.. - - () + + EXPERIMENT T2 T3 T4 T4+ 0 Tl0 0 0 ~ stimulation - - + 0 ~ + 0 ~ + -- --- - - -- - + -+ --0 4 10 18 stimulation stimulation stimulation stimulation stimulation cord transection stimulation 2 The symbols represent: + = the author believed that pupillary dilator fibers were contained in the spinal root; 0 = the author denied that pupillary dilator fibers were contained in the spinal root; - = no statement; the numbers below the symbols for Ray et al. (1943) show the number of experiments that were positive. Table 6-4. The emergence of pupillary and vascular fibers from the spinal cord of cats Pupil Dilation Cat CB none Tl good moderate T2 Stimulation ventral of root numbers Contraction of Ear vessels Cat 2,3,4,5,6 none 2,3,4,5,6 1,3,4,5,6 2 none 2,3,4,5,6 good 1,2,3,4,5,6 good slight 3,4,5,6 2 T3 moderate slight 3,4,5 1,2,6 good moderate 3,4,5,6 2 T4 none 2,3,4,5,6 good moderate-good slight 3,4 2 5,6 T5 none 2,3,4,5,6 moderate slight ? 4 3,5,6 2 T6 none 2,3,4,5,6 trace none 2 3,4,5,6 T7 none 2,5,6 none 2,5,6 TB none 2 none 2 After Langley, 1897. Note that the vascular dilator fibers. nerve fibers leave the cord at lower levels numbers than is true for the pupillo- 6. Reflex Dilation the po tganglionic nature of the defec~. Trauma or pace-con urning lesions can also cause disturbances of the oft palate, pharynx, and larynx by press~re or oth~r damage to the ninth, tenth, and twelfth cramal nerves m the retroparotid space. Complete de truction of the superior cervical ganglion or the internal carotid nerve is followed by degeneration of all ympathetic peripheral fibers to the eye, for there i no synap e peripheral to the superior cervical ganglion. However, because a degree of sympathetic function sometimes remains after the operation, the idea has arisen that the iris is supplied by additionaJ ympathetic ganglia-distal to the superior cervical ganglion-in the carotid plexus or the orbit, or even within th eye or iris. This, however, is not true. Any occa ional remaining sympathetic fibers are anomalous, originating from stray neurons scattered along the preor postganglionic nerve path. Such stray cells are not uncommon in autonomic ganglia (Langley, 1893, 1900; ee Chapters 3 and 11 ). Among many others, we encountered such anomalous neurons in experiments on cats after we removed the superior cervical ganglion by snipping all its branches with fine scissors and lifting it out. In later experiments we held on to the preganglionic chain with several silk threads knotted about it, and after the ganglion was dissected free of all branches except the rostral internal carotid nerve, we grasped the ganglion firmly with strong forceps and ripped it out. When this was independent bundle along ide the artery and that pupillary dilation can be elicited from there but not from the fiber that pin around the artery (Fran~oi -Franck, Braun tein, and other ). In fact !he internal carotid nerve i quite long, a i how~ m mo t anatomic illu tration (and was een in the cat we operated on). If the motor fiber to the ocular mooth muscles do become part of the internal carotid plexu , they thu cannot form part of the plexu much before they enter the carotid canal together with the artery. A mall group of va omotor and sudomotor fiber travelling to a patch of skin above the ip ilateral brow also run with the internal carotid nerve. But the re t of the facial vasomotor and sudomotor nerve from the superior cervical ganglion join the external carotid plexus. For thi rea on po tganglionic pupillary deficit i not as ociated with facial vasomotor and udomotor lo except for the mall upraorbital area 10 (see Figur~ 43-3). The internal carotid nerve can be impaired by a number of different pathologic condition in the area about the angle of the jaw (see Chapter 25). When the superior cervical ganglion is involved also, the denervated territory is the same as in preganglionic lesion in the upper neck, and drug tests are needed to establish 10. The blood supply of this patch of skin is derived from the internal carotid tree. In patients with internal carotid occlusion, this area _can ~e seen as a cool spot in thermogram , and as a dark spot in facial nuore cein pictures. Figure 6-8. Diagram of pupillary and other sympathetic pathways to the eye and face. Preganglionic neurons in the lateral cell column of the cervicothoracic cord (see Figure 6-7) leave the cord by its ventral roots and travel via the first thoracic ympathetic ganglion and inferior cervical ganglion, the subclavian ansa of Vieussens, and the middle cervical ganglion of the superior cerivcal gamglion, the site of their peripheral synapse. From here the vasomotor, sudomotor, and pilomotor fibers for the face travel with the external carotid plexus. Tho e for the extra- and intraocular smooth muscles, the ocular blood vessels, va omotor and sudomotor fiber for a patch of skin above the brow, and fiber to the lacrimal gland follow the internal carotid nerve and plexus to their intracranial path. The sympathetic fibers to Muller's mu cle, the nictitating membrane and the pupil are shown to pass through the middle ear, and those to the forehead with the internal carotid plexu and along ves els that supply the innervated area (see text for controversial points). In man and monkeys the ocular vasomotor fibers traverse the ciliary ganglion (sympathetic root), and those for the lacrimal gland, the sphenopalatine ganglion. either of these postganglionic sympathetic paths synapse with cells of these ganglia. In subprimate specie the ocular va omotor fiber circumvent the ciliary ganglion. The abbreviations mean: GG, Gasserian ganglion; CG, ciliary ganglion; SPG, spenopalatine ganglion; icg, inferior cervical ganglion; Tl and T2, fir t and second thoracic sympathetic ganglia. 331 / ophthalmic 5° nerve nasoclllary fibers ... • • • • ··• ..• ••• (o~::=:::=:::§~~--·--· vasomotor & sudomotor fibers to forehead ___ puplllo-dllator ......... CG :::::._motor fibers to nlctltatlng -::::-.... membrane '--" ......._ vasomotor fibers to eye ••••G .. ··•·· vasomotor to SPG '- lacrlmal gland external 1------------cervlcal ti~-----~~ .8 . I?h -\ . .-· ,. ,-----------)------------ ..>----------- fibers ..:._- motor fibers to Mueller's carotid plexus sympathetic middle cervical ganglion ansa of Vleussens stellate ganglion chain muscle 332 / I. Anatomy and Physiology done successfully, about 1 or 2 centimeters of the postganglionic nerve came away with it. We also removed a centimeter or so of the preganglionic nerve, leaving a tight silk knot about its proximal end that had been looped backwards. After such complete lesions, no residual sympathetic functions were encountered for several years postoperatively; and fluoresceine histochemical examination failed to show any sympathetic fibers in the iris at all, as determined by Laties (1972). 11 (d) Relations of Oculopupillary Fibers to the Middle Ear Although most contemporary texts say that the oculopupillary fibers pass with the internal carotid plexus and reach the orbit via the cavernous plexus, along with the branches for the blood vessels and cranial nerves, there is strong evidence that, at least in many - - • - • • • - - to nictitating membrane and eyelid 1st division of 5th nerve • - • - • • - - - - - 2nd division of 5th nerve - - -x .. -- 3rd division of 5th nerve ' , Gasserian ganglion vidian nerve ._ ----·. -- middle ear - • - - - -- foramen rotundum - .. - . __ . . .. . - internal carotid artery • - - - • .. • - • - • - ...""superior cervical ganglion Figure 6-9. Relation of oculosympathetic fibers with the middle ear in cats. The diagram shows the postganglionic sympathetic fibers for the pupil, palpebral fissure, and nictitating membrane (marked x ). The left side is shown, as seen from the ventral aspect. The work was based on stimulation experiments and dissections. The broken lines indicate nerve path within the bone. In cats not only the pupillary fibers but also those for the smooth muscle of the lids and for retraction of the nictitating membrane were found to pass through the middle ear. This agrees with other findings in cats (see text). But only the pupillary fibers are shown to travel by way of the ophthalmic fifth nerve. (From A. deKlcijn and C. Socin, Pfluger's Arch. ges. Physiol., 106 [1915):407) animals, the fibers do not follow the artery but leave it shortly after its entry into the carotid canal. They pierce the anterior wall of the tympanic cavity and cross the anterior part of the promontory. They leave the middle ear via the bones at the base of the skull, emerging within the cranial vault from between the articulating surfaces of the petrous and the alisphenoid bones, just lateral to the vidian nerve. They approach the ventral surface of the Gasserian ganglion near its peripheral end (Figures 6-9 and 6-10). Up to this point the fibers for the orbital smooth muscles and for the nictitating membrane run with the pupillodilator fibers, since they can be stimulated or destroyed together in the middle ear (Table 6-5,A). According to Franc;ois-Franck, Littauer, and Metzner and Wolffiin, who watched for reactions of conjunctiva), retinal, and iris vessels, this is not true for the course of the vasomotor nerves. These are assumed to continue along the internal carotid plexus without entering the middle ear. In cats it is easy to block conduction of the oculopupillary path by introducing a few drops of cocaine solution into the middle ear. For example, in a cat we produced maximal pupillary dilation together with retraction of the lids and nictitating membrane, exophthalmos, and constriction of the vascular bed of the ear auricle by electric stimulation of the cervical sympathetic nerve. Five drops of a 4% solution of cocaine were then instilled into the cat's external auditory meatus (the ear drum having been punctured in an earlier experiment). A few minutes later, repeated stimulation of the cervical sympathetic nerve failed to elicit the ocular responses, while vigorous contractions of the ear vessels (which derive their vasomotor supply from the external carotid plexus) testified to the undiminished effectiveness of the stimulus. The experiment proved again that in cats the oculopupillary fibers run through the middle ear. The fact that they are here accessible to anesthetics is useful when temporary postganglionic sympathetic paralysis is desired in an experiment. The human oculosympathetic path may take the middle ear course, but this matter is still too confused to be certain. As seen in Table 25-16, postganglionic Homer's syndrome has been common among patients with middle ear disease. Among 712 cases described in the literature we have reviewed, 314 had oculosympathetic pupillary deficit ( 44.1 % ); and of 180 patients subjected to radical middle ear surgery, 134 (74.4%) had the defect. These numbers, however, may be weighted by the facts that the 11. Occasionally it has been said that damage to one superior cervical ganglion influences not only the eye on the side of the lesion but also the contralateral eye via crossed sympathetic connections (Seitz, 1955; Sears and co-workers, 1964, 1966). But this is incorrect. Unilateral excision of the superior cervical ganglion results in strictly ipsilateral sympathetic dencrvation in all animals tested (Ehinger, Falck, and Rosengren, 1969). 6. Reflex Dilation / 333 reports were concerned pecifically with sympathetic damage, and that much of the material predated modern microsurgical techniques and antibiotic control of infections; thus, the percentages of sympathetic involvement may have been larger than would be the case today. Further, the anterior wall of the human tympanic cavity varies from dense bone to a thin, membranous septum. The disease process or the surgical trauma may therefore have exceeded the confines of the middle ear to involve sympathetic fibers running along the carotid artery nearby. Conversely, exenteration of the human tympanic cavity with careful scraping of the mucosa did not always lead to sympathetic ocular impairment. This could be accounted for by individual anatomic variations within the middle ear: along the floor of the promontory the tympanic sympathetic fibers sometimes run superficially beneath the mucous membrane, while in other cases they run in grooves or tunnels in the bone so that they would be protected from injury (Frenckner, 1959; Hofnagel and Joseph, 1961; see Figure 6-11). Further, Homer's syndrome often has been described in patients with internal carotid disease, apparently at various levels, Figure 6-10. Monkey after interruption of the superior caroticotympanic nerve branches on the left side. The nerve fibers were destroyed in the middle ear. Note the typical sympathetic ptosis on the left side. The pupillary edges were marked by us with small white dots since they were hard to see in re-photographs from the original publication. The miosis does not appear marked because both pupils were contracted by the bright light needed for the photograph. It was di tinct in dim light and enhanced by sensory stimulation. (From W.E. Wiesinger, Laryngoscope, 69 [1959):1287) Figure 6-11. Individual variations of the tympanic plexus running over the middle ear promontory (human specimens). In the top picture (Figure 3A of the original), the nerve runs over the s1:1ooth surfac~ of the pro~ontory. In the middle picture (original Figure 3D), 1t 1s contamed tn a deep groove in the bone; and in the bottom picture (original Figure 3E) it was hidden in an almost roofed-over groove that formed a canal in the bone. (Specimens provided by H. Engstrom, Stockholm, and published by P. Frenckner,Arch. Otolar., 54 [1951):347) 334 / I. Anatomy and Physiology A Dilator pupillae muscle Ciliary body Long ci I iary Maxi I lary Int. carotid sympathetic plexus --.;-----rn,'---Trigeminal --- nerve Mandibular nerve ganglion Pupillociliary sympathetic postganglionic fibers B Figure 6-12. Diagrams showing the anatomic relation of the postganglionic sympathetic fibers. A. View from above. The sympathetic fibers join the fifth nerve near the distal end of the Gasserian ganglion. Note the close relation to the internal carotid artery. (From A.O. Solnitzky, Georgetown Univ. Med. Ct. Bull., 14 [1961):210.) B. View from the right side, in the area of the cavernous sinus (heavy dashed line). The sympathetic fiber path is shown by the crossed line. (Slightly modified from B.D. Parkinson, J. Neurosurg., 23 [1965):474) from the origin of the artery at the carotid bifurcation to its intracranial division. This would be difficult to explain if the ocuJopupilJary fibers left the artery already within the carotid canal. On the other hand, sympathetic damage in patients with lesions in the lateral fossa could not be accounted for by a pericarotid path of the oculosympathetic fibers. According to Picquet and Coulouma (1935), some sympathetic fibers that traversed the tympanic cavity rejoined the arterial plexus further downstream, while others never entered the middle ear at aU, and the arrangement varied in individual dissections. Occasionally there have been reports about special "otogenous," "cochlear," or "vestibular" pupillary reflexes (Table 6-5,B). These were reactions to auditory stimuli, sometimes used to test the individual's acoustic sensitivity. It should be stressed that such reactions are not specific reflexes. The stimulated ear simply is the source of sensory impulses that elicit bilateral psychosensory reflex dilation in the same way as any other sensory input. (e) Relations of Oculopupillary Fibers to the Gasserian Ganglion and the Trigeminal Nerve A short distance from their entry into the cranial vault, the pupillary dilator fibers pass to the ophthalmic branch of the trigeminal nerve near its emergence from the Gasserian ganglion or more peripherally. They do not enter the ganglion itself, but travel with the ophthalmic nerve through the superior orbital fissure into the orbit and continue in its nasociliary division and the long ciliary nerves to the eye (Figure 6-12). The sympathetic anastomosis with the fifth nerve was known very early (Eustachius, 1552; Willis, 1664; Vieussens, 1685; Palfin, 1718). As described above, until Pourfour du Petit's experiments, the fifth nerve had been considered the main cephalic root of the sympathetic nerve. And toward the middle of the nineteenth century Budge, Waller, and many others furnished physiologic evidence for a relation between the pupillary dilator pathway and the fifth nerve (Table 6-6). When the ophthalmic branch of the nerve was cut, the pupil became smaller than the normal one, and subsequent stimulation of the cervical sympathetic chain failed to evoke pupillary dilation as it normally did. But stimulation of the peripheral end of the severed nerve produced pupillary dilation at once. Statements in the literature do not agree about the ocular sympathetic pathways along this segment of their course. As seen in Table 6-7, several descriptions have been given. 12 (1) The one just mentioned, namely, that the pupillary dilator fibers from the middle ear enter the base of the skull by passing between the alisphenoid and petrous bones, and then join the 12. As already stated, there appears to be considerable individual variation in the course of these fibers. 6. Reflex Dilation Table 6-5. Experiments on the postganglionic A. STIJ\IULATION Oi,;- ANIMALS YEAR I THE MIDDLE I cut fibers destroyed cut fibers destroyed in the tympanic capsule tympa.nic bulla in the tympanic capsule mucosa in the foramen rotundum destroyed the middle Zanzucchi Jarcho & Root Byrne Barlow &Root cat cat rabbit rabbit cat cat,rabbit guinea pig pigeon cat cat cat Staffieri guinea pig destroyed Frenckner Zaoli Botner & *** Comoretto man guinea pig hedgehog rat Wiesinger monkey destroyed tympanic plexus destroyed the middle ear stim. & cut nerves in the middle ear; (stim. & cut fibrils that accompany the stapedial artery; present in man only in early embryonic life) destroyed fibers in the middle car 1938 1940 1942 1949 1950} 1951 1951 1954 1956 1 EAR. EFFECTS Pupil Lids* PROCEDURES cat dog cat cat rabbit ~S~c~h~iff _____ -,-_ Fran9ois-Franck Littau er de Kleij n Metzner & \V-6lfflin de Kleijn &Soc in de Kleijn&Magnus Karbowski Zanni Zernick Arslan * SPECIES FIBERS short 1867 1878 1892 1912 1914} 1915 1915 1918 1923 1927 1928 1932 1959 sympathetic fiber path through the middle ear AND DESTRUCTIO OF OCULO-SYMPATHETIC ( For clinical conditions, see Table 25-16) AUTHOR 335 / note + - EXPERIMENTS I NM** --- + + + + + + (+) (+) stim. &destroyed fibers in the middle ear cooled external auditory m.eatus injected formaline into the middle ear labyrinthectomy cut nerves fibers in the middle ear + + + + + destroyed + + + + + - + middle ear ear mucosa stimulation or cocaine in ear canal destroyed Iibers by labyrinthectomy cocaine in tympanic bulla destroyed fibers in the promontory middle = Ftosis - _o;:___ 0 0 + + ear and/or enophthalmos ** = NM means nictitating membrane dogs and rabbits but could not find mydriatic effect of stimulation. and -,not mentioned. Paralysis usually was proven by stimulating after the procedure. ophthalmic branch of the trigeminal nerve; and that they then continue in its nasociliary division and reach the eye by way of the long ciliary nerves. For cats, dogs, rabbits, and monkeys we have adopted this view as probably the most common path because, at least at present, it is the best supported by anatomic and physiologic experiments. (2) After passing through the middle ear, the sympathetic fibers rejoin the carotid plexus and pass to the ophthalmic nerve more peripherally in the cavernous sinus and superior orbital fissure. (3) The fibers continue along the internal carotid plexus and the cavernous plexus without relation to the middle ear or the ophthalmic fifth nerve. The existing descriptions are even more diverse for the sympathetic fibers that serve the nictitating membrane, the orbital smooth muscles, the ocular vessels, the vessels to the forehead, and the sweat glands to that area. At one extreme, according to Adler's Physiology of the E e 5th ed., 1970 all ocular sympathetic fibers travel ith the fifth nerve: u illod· tor fibers as well as those or iiller's muscle and the ocular blood vesse s, and possibly even those for the lacrimal gland. At the other extreme, de Kleijn and Socin (1915) said that in cats, lid + + + lvessels - no details anatomic study + + + + *** = Authors tried experiments also on + indicates positive effects; O,no effect; the cervical sympathetic nerve before and retraction and contraction of the nictitating membrane could still be obtained after the second, third, fourth, and sixth nerves, all branches of the trigeminal nerve, the long and short ciliary nerves, and the ciliary ganglion had been destroyed. Zemick (1928) observed the same. Others think that the fi rs for the u il run with t fifth nerve, but those for the lids by way of the third nerve; those to the ocular vessels and supraorbital skin 'with the carotid and ophthalmic arteries; and those to the lacnmal gland via the maxillary branch of the fi th nerve and s heno alatine an lion and then with the zygomatic and lac rimal nerves to the gland. 13 e ave no et opinion on this matter and hope the question may be elucidated by future anatomic and physiologic work; but the following points should be considered in the meantime. (1) Raeder's original case and many described since with "paratrigeminal" middle fossa lesions had the typical "upside-down" sympathetic ptosis and slightly decreased intraocular pressure along with miosis on the 13. Using histochem!cal tech~iques, Ehinger (1964) was unab_le to fin~ adre~erg1c fibers m the lacrimal gland of the rabbit and gmnea pig except for those associated with blood ve sels. 336 / I. Anatomy and Physiology Table 6-5 (continued) B. PUPILLARY YEAR REACTIONS AUTHOR Udvarhelri Cemach Wodak Benjamins Udvarhelyi Wodak Nelissen Weve Wodak & Fischer Nishimura Gladkow Thzuka Arslan Sommer ten Cate 1935} Ozaki 1936 Goto & Matsuhara Miyake 1937 1937 1938 Frenzel Maehara Utumi (a-d) 1938 Vega Herrera (a&b) (a&b) Zanzucchi (a) ~) 11 1~~8} (c&d) II Maehara (a) 1~~9} II 1939 {b) Ozaki & Utumi 1940 1939 Zanzucchi Zanzucchi 1946 1954 1954 Montandon Brailovs kii (a&b} Shakbnovich 1957 Nishimura 1958 Yamashita narano Nishida 1971 1979 1984 1985 BY AUDITORY OR VESTIBULAR STIMULI STUDIES 1913 1920 1920 1921 1921 1921 1922} 1923 1923 1927 1929 1930 1931 1931 1933 "1936 " ELICITED (a&b) & Shiga & Ohkuba Oono, Masaki &Kawano Oono (a and b) reactions to stimulation of the labyrinth (cited after Nelissen+Weve. 1922-23) cochlear reflexes : small I bilateral ]2UJ2ilconstrictions [ 12robably involuntary blink] vestibular reflex: pupil dilation during rotation with sudden stop l probably sensory reflex] acoustic reTiex (n.r.) remarks on Wodak' s eaeer ( 1920 1 n. r.} reflex dilation elicited b_y stimulation of the lab_yrinth (n.r.} reflex dilation elicited by stimulation of the labyrinth with cold water in normal subjects, and in 12atients with dementia 12raecox 1 deaf-mutes without labyrinth I and those 12ueillary reflexes elicited by stimulation of the 8th nerve (n.r.) EUJ2illary dilation upon stimulation of the 8th nerve ]2Uf2illary dilation elicited by acoustic stimuli pupillary dilation elicited by acoustic stimuli (tuning for!<) bilateral reflex dilation, elicited nv vestibular stimulation (with preceding slignt contraction) bilateral dilation elicited b,l sudden air pressure upon the eardrum cats: pupillary dilation to acoustic stimuli, said to be abolished by extirpation of the acoustic area of the cerebral cortex ( later return of some function) rabbits: pupil dilation to acoustic stimuli (tuning forK) loss of reactions after the rabbits' cochlea had been destroyed by toxin pupillary reactions (mostly dilation) to acoustic stimuli in patients with acute or chrome 12urulent middle ear disease due to 1939, fleeting pupil contraction with following dilation, according to Maehara, acoustic stimulation miosis I followed by mydriasis u:12onvestibular stimulation (rotation) recording of acoustic reflexes in animals (method described} "acoustic pupil reactions", i.e., reflex dilation elicited by loud whistle, before rabbits: and after cuttine: the ear drum, or placine: cocaine uoon it occasionally fleeting vestibular stimulation by rotation in 50 normal human subjects: contraction, followed by dilation and pupillary oscillations pigeon: stimulation of the semicircular canal caused pupil dilation and oscillations, \vith ocular rotatory nystagmus pigeon: pupillary reactions to cold water stimulation of the labyrinth caused fleeting coniraction by dilation 1 followed acoustic stimulation in 1468 normal human subjects and in 244 patients, hard of hearing: dilation was inverseli related to age, and was weak or lost in the eatients ehoto-records of rabbits: tuning fork stimuli and Galton whistle caused strong dilation reflex dilation to sound before and after middle ear damage induced by bacterial rabbits: infections summarv on ouoillarv reactions to stimulation or the labvrinth miosis during rotation, followed by mydriasis and 11 hippus" at the end of stimulation ~igeons); th is eersisted after labyrinthectomy and after introduction of cocaine labyrinth versus autonomic nervous s_ystem (J2UQil on Qages 105-06) 11cochleo and cochlear vs. vestibular receptors -pupillary reflex" for hearing tests; stimulated by sound (n.r.) the reactions records of reflex dilations elicited by sound in normal human subjects: tended to fade after re:eeated stimulation (in rabbits) versus age: dilation to sound with normal or with acoustic pupillary reflexes im2aired function tested various intensities and frequencies of sound acoustic reflexes : in young rabbits, in light and in darkness "signilicance or pupillometry in otorhinolaryngology" (pathology) pupillary responses to auditory stimuli (n.r. 1988) analysis of averaged res pons es to auditory stimuli in normal human subjects : found pupil dilation to consist of an early (parasympathetic-inhibory) phase that was reduced in darkness and abolished by atropine; and a later (active sympathetic) phase that was suppressed } by thymoxamine 6. Reflex Dilation Table 6-6. 337 Authors who reported that the postganglionic sympathetic path joins the fifth nerve YEAR AUTHOR SPECIES YEAR 1727 1827 1a4o} 1846 1840 1R42 1851 1852 1855 1858 1962 1862 1864 1868 1875 1877 1878 1878 1878 du Petit Desmoulins dog 1 wolf 1893 Ruete man, animals Stilling Longet Budge & Waller Budge Budge Schiff Balogh Oehl Donders Stellwag Gradle Surminski Hurwitz Hensen & Voelckers Raehlman & Witkowsky Fran9ois-Franck Ott Leeser man dog (?) rabbit rabbit rabbit cat rabbit rabbit {?} rabbit rabbit {?) aog rabbit cat, dog,rabbit dof?i general statement dog cat literature cited monkey, cat, dog dog frog rabbit cat rabbit, dog 1878 1879 1881 1886} 1888 1886 1886 1889 1892 1893 / Jessop Jegorow Schi2olow Morat Littauer Spalitta & Consiglio ? side of the lesion. Raeder s patient and a number of others described since had tumors that involved the Gasserian ganglion and branches of the fifth nerve. Such lesions could, of course, have injured para-carotid sympathetic fibers indirectly by pressure, in view of the close proximity of the artery and nerve (Figure 6-12). But this is not true of patients who developed Homer's syndrome after resection or neurolysis of the Gasserian ganglion for trigeminal pain, nor was it likely in a case described by Bader (1959) with stenosis of a nutrient vessel to the area of the Gasserian ganglion. Further, as Table 25-17 hows, the sixth nerve was often but the third nerve seldom damaged in patients with Homer's syndrome due to middle fossa lesions. This would indicate that the lesion wa located lower and more lateral than the carotid artery and third nerve (Figure 6-12,B). On the other hand, according to Parkinson and his co-workers (1973-1975) sympathetic fibers in the carotid plexus run for a short distance with the sixth nerve before passing to the ophthalmic fifth. (2) Since the presence of oculosympathetic fibers in the fifth nerve has been demonstrated in many species, the same is probably true for the human trigeminal nerve. And indeed, Grimes and von Sallmann found no roots of the ciliary ganglion of human specimens other than those from the third and to the nasociliary fifth 1894 1894 1895 1898 1903 1904 1904} 1906 1908 191~ 1913 1914 1915 1923 19~4 1924 1924 1924 1925 19~6 19~6 1926 1936 1938 1938 1942 1949 1961 AUTHOR awrocki & Prz;yb;y:lski Braunstein Langendorff v. Bechterew Schultz Anderson Parsons Tschirkowsky Bach de Kleijn Landois Metzner Wolfflin Buriet de Lapersonne & Cantonnet Behr Hartmann de Kleijn & Socin Raeder Braunstein Balado Leriche & Fontaine Windle Christensen Bender & Kennara Thiebaut & al. Weinstein & Bender Barlow & Root Hoernagel & Joseph SPECIES cat cat! aog cat man,rabbit rabbit cat cat, dog, monkey rabbit rabbit,cat cat cat,dog rabbit cat man man man cat man man rabbit, dog, cat man cat cat monke;y man cat, monke;y cat man nerves. Clinical data further support this view (see Chapter 25). (3) ~eral in~tigatars haye failed to find sympaJ:hetic anastomoses with the third nerve. Koch (1916) and Sunderland and Hugh~ {1946) stressed especially that there were no anastomoses between sympathetic fibers of the cavernous plexus and the oculomotor nerve. Koch said: "No such communications from the sympathetic system were seen in connection with the IIIrd and IV th nerves. Branches of the cavernous plexus which on gross dissection could be seen to join the lllrd nerve, on microscopic examination were seen to accompany the nerve for a short distance and again separate from it farther distalward, without entering into intimate contact with its fibers"; and "The unmyelinated fibers remained grouped in the nerve sheath and did not enter into its substance. More distally they separated from the nerve completely." Sunderland and Hughes said: "The [third] nerve is described in textbooks of anatomy as communicating, in its course in the [cavernous] sinus wall, with the ophthalmic nerve and the internal carotid sympathetic plexus. Minute bundles of sympathetic and somatic fibers approximated to the oculomotor nerve in the sinus wall but there was never any communication or exchange of fibers with the latter." 338 / l. Anatomy and Physiology Table 6- 7. The path of sympathetic fibers from the middle ear onward: Descriptions in the literature SPECIES DESCRIPTIO de Kleijn & Socin cat 1915 Burlet cat (anat) 1935 Picquet & Coulouma n~an (anat) 1928 Zernick cat 1938 List & Peet man 1949 Barlow Root cat 1961 Hoefnagel Joseph 1969 Walsh & Hoyt n1an 1970 Adler man from the promontory the fibers enter the base of the skull lateral to the Vidian nerve; within the cranial cavity pupillary fibers enter the first branch of the fifth nerve and continue in its nasociliary division and the long ciliary fibers to the eye; fibers for the lids and nictitating membrane do not run aboard any cranial nerve: reactions could still be elicited by cervical sympathetic stimulation after the 2nd, 3rd, 4th, 6th, all branches of the 5th nerve and the ciliary ganglion had been destroyed from the anterior end of the promontory the fibers enter the cranial vault by a fissure between the cochlear and the posterior rim of the alisphenoid bones ; some fibers enter the Gasserian gangl10n and others can be followed next to the ophthalmic nerve as a se2arate bundle from the middle ear the fibers re-join the internal carotid plexus and finally reach the dilator muscle by way of the long ciliary nerves after crossing the tympanic capsule, the sympathetic nerve thread for the nictitating membrane passes through the base of the skull. It does not follow any known nerve (same results as de Kleijn & Socin 2 1915} the first division of the fifth nerve carries sweat fibers for the forehead that it receives intracranially from the promontory, the pupillary fibers and the fibers to the nictitating membrane run between the petrous portion of the temporal and the alisphenoid bones and join the inferior surface they run to the orbit in the first diof the Gasserian ganglion; vision of the trigeminal nerve the fibers leave the middle ear via the bones of the skull, as a this intraseparate nerve bundle lateral to the Vidian nerve; nd osseous course ends when, between the foramen rotundum the Vidian nerve, the sympathetic fibers enter the orbit thrcugh the superior orbital fissure and join the first branch of the 5th n. after passing through the tympanic plexus, the sympathetic hbers rejoin the carotid plexus which enters the middle cranial Iossa through the foramen lacertum, where the plexus is in close rel\1ost, if not all of the pupillation with the Gasserian ganglion. lary fibers anastomose with the first branch of the fifth nerve and run \vith it and its nasociliary branch to the orbit the fibers run along the internal carotid artery to the Gasserian vasoconstrictor ganglion and then follow the nasociliary nerve; fibers and fibers to Mliller's muscle reach the eye by way of the In addition, long ciliary nerves , and the pupillary fibers also. fibers from the cavernous plexus run via the superior orbital fissure to the ciliary ganglion and then j oun the short ciliary nerves YEAR AUTHOR 1915 & & man mammals (f) Sympathetic Fibers in the Orbit Entering the orbit with the ophthalmic branch of the fifth nerve, the sympathetic pupillary fibers follow its nasociliary division and reach the eye by way of the long ciliary fibers (Figures 6-13 and 6-14,A). Detailed anatomic descriptions of the ciliary ganglion date back a surprisingly long time (Fallopius, 1552; Willis, 1664; Vieussens, 1685; Schacher, 1701; Palfin, 1718; Saint Yves, l 772; Winslow, 1732, and countless later anatomists). • ranches were shown clear! , and its effeJ:C.m-tib raced to the e e and between the sclera and the choroid until they enter the iri . e c anty of the early descriptions an t e beauty of the illustrations are admirable. JS ln rabbits, cats, and dogs, the ciliary ganglion has no anatomic connection to the fifth nerve, and no sympathetic fibers enter it from any source. In these species the ganglion is a purely parasympathetic gang! ion, and the short ciliary nerves emerging from it carry cholinergic fibers only (Figure 6-14,B). Consequently, the ciliary ganglion can be removed without the slightest change in sensory or in sympathetic innervation of the eye. In contrast, C_!!..ttingthe long ciliary nerves that branch from the nasociliary nerve distal to the ciliary ganglion abolishes the pupillary dilation elicited by stimulation of the cervical sympathetic chain; and stimulation of these nerves dilates the pupil (Table 6-8). When only a single long ciliary nerve twig is stimulated, segmental dilation results in di tortion of the pupil 6. Reflex Dilation / 339 Figure 6-13. The human cilia1?' ganglion and nerve~. (From F. Arnold, Der Kopfteil des Vegetahven Nervensystems be1m Menschen in Antomischer und Physiofogischer Hinsicht [Heidelberg and Leipzig: K. Groos, 1831): Plate 5) A scN CG 3°nerve --scH lat med 30 f-'i<-', N,lo :ID B Figure 6-14. The ciliary ganglion and its branches. A shows the human ciliary ganglion and B that of the cat. The two diagrams were relabelled to conform with each other. ICA, internal carotid artery; CG, ciliary ganglion; aCG, accessory ciliary ganglion; GG, Gasserian ganglion; lat, lateral and med, medial; lcN, long ciliary nerve; NcN, nasociliary nerve; scN, short ciliary nerve; ON, optic nerve; Ir, long root of the ciliary ganglion to the fifth nerve (in man); sr, short motor root of the ciliary ganglion; syr, sympathetic root to the ciliary ganglion (in man); 3° , io, third nerve branch to the inferior oblique muscle. The pupillary constrictor fibers come from the third nerve branch to the inferior oblique muscle, pass through the short root of the ciliary ganglion, and synapse with its neurons. The postganglionic short ciliary nerves surround the optic nerve and run with it to the eye. The sympathetic pupillodilator fibers enter the ophthalmic branch of the Gasserian ganglion and continue in its nasociliary division. They bypass the ciliary ganglion and reach the eye by way of the long ciliary nerves. The "long root" of the human ciliary ganglion carries sensory fibers from the eye to the nasociliary branch of the fifth nerve, and the "sympathetic root" carries vasomotor fibers from the cavernous plexus to the eye. The fibers contained in both these roots merely traverse the ganglion without synapse. In cats and dogs there are no such roots. Some of the sympathetic fibers in the long ciliary nerves may merge with the short ciliary nerves beyond the ganglion. There may be accessory ciliary neurons strewn among the short ciliary nerves. Aggregates of these are called "accessory ciliary ganglia." (A modified from E. Wolff,Anatomy of the Eye and Orbit [Philadelphia and Toronto: Blakiston, 1951 ); B modified from D. Whitteridge, 2d int. neurof. Congr., London, Abstr. [1935]: 96) 340 Table 6-8. YEAR I. Anatomy and Physiology / Experiments and anatomic work on the pupillodilator AUTHOR SPECIES EXPERIMENTS described CG roots from the 3rd and from the ophthalmic 5th nerves (1) the 3rd nerve and a small branch from the ophthalmic 5th merge to form the CG from where ciliary nerves reach the eye; (2) from the SCG (via the carotid plexus) the 5th nerve is joined by a small branch which 11 furnishes es2rits 11 to the eye in cats the CG has no connection with the 5th or tlie sympathetic nerve saw the short root of the CG on the 3rd nerve branch to the inferior oblique muscle, the long root to the 5th nerve, and the sympathetic root from the cavernous nle:x.'US. runninQ· alon!! the onhthalmic artery the iris receives nerves from the CG which has roots trom the 3rd nerve for pupillo-constriction, and from the 5th nerve for pupillo-dilation the CG receives a branch from the 3rd nerve, a long branch from the 5th nerve 2 and a sym.eathetic branch in cats the CG has no connection to the sympathetic, only to the 3rd nerve H~~ Winslow Palfin man man 1815 1831 Muck Arnold cat man 1834 Fario 1839 Faesebeck man& animals man 1842 Bidder & Volckmann nan Budge cat 1867} 1870 1875 Adamiik cat,dog Reichart man 1878 1878 Fran5:ois -Franck Hensen & Voelckers Schwalbe dog 1846 1852 1879 animals man& animals dog ltsl:55 Krause Neglinski bird, rabbit, sguirrel rabbit pigeon 1885 1885 Jegorow Reche cat 1 dog cat,rabbit 1882 1886} 1 7 CG = ciliary ganglion; SCG described short, long, and sympathetic roots of the ciliary ganglion saw sympathetic fibers from the 5th nerve run via the CG; but in cfocken these joined the ciliary nerves distal to the ganglion and ran independently to the globe dissertation on long ciliary nerves {see 1886-87} the CG sits on the inferior oblique branch of the 3rd nerve, and there are no connections to the 5th or to the sym2athetic nerve the CG is related to the 5th nerve and to microscopic fibers from the arterial plexus the CG has no relation to the 5th nerve or the sympathetic; sympathetic fibers bypass the ganglion, and their section caused moderate miosis sheep = superior AND CONCLUSIONS the 5th nerve branch :ea.sses througii the CG without terminating in it for pupillo-dilation the sympathetic sends fibers to the 5th nerve which continue by way of the nasociliary and long ciliary nerves; in cats these bynerve also carries sensation from the eye 2ass the CGi the na.sociliary after removal of the CG, the pupil dilated to stimulation of the cervical sympathetic nerve; there is no connection to the sympathetic in cat & dog saw fine sympathetic "vasomotor" fibers from the carotid plexus to reach the CG; other sym.eathetic fibers bypassed the ganglion stimulation of the long ciliary nerves dilated the pupil pupillo=ailator fibers in the nasocihary nerve bypass the CG; they travel via fine twigs grou2ed around the optic nerve in these species the ciliary ganglion has no connection with the 5th nerve cat,dog Jegorow path and the ciliary ganglion cervical ganglion. shape disproving the old idea that the sympathetic fibers form terminal nerve nets that spread diffusely over the entire iris (see Chapter 1). Distal to the ciliary ganglion, the short and some of the long ciliary nerves often intermingle in their course toward the globe. In primates, the relations between the ciliary ganglion and the sympathetic pupillary fibers are more complex. The ciliary ganglion is connected to the nasociliary nerve by a "sensory root," and it may receive fine fibrils from the periarterial sympathetic plexus, the so-called sympathetic root. This has given rise to the belief that the pupillodilator fibers in primates run through the ciliary ganglion. As described in the clinical part of this book (Chapter 19), some authors even assumed that the ganglion was a "peripheral nerve center" where functions of afferent and efferent, sympathetic and parasympathetic pathways are coordinated. In fact, however, the sympathetic fibers merely pass through or along the ciliary ganglion without synapse; and further, it is certain that at least some of the sympathetic pupillodilator fibers bypass the ganglion. That some of them may run through the ganglion appears possible but by no means proven, and may indeed be subject to individual variation. We used to think (Lowenstein and Loewenfeld, 1950) that in monkeys all pupillodilator fibers pass through the ciliary ganglion because we found both sympathetic and parasympathetic reflexes impaired after the ciliary ganglion had been crushed. However, electric stimulation of the ciliary ganglion of the monkey (after its neurons were paralyzed with nicotine to avoid contraction of the pupillary sphincter) failed to dilate the pupil while stimulation of the sympathetic nerve in the neck and stimulation of the long ciliary nerves continued to cause vigorous enlargement of the pupil. Clinically, also, patients with lesions of the ciliary ganglion (traumatic or other) have no defect of sympathetic pupillodilation. In monkeys the ciliary ganglion is hidden deep within the orbital cone, and surgery in the area is 6. Reflex Dilation Table 6-8 - YEAR AUTHOR SPECIES Parsons ? cat or dog man & animals cat& other seecies man & comparative dog rabbit horse, cow, pig, dog, cat, sheep general EXPERIMENTS AND CONCLUSIONS sympathetic pupil dilation was not reduced by ciliary ganglionectomy; thus the s;ym,eathetic has no connections with the ganglion described CG connections with the 3rd 1 5th 1 and s;ym,eathetic nerves pupillodilator fibers in the nasociliary and the long ciliary nerves bypass the ciliary ganglion described short (motor), long (sensory) and sympathetic connections to the ciliary gan~lion 3rd nerve fibers synapse in the CG, but sensory fibers to the 5th nerve do not pupillo-dilator fibers running in the long ciliary nerves bypass the CG synipathetic long ciliary nerves from the 5th nerve pass through the CG without syna:ese the long ciliary nerves bypass the CG and join the short ciliary nerves in loose association man: the CG has a short root to the 3rd nerve, a sensory branch to the 5th nerve, and s,vmeathetic fibers from the carotid elexus stimulation of the long ciliary nerves oauses dilation , section slight miosis tound no degenerating fibers in the CG atter removal ot the SCG cat & horse had no the short CG motor root to the 3rd nerve is constant; long root, and none of these animals had a sympathetic root pupillary dilator fibers bypass the CG Anderson cat the CG receives Bach Lanciois Magitot general cat, dog dog pupillary dilator fibers bypass the CG no eupillary dilator fibers run in the long 5th nerve root to the CG cutting the short pupillo -dilator fibers run in the long ciliary nerves; ciliary nerves does not interfere with sympathetic pupillary dilation pupillo-dilator fibers run in the long ciliary nerves and bypass the CG (1) motor root from the 3rd nerve to the inferior oblique; (2) sensory root in (3) sympathetic root (missing in 10% of specimens): to the 5th nerve; these cases the sympathetic fibers probably pass to the 5th nerve in the cavernous sinus and then follow the sensory root or the ophthalmic artery to the CG the sympathetic fibers in the long ciliary nerves bypass the CG (electrophysiol.) the CG has neither a sensory nor a sympathetic root; the long ciliary fibers by:12ass the ganglion believed synipathetic ganglionated vasomotor fibers from the carotid plexus nassed through the CG and mingled with the postganglionic fibers the long (sensor;y} and symEathetic fibers by,eass the CG without synapse damage to the CG did not interfere with sympathetic ,eu:eillo-dilation crushing the CG impaired sympathetic pupillo-dilation removal of the CG did not abolish sympathetic pupillo-clilation; and stimulation of the CG after retrobulbar nicotine did not affect the euEil the CG in cat &rabbit has only a 3rd nerve root; in monkeys and man branches of the nasociliary nerve join the ganglion; postganglionic short and long ciliary fibers are intermingled awrocki & Przybylski 193 Peschel ~ Braunstein cat rabbit cat man & other s12ecies man D'Erchia Michel ~ v . Bechtcrew 1896 Apolant 1896 Boltzmann 1899 Fritz --1900 1900 1902 1904 1905} 1906 1908 1913 1921 1924 1926 --1935 Giurato Hertel Szakall Behr Beauvieu.x Dupas man man (anat) & Whitteridge Christensen cat cat 1936 Ernyei (anat?) 1950 1950 BenninghoIT Lowenstein & Loewenfeld Loewenfeld man cat 1 rabbit monkey monkey 1936 --- 1953 1960 341 (continued) 1893 1894} 1895 1894 / Grimes & von Sallmann - cat, rabbit monkey,man more difficult than it is in cats and rabbits. We therefore became suspicious that the functional sympathetic loss we had recorded after the ciliary ganglion had been crushed might have been due to inadvertent damage to fibers not connected to the ganglion. We therefore re-examined the question, using monkeys with wide orbital dissections. After freeing the ganglion-without touching it or its branches-from surrounding orbital fat, we found impairment of ympathetic dilation in the temporal iris segment; but these defects were not made worse when the ciliary ganglion was subsequently removed. We had thus been unable (in six monkeys) to prevent trauma to some of the sympathetic pupillary fibers that were not visibly connected to the ganglion and the remaining dilation could not have passed by way of fibers running through the ciliary ganglion. We concluded that in no sympathetic pupillo -dilator fibers monkeys not all pupillodilator fibers pass through the ciliary ganglion, and that it was uncertain whether some of them do. If some of these fibers enter the ganglion, they probably accompany its nasociliary root, while those that bypass it reach the eye by way of the long ciliary nerves. This view agrees with the beautiful dissections of Grimes and van Sallmann (1960), which showed that some but not all of the long ciliary nerve twigs in man and monkeys (but none at all in cats and rabbits) run close to or anastomose with the ciliary gangLion. The ciliary ganglion and nerves are variable among individuals and between species, as described in Chapter 3. In man there usually are two or three long ciliary nerves (sometimes more, or only one). They may run to the eye as separate strands, or they may enter loose 342 / I. Anatomy and Physiology connections with the short ciliary nerves. In the latter case the ciliary nerves distal to the ganglion contain sympathetic, parasympathetic, and sensory elements. Usually the ciliary nerves surround the optic nerve and may even run within its sheath. They enter the posterior part of the globe. The pupillary fibers run between the sclera and choroid toward the anterior segment of the eye. Their further course is described in Chapter 1. A considerable literature was generated during the last quarter of the nineteenth century concerning a possible sensory role of the ciliary ganglion. Many authors likened the ciliary ganglion to the dorsal root ganglia of the somatic system and believed that it contained cell bodies of sensory neurons for the eye (see Table 3-44). However, it was later established that the "long sensory" root of the ganglion is also not related to the neurons of the ganglion but is composed of sensory fibers that traverse the ganglion on their way to the fifth nerve. The cell bodies of these fibers are located in the Gasserian ganglion. (g) Assumed Sensory Fibers in the Cervical Sympathetic Nerve Occasionally it has been said that sensory elements in the sympathetic chain bring about changes in the contralateral pupil when the sympathetic chain is cut or the superior cervical ganglion removed on one side. Ipsilateral miosis was supposed to be accompanied by enlargement of the opposite pupil; and conversely, stimulation of the sympathetic nerve on one side was supposed to bring about contraction of the opposite pupil. However, it was shown almost a century ago that such effects are due simply to a consensual influence of light: as the ipsilateral pupil becomes smaUer, less light enters the eye; and the reverse happens when it enlarges. When the eye on the side of the procedure was shielded from light, no pupillary movement occurred in the contralateral eye (see for example, Schenk, 1895). Afferent fibers in the sympathetic chain were also blamed for pain in certain cases of intractable neuralgia that had not yielded to transection of somatic sensory nerves (Shaw and Cunliffe, 1933, and others). But Fluorens (1842) had already described that vigorous squeezing of the superior cervical ganglion in awake rabbits did not cause pain. Similarly, stimulation of the well-insulated central stump of the divided sympathetic chain does not produce any reaction that could be interpreted as pain (Cleveland, 1932; Davis and Pollock, 1932; we have also found this in cats). Further, no afferent nerves could be demonstrated anatomically in the cervical sympathetic trunk (Cleveland, 1932; Foley and DuBois, 1940). This nerve contains smaU myelinated preganglionic fibers: when they are cut, they degenerate totally, and only in the direction of the superior cervical ganglion. None of them pass beyond the ganglion, for preganglionic lesions do not cause degeneration in any of its postganglionic branches; and no sensory fibers could be traced between the superior cervical ganglion through the rami communicantes to the spinal nerves Cl to C3. 14 Davis and Pollock (1932) found that electric stimulation of the superior cervical ganglion caused pain reactions in cats. These reactions persisted when the ganglion was stimulated after its connections were cut to the ganglion nodosum, to the anterior spinal roots, the posterior spinal roots, or both. Similarly, they were still present after the anterior spinal roots plus the posterior root of the trigeminal nerve were divided. But when the posterior spinal roots Cl to TS and the posterior fifth nerve root were cut together, there were no signs of pain. The authors concluded that painful sensations were "produced by stimulation of the efferent sympathetic fibers, the results of which in turn stimulated ordinary accepted sensory pathways in the cranial nerves." It should be remembered that the superior cervical ganglion sends postganglionic fibers to the carotid body and carotid sinus. This explains why in decerebrate cats preganglionic cervical sympathetic stimulation is followed by hyperventilation and blood pressure changes (Mills and Sampson, 1969). These effects are mediated by the sinus nerves since cutting them eliminates the response. The carotid sinus and carotid body, in turn, increase afferent chemoreceptor and baroreceptor impulses in response to cervical sympathetic stimulation. Pentobarbitone (10 mg/kg) and chloralose ( 40 mg/kg) abolish these reactions. Such changes in blood pressure and respiration upon preganglionic sympathetic stimulation must not be misinterpreted as signs of pain. (h) Structural Changes after Interruption of the Sympathetic Nerve Supply Chronic sympathectomy causes some structural changes in the area supplied by the nerve; these are only slight in adults but more marked when the injury occurred at birth or in infancy. Not only postganglionic lesions but preganglionic damage as well can have such results. For example, babies with birth trauma to the brachia! plexus and to the sympathetic fibers contained in the ventral roots Tl and T2 may grow up with the face on the affected side slightly underdeveloped; and the iris will remain somewhat thin and flat and have a paler color than on the normal side. Such early preganglionic lesions cause transsynaptic changes that interfere with the normal development of the postganglionic neurons. In such cases the pupil may react poorly to hydroxyamphetamine even though the location of the injury is documented to be in the preganglionic neuron. These interesting phenomena are considered in more detail in Chapter 11. 14. It is, however, not uncommon for fibers of the vagus to travel abroad the cervical sympathetic nerve for some distance along its course (see Table 15 in Chapter 11); and further, stray postganglionic sympathetic neurons may be scattered among the preganglionic sympathetic fibers. 6. Reflex Dilation Table 6-9. YEAR 1524 1719 1732 1820 1834 1845 1845 1846 1862 1862 1862 1862 1863 1864 1866 1867 1868 1869 1869 1874 1878 1878 1879 1880 1880 1880 1883 1886 / 343 The assumption of secondary sympathetic pathways to the iris, in addition to the cervical chain AUTHOR ASSUMED Achillini Morgaggi Winslow Meckel Fario Guarini Vollanann Weber Balogh Balogh Oehl Rosenthal Hirschmann Guttmann Trautvetter Schiff Stellwag Nawalichin Schoeler Vul:eian Fran~ois-Franck Vulpian GrUnhagen Guillebeau & Luchsinger Luchsinger Fran9ois - Franck BecEterew Kowalewski F. Mechanism PATHS 6th nerve 6th nerve 5th nerve 5th nerve 5th nerve upper cer.:vical nerves 3rd nerve 3rd nerve 5th nerve h~oglossal nerve Gasserian ganglion Gasserian ganglion uns2ecified Gassorian ganglion Qeri-vascular nerves Gasserian ganglion hypogiossaI nerve unspecified Gasserian ganglion vertebral nerve vertebral nerve 5th nerve 6th nerve vertebral nerve unsi2ecified 5th nerve 5tn, 7tn nerves vertebral nerve of the Residual (?) 1886 1886 1893 1893 1894 1895 1895 1900 1923 1926 1926 1933 1936 1943 1944 1946 1948 1952 (?) 1952 1952 Reflex Dilation Since stimulation of the sympathetic pathways anywhere along their course from the spinal cord to the iris caused marked dilation of the pupil, while destruction of these nerves rendered the pupil smaller than normal, it appeared likely that the pupillary reflex dilation due to psychosensory stimuli was mediated by this path. This is undoubtedly true, for the amplitude and speed of the reaction are much reduced when the sympathetic nerves are cut. But the reflex is not entirely abolished after such lesions, and its threshold is not raised. What could cause these residual reactions? 1. Assumed Secondary Sympathetic YEAR Pathways Many authors thought that there must be secondary sympathetic pathways that were spared when the cervical chain or its connections to the eye were destroyed. Thus pupiIJary dilator impulses were said to travel by way of the third, fourth, fifth, sixth, seventh, and twelfth cranial nerves, the upper cervical nerves, or the vertebral nerve; or they were thought to arise from the Gasserian ganglion (Table 6-9). It can be said flatly that none of these theories was ever proven, and that alJ of them can be dismissed on the basis of a single experiment. But they have to be considered, for they raised much dust until the not-too-distant past. AUTHOR Jesso:e Schipolow Nawrocki & Prz;y:bylski Peschel Steil Bechterew Turner Herbert de Lapersonne & Cantonnet Leriche & Fontaine Magitot & Bailliart K.Lowi Foerster & al . Langworthy & Ortega Spiegel & Sommer Kuntz & Richins Morone & Andreani Burn & Robinson Boros & Takiits Hoorens after Destruction ASSUMED PATHS 5th nerve hypoglossal nerve m1spec ified intracranial ganglia 5th nerve 5th nerve 5th nerve 5tn nerve sympathetic 5th nerve pericarotid sympa thetic :elexus 5th nerve 7th nerve i2eri-carotid 12lexus unspecified sympathetic ganglia vertebral nerve 3rd nerve cells in the carotid sheath stellate ganglion & along the vertebral arter;y: "plexus sympathicus" 3rd or 5th nerve of the Sympathetic Path (a) Assumed Sympathetic Fibers via the Trigeminal Nerve Root Stimulation of the ophthalmic fifth nerve causes mydriasis, and section of this nerve is followed by pupillary signs of sympathetic palsy. Many authors therefore believed that extra sympathetic fibers reached the eye directly from the brainstem through the fifth nerve root and Gasserian ganglion or that they arose in that ganglion. However, as described in the previous section, sympathetic fibers only join the fifth nerve near the distal end of the Gasserian ganglion; they come from the superior cervical ganglion and not from the brainstem. Stimulation of the fifth nerve root in anesthetized animals is not followed by sympathetic pupillary dilation as long as stray of current to the more distal fibers in the ophthalmic fifth nerve is prevented, or-even better-when the superior cervical ganglion is removed some days before the experiment, so that its postganglionic fibers have had time to degenerate (Table 6-10). (b) The Mystery about the Miosis upon Trigeminal Stimulation: Prostaglandins, Substance P, and Ocular Inflammation In this connection a phenomenon has to be considered that again and again has given rise to conjectures about the presence of pupillomotor fibers contained in the fifth nerve. 344 / I. Anatomy and Physiology Table 6-10. The question of pupillodilator fibers via the fifth nerve root, or arising in the Gasserian ganglion: Experimental work YEAR AUTHOR SPECIES 1851} 1 51 1 52 Budge & Waller Waller & Budge Budge rabbit 1862 Balogh rabbit 1862 Oehl rabbit 1862 1864 Rosenthal Donders rabbit rabbit X 1864 Grlinhagen 1864 Guttmann 1868 1869 Seniff Schoeler 1878} 1879 1878 1878 1883 1886 Hurwitz cat, Vulpian Fran2ois-Franck Bechterew Jessop 1894 Braunstein 1895 Bechterew dog aog aog cat,dog, rabbit cat, dog, rabbit dog 1898 1901 Schultz Parsons general cat,monkey 1903 Anderson cat 1905 Angelucci ? 1909 Langendorff general 1916 1924 Gaskell Hartmann all vertebrates man 1976 GG Alper = Gasserian rabbit X X frog frog cat dog monkey EXPERIME TS AND OPINIONS electric stimulation of the 5th nerve became ineffective after the SCG had been removed some days before; electric stimulation of the 5th nerve root failed to dilate the pupil: sympathetic fibers from the SCG :eass via the 5th nerve dilation upon stimulation of the 5th nerve root or the GG (no precaution against stra;y current, and the SCG had not been removed (1) persistent reflex dilation after the sympathetic chain was cut; (2) stimulation proximal to the GG failed to dilate the pupil: sympathetic fibers arise in the GG saw the same as Oehl {1862} and therefore did not eublish his findings section of the 5th nerve root did not impair sympathetic pupillo-dilation; miosis on cutting the 5th nerve faded and differed from sympathetic miosis some days after removal of the SCG, stimulation of the ophthalmic 5th nerve failed to dilate the 12u12il (1) intense miosis upon destruction of the GG; (2) no dilation upon stimulation of the 5th nerve root: dilator fibers must arise in the GG the pupil contracted unon section of the GG or the 5th nerve root (1) persistent rc±lex dilation after sympathectomy; (2) no dilation upon stimulation of the 5th nerve root: sympathetic fibers arise in the GG stimulation of the 5th nerve failed to dilate the pupil some days after the SCG had been removed reflex dilation persisted after removal of the SCG and ganglion Tl rellex dilat10n Eers1sted alter removal ot the SCG and ganglion Tl reflex dilation persisted after removal of the SCG stimulation of the 5th nerve caused pupillary d1lahon cutting the ophthalmic 5th nerve or the 5th nerve root did not affect the residual reflex dilation after symEathectom;y residual dilation to cortical stimulation was not affected by cutting the 5th nerve {nevertheless believed in a 5th nerve Eath) all pupillo -dilator fibers travelling in the 5th nerve come from the SCG residual (reflex or cortical) pupillary dilations were not dim1111shect by cutting of the 5th nerve some days after excision of the SCG, stimulation of tho 5th nerve failed to dilate the EUEil after transection of the sympathetic and 3rd nerves, adaitional section of the 5th nerve had no e-ffect unon the pupil a.tter sympathectomy the pupils continued to dilate to sensory stimuli and to CO2 anatomicall;y the 5th nerve is a Eure sensor;y nerve miosis sometimes developed after retro-Gasserian section of the 5th it should have been immediate nerve, but it took weeks to appear; if it had been due to cutting the pupillo-dilator path no sympathetic deficit al:ter cutting die 5tn nerve root - C* 0 --+ -+ --+ 0 -0 -- + --+ + 0 + + + -- + 0 -+ ~ 0 -0 -0 -+ --0 -0 ~ ganglion; SCG = superior cervical ganglion; ganglion Tl = first thoracic sympathetic ganglion; "5th nerve root" means the portion of the 5th nerve between its exit from the brain stem and the Gasserian ganglion; In the column on experiments and conclusions, the authors' opinions are preceded by-'-; in column C*, + means that the author believed in an auxiliary sympathetic path from the brain stem via the 5th nerve, or from cells contained in the Gasserian ganglion; O means that the author did not believe in the existence of such a path. In the publications marked x, the 5th nerve phenomenon described in Table 6-11 probably played a role. 6. Reflex Dilation In 1824 Magendie first succeeded in cutting the fifth nerve in rabbits and observed an unusual reaction: shortly after the nerve was cut, the pupil on the side of the lesion began to contract. This movement differed from the contraction upon stimulation of the third nerve. It was extensive but very slow. It took several minutes to reach its peak, and then it lasted a long time, anywhere from 20 or 30 minutes to more than 2 hours. At the same time the rabbit's face and ear on the side of the lesion flushed as if they were inflamed. And within some days the cornea clouded and ulcerated, and eventually the eye was lost. Mainly because of these "trophic" effects, the consequences of fifth nerve lesions attracted wide attention, and many experiments were done (Table 6-11). As to the pupillary behavior, the following facts were established. The miosis was produced readily in rabbits and in frogs, but not in man, monkeys, cats, dogs, and birds. ln rabbits it occurred in experiments involving any kind of stimulation of the fifth nerve root, the Gasserian ganglion, the ophthalmic trigeminal branch, or the trigeminal tract in the brainstem as far down as the second cervical segment of the spinal cord. Slight mechanical stimulation of the cornea or the iris, or even an energetic pull on a healthy rabbit's ears would bring it about. In other species, such mild stimuli failed to contract the pupil, but a similar miosis did occur upon paracentesis or during other surgical procedures on the eye. 15 Mechanical or electric stimulation of the peripheral stump of a divided fifth nerve caused the same slow, intense, and long-lasting miosis, but stimulation of the central stump did not. The reaction therefore could not be a reflex phenomenon. Further, cutting the second, third, fourth, sixth, or seventh cranial nerves or chronic sympathetic denervation did not prevent it, nor did instilled or systemic atropine. It was thus clear that this miosis had nothing in common with any other known pupillary motion. It had to be produced by some antidromic mechanism of the fifth nerve. This mechanism had to be irritative in nature because the miosis faded soon, and because it could be elicited by stimulation as well as by injury to the nerve. It could not be due to vascular events because it was obtained in rabbits freshly killed by bleeding; it was not parasympathetic because it persisted after cholinergic denervation and was resistant to atropine. And it was not due to sympathetic denervation because of its great extent and temporary nature, and because it could still be produced after removal of the superior cervical ganglion and degeneration of its postganglionic fibers. 15. This was known early. For instance, according to Budge, Muller (1760) had said that in animals the pupil contracted when aqueous was lost, and that this reaction was well known to all who operated for cataract. Schmidt ( 1803) described a patient whose cataract was needled, and two in whom the operation was done by knife. Tight miosis developed despite the use of extracts of belladonna leaves that normally caused mydriasis. I 345 While there was, then, much information about what this reaction could not be, its true mechanism remained unknown, and the entire problem was more or less forgotten. The only conclusions evident in regard to pupillary reflex dilation were, first, that the pupillary phenomenon was a peculiarity unrelated to normal pupillary movements; second, that the contraction had nothing to do with parasympathetic action or sympathetic paralysis; and third, that it failed to prove that sympathetic fibers reach the eye from the brainstem directly by way of the fifth nerve root. In 1956 the problem again attracted interest because Ambache found a substance in the iris of rabbits that was able to mimic the reactions of fifth nerve stimulation in all respects. He named the substance "irin," purified it, and analyzed its pharmacologic properties. He found that it was not acetylcholine or histamine, hydroxytryptamine, bradikinin, the substance of Major, Nanninga, and Weber, or adenosine triphosphate. Besides in the iris it was also found in extracts of trigeminal nerve. Lt then became apparent that "irin" was one of the prostaglandins, probably prostaglandin E 2 or F. And because this mechanism is involved in the ocular reactions to injury, it was investigated by many research groups. Complete rendition of this subject exceeds our purpose. Table 6-11 contains a fragmentary list of work limited to the eye. The vast body of work concerned with prostaglandins, substance P, and other biologically active substances upon injury of non-ocular tissues is omitted. In summary, it was established that the miosis elicited by fifth nerve stimulation, by chemical irritation of the eye, or by trauma was not confined to rabbits. The pupils of cats, dogs, guinea pigs, and monkeys also contracted when the trauma was sufficiently severe, or when prostaglandins or substance P were introduced into the eye. But the reactions were less energetic than they were in rabbits, and they were easily overlooked when they were obscured by the miosis due to anesthesia. The prostaglandin responses could be unmasked by abolishing the narcotic-induced miosis by pretreatment of the animals' eyes with atropine. Further, not only the rabbit's iris but iris and ciliary body extracts of other animals such as cattle or sheep contained prostaglandins and could be used to cause miosis in other species. In human eyes also, tight, atropine-resistant miosis may accompany inflammatory conditions and penetrating trauma; and after such insults prostaglandins were found to be released into the aqueous fluid. Simultaneously, there was a rise of intraocular pressure and a breakdown of the blood-aqueous barrier, as revealed by increased protein in the aqueous fluid. These effects were reproduced when prostaglandins were applied to normal eyes. Indeed, the anti-inflammatory action of drugs like aspirin or indomethacin was found to be due to their prostaglandin-blocking effect. More recently, differences were shown to exist 346 / I. Anatomy and Physiology Table 6-11. subjects - Experiments on miosis produced in rabbits by stimulation or injury to the fifth nerve, and related YEAR AUTHOR YEAR 1 03 Schmidt (paracentesis in man} Weber l\Iagendie Desmoulins Fario (birds) Fario Langen beck Constatt Valentin Longet 1875 1821 1824 1825 1828 1834 1837 1839 1839 1842 1846 1851 Hall Budge & Waller Waller & Budge 152 Budge 153 DeRuyter 1854 von Graefe 1854 Vulpian & Philli12eaux 1855 Bud~e 1 55 Sohn 1857 von Graefe 1858 Bernard T"""5"" Snellen 1858 Schiff 1860 van Biervliet 1860 Samuel 1862 Balogh l8i:i2 Oehl 1864 Donders 1864 Grtinhagen 1864 Guttmann (frog} 1864 Rosenthal 1860 Bernstein & Dogiel 1866 Grtinhagen 1867 Rogow 1867 Salkowsky 1867 Schiff 168 Vo Rippel & Grtinhagen 1868 Schur 1869 v. Arlt 1 Jr. 1869 Edes 1872 Kondracki 1872 v. Carion Gradle 1875 -rn-- The publications discussions). ADDITIO ·- S 1975 1975 1977 1978 1979 1979 1979 1980 marked van Alphen & Angel* Neufeld & Page* Unger* Sakata* von Denffer & al.* Ghadyan & al* Silbert & Baum* Bito & al. * 1875 1875 1878 1878 1879 1880} 1881 1881 1881 1884"" AUTHOR YEAR Grtinhagen & Samkowsky Senftleben Vulpian Argyro12olous Frat1!'tois -Franck Mayer 1950 1953 1953 Beaunis Leeser Gudden 186 Schi12olow (frog} 1886 Jesso;e ~ Eckhard T89T Eckhard 192 Grtlnhagen 1892 Spalitta & Consi!£liO 194 Braunstein 1895 Moll 1900 Angelucci 1904 Levinsohn Bach & 1904} 1905 Mayer 1905 Schreiber (pulled rabbit's ear} 1906 Gros {pulled ears} ~ Bach 1921 Winkler 1924 Behr 1924 Papilian & Conceanu T§"2"6 Magitot & Bailliart 1927 Rochat 1928 Magitot 1929 Schaefer-Iske (alligator} 1929 Tessier 1929 Winkler 1931 Imachi 1931 Linksz Zimkin & 1939 Lebedinsky Bakker 193 (paracentesis) * deal with prostaglandins 1981 1981 1982 1983 1983 --- 1983 1984 Cohen & al. Mandah 1 & Bill* Shimizu & al.* Bynke & al.* Keulen de Vos & al.* Matsushita & al.* Keates & Mc Gowan* 1955 1956 1957 1957 1959 1960 1960 1961 1963 1963 1964 1965 1967 1967 1967 1967 1968 1969 1969 1969 1970 1971 1971 1971 1971 1972 1972 1973 1973 1973 1973 1973 1974 1974 1974 and other YEAR Lebedinsky & Zimkin D'Ermo Maurice Nash & Woodbury Ambache* Ambache* Ambache* Perkins* Ambache* Konno* Sears* Saman* Waitzman* Ragnetti* Aogard & Samclsson* Ambache &al;!' von Euler & al:+' Hanna & Keatts * Waitzman* Waitzman & King* Ambache & Brummer* Beitch & Eakins* Fortenberry & al:" Waitzman* Waitzman* Demailly & al'!' Kelly & Starr* Kessler* Posner* Eakins & al;!' Neufeld & al:" Cole & Unger* Neufeld & al:+' Neufeld & Sears* Posner* Whitelocke & Eakins* Bhattacherjee & Eakins* Casey* Cole & Unger* 1940 Moriggia AUTHOR biologically 1984 1984 1984 1984 1985 1985 1985 1985 1985 active 1974 1974 1974 1975 1975 1975 1975 1975 1975 1975 1975 1975 1!)7fl 1976 1976 1976 1976 1976 1976 1976 1977 1978 1978 1978 1979 1979 1979 1979 1979 1980 1980 1980 1980 1980 1980 198] 1982 1982 1982 1982 1982 1983 substances Mandahl & Bill* Namba & al.* van Rij & al* Wahlenstead & al.* Bynke & al. * Fukutomi & al* Hoyng* Mandahl* Ohara & Tsuru* 1985 1986 1987 1987 1987 1977 1972 1982 1982 AUTJIOR Dray & al;" Takats* Unger & al:" van Alehen* Bhattacherjee & Eakins* Dellow & Miles* Green & Kim* Gustafsson & al;!' Jampol &aH' Pedersen* Perkins* Szalay &al'!' Unger & al~ Laties ~ al:" Floman & al;!' Maul & Sears* Morris* Okisaka* Salay & alt Takats* Eakins* van A112hen* Crawford & al:+' Kottow* Bill & al'!' Foster & aH' Jampol & Noth* Waitzman & al!'' van der ZYJ2en & al'!' Butler & alt Gustafsson & al1 Soloway & al'!' Spinelli & Krohn* Stj erns chantz & Bill* Soloway & al:" Tervo* Bito & Klein* Engstrom & Dunham* Nishiyama & alt Stone &al'!' Tornquist ~ aH Duffin & al.• ( experiments and Tervo & al.* W. J . Stark & al. * Bonomi & aL * Jonasson* Zhang & al.* Unger* Ernest * Duffin * Zhang & al. * 6. Reflex Dilation between the effects of mechanical injury to the eye or iris on the one hand and chemical irritation (such as intracameral applications of formaldehyde) and fifth nerve stimulation on the other. While all forms of stimulation resulted in elevated intraocular pressure and miosis, only mechanical damage could be blocked by indomethacin. This indicated that prostaglandins played a role in the reactions to mechanical injury, but chemical irritation and stimulation of the fifth nerve called forth a different mechanism. These facts agreed with the findings that the disruption of the bloodaqueous barrier produced by topical use of chemical irritants depended upon an intact sensory supply of the eye. These reactions occurred not only on the injured side but on the healthy contralateral side as well; but they were abolished when the fifth nerve was blocked by anesthesia or transection. In contrast, paracentesis continued to increase protein in the aqueous fluid after sensory denervation, but only on the injured side. The effects that developed after chemical irritation and those due to mechanical injury thus appeared to be mediated by different mechanisms. It was further found that substance P, injected into the anterior chamber, the vitreous, subconjunctivally, or intra-arterially, caused strong and sustained miosis without hyperemia or increased protein in the aqueous fluid. This reaction was not affected by blockade of muscarinic, nicotinic, and alpha- or beta-adrenergic receptors. It also was not prevented by indomethacin, thus ruling out prostaglandin release as cause. This further supported the idea of a dual mechanism of transmission for the reactions produced by different kinds of ocular injury. We cannot continue to follow this rapidly expanding field. As to the tight miosis that develops in response to ocular injury or to stimulation of the fifth nerve, the important point is that it is not due to parasympathetic stimulation nor to impairment of auxiliary sympathetic fibers to the eye that were thought to pass directly from the fifth nerve root to the ophthalmic branch of the trigeminal nerve. (c) Other Assumed Sympathetic Pathways In 1855 Budge wrote that "a strange error has crept into the literature." He referred to reports that pupillary dilation had been obtained by stimulating the third cranial nerve (Volkmann, 1841; Weber, 1846). Four years earlier Waller and Budge had pointed out (1851) that the pupil sometimes enlarged when the third nerve was stimulated electrically, but that these reactions were not due to stimulation of fibers contained within the third nerve itself. Stray current reached the postganglionic sympathetic fibers nearby in their path with the ophthalmic fifth nerve. Direct sympathetic excitation was thus produced inadvertently when stimulation of the third nerve alone had been intended. This could be prevented by removing the superior cervical ganglion at least four days beforehand, so that its postganglionic fibers had time to degenerate. / 347 Since Waller and Budge's time the same experimental error repeatedly led to the same erroneous conclusion. As late as 1949 Kuntz and Richins revived the idea that third nerve stimulation will produce mydriasis. Their work was well received and is still cited in current texts, but it was based on artifact. In order to avoid pupillary constriction due to the cholinergic effect of third nerve stimulation, Kuntz and Richins had pretreated the eye of cats with atropine; and under these conditions, electric stimulation of the nerve evoked prompt mydriasis. But again, no precautions had been taken to avoid stray stimulation of sympathetic nerves. When we repeated this experiment 2 weeks after removal of the superior cervical ganglion, no dilation was observed. Similarly, we stimulated the ciliary ganglion of cats 2 weeks after removal of the superior cervical ganglion. In such animals extensive pupillary contractions were obtained over many hours with currents of low intensity. But when the iris was atropinized, supramaximal stimuli failed to elicit the slightest pupillary movement, either contraction or dilation. Occasionally, the fourth or sixth nerves were said to contain sympathetic pupillodilator fibers. Such reports belong in the realm of pure conjecture. All investigators who actually stimulated these nerves reported that no pupillary movement occurred when precautions were taken to avoid stray stimulation of sensory nerves or of sympathetic fibers (Waller and Budge, 1851; Schoeler, 1869; Hurwitz, 1878; Anderson, 1903; Lebedinski and Zimkin, 1940). Many others have categorically denied a pupillomotor influence of the fourth and sixth nerves without citing experimental protocols. As already mentioned, Parkinson and his coworkers (1972-1975) described (in human autopsy specimens) a junction between postganglionic fibers from the superior cervical ganglion and the sixth nerve. These fibers left the sixth nerve further distally to join the first branch of the fifth nerve. Similar observations were made of apparent junctions of postganglionic sympathetic fibers with other cranial nerves (such as the third or fourth). But in none of these cases was there an intermingling of nerve fibers; and the sympathetic fiber bundles, after travelling short distances aboard these nerves, left them again later in their course. After injury to the seventh nerve, the pupil was sometimes found to enlarge when small doses of adrenaline were instilled into the conjunctival sac; and this was taken to prove "denervation supersensitivity" and hence a loss of sympathetic pupillary dilator fibers said to travel in the normal seventh nerve. But the positive adrenaline reaction in these patients was merely due to exposure keratitis, caused by impaired lid closure after the seventh nerve defect. Such eyes react more extensively than normal to all instilled drugs. The upper cervical nerves (Cl to C3) were said to carry pupillodilator fibers merely because of their anatomic connection with the superior cervical ganglion 348 / I. Anatomy and Physiology ·. 111 II I .. .. : "' Figure 6-15. Segmental pupillary dilation with consequent distortion of the pupil shape, brought about by electric stimulation at the cleral limbus of a cat. The cat was anesthetized so that its pupil was small before stimulation (I); II: Stimulation by a pair of electrodes placed at 11 o'clock, as indicated by the mall dots; Ill: A second pair of electrodes was applied at 4 o'clock; IV: A third pair was placed at 6 o'clock. V: The third pair of electrodes was moved to 1 o'clock. (From J.N. Langley and H.K. Anderson, J. Physiol., London, 13 [1892]:554) JP=== A •;/ I -- ',, +y E E - I I I ' '' II ~ rl I .'\·I I ' ' • ----lI I .. --- I I ~ I I '; ; . n_, ' A -, II I ;' ' ' I I ; • ' ~ I '' I ! !=tJ ,,,- __,,,,, ' ' --i- 0 ---- ______. --_____ ,,,.__,,,. I [ ~ B I ~- ,j_, - .. I t-------, ' I 5 r--... - r" I I I I I I I&. ..... \ _j'"~""------- ' Figure 6-16. Loss of the sympathetic component of reflex dilation in a cat. A, B, and C: Pupillograms of a conscious cat. Pupillary diameter (in millimeters) was recorded against time (in 0.1second units). The right eye is represented by the solid lines, the left eye by broken lines. The arrows mark time of presentation of loud sound stimuli. Al, Bl, and Cl: The curves show increasing and decreasing speed of the reactions A, B, and C (in mm/second). A and AJ show the normal reaction. After the sound stimulus, both pupils dilated rapidly and extensively. B and Bl were recorded 2 days after preganglionic sympathectomy on the left side. The left pupil now was considerably smaller than the normal right one, and reflex dilation was reduced in amplitude and speed, but it was not abolished. C and Cl were recorded 2 hours after B and Bl, after the animal had been given an intravenous injection of 20 mg/kg dibenamine. The normal pupil had contracted and had lost the fast, extensive sympathetic part of the dilation reflex. The two pupils now reacted symmetrically. (From I.E. Loewenfeld, Documenta ophthal., 12 [1958]:185) (Figure 6-6). But stimulation of these nerves did not yield pupillary dilation (Budge, 1855; Fran~ois-Franck, 1878, 1879; Langley, 1900; and others). It also has been said that the small branch of the superior cervical ganglion to the hypoglossal nerve carried pupillodilator impulses from a medullary center. This also is not true. The vertebral nerve or vertebral periarterial plexus were believed to conduct supplementary pupillary dilator impulses; and, as can be seen in the clinical section of ' this book, defects of these fibers were held responsible for a number of pathologic conditions. These theories also were based on speculation without experimental proof. Neither transection of the vertebral nerve nor stimulation of its well-insulated peripheral stump have any influence upon the pupil (Fran~ois-Franck, 1887 and later; Nawrocki and Przbylski, 1893; Braunstein, 1894; Langley, 1909; Hoorens, 1952). The sympathetic nerve fibers in the vertebral nerve are postganglionic: their cell bodies are located in the stellate or the middle cervical ganglion, and they do not travel to the eye. Nagashima and Iwama (1972) stimulated the vertebral peri-arterial plexus electrically in patients under local anesthesia. The stimuli produced complex eye movements (nystagmus, oscillopsia, horizontal or convergent movements) of either or of both eyes; a dull occipital headache, or pain in the neck, shoulder, chest, or arm; nausea or vascular hypertension and blurred vision; and slow, delayed pupillary movements in either or in both eyes, including dilation, constriction, and hippus-like oscillations. These reactions differed in all respects from the prompt, complete, purely ipsilateral mydriasis-without sensory changes or extraocular movements-that were evoked in the same patients by stimulation of the stellate ganglion or the sympathetic trunk. The sensory effects of vertebral stimulation do not occur when the afferent path is interrupted by cutting the dorsal roots of the upper cervical segments (Cl to C3; Ray and Wolff, 1940, cited after Nagashima and Iwama). Finally, residual sympathetic innervation after destruction of the cervical sympathetic chain, as already mentioned, was credited to sympathetic ganglia in the postganglionic nerve path or within the iris. Fluorescent histochemistry has confirmed that, aside from stray cells of the sympathetic ganglia, no such structures exist. 2. Evidence Disproving the Existence of Secondary Sympathetic Pupillodilator Pathways None of the nerves considered as possible secondary pathways for pupillodilator impulses thus has ever been proven to contain such fibers. In addition, there is good experimental evidence that they do not. First, while electric stimulation at the scleral limbus normally elicits vigorous segmental enlargement of the pupil (Figure 6-15), these reactions can no longer be obtained when the superior cervical ganglion has been 6. Reflex Dilation removed some days before and all its axons have degenerated (Budge, 1852; Griinhagen, 1864, 1867; Schur, 1868; Hurwitz, 1878; Tiiwim, 1881; Langley, 1900; Anderson, 1903; we have observed this also). Since nerves from any source must pass the area of the limbus, close to the iris root, to reach the iris, any auxiliary pupillodilator fiber that escaped cervical sympathetic deneivation should still be active. But not the slightest twitch of dilation can be seen upon supramaximal stimulation, while the sphincter segment which derives its innervation from short ciliary nerve fibers passing through the stimulated limbus region constricts briskly. When such an eye is atropinized to prevent possible masking of a dilation by this activity of the sphincter muscle, no pupillary movement whatsoever can be evoked. 16 Second, the residual pupillary reflex dilation that is still seen after cervical sympathectomy can be shown to have nothing to do with sympathetic neives. When a sympathicolytic drug such as dibenamine is given systemically to a unilaterally sympathectomized animal, the fast and extensive part of the reflex in the normal eye is lost· but the slow residual dilation in the sympathectomized eye is still present, and the two pupils / 349 now react symmetrically (Figure 6-16). If this residual response had been due to adrenergic impulses reaching the eye from some source other than the cervical sympathetic, it should have been abolished by dibenamine. 3. Inhibition of the Pupillary Sphincter Muscle Since there are no sympathetic fibers for the iris except those traveling in the cervical sympathetic nerve, how can the residual reflex dilation after sympathectomy be explained? The answer became apparent when it was observed that this remaining movement was much more extensive in room light than it was in dim illumination. Obviously, the sensory stimulus must become effective by inhibiting the parasympathetic tone of the sphincter muscle. Thus, when (in darkness) the sphincter was relaxed already before the sensory stimulus was given, the range of the dilation movement was limited. And indeed, when the third nerve was cut in addition to the sympathetic, or when atropine was instilled into a sympathectomized eye, the residual dilation was abolished, and the pupil failed to respond to sensory stimulation. Many authors have reported this. G. The Efferent Mechanism: Sympathetic Activation versus Parasympathetic Inhibition 1. Historical Background It thus became clear that pupilJary reflex dilation was not due to sympathetic activation alone but that, in addition, the parasympathetically innervated sphincter muscle relaxed. The relative importance of the activesympathetic or the inhibitory-parasympathetic mechanism has been the subject of endless discussions over more than a century; and so great was the confusion that some famous texts in their physiologic section denied a pupillary dilator role of sympathetic nerves but then in the clinical section explained the loss of reflex dilation in Homer's syndrome as sympathetic paralysis. Much of this disagreement was based on the long and bitter quarrel about the existence of the dilator muscle in the iris (see Chapter 1). Naturally, those unwilling to believe in a radially pulling iris muscle had to look for alternative mechanisms for pupillary dilation movements. And various assumptions were then perpetuated by unthinking repetition of previous arguments for many decades after the existence of the dilator muscle had been proven beyond all doubt. Since these controversies have pervaded the literature until the recent past, it is necessary to be aware of them in order to dismiss them, should they again raise their ugly heads. 2. Passive Pupillary Dilation Many authors have thought of pupillary dilation as a passive movement that happened when the active pupilloconstrictor force abated. This idea formed part of a 16. In rabbits, however, strong local stimulation may set off the fifth nerve miosis just described. number of theories about pupillary movements. For example, during the eighteenth century it was said that the pupil was constricted by circular fibers in the iris which were activated by an effort of will; and when the effort was discontinued the pupil returned to its natural "state of rest," that is, mydriasis. Similarly, the old "erectile" vascular theory postulated that the pupil enlarged by elastic recoil of the iris tissue once it no longer was distended by blood. Later this was said to happen when the sphincter muscle relaxed and stromal elasticity or contraction of iris vessels enlarged the pupil. This version has survived to the present. As described in Chapters 1 and 9, all these theories conflicted with anatomic facts. Except for the dilator muscle there is no tissue in the iris that by elastic or contractile force is capable of exerting the radial pull required for pupillary dilator movements. In addition to these anatomic objections, vascular and pupillary movements can be dissociated in several ways. For example, they differ in their thresholds, their central representation, and their sensitivity to certain drugs (Figures 6-17 and 6-18 and Table 6-12). and further, vascular contractions are exceedingly slow. They lag behind pupillary dilation in time, and for this reason alone could not possibly be its cause (Figure 6-19 and Table 6-13). 3. "Active Sympathetic Sphincter Inhibition" Griinhagen and his group, the great enemies of the dilator muscle, proposed that the pupillary dilation due to sympathetic stimulation was brought about by inhibitory fibers traveling by way of the cervical sympathetic 350 / I I. Anatomy and Physiology nerve to the sphincter muscle. Impulses conducted by these fibers were said to actively force the sphincter to relax, so that the pupil enlarged. This form of inhibition was said to be the main cause of pupillary reflex dilation. Several experiments were offered as proof for this theory. Strips of isolated sphincter tissue from animal eyes were suspended in a moist chamber by attaching one end of the tissue to a fixed point and the other to a lever. The changing tension of the preparation could then be recorded on a smoked drum. The temperature and moisture in the chamber could be varied, and the tissue could be exposed to drugs or to electric stimulation. It was found that the normal sphincter muscle contracted to electric stimulation; but after these contractions were abolished by atropine, the muscle elongated each time it was given an electric shock. These experiments were the forerunners of many investigations, continuing to the present, in which the in vitro behavior of intraocular smooth muscles was studied. With the passage of time, elegant instrumentation was developed to control all conditions influencing the preparations and to record the tissue responses photoelectrically or with pressure sensors and electric recording devices (Table 6-14). Among the many results of such studies, the reactions of the isolated pupillary sphincter to adrenaline and noradrenaline have been considered the crucial experiments for the question at hand: when small amounts of these substances were added to a bath containing the sphincter tissue of a human or animal eye, the muscle lengthened. This was said to prove that sympathetic nerves inhibited the sphincter and that, consequently, a dilator muscle was "not needed" for pupillary reflex dilation or that it played, at best, a secondary role by providing the iris with an unchanging, radially directed pull. Since, further, the pupil could become tiny in bright light and large in darkness, sphincter innervation and sphincter inhibition seemed able to control pupillary movements over the entire physiologic range. And the persistence of pupillary reflex dilation after sympathectomy and its loss after additional parasympathetic paralysis were thought to prove that the reaction indeed owed its existence to active sphincter inhibition. It appears curious that the many authors who held this view failed to realize ( or forgot) that parasympathetic paralysis alone by no means abolishes reflex dilation of the pupil. As shown in Figure 6-5, the reaction (though limited in extent because of the already large pupil size) is quite as brisk and quite as sensitive in a parasympatheticaUy denervated eye as in a normal eye. This would not be possible if sphincter inhibition were the only mechanism for pupillary reflex dilation. The error of the argument was not the assumption that the residual pupillary dilation after sympathectomy is due to parasympathetic relaxation (which it is) but the extrapolation from this fact to the belief that reflex dilation as such is caused by relaxation of the sphincter muscle alone. In fact, the active-sympathetic component of the reaction exceeds the passive-inhibitory part in speed and amplitude (Figure 6-20). ......:.•. • ~ .•• St. s Mi 11,z Ms St. Gl. St. L Figure 6-17. Action potentials from the cervical sympathetic nerve of a cat. Diagram A shows the experimental setup. GI represents the superior cervical ganglion; G, ground lead; L, pick-up electrodes, leading to the cathode ray oscilloscope; St, stimulating electrodes (pre- or postganglionic). B shows the different action potential waves. The ordinate shows voltage, the abscissa time. St, stimulus artefact; S, potential wave found in rats but not in rabbits, due to aberrant vagus fibers travelling aboard the sympathetic chain. M., potential wave for pupillary and other motor fibers; M,, more slowly conducting fibers, responsible for vasoconstriction. This group also had a higher threshold than the M 1 group. The average conduction speed was 12 m/second for M 1 and 8 m/second for M,. M 3 and U are potential waves of fiber groups if unknown function. (From G.H. Bishop and P. Heinbecker,Amer. J. Physiol., 100 [1932):519) u 6. Reflex Dilation Reflex dilation of the pupil, then, is due to the combination of two factors: sympathetic activation of the dilator muscle and simultaneous parasympathetic relaxation. As just described, Grtinhagen and many others have attributed the reaction to active (sympatheticinhibitory) impulses to the sphincter muscle in the periphery. This is not correct. Pupillary reflex dilation foUows the law of Sherrington's reciprocal innervation: peripheral activation of the agonist (the dilator muscle) is associated with inhibition of the motor nucleus of the antagonist (the sphincter muscle) within the central nervous system. Many facts support this view. A 1 --- -~ -;," .__ 1-1-- I- ,-1- I-~ t--~-- I- ~·I- - ~ I- I- ~ ,_ I- " '--LJ - 1- L-..~ •• I- '-'- - t-- --h<--~ "'I"' f- 0 ~ "-'·· 1-1- --- !- - 1- IZO IU \ --:-1;:,- l ,- ·1--r-t--» ~ Figure 6-18. Autonomic responses to diencephalic stimulation (cats). The animals were in chloralose anesthesia, with artificial respiration. Blood pressure and intraocular pressure were measured with pressure transducers, and blood flow in the ear auricles photoelectrically. The symbols along the abscissa show the state of the pupil at various times during these reactions. The double arrows show time of stimulation with bipolar electrodes (squarewave pulses, 2 milliseconds at 4 volts and 60/second). A: Stimulation of four hypothalamic sites: l, marked vascular constriction with prompt relaxation at the end of the stimulus; 2, slight constriction, followed by poststimulus vasodilation; 3, shortlasting vasodilation; 4, longer vasodilation with prolonged aftereffect. During all four reactions the pupils dilated maximally and returned promptly to their baseline diameter at the end of stimulation. In reactions l and 2, then, the pupillary dilation coincided with vascular constriction, and in 3 and 4 with vascular dilation. (Slightly modified from I.E. Loewenfeld, Documenta ophthal., 12 [1958):185) ~ I- t- '\ _,_ ~IA,!, ::t:1-- 10 ff JO I .r.:: \ 1-1~ --0 2- 11"\l,.,,l]' • - 0-l- \ - . -1- ,' -t- I 210 -··- .. \ -- -- 1 ---'- -- -~ t--+--1- ., 60 -- I - ~ 1-- \A --~-- =:f ,_ __ l.h I- 2 ,--- _µ_ 351 (1) There is no other reflex mechanism in t?e body in which inhibition takes effect by antagomstic impulses that are conducted to the effector muscle by special inhibitory nerves. Excitatory or inhibitory consequences of sympathetic stimulation are not the function of special types of sympathetic nerves but are determined by the type of receptors contained in the cell membranes of the innervated tissues. (2) As to the pupillary sphincter, efferent sympathetic discharges are neither necessary nor sufficient to inhibit the parasympathetic light reflex; and while psychosensory as well as brain stimuli BLOOD FLOW IN EAR AURICLES L ·--'- / .~!(''W .,: "', ; -1-- :--4I ~!t -I•, --, '"' ·r 60 90 1--1- ~ ~~ ,SO 120 =r- - 1-1- I, - ~ - - ,.,.• ,. I- M,V 1-- '-'- '-- /50 2,0 l fl .. 11 Uhl~ B l ~I 0 50 100 SECONDS -1-- -,_ __ .... _, "- 1-'1. I 120 B: Simultaneous fall of intraocular pressure and vasodilation in the ear auricle, without corresponding blood pressure change, and without pupillary movement. (Slightly modified from L. von Sallmann and 0. Lowenstein,Amer. J. Ophthal., 39, II (1955):11; published with permission from The American Journal of Ophthalmology, 0 The Ophthalmic Publishing Company) ~ 150 Table 6-12. separately - 1862 1867 YEAR Experiments showing that pupillodilator and vasomotor fibers are distinct and can be stimulated AUTHOR EXPERIMENTAL Bernard dog Adam.Uk cat cat, dog rabbit cat cat cat cat st. of ventral roots Tl and T2 St. of ventral root T3 st. of the cervical chain after cuttirnr tlie Ione: ciliarv nerves st. of the cervical chain after cutting the vascular fibers in the orbit st. of the cervical chain with threshold currents thresiiolo st. oi tlie cervical sympathetic st. of ventral roots st. of dorsal roots st. of the noste:ane:lionic branch of the SCG st. of the cervical chain after cutting the postganglionic branch of the SCG st. of the posterior branch of the ansa of Vieussens st. of the anterior branch of the ansa of Vieussens st. of lone: ciliarv nerves st. of the cervical chain with threshold currents st. of the cervical cord with weak currents st. the cervical chain after cutting the long ciliary nerves st. ol' Ione: ciiiarv nerves st. of the cervical chain after cutting the long ciliary nerves thresiiolcl stimulation oi the cervicaI sympathetic nerve st. oi the ventral roots Tl ancl T2 st. of the ventral roots ( T3) and T4 st. of the ventral roots T 1, T2 , (T3) st. of the ventral roots ( T3) 1 T4 1 ( T5) st. of the cervical chain after cutting the pupil i'ibers in the tympanum low intensity sensory stimulation st. of the cervical chain after cutting the postganglionic pupillary fibers threshold st. of the cervical sympathetic nerve cat threshold cat cat threshold st. of the threshold st. of the with electrodes held cliencephalic stimuh at other sites T""6"9 v. Arlt 1872 1 73 1878 1878 1879 1883 1886 1 6 1892 SchiH Vulpian 1 Jr. rabbit dog dog dog, Fran9oisFranck Fran9oisFranck Fra119oisFranck Schiff Dogiel Jegorow dog, cat dog, cat dog dog: cat, dog cat, do!/i, rabbit Langley & Anderson ~ Langley 192 Littauer 1 9 1915 1932 Schultz Gruber Bishop & Ileinbecker Eccles Loewenfeld ~ Braunstein 1935 1952 1955 v. Sallmann Lowenstein & cat PROCEDURES st. of the cervical ----- -p SPECIES sympathetic nerve cervical sympathetic nerve cervical sympathetic nerve to different areas of the nerve at various sites + - ~ + --+- -- --- V -+- -+,_ -- ---+ -+- ----+- --+-- - + --+ --- ++ ------ +- -+----:i:- -------- -+-+- -+- -+--- --- + -- - + --+- --- --+- ---- ---- -+---- -+----+- -+--- + - --+- --- --++ Column P = pupillary dilation, and V = vascular contraction; + = positive and - = negative responses. Brackets for ventral roots in Langley's experiments mean weak responses, or responses not found in all cats, due to individual variations;in our experiments vascular dilation, vascular contraction, and pupillary dilation were obtained from various sites and with stimuli differing slightly in intensity; pupillary and vascular reactions sometimes occurred together, and sometimes independently. NOTE: The objection has been raised that some of these experiments were carried out by measuring blood flow in the ear auricles, and that the results need not apply for the iris: the ear auricles derive their blood from the external, and the iris from the internal carotid supply. But the same phenomena were found in reactions of the internal carotid artery, the conjunctiva! and retinal vessels, the intraocular pressure, and the iris vessels. Table 6-13. SPECIES VASCULAR 1853 1869 1869 1878 1879 Waller Schoeler v. Arlt, Jr. Fran2ois -Franck Fran9ois-Franck rabbit cat rabbit dog 1 cat dog, cat 1884 1886 1888 1892 V. 1894 1902 Schulten Bellarminow JessoE Langley & Anderson Braunstein Levinsohn 1904 Parsons rabbit cat cat rabbit, rat cat, do~ cat, dog, monkex cat, dog ear & conjunctiva! vessels intraocular pres sure ear vessels ear vessels b.p. in carotid artery, fundus- and 2ial vessels retinal and choroidal vessels b.p. in carotid arterl b.p. in carotid artery 1955 von Sallmann Lowenstein YEAR 1957 AUTHOR Loewenfeld See Figure 352 Authors who showed that pupillary dilation preceded vascular contraction 6-19. & cat cat iris b.p. BED EXAMINED chain chain chain chain sympathetic chain sympathetic chain sensory nerve sympathetic chain sympathetic vessels in carotid sensory artery chain nerve cortex ? intraocular STIMULATED sympathetic sympathetic sympathetic sympathetic superior cervical ganglion pres sure intraocular pressure, femoral artery pressure blood flow in ear auricles ear auricles diencephalon 1 diencephalon 6. Reflex Dilation / 353 .,. __ 31---- +2 E, Ea.::oJ:-;-~~:ur~Ill"IIIr'.w-rJir".lll:rLIIruirN~Ji~~~~~.iiF~:ffi~LDP~JD 0 sec.. Figure 6-19. Dis ociation in timing of vascular and of pupillary responses. Cat in deep nembutal narcosis. During the time framed by the double arrow, bipolar square-wave stimulation was given (3 v, 60/second) in the hypothalamus. The broken line shows the pupillogram, the solid lines the blood flow in the ear auricle on the same side. measured photometrically. A: the pupillary and blood flow traces were superimposed upon a common time axis. The insert B shows the entire vascular response, with the portion u ed in A outlined by the thin broken line. More than two-thirds of the Figure 6-20. Time-amplitude pattern of pupillary dilation to ensory stimulation and to stimulation of the cervical sympathetic nerve (anesthetized cat). All records were obtained from the same cat in nembutal anesthesia. All timuli were thyratron pulses at SO/second rate (voltages indicated). The olid lines represent the right pupil. the broken lines the left pupil. The animal had been ympathectomized on the right side at the beginning of the experiments. ln A, D, and E, the central stump of the divided right sciatic nerve was stimulated, and in B, C, and F, the peripheral stump of the divided right sympathetic chain. In the experiment shown in D, the animal's right pupil had been dilated with atropine the day before. Before timulation, the cat's pupils were very small becau e of the barbiturate narco is. ote that sciatic timuli evoked slow, relatively long-lasting dilations of both pupil (A; in D this did not happen in the previously atropinized eye). These reactions were inextensive even when maximal stimulis intensity was used: sciatic stimuli never enlarged the pupil beyond about 9 mm, the same size it reached after parasympathetic blockade with atropine (D). The dilation movements obtained by sympathetic stimulation were much more vigorous, and max.imal pupil ize was reached quickly. Recontraction of the pupil also was more rapid after !.)'mpathetic than after ciatic timulation (compare Band C with A and D). Further, after the pupil had dilated in response to sciatic stimulation as far as it would go (E) additional stimulation of the cervical sympathetic nerve readily enlarged it further (F). (From I.E. Loewenfeld, Documenta ophthal., 12 [1958):185) pupillary dilation fell within the latent period of the vascular reaction, and the pupil reached maximal size at the time when the vessels had barely begun to constrict. At the end of the stimulus, the pupil recontracted promptly. In contrast, the vessels continued their sluggish contraction that finally reached its peak during the sixteenth second after the beginning of the stimulus, and then slowly relaxed. (From I.E. Loewenfeld, Documenta ophthal., 12 [ 1958]: 185) ♦ ....... ......_ ........ I ,,_ ..,_____ _...____ _., __E-'"'-'------1-'----------------------=:::::.-i ,,-,1-f ,-----------------1 1,__ '\,____ 161--U~~-----✓ / , I -'--"---11-.1 , I '-... h>:l- / -.._ ., Ii ------------------,. ---... ----r I l[ ~,."-✓-~-----------------------------~ .. s 0 ~ll----------------1-F / . / t 11---b, ---1:: E• ,, / / ./ 7/------------------------------I 354 / I. Anatomy and Physiology Table 6-14. Experiments indicating adrenergic relaxation of the pupillary sphincter muscle: Isolated preparations in vitro - YEAR AUTHOR SPECIES PROCEDURES AND EFFECTS: 1 68 Schur el. st. relaxed atropinized sphincter strips 1875 Grlinhagen & Samkowsky Pfaltz rabbit, cattle sbeee 1 frog rabbit, rabbit atropinized atropinizeo sphincter sphincter strips strips Grtinhagen rabbit el. st. relaxed el. st. relaxeo el. st. relaxed atropinized sphincter strips Langley & Anderson cat el. st. relaxed atropinized sphincter strips mostly cattle cat 1 dog cat cattle 1 dog rabbit I dog I man cattle,pig adrenaline relaxed sphincter strips svmoathetic stimulation relaxed the sphincter adrenaline relaxed SQhincter stri12s adrenaline and strong cocaine relaxed sehincter strips adrenaline and cocaine relaxeo sehinctcr stries adrenaline, tyramine, ephedrine, cocaine relaxed, and crgotamine contracted sphincter strips adrenaline relaxed sebincter stri2s adrenaline I cocaine, eehedrinc relaxed sphincter stries adrenaline relaxed sphincter strips and reversed ergotamine induced contraction low concentrations of adrenaline relaxed sehincter stries adrenaline, cocaine, and ephedrine relaxed crgotamine-contracted sphincter strips adrenaline relaxed sphincter strips adrenaline reiaxcd sehincter stries I exceet m verl n~Ei doses assumed sehincter relaxation in pueil dilation of isolated iris adrenaline, noradrenaline, cocaine and other sympathomimetic drugs relaxed sebincter stries adrenaline relaxed sehincter strips adrenaline relaxed sphincter strips adrenaline relaxco sphincter strips 1882 1886} 1 92 1892 1917} 1921 1922 1926 1926 1927 Joseph ten Cate Miller Poos Leyko ~ Poos cattle, sheep cat,rabbit dog 1 cattle dog, cattle 1930 1931 Yonkman Yonkman 1932 1932 Yonkman Kitahara 1933 1936 1936 1939 Velhagen Shaklee & al . Shen & Cannon Gunter &Mulinos 1939 1940 1941 1941} 1942 1950 1950 1951 lleath & Geiter Guyton Bean & Bohr Sachs & Heath Hess & Koella Iless & al. d'Ermo 1952 Boros 1952 1953 1955 1963 Koella & Ruegg Ruegg & Hess Boros & Takats van Alphen Qig I Cattle rabbit, pig, cattle cat cat 1964 cat 1964 Schaeppi Koella Tak:its 1965 van Alphen 1965 Freundt 1966} 1966 1969 Dennison Schaeepi Patil 1971 Kern man 1971 rat 1972 Persson & Sonmarck Takats 1976 van Alphen man & Takats & & al. dog, cattle cat, rabbit, cattle cat I rabbit I cattle cat, rabbit, 2ig cat cat,dog, rabbit I cattle rabbit ? dog, cattle, rabbit adrenaline relaxed sphincter cat, pig I cattle cat 1 Qig 1 cattle horse, cattle calf I rabbit cat,rabbit adrenaline adrenaline adrenaline relaxed relaxed relaxed sphincter strips sphincter strips and ergotamine contracted sphmcter strips reaction was enhanced after adrenaline relaxed sphincter strips; sympathetic denervation (superscnsitivity) adrenaline relaxed SQhincter strips adrenaline relaxed sphincter strips adrenaline relaxeo sphincter strips adrenaline, noradrenaline, isoprotercnoI relaxed sphincter strips ( blocked by phenoxybenzamine, tolazine, dichloroisoproterenol) : the s2hincter contains mostly beta-adrenergic rece2tors I few al2ha noradrenaline contracted or relaxed, isoproterenol relaxed sphincter stri2s: relaxation bl beta-adrenergic receetors adrenaline and noradrenaline relaxed sphincter strips (blocked by receptors dichloroisoproterenol) : inhibition by beta-adrenergic contains mainly adrenergic mediators and blockers : the sphincter beta-adrenergic receptors (some alpha) in cat and rabbit, mainly aleha in monkeys intravenous alpha and beta-adrenergic agonists and antagonists: mouse has aloha and beta (inhibitorv) receptors intact iris, normal and sympathetically denervated: oeta-aarenergic s;ehincter inhibition was shown by el. st. and by drugs isoproterenol » pheny lephrine relaxed sphincter strips ( blockeo by salotol but not bl eropranolol}: beta-adrenergic inhibition adrenaline, noradrenaline & isoproterenol relaxed sphincter strips (blocked by phenoxybenzamine, priscoline & diisoproterenol): beta and alpha-adrenergic receptors, both inducing relaxation cat, rabbit, cattle cat, rabbit, monkey cat cattle pharmacologic (n.r.) evidence for adrenergic inhibition of the sphincter «< isoproterenol relaxed sphincter strips; adrenaline < noradrenaline this was not enhanced by previous c-eserpine but was increased by erevious Slmeathetic denervation noradrenaline relaxed sphincter strips (blocked by propranolol): alpha and beta receptors, both inducing relaxation cat el. st. = electric stimulation; For anatomic work, see Table strips , but a few contracted rabbit,cat mouse & al. CONCLUSIONS ( n. r . ) 1-26. = not read by reviewer. 6. Reflex Dilation Table 6-15. YEAR Pupillary dilation by sympathetic activity after parasympathetic AUTHOR SPECIES l LOSS OF BLOOD OR NERVE SUPPLY At DE Ex px 1845 1846 1846 1847} 1849 1851 Guarini Ruete Weber mammals mammals rabbit.cat ,_+ Brown-Sequard 8 species Budge & Waller ~ Budge rabbit rabbit + --+ --+ 1852 1853 1853 1855 1858 1858 1859 Budge & Waller GrUnbagen Wagner Koiliker Bernard Schiff Brown-Sequard rabbit,man cat, rabbit dead animals rabbit dog, rabbit dog, cat, rabbit 5 classes of "l'rf:filmals cat, rabbit rabbit, dog, cat rabbit cat, rabbit man cat TI59 Wa~er ~ Griinhagen 1863 Hirschmann 1864 Donders 1864 Grilnhagen 1864 Stellwagv. Carion 1865 Griinhagen 1866 Volckers & Hensen --1866 Bernstein & Dogiel 1867 Bernstein 1867 Bezold & Bloebaum 1867 Griinhagen 1867 Rogow 1867 Schiff 1868 Hensen & Voelckers 1868 Schur 1868 Stellwagv. Carion 1869 v. Arlt, Jr. 1869 Edes 1869 Engelhardt 1869 Robertson 1869 Schoeler 1874 Rossbach & Frohlich --1877 Surminski 1878 Fran9ois-Franck 1878 Hurwitz 1880 Fran9ois-Franck 1881 Tilwim 1882 Moriggia 1884 Kuhe 1883 Weischer 1884 Weber 1886} Jessop 1888 dog + --+ - --- - -- - - I paralysis STIMULATION Ad Sy Str Co --+ .i..... -+ -- ---- -- -- -,_ -- Li -- + + --- --- -- -- ---++ - --- --- --+ -- -- ---+ --+ --+ -- -- -- - --+ --- --- ------------ --- - - -+ --:i:- + + ---- -- - --- - + + + + - _±.. --+ --- ------ - .---+ -+ --++ ----+ -- + -- - --+ -,__ -----+ -- + + + + ----....±...-+ ---+ --+ -- + -+ -+ ---+ --+ - --- - ------- -- -- + - -- -- mammals dog general statement cat rabbit cat -- ---+ -- --- --+ -- -----+ --- + ,- + --+ -- -- -- --- -- -- -+ -- -- dog rabbit rabbit rabbit cat rabbit rabbit cat ---+ ---- --+ --+ -- rabbit rabbit cat cat, dog, rabbit cat rabbit rabbit frog, toad bird man cat -- --+ -+ -- -- -- --+ - -- -- --- --+ -- --- -- + -- -- - --- -- ---++ -- ----+ -- --+ --+ --+ -- -- + ,____ --+ --+ -+ + + ---+ -- --- ----++ -- --- + -- ------ -- --- -- - -- + + + -- -- -- ---- --- -,_ --- + -- ---+ -- --- --- --+ -+ --- --++ ---- --++ -----+ + -+ -- ---- ------ - ---- + -- - --- -- --1-....±... ....±...-- + -- -- - -- --+ --+ ---- ----+ + -- -- -- --- -- -- - + + + + -- + + -- ---- - ------- -- - The symbols mean the following: DE= death or enucleation of the globe; Ex= excised sphincter muscle in vitro; Px = parasympathetic denervation by cutting the 3rd nerve or removing the ciliary ganglion; At = atropine or other atropinic drugs; Li = electric stimulation at the limbus; Sy = electric stimulation of the sympathetic nerve; Str = stress by asphyxia, CO2, toxins, or other; Co = cocaine instilled into the eye; Ad = adrenaline, noradrenaline, or other adre nergic drug instilled into the eye (ephedrine, hydroxy-amphetamine, etc.). / 355 356 / I. Anatomy and Physiology Table 6-15 YEAR 1886 1887 1887 1891 1892 1892 1892 1892 1892 1893 1894 1894 1895 1895 1898 1900 1900 1901 1903 1903} 1904 1904 1904 1904 1905 1906 1908 1908 1908 1908 1909 1909 1909 1909 1909 1909 1920 1911 1921 1922 1922 1922 1922 1923 1924 1924 1925 1926 1926 1927 (continued) AUTHOR Ffliiger Holtzke Long & Barrett Langendorff Heese Langendorff Langley & Anderson Limbourg Liti:auer Nawrocld & Przybylski Braunstein Langendorff Groenouw Reid Schultz Langendorff Wessely Langley Anderson Meltzer & Meltzer-Auer Ba.ch & Meyer Best Tschirkowski Ehrmann Ehrmann Ba.ch Frohlich & Loewi Schur& Wiesel Waterman & Smit Karplus & Kreidl Meltzer Comessati Kahn Schultz Wesselv Hyatt Cords Magitot Feenstra Hartmann & al. Murase Naito Hartmann & Hartmann Cushny Gautier Rizzo Junkmann Padovani Rizzo SPECIES rabbit man man cat, rabbit cat cat cat rabbit cat cat cat cat man cat cat cat, rabbit, dog rabbit, frog cat cat frog rabbit man rabbit frog frog rabbit dog, cat frog frog cat frog frog frog frog frog, mammals man frog dog cat 1 rabbit cat frog man cat man frog man frog frog frog I LOSS OF BLOOD OR NERVE SUPPLY At DE Ex px + -- - -+ + + - + --- + + --+ -- -- -----+ --+ --- -- -+ - ---- -- - --- --+ --- -- ---- --+ -- - --+ - + - - --+ --+ -+ ----- --+ -+ -- -- --+ - -- ,- + --- - -+ -- -+ ,_ -- ---+ - -- -- ---:r -- -- + --- + --+ -- ,_ - - + -- -- + --+ -- -- + - -- - --+ -- --+ - -+ ----+ -- -+ + -- -- -- - + --+ -- -- --- --++ -- + --- -- -- - ---- + -- + -- - -+ + --- + + -- -- -- ---+ -- - --+ -- --+ -- -- --+ -- -- ---+ - -- --+ -- I STIMULATIO Li Sy Str Co Ad + ---+ + ,_ + ---- -+ --- --+ ---+ - --- -- - -+ - -- ....±...-- -- --- -- -+ + -- -- -- --+ --- -- -- -- -- -- - --++ --+ - -- - + --- - --- --+ ,_ -- --+ + -- -- ,- --- - -- --- - - --- -- --- -- -- --- --+ - --- -- -- --- -- -- -- ,_ - --- -- -- --- - -- -- -- -- + -- --+ ---++ ~ -- + -~ ~ ,_ --++ - -- --+ -- - -- - - --- --+ - ------ -- ---+ --+ -- -- -,_ + + -- -- -- -- - -- - -- -- + --- - + - -- --+ -- -- - -- - - - -+ -- - -- - -- + -- ----------- ~ ~ --++ -- + -- + --+ -- + -- -- + -- -- -- - -- -- + --+ - - -- -- --- - -- ++ --- -- + - 6. Reflex Dilation Table 6-15 YEAR 1927 1928 1929 1929 1929 1930 1930 1930 1930 1931 1931 1931 1932 1935 1936 1936 1937 1937 1938 1938 1938 1938 1939 1940 1940 1940 1941 1945 1946 1949 1949 1949 1950 1950 1952 1952 1953-1 1958 1968 1976 1976 (continued) AUTHOR Sugawara Ko1212anyi Uvy &Hazard Niitani Orr Behr Pak & Tan Pollak Veil Cannon & Bacg Hartgraves & Kronfeld Yonkman Blume Saito Itikawa Lauber Cozzoli Post Baratta Donatelli & Wiechmann Tassman Wiechmann Weekers & al. Hodes Marron SchuEfer Amsler & Verre:y: Swan & White Kuntz & Richins Amsler & Verrey He,rmans Nag:aKura Andersen Lowenstein & Loewenfcld Hoorens Reiter Loewenfeld Armstrong & Bell Norris Small & al. SPECIES cat rat I LOSS OF BLOOD OR 'JETi VE mP:?LY DE Ex Px At -- -- -+ frog dog man man man man man -----+ -- cat cat cat n.s (abstract) dog man frog man man cattle man cattle man cat man cattle ---- -- -- --- -- -- -- -- - - - -- man -- cat 1 rabbit do1r man monkey + --- -- ++ -- --- ++ -- -- ---- -- ---- ----- -------- -- -- --- -- ,_++ --- -- _±_ ......±.... --- -- _±__ -- -- --+ -- -- --+ --- -- + -- -- --- --- + -- + -- -- + + -- -- -- + + -- + -- + --- + --- - ---- --++ --+ - -- --++ -- -- --- -- -- --+ --+ --+ -- -- ---- - Ad -- + -- -- ---- -- Co -- -- - -- Str Sy -- + _±... -- ++ --- ++ -- -- -- Li -- ---+ --- -+ --- --- --- -,- --- -- -- -- -- + -- man man dog man STIMULATION ---------- -- --- + -+ --- --+ - -- cat -- ++ -- -- -- ---+ -- -- --+ --+ --- ---+ --- --- - man toad toad man - -- man cat, - -- -- + ---- + ------ I + --+ -- + --- + -- ----- -- __±_ _±_ -+ ---+ --+ -- --- --++ - -- ~ -+ + -- -- --+ --+ -- -- ...._ -- -- --- -- ,_ ---+ --+ -- --+ -- -- -- -- -- --- -- -- --- -- -- --- -- --+ -- ,- -- --- -- -- --+ -- -- -- -- -- -- --- -- -- ---+ ---- -- -- -+ + + -- -- -- --++ --+ + I- - 1- --- + - --++ --- -- ,_ -- --++ -- + -- + --- + --+ --+ --+ ,_+ --+ + --+ --+ / 357 358 / I. Anatomy and Physiology Table 6-16. Authors who showed that (after parasympathetic sympathectomy contracts the pupil YEAR AUTifOR SPECIES PARASYMPATHETIC DENERVATIO BY atroEine atropine atro2ine atro2ine atro12ine atro2ine atro2ine atro2ine atro2ine atroEine 3rd nerve atro2ine 3rd nerve atropine atropine atropine 3rd nerve atro2ine atro2ine atro2ine atro2ine 1846 1847 1853 1855 1856 1856 1859 1864 1864 1867 1867 1869 1876 1882 1886 1863 1892 Biffi Valentin de Ruiter Budge Johnen Harley H.Braun Gianuzzi GrUnhagen Salkowski Schiff Horner Drouin Moriggia Jessop Hirschmann Littauer rabbit rabbit ? rabbit mammals & am12hibia cat rabbit dog rabbit rabbit cat clinical syndrome ? rabbit cat, rabbit rabbit, cat, birds cat 1892 1898 1913 1924 ? dog ? 1931 1938 1958 Limbourg Schultz Landois Papilian & Conceanu Yonkman Gullberg & al. Loewenfeld. rabbit cat rabbit cat 1971 Adler general 1976 Small & al. denervation) 1 rabbit 1 cat statement man Figure 6-21. Electric stimulation at the scleral limbus of a cat. Placement of the electrode tip is indicated by the black dots at 10 o'clock. In the iris portion near the electrodes, the sphincter muscle was tightly constricted. Nevertheless, that sector showed strong pupillary dilation. The entire iris had been dragged across the midline toward the stimulated side, and the ciliary iris tissue was thrown into concentric folds. Such reactions to stimulation at the scleral limbus can still be obtained when the eye has been treated with eserine (Engelhardt, 1869; we have observed this also). The reaction is abolished after postganglionic sympathectomy and degeneration of nerve fibers coming from the superior cervical ganglion. (From J.N. Langley and H.K. Anderson,J. Physiol., London, 13 [1892]:554) • • section transection - transection, transection of 3rd nerve atro2ine 3rd nerve transection 3rd nerve transection, ciliar_y ganglionectomy, atro21ne 3rd nerve transection or atro2ine atropine 6. Reflex Dilation 12 '-- ST 2 ST 1 ST3 1F===-- !~ 10 8 359 / - ½lE:::PUPIL . 6 : t4 E 2 E NORMAL PUPIL --~-----------------------....-.~www ______________ ......__.., ________ . 0 5 seconds__., '" '"" 10 Figure 6-22. Pupillary dilation due to sympathetic stimulation after chemical sphincterblock. Cat in deep nembutal anesthesia. The parasympathetic supply of the right pupil (solid line) had been abolished by conjunctival instillation of I% atropine drops. The right pupil therefore was large, while the normal left pupil was small, due to the narcosis (broken line). The arrows indicate L A R Figure 6-23. Iris incisions. The two photographs were taken of the same cat iris. The cornea and posterior half of the globe had been removed, leaving a scleral ring with the iris, lens, and ciliary body attached. The preparation was placed in warm Ringer's solution. The pupil was small but not maximally constricted (A). Using iris scissors a cut was made parallel to the sphincter muscle in the 15 ""'" 20 25 short electric stimulations of the right cervical sympathetic nerve (square/wave, 2 milliseconds, 6 volts, 60/second). Note the prompt dilations of the parasympathectomized pupil. The time-amplitude pattern of these reactions was typical for sympathetic responses. (From I.E. Loewenfeld, Documenta ophthal., 12 (1958]:185) L B R right half of the iris. Within seconds, a gaping half-moon-shaped hole had formed. The ciliary iris portion had receded peripherally, and the entire iris to the left of the cut was dragged toward the intact side. The natural pupil had closed to a slit (B). (From I.E. Loewenfeld, Documenta ophthal., 12 [1958]: 185) 360 / I. Anatomy and Physiology suppress firing of the pupilloconstrictor nucleus with ease, the peripheral parasympathetic nervemuscle apparatus is not inhibited at all (see Chapters 3 and 9). (3) It would be difficult to ascribe the residual reflex dilation after cervical sympathectomy to adrenergic inhibition of the sphincter muscle because all adrenergic ocular fibers are interrupted by this operation. And since there is no secondary oculosympathetic path, how would such adrenergicinhibitory impulses reach the eye? (4) It is easy enough to demon trate that extensive pupillary dilation can occur without participation of parasympathetic inhibition. Thus, electric stimulation of the cervical sympathetic nerve dilates the eserinized pupil even though eserine prevents relaxation of the sphincter mus- Figure 6-24. Effect of drugs upon the iris sphincter in situ. The experiments a, b, and c were done on an enucleated rabbit eye (a) and on cat eyes b and c ). The experimental procedure was the same as in Figure 6-23. In each experiment, flash color slides were taken about 3 to 5 minutes apart. The pictures show camera obscura outline drawings of these color slides. In each experiment, 4 small incisions were made between the sphincter and dilator portions in each iris (broken lines in al). The four remaining tissue bridges held the sphincter muscle in place: al shows the normal rabbit iris, and a2 the same iris 3 minutes after the cuts were made. The iris tissue peripheral to the sphincter had receded radially, so that half-moon-shaped holes had formed. The natural pupil had contracted; a3 shows the same preparation 2 minutes after noradrenaline hydrochloride (concentration about 1:100 000) had been added to the bath. The pupil had enlarged and the peripheral iris tissue had contracted more. Note the squarish shape of the pupil, and the straightness, lengthening, and thinning of the sphincter bands under the influence of the radial pull by the tissue cle. Similarly, stimulation of long ciliary nerve twigs at the scleral limbus leads to marked segmental pupillary dilation even though the sphincter in the stimulated iris sector can be seen to constrict tightly, due to simultaneous excitation of short ciliary nerve branches (Figures 6-15 and 6-21). Further, the pupil still dilates vigorously to sympathetic stimulation and to instillation of adrenergic drugs after the sphincter had been paralyzed by interruption of its parasympathetic nerve supply, by atropine, or by the death of the animal or enucleation of the eye (Table 6-15 and Figures 6-5, 6-22 and 6-25). And the ciliary portion of the iris is still able to retract radially after surgical disconnection or removal of the sphincter from the eye (Koelliker, 1855; Hurwitz, 1878; Heese, 1892; see Figures 6-23 and 6-24). bridges; a4 was recorded 3 to 4 seconds after three of these tissue bridges had been cut. The natural pupil had con tricted to its mechanically possible minimum. In bl to b4, the same experiment was done on a cat eye, and in cl to c4, a second cat eye was used. In cl the iris is shown after the cuts had been made. In c2 the sphincter had been paralyzed by addition of 1:5000 atropine sulfate to the bath, and the pupil had enlarged. The tissue was then washed with Ringer's solution, and 1: 100 000 adrenaline hydrochloride was added. Note the increased enlargement of the pupil in c3 and the rectangular shape due to radial pull of the tissue bridges. When the sphincter was freed by cutting three of these bridges, it contracted a little, but remained flaccid because it was paralyzed. Note the large holes surrounding the sphincter ring in a4, b4, and c4, due to constriction of the peripheral iris tissue. The tissue could be seen to roll under, indicating that the contractile elements were at its posterior surface. (From I.E. Loewenfeld, Documenta ophthal., 12 [1958]:185) 6. Reflex Dilation • nerv ith th t para-16). ca p In the e could n t becau uc mu cle had alre applied. hat, t in vitro adrener that Grunhagen In 1953-195 anatomic exi t phincter mu cl rea on and be preparation , ponded t ~n n I decade , t phincte ne lee (Chapter . pecie r lati . ergic networ dilat r erve ome function. And tt Figure 6-25. Rea tion of phin1.:t iru to mpathelic timulation. a: from the eye of a fre hi) lilied cat. right ide of the phincter r m the Figure 6-23. half-moon• hapc phincter, held fa ton t p and bout20 ec nd. aft ra. ln r the cervical ympathetic •• and the iri h le h d enl· wa tretched verti •a traighter than in \ turned to the me d1 The eye had been c ride in . a line (I: 100.000) effects f • ti About 30 e b not hindered ·n ticking t th f pulled radial II cep ere withdra\\.n, th tion (c'). (From 1. 1 5) u 1 e of the hinter ed? m, the in the or thi • e -~ rve d q with ical technique pc • nd in all e adrene mu t act ju t •• rtion in rem ed rated the i n as in the and. a': ti n f al pupil ed. lt and ·e had reafter b. ·drochloeen the d b'). c: cter uch gen a the forght po i., 12 [19 J: / 361 enumerated make it difficult to imagine this function to be f th ordinary (phasic) motor kind. . I think that the sympathetic (inhibitory) sphmcter innervation does not by itself, elicit dilation of the pupil. In thi regard it is important that beta-adr~ner~ic bl eking drugs like timolol or pindolol, even m _high concentrations a used in glaucoma therapy, fail to affect th pupil, a alpha-adrenergic antagonists like thymoxamine or tolazoJine do. This certainly _wo~l? be urpri ing if pupillodilation depended on mh1b1tory (beta) receptors of the pupillary sphincter rather than xcitatory (alpha) sites of the dilator muscle. But adrenrgic phincter inhibition may facilitate reflex dilation by cau ing a reduction of sphincter muscle tone so that the phincter is able to ' give" readily at the moment when the dilator constricts. This would explain the divergent re ult obtained with isolated sphincter strips in vitro, compared to the reactions observed in my experiments with the e muscles in situ (Figures 6-23 to 6-25): in the in vitro ituation the preparations were stretched out in the bath by a small weight or other mechanical device that placed them under tension; and when adrenergic ub tance were added to the bath, the muscle lengthened under the influence of this tension. But in situ in th i olated eye, the muscle was not under tension, and thu it did not lengthen in response to adrenergic drugs. In ummary, a large number of experimental facts indicate that pupillary reflex dilation is composed of two main factor that are simultaneously called into play, as a cla ic example of Sherrington's reciprocal innervation: sympathetic discharges reach the dilator muscle of th iri and cause it to contract; and central inhibitory impul e impinge upon the Edinger-Westphal nucleus and reduce the rate of cholinergic firing to the pupillary phincter, causing the muscle to relax. The activeympathetic reflex component is faster more extensive and horter-lasting than that due to 'parasympatheti~ inhibition. In addition to these mechanisms, which have ?een known for many years, adrenergic impulses, reaching at least part of the sphincter by way of collateral branche. of the sympathetic preterminal fibers, may act upon this muscle to reduce its tone at the time the dilator mu cle contracts. (see Chapter 9). 4. The Role of Anesthesia A look at the voluminous literature on the efferent mechani m of pupillary reflex dilation reveals the curiu fact that opinions about the relative importance of . ympathet_ic acti_vation and parasympathetic inhibition in. producing this reflex have undergone some radical htft over time (Table 6-17). Mo t of the early authors stressed the activeympath_etic _component of the reaction. They said that the pupil dilated fast and maximally, while the palpebral fi ures widened, the nictitating membranes retracted, a~d the ocular blood vessels blanched. Other ympath~ttc re ponses were also seen, such as arrest or acceleratt0n of breathing, elevation of heart rate and 362 / Table 6-17. YEAR I. Anatomy and Physiology The mechanism of pupillary reflex dilation in response to sensory or emotional stimulation AUTilOR 1862 Balogh ~ Bernard 1862 Prokowsky 1867 Schiff 1868 Schur 1869 Rogow 1874 Schiff & Foa """Tii7"8Fr!ifois -Franck T""7"8 Rae mann & Witkowskv 1879 Bochfontaine 1880 Luchsinger ~ Ttiwim 1882 SPECIES ANESTHESIA STIMULATION rabbit dog.rabbit rabbit cat rabbit rabbit cat 1 dog dog,cat none none none none none curare curare curare asphyxia any sensory nerve CO2 intoxication anoxia or CO2 CO2 intoxication asphyxia any sensory nerve sensory stimuli man none sudden awakening dog goat,cat rabbit cat none or curare curare dura sensory nerves, or asphyxia crural nerve curare EFFFr.-rn SYMPATHETIC INHIBITORY p INM p 0 SI 3i s1 3i +-I+ PF + --+ -- -- + -- - -- -- ---++ --++ - --+ -- -- -- -- -- -- ,- ,- -- -- ---+ -- - --+ 0 -- --- -- - -- 0 - ---- -- -- -+ -- - - - -... - - - -strychnine, none or curare ulnar nerve or picrotoxin rabbit rabbit dog,cat cat frog dog (?) dog cat none or curare curare (?) curare curare none curare stop cerebral blood flow stop cerebral blood flow femoral nerve sciatic or other sensory nerve sensory stimuli sciatic curare none ~ Grtlnhagen cat none cat curare sciatic 11pliys10Iogic stimuli", aspnyxia sensory nerves sensory nerves asphyxia sciatic, splanchnic 1894 1894 1894 Steil 1895 1896 Spalitta Schenk & Fuss ~ Waller 1900 Fuss 1903 Anderson cat.rabbit catbd~f• _ra b1 cat,rab~ ? cat statement cat,dog cat 1904 Parsons ? 1904 1909 Tschirkowsl<v Langendorf£ 1910 1912 1918 1925 1927 Kar:Plus & Kreidl Karplus & Kreidl Karplus & Kreidl McDowall Nishimura rabbit cat,rabbit cat cat cat cat cat cat (?) In column I curare curare chloroform ether and curare none none or chloroform none none light alcohol -ether chloroform light alcohol-etherchloroform none ? curare light ether or curare light ether light ether chloralose ? ---+ laryngeal, sciatic, sensory nerves depressor sciatic vagus any sensory nerve vagus sciatic, light touch sensory --+ --- nerves pain, emotional stimuli sciatic dyspnoea, poisons sciatic sciatic sciatic somatic &visceral nerves 8th nerve "SYMPATHETIC", the signs of sympathetic activity are recorded. P+-1+ means fast, retraction of the nictitating membranes; PF, widening of the palpebral fissures; O, other reduced by sympathectomy; and 3+• reactions abolished by parasympathetic denervation. incomplete, slow pupillary dilation, and S.,l. and 3J. mean the same as in "SYMPATHETIC". spaces, no comment. O means not found, though looked for. + -- + - -+ ----- + --+ -- cat Nawrocki & Przybylski Braunstein Dogiel + + + Guillebeau & Luchsinger 1884 Grlinhagen &Cohn 1884 Meyer &Pribram 1886 Jegorow 1886 Kowalewski 1886 Schipolow 1886 Schiff 1891 Bechterew & ~Mislawski_ ~ L1ttauer 1893 ... + -- -- --- -- I-- --+ -- '----- -- --++ + -- --- - + + --+ + + -- -'----- -- - --- """"+--+ -- -- """+ --+ -- ---+ -- --- ---++ -- ---+ -- ---+ --+ -~ + + + + """+ + + -+ -- - -- -- --- -- - --- --- -- -- ,_ -- -- ----- -- -- --- -- ~ + ---- --+ ,__ -- - --0 ------- --- ---:j:'""" 0 """+"" ---:j:'""" """+ ---:j:'""" --- -+ -- -----++ ---+ --+ -+ -- + ,_+ + --++ -+ + + ---:j:'""" -- ~ -- -- - -- --- --I- - - 0 ,__ lJ - - -- - -- --- --- --- --- -- -- ---- --+ -- -+ -- ,_ -- -- -+ -- -- -- -- -- -- . --- -- -- -- -- -o- --- --- -- - -- -- --- -- -- --- -- -- - - -- --- - -- -- +-- -- -- --:j:'"""-- -- - - - - + -- --- ---+ -+ + -- -+ + - -- -- -- -- --- - - -- - -- -- -+ -o- -- maximal pupillary dilation; NM, sympathetic effects; SJ., reactions In column "INHIBITORY", P+ means + means positive reports, and blank -- --- -- - -- -- 6. Reflex Dilation Table 6-17 I 363 (continued) YEAR AUTHOR SPECIES ANESTHESIA EFFECTS INIDBITORY SYMPATHETIC .P p NM 0 3~ + s~ 3~ +++ ..!:I -- STIMULATION 3:. - ~ Blier 1928 1930 1930 Karylus &.Kreidl Ihzuka Lieben &.Kahn cat.rabbit cal cat cat 1935 Bain&. al. cat 1936 1937 Iwasaki raboit Harper & cat Mc Swiney Ka!:Elus cat Irving&. al. cat Ury &.Gellhorn rabbit Gullber1r &.al. rabbit Mc Swinev &S111101cat Ury & Gellhorn cal 1937 1937 1938 1938 1938 1939 1940 1940 1940 Hodes cat Rfo Seybold & Moore dog cat 1941 Weinstein &. Bender 1942 Hodes & Magoun 1944 Harris &.al. 1945 Gellhorn &.Levin 1946 Kuntz&. Richins 1949 Jaffe 1950 Adler 1950 Lowenstein & Loewenfeld 1952 lloorens 1953 Rossi & Steffanon 1953-J Loewenield 1957 1960 Okada &.al. 1962} Bonvallet & 1963 Zhrozyna 1966 Voloshin &. Bonvallet monkey cat cat cat cat cat.dog cat cat rabbit,cat, monkey statement cat ? light ether none none deep ether chloralose none chloralose -- lil!-rt ether or curare c oralose Urethane none chloralose deep ether (+eserine) none urethane (+ eserine) dial-urethane, ether or nembutal morphine ether (eserine) none none Light ether nembutal chloralose, urethane nembutal, chloralose dial -urethane nembutal light ether sciatic sciatic acoustic sensory and emotional senso~ stimuli v~s, ~lanchnic nerve, viscer orfilans hign atmosp enc pressure visceral sensory sensorx visceral sciatic darlmess visceral sciatic sensory sensory nerves sensory afferent nerves, nerves metrazol asphyxia ? sciatic sciatic strong sensory (sciatic) darlmess sciatic sciatic sciatic sciatic, s12lanchnic anoxia, asQh~ia sciatic sciatic sciatic none sound, ? sciatic cerveau isolt:! cat, monkey none nembutal cat very light cat none chloralose, nembutal cat none pain olfactory sensory sensory sciatic nerves nerves - - + --0 - --- --- --+ """a"-- -- ~ + + -- -- -- -- --+ 0--- -- -- -- - 00 --- -- -- - ~ 0 -- - + 0 -- -- -+ 0 -- -- - - -- - -- 0 -- - - - + --- -- - -- -- -- -- 0 -------- -- --+ 0 + -+ --- 0 -- --- - - - - + --- --+ -- -- -- ---- -- --- -- - - + _Q_ - - - -- --- -- + -- - -- -+ + ----+ --- - -- -- - -- -- --- -- - -- -- - - --- -- - --+ -- - - --- -- - -- - ----+ -- - -- + + --- - -- --- - - -+ -- - - -+ + + 0 + -- + -- -- - --- -- - - -- -- -- ------ -- ---+ --+ -+ --+ --0 + 0 + + I- long ciliary median and radial same stimuli nerves tactile, awakening auditory, Addition: 1984 and 85 1 Oono &co-workers: auditory and m dian nerve stimulation in normal, thetic-inhibitory and a later sympathetic-excitatory phase, as described in Table 6-5. + -+ --- - -- - --- --+ -I- + -- -+ - + -- -+ -- - __±_ -+ -+ -+ -- + + nerve potentials + -+ alert man elicited --0 - -- -- --+ --+ -- -- an early parasympa- Note that with only analgesia or light anesthesia by volatile agents, the sympathetic reflex components were prominent. But with deep anesthesia these reactions were abolished. The parasympathetic-inhibitory features of the reactions, in contrast, persisted in anesthesia. Asphyxia, anoxia, and poisons always elicited sympathetic excitation, with or without anesthesia: they became effective by reaching sympathetic centers with the blood, not by neural transmission. 364 / I. Anatomy and Physiology blood pressure, secretion of sweat and saliva, and inhibition of gastrointestinal motility. The ocular reactions were much reduced by cervical sympathectomy and they persisted after the third nerve was cut. But toward the end of the nineteenth century and until the mid1950s, many workers said that the reaction was due mainly or entirely to inhibition of the pupillary sphincter. In response to sensory stimulation the pupil was said to dilate submaximally, without participation of the orbital smooth muscles or other sympathetically innervated effectors. And the response was not diminished by sympathectomy but was abolished after cholinergic paralysis. Weinstein and Bender (1941) suggested that this disagreement was due to species differences, and others agreed with them: in monkeys the active-sympathetic and in cats the passive-parasympathetic signs were said ~o be promi~ent. Finally, during the last decades, opin10ns have shifted back to the original ones. How is it possible that competent workers came to such_ different conclusions in a problem so intensively studied? The puzzle was solved when the experimental conditions used by the different investigators were considered (Loewenfeld, 1957-1958). Among these conditions the most important one was anesthesia. The active-sympathetic reaction does not occur in the ab~ence of ~onsciousness. It is abolished in normal sleep, m narcosis, and in pathologic coma. ln contrast, inhibition of the Edinger-Westphal nucleus is not hampered by anesthesia and may even be enhanced. And for this reason those who experimented without anesthesia, or who _used only analgesia or very light anesthesia by volatile agents, found sympathetic responses, while those who worked with deeply anesthetized animals did not. 17 General anesthesia for surgical procedures had not been introduced until the middle of the nineteenth century, when, in quick succession nitrous oxide, ether, and chloroform came int~ universal use; 18 and local anesthesia with cocaine had an equally spectacular start roughly forty years _later (Koller, 1884; see Chapter 14). Early e~e~1ments on the mechanism of pupillary reflex dilation were thus done without anesthesia often . curare to immobilize the animals· later ' ether with chloroform, or morphine analgesia ' were ' used. ' Langley and his school used mixtures of alcohol ether, and chloroform up to the point of analgesia'. Many later workers (for example, Karplus and Kreidl) anesthetized their animals with ether during surgery and then switched to curare and infiltration of the wound with local anesthetics for the experiments. Because of their steadiness and 17. Even the apparent species difference in Weinstein and Bender's experiments was explained: these authors gave light ether to monkeys and deep nembutal to cats. 18. A short, fascinating account of this history and of various theories about the mechanism of anesthesia is given by P.J. Cohen in Goodman and Gilman's pharmacology text (5th ed., 1975, pp. 53-58). ease of induction, nonvolatile agents (chloralose urethane, dial, and especially barbiturates) be~ came popular for neurophysiologic experiments during the first half of the present century. More recently, deafferentation by transection of the rostral cord or brainstem, and stimulation with permanently implanted electrodes, made it possible to perform experiments without anesthetics. Anesthesia does not merely reduce pupillary reflex dilation but selectively wipes out its active-sympathetic component. This can be proven easily by experiment. When a cat has been sympathcctomized unilaterally, the pupil on the normal side dilates very much faster and more extensively to sensory stimuli than does the pupil on the operated side (Figures 6-16,B and 6-28,A). But when the same animal is examined in anesthesia, the two pupils are equal and respond alike: both pupils now enlarge only sluggishly to sensory stimulation, and they never reach maximal size. Further, retraction of the nictitating membranes, widening of the palpebral fissures, and all other sympathetic and somatic signs that normally accompany the pupillary dilation remain absent. The same is true for stimulation of many cerebral areas (Figures 6-26 and 6-27,A and Tables 6-18 and 6-22). In parallel with these differences between motor responses with and without narcosis, Bonvallet and Zbrozyna (1963) recorded changes in the action potentials evoked by sensory or by brain stimuli when the animal was anesthetized: without anesthesia such stimuli augmented neuronal firing in the cervical sympathetic and the long ciliary nerves, and they inhibited parasympathetic discharges that reach the sphincter muscle in the short ciliary nerves. Anesthesia abolished the sympathetic-excitatory and enhanced the parasympathetic-inhibitory action of these stimuli. During anesthesia, the_n, the normal pupil reacts to sensory and to brain stimuli as if it had been deprived of its sympathetic nerve supply. But as soon as consciousness returns, the active-sympathetic reflex component is restored. In contrast, hypothalamic stimulation evokes full-blown reflex dilations both with and without anesthesia (Figure 6-27,B). This is the reason for the unanimity in the literature as regards the mechanism of pupillary reactions to hypothalamic stimulation: everyone found active-sympathetic signs, together with mass discharges to all sympathetically innervated effector organs, because they were present in deep narcosis as well as in awake animals (Table 6-19). 5. Experimental Errors Those unaware of the effect of anesthesia upon pupillary reflex dilation and upon the reactions to central nervous stimuli, that is, the selective suppression of its active-sympathetic component, naturally concluded that these responses were mainly or entirely due to parasympathetic inhibition. A number of experimental errors have bolstered this view (sec Loewenfeld, 1958). In summary, the most frequently encountered 6. Reflex Dilation Table 6-18. AUTHOR 1876 Balogh Bochfontaine Hensen & Voelckers 1878 ~ Ferrier 1887 1891 Fran<;:ois-Franck Bechierew & Mislawski Braunstein Bechterew Parsons EFFECTS INIDBITORY SYMPATHETIC p p NM NM 0 s,i 3* + PF 3i +++ PF SPECIES ANESTHESIA STIMULATION dog dog chloral hydrate light chloralose caudal striate bodies striate bodies dog morphine rabbit dog,cat ? curare thalamus from knee of fornix to midbrain tegmentum colliculi corona radiata, internal caps. dog curare thalamus cat rabbit dog,cat, monkey striate bodies, thalamus rostral thalamus corona radiata, internal capsule analgesia --+ - - -- - -- -- - --+ -- 1932 Karplus & Kreidl Herzfeld & al. Spiegel &Takano Frie<1t>erg Ingram & al. cat rabbit cat cat cat,monkey ether or none urethane light ether anesthesia ether 1933 Ranson & Magoun cat ether & nembutal 1935 Kabat & al. cat none 1936 1936 1937 Crouch & Elliott Miller Riech & Brenner cat cat cat anesthesia barbiturates ether 1938 1939 Ectors & al. Harrison & al. Hess cat cat cat ether urethane none 1941 Carlson & al. cat anesthesia 1941 Weinstein & Bender Hodes & Magoun Hess & al. cat monkey cat cat nembutal li~ht ether c oralose none Hunter & Jasper cat Loewenfeld cat Hess & Akert Lowenstein von Sallmann & Lowenstein Matsui Akimoto & al. Yoshioka Matsushita cat cat,monkev none nembutal none none chloralose, cat chloralose dorsal man cat,rabbit rabbit cat none dial urethane dial I urethane dial, urethane thalamus --+ -thalamus, rostral midbrain -central grey & surrounding area -c audal tha_l~mu13, sup. colliculi, rostra 1 m1 ram -fornix, septum pellucidum, ant. + thalamus -thalamus ( Forel' s field) + subthalamus, incl. zona incerta + -thalamus (Forel's field I-I) + + thalamus I For el' s preru bral f. + subthalamus + + substantia nigra + + -subtbalamus + subthalamus ( zona incerta) + + -subthalamus, ventral thalamus + --subthalamus (prelemniscal + radiation) 1909 1912 1929 1929 1931 l93il 1942 1945 1949 1953-} 1957 1955 1955 1955 -- 1957 1957 1957 1959 1962 Umbach & Schmidt man none 1964 Spiegel Mundinger Nashold &Gills Nashold & al. Kim & Buscher WinkelmUller Schiffter & Pohl Kim &Umbach Sug!ta & al. Ito man man man man man cat man man man man none none none none none none none none none none 1965 1967 1967 1970 1971 1972 1972 1972 1973 nembutal hypothalamus, thalamus -- -- -- -- -- ,_ -- -- -- --+ -- - -- --- -- -- -- --- - -- - + -- - -- -- -+ + + - -- -- - -- -- -- -- -....±.... .i... - ....±.... -- - - -- -+ + -- ....±.... -- -- - -- -- dog cat,monkey medial thalamus medial thalamic nucleus pulvinar & surrounding area medic-ventral thalamic nucl. corr,1us callosum head of caudatc nucleus internal capsule, pes pedunculi thalamic nuclei, supraoptic & preoptic areas septum, thalamus (dorsal dience:ehalon} strong thalamic stimulation weak stimuli in thalamus , se2tum 1 int. ca2sule subthalamus caudal nucleus, thalamus thalamus ,septum,floor of --lateral ventrifle thalamic surface o 3rd ventr. internal ca:esule rostral hypothalamus, weak st. same sites I higher intensity thalamus, caudate, lenticular nucleus , corona radiata dorsal hypothalamus, thalamus same sites basal telencephalon corona radiata, stria terminalis basal septum fornix I rostral thalamic nuclei thalamus, rostro-dorsaI hypoth. same sites dorsal thalamus I striatum dorsal hypothalamus, thalamus --- + Bechterew Sachs 1909 + --+ -- + curare none (curare ? ) very light ether or ether-alcohol--chloralose none ether or chloroform 1894 1895 1901 365 The mechanism of pupillary dilation in response to the stimulation of subcortical telencephalic structures YEAR 1878 / + + -- _±_ _±_ + + + + + + + + -- + -- + -- --+ --+ -:;:- --- + + + _±_ --+ + - _±_ + + -- - -- -- -- --- -- -- -- -- -- -- -- --- -- -- ---+ .i... _Q_ -- -- -- ,_ -- -- -- --- -- -- -- ,_ -- --- - -- -- -_±_ + --- -- + 0 -- -- -- --- -- -- --+ --0 ,_ ---- -- -- -- - -_Q_ ....±.... + + - -- - + -- -+ + - - -- - -- -- --- -- - -- -- 0 -- -__Q_ - ---+ --+ -- -- - -- -- -+ 0 -- -- - - - --+ --0 --+ -- -- -- --:;:- 0 ~ -- ,- -- --- ---+() ~ -- --- - -- -- -- -+ + --+ --+ -- -- -- - -- -- -- -- + 0 + + + ""'+ --+ -- -- -- + 0 --+ -- - --- - ---- + --- - -- + + - - - -- -- + -- -- --- -:;:-- -- 0-+ 0 -- - --- --+ ---- --+ -+ -- -- -- -- -- - ++ -- -- -- -- -- - -- -- ---+ - -- -- -- -- - -- -- ---+ -- -- -- -- --- -- -- -+ --- --- -- --- -- -- -- -+ Note: subthalamotomy bas been done fairly routinely in recent years, and the pupillary responses to stimulation were used as guide for the placement of lesions. These stimuli had uniform results: fast, maximal pupillary dilation and other sympathetic effects, unless anesthetics were used during the procedure. The symbols mean: P+++ = fast, maximal pupil dilation; P+ = slow, submaximal pupil dilation; O = other sympathetic effects; S ♦ = reduced or abolished by sympathectomy; 3.j,=reduced or abolished after the 3rd nerve was cut; NM= retraction of the nictitating membranes; PF= widening of the palpebral fissures. +=reaction present; O = reaction absent. --------- ---- ---- ---- 366 / I. Anatomy and Physiology Table 6-19. YEAR 1878 1902 1909 1909 1910 1912 1926 1927 1928 1929 1930 1931 1932 1932 1932 1933 --1935 1935 1935 1936 1936 1936 1936 1937 1937 1937 1937 1937 1938 1938 1938 1938 1938 1938 1939 --1939 1939 1941 1941 1941 1942 --1943 1945 1945 1946 1947 1949° 1951 1951 1952 1955 1955 Under Pupillary and other sympathetic effects due to hypothalamic stimulation: Experiments on animals AUTHOR SPECIES ANESTHESIA STIMULATION EFFECTS p NM +++ PF Hensen & Voelckers Levinsohn Bechterew Karplus & Kreidl Karplus & Kreidl Karplus & Kreidl Einthoven & al. Lewy Karplus & Kreidl Shinosaki Shigematsu Ingram & al. Ingram & al. Magoun & al. Wang & al. Ranson & Magoun dog morphine lmee of fornix cat 1 monkey dog cat,dog cat cat cat cat monkey cat cat cat cat 1 monkey cat cat cat none none /?) ether or curare ether or curare ether or curare curare ? ether ? "narcosis" ether ether narcosis dial ether and nembutal Kabat & al. cat "dience2halon" "floor of 3rd ventricle; thalamus" 2ostero-lateral hypothalamus 2ostero-lateral hy-pothalamus postero-lateral hypothalamus caudo-lateral hypothalamus "corpus Luysii postero-lateral hypothalamus "corpus Luysii" "corpus Luysii" diencephalon and caudal to it hypothalamus ana midbrain hypothalamus tuber cinereum lat. hypothalamus (mamillary area lateral hypothalamus lateral hypothalamus hypothalamus lateral hypothalamus lateral hypothalamus lateral hypothalamus hypothalamic nuclei hypothalamic nuclei hypothalamus hypothalamus hypothalamus hypothalamus posterior hypothalamus "corpus Luysii 11 wall oi the 3ro ventricle hypothalamus (from cranialiloor hypothalamus hypothalamus to midbrain 0 si 3,! ----+ --+ + + --++ + + + + ---++ ---++ ---++ ,_+ + -- --+ -- ---+ + -- --+ -+ ------ -- + -- ------:+" + -+ '""'+ +"" + ---:+" +"" --- -- ---+ -- -- -,_+ --+ --+ -+ + + '""'+ +"" -+"" ------++ --+ --++ ,_ -- -+ --+ ++ -+ ----++ ++ ++ -+ + --++ ---..Q_ ---,-0 -------- none -nembutal or ether -Ranson &Magoun cat light pentothal -Ranson & al. cat none -nembutal or ether -Crouch & Elliott cat anesthesia -Kabat cat nembutal and ether -Kabat & al. cat nembutal and ether -Stavraky cat dial or ether + -:r ""+ '""'+ -- -Ectors monkey ether or nembutal + + + -- +"" +"" -Kar2lus cat,monkey ether + -Masserman cat none + ---:+" +"" -:r +"" +"" ---- ,_-Rioch & Brenner cat ether and local Shinosaki cat none '""'+ -:r -:r -- -- -Ectors & al. cat ether or barbiturate - ++ +"" Grinker & Serota cat nembutal I ether +"" '""'+ -- -Harrison & al. cat nembutal, dial,urethane + '""'+ -- -cat + +"" '""'+ nembutal Ma~oun ---Masserman & none or very light cat Haertig ether hypothalamus + + + --+ -Monnier monkey nembutal lateral hy-pothalamus + + + cat Hare & Geohegan ether, chloralose, hypothalamus + + + nembutal -- ---cat caudo-lateral hypothalamus + + + -Hess none ---+ cat curare or nembutal hypothalamus + Ranson & Magoun --++ + + -hypothalamus cat anesthesia + Carlson & al. -- -- -- -cat ether, nembutal, Hare &Geohegan + hypothalamus + chloralose -hypothalamus + + + cat nembutal Weinstein & -:r monkey hypothalamus + 0 ether Bender ----cat urethane, cbloralose, Hodes & Magoun + hypothalamus + 0 nembutal -- - + -- -cat none hypothalamus + Hess & Magnus -- -hypothalamus cat + '""'+ + none Hess &Br!iggcr --medial hypothalamus cat none +"" Hess & al +"" +"" ---+ hypothalamus 0 monkey light ether or dial ward &Reed --+ --+ -cat none hypothalamus + + Hess ----+ ,cat none hypothalamus + + Hunter &Jasper -"ventromedial hypothalamic nucl'~ + +"" + none, chloralose, or rabbit Ban & al. urethane --+ --+ --+ -- -rabbit urethane "ventromedial b~th. nucleus" Naf:ai & al. -:r +"" -:r ""+ 0 cat bvootbalamus Wison dial hypothalamus cat none + + Hess & Akert + hypothalamus cat nembutal I chloralose + + '""'+ + 0 Lowenstein EFFECTS, the symbols mean the following:P+++ = fast, maximal pupillary dilation; NM= retraction of the mctitating membranes; PF = widening of the palpebral fissures; O = other sympathetic effects; S+ = reduced by peripheral sympathectomy; 3..J.abolished by section of the 3rd nerve. + means the effect was observed, 0 that it was not seen though looked for, and blank spaces that no mention was made. For similar - 'o ~ results in man, see Chapter 25. 6. Reflex Dilation Table 6-19 367 / (continued) - YEAR AUTHOR SPECIES ANESTHESIA EFFECTS STIMULATION NM r' 1955 1956} 1957 1956 1957} 1958 1958 1959 1960 1960 1969 1970} 1971 --1972 1974 von Sallmann Lowenstein Gloster & Greaves von Sallmann & cat chloralose hypothalamus cat cbloralose hypothalamus & aL cat ,-chloralose hypothalamus - --- --- --- --- Loewenfeld cat,monkey none or nembutal hypothalamus cat cat cat chloralose chloralose none or anesthesia none "anterior columns diencei;1halon hypothalamus ventromedial cat local _. h~thalamus cat Koss & Wang Johansson & al. cat cat none (local) __., sodium 2entothal chloralose none nembutal 6 A',,- --~ I~"' 5 ~ ,,~ ~,.c;L..c 3 ·~- '~ .2".,..,. __ ~ -- ~ ,::,z s ,o + + + + {action potentials} --+ + :eosterior h~halamus ventromeclia:r- ypothalamus + + -- -- ' , ✓- ,I - 1-l,. • • ........ -- -- --- -- -- ........__ 0 - ' I -I -- ·- -------- 6 --G - ---------~ ~ ._........ __~,, ' --- ---- 0 -- 7 ,' 2 --- -------=- 7 I 3 ~ --+ 0 -- ........... '\. / ~I-- + -- - / II 5 + + ...±,_ ...±,_ ·rage reactions hypothalamus - --- --...±,_ -- + l0 + -- -+ -- _±_ + + + -- -- -+ + of fornix" ' -/-- ,,,,-_,------~ ' ' ', IJ~L ,, '' ",~ + -- I ~----, + + II p"- + --+ ✓- 9 + hypothalamus 11~ •,.___-A PF -- Gloster &Greaves von Salimann Abrahams &al. Glusman & Roizin Sigg & Sigg Sigg & al. cat s,1, 3,j, 0 +++ • ~- ---- ----- ~ - ~------- --- JJ ,o Figure 6-26. Effect of anesthesia on pupillary dilation elicited by brain stimuli. Two cats were used, each with a permanently implanted brain electrode. At the beginning of the experiment, each animal's left cervical sympathetic nerve was cut, so that the left pupil was acutely sympathectomized (broken lines as compared to the normal right pupil, represented by the olid lines). Cat 1, (A and B): The cingulate cortex was stimulated with square-wave currents (2 milliseconds, 4 volts, 120/second). In A, the animal was in deep nembutal narcosis. The normal and the sympathectomized pupil were equal, and both dilated slowly and submaximally to the brain stimulu . There were no other signs. Five hours later, when the cat had awakened, the normal pupil was spontaneously larger than the syrnpathectomized one, and in response to the same cingulate cortex stimulus it now dilated quickly to maximal 0 s ·,0 size, while the sympathectomized pupil reacted as it had in anesthesia. The animal, still sleepy before the stimulus, showed somatic signs similar to sudden awakening or "attention." It lifted its head and opened its eyes widely, and the nictitating membrane retracted. The general somatic muscle tone increased, and breathing became faster. There were no signs of pain, anger or fear. Cat 2, (C and D): Similar experiment with the electrode placed stereotaxically in the rostral thalamic area. In C the cat was in deep nembutal narcosis. In D it was awake. Together with the brisk, extensive dilation of the normal pupil, it opened its eyes widely, lifted its head, and looked "apprehensive." About 30 seconds after the stimulus, it tried to run away. There were no signs of pain or aggressiveness. (From I.E. Loewenfcld, Documenta ophthal., 12 (1958):185) 368 / I. Anatomy and Physiology errors in the literature were first, inadvertent destruction of the postganglionic sympathetic fibers in their intracranial course while trying to cut the third nerve, with consequent loss of both the active-sympathetic and the passive-parasympathetic mechanisms; second, difficulties in observing dilation movements of already large parasympathectomized pupils and discounting of the residual reactions as too weak without realizing that they were limited only by mechanical factors; or using miotics ( especiaJiy eserine) to improve the mechanical range for pupillo-dilation without realizing that this hinders the pupillary dilation reflex; and third, confusing pupillary reflex dilation upon sensory stimulation (which is much reduced after sympathectomy) with redilation after contractions to light (which becomes only somewhat slow but not greatly reduced in amplitude after the operation). It is probably safe to conclude that a certain amount of prejudice, stemming from the disagreement about the existence of the pupillary dilator muscle, has crept into these deliberations. Even when sympathetic pupillary dilation was actually observed, other mechanisms were sought for on the grounds that there was no dilator muscle, or that-because of its unusual anatomic appearance-this muscle must be too weak to produce so extensive an effect. H. Location of the Reflex Center As discussed already, parasympathetic inhibition due to psychosensory stimulation is caused by central impulses that suppress firing of the pupilloconstrictor nucleus· and efferent volleys from the nucleus to the sphincter mu cle are thereby reduced. The "reflex center" for parasympathetic suppression-if this term can be used for an inhibitory phenomenon-is thus the Edinger-Westphal portion of the oculomotor nucleus. The site of the reflex center for the active-sympathetic part of the reaction remain to be determined. 1. Budge's Center Budge believed (1852) that the "cilio-spinal center" in the cervicothoracic spinal cord was the reflex center. This area contained the cells of origin of the cervical sympathetic fibers. Afferent impulses from the body were thought to stimulate these neurons, and they would then transmit efferent discharges to the eye. But it was soon found that damage to the spinal cord cephalad to Budge's center could be followed by oculosympathetic paralysis (Schiff, 1855; Table 6-20). When an animal's spinal cord or brainstem was transected between C8 and a level just caudal to the third nerve nucleus, pupillary dilation to sensory stimulation of the body below the neck was entirely abolished. The pupils still dilated slowly and incompletely to stimulation of nerves that entered the central nervous system above the transection, or of the brainstem above the cut. These latter reactions were not accompanied by sympathetic signs such as retraction of the nictitating membranes or widening of the palpebral fissures; and they were not reduced by peripheral sympathectomy but were abolished by atropine or by cutting the third nerve. They were therefore caused by parasympathetic inhibition. These experiments showed clearly that afferent impulses from the body had to ascend to some center in the brain; and efferent impulses then descended to the spinal cord. "Budge's center" therefore was not a reflex center for the reaction but only a cell station in the efferent oculosympathetic path. Direct transmission by Budge's center of sensory impulses to the eye was E 2 E 0 seconds--+ 5 10 Figure 6-27. Thalamic and hypothalamic stimulation during anesthesia (unilaterally sympathectomized cat). Two pupillograms of a young cat. Thirty minutes before these reactions were recorded, the right (preganglionic) sympathetic chain had been cut. The right pupil (solid line) and the normal left pupil (broken line) were both small due to the nembutal narcosis. A: Square-wave stimulation (2 milliseconds, 4 volts, 20/sec., located in the dorsal 0 5 10 diencephalon, 1.5 mm from midline), elicited slow and submaximal pupillary dilation, equal on the two side . B: Some minutes after A, the electrodes had been lowered into the ventral hypothalamic area. The same stimulus was used. The normal pupil dilated rapidly and completely, but the sympathectomized pupil continued to enlarge slowly and inextensively. (From I.E. Loewenfeld, Documenta ophthal., 12 [1958]:185) 6. Reflex Dilation possible only when the cord had been rendered pathologically hypersensitive by local applications of strychnine or picrotoxin. In patients with chronic lesions in the upper cervical cord, supersitivity to afferent stimulation developed in the decentralized spinal neurons below the lesion, and hence tran mission from the afferent paths directly to the preganglionic sympathetic neurons became possible (Table 25-26). These reactions, of course, were not related to normal function. In view of the impressive list of investigators who performed these experiments with uniform results, it is surprising how generally little known these facts have remained. For more than a century the unsupported statement continued to be published that "Budge's center" was the reflex center for pupillary dilation to sensory stimuli. Some of the rather nonsensical elaborations of this idea have long plagued the clinical literature, as described in Chapter 25. / 369 fissures and retraction of the nictitating membranes could still occur in animals after removal of the entire cortex or interruption of the corticodiencephalic connections (Table 6-21). As a matter of fact, the reflex threshold often was lowered by such lesions. Ocular reactions as well as other autonomic and somatic functions normally associated with emotional arousal showed this hypersensitivity after destruction of the hemispheres. Much earlier, Goltz (1892), Woodward and Sherrington (1904), Weed (1917), and Rothmann (1923) remarked upon the unusual irritability of their decorticate animals, who would fly into paroxysms of rage upon the slightest provocation; and many later authors have described the same reaction. Braunstein (1894), who also had observed that some weeks after the cortex had been excised reflex dilation could be elicited more readily than in the normal animal, suggested that 2. The Diencephalon Reflex transmission for the active-sympathetic reflex component of pupillary dilation to sensory stimuli is, then, impossible with lesions caudal to the oculomotor nucleus. Rostral to this nucleus, destruction of the dorsal midbrain-the colliculi and periaqueductal greydid not hamper the response (though stimulation of these structures dilated the pupils). In contrast, transections of the midbrain tegmentum or between the midbrain and the diencephalon abolished it. After such operations the pupils still enlarged upon stimulation of the body, but the responses were incomplete (Figure 6-28 and Table 6-21). The remaining slow dilations were not accompanied by other sympathetic reactions. They were due entirely to inhibition of the third nerve nucleus, since they were not diminished by cervical sympathectomy but disappeared after the third nerve was cut or the eye was treated with an atropinic drug. Hypothalamic lesions also led to sympathetic deficit: miosis, ptosis, protrusion of the nictitating membranes, and dramatic reduction of pupillary reflex dilation. 19 Bilateral damage left the animals in a greatly depressed condition: somnolent, cataleptic, and poorly responsive to their environment. The picture was entirely different when the injury did not include the brainstem and instead affected higher brain structures: maximal pupillary reflex dilation with widening of the palpebral 19. Okada and co-workers (1960) described firing of long ciliary nerve fibers upon sciatic stimulation in anesthetized cats. This activity (as well as an inhibitory afterdischarge) was much reduced by me o-diencephalic decerebration; but it was not entirely abolished as long as the medulla remained intact. I think these residual ympathetic nerve impulses do not serve the pupil, since sciatic stimuli fail to affect the atropinized pupil after brainstem transections as far cephalad as the diencephalon, which leave the medulla unharmed. In cats the long ciliary fiber carry vasomotor as well as pupillomotor fibers; and the vessels remain able to respond reflexly as long as a brainstem lesion spares the vasomotor centers in the medulla and their connections to the spinal cord (Chapter 9). 10 91------J-:____=:::~~----===-----1 8 t-----•--------------""""-----1 7 1-----1---,1-----------------1 6 ----------, 5 4 ---"'--"' ,, '- ------ii' ---------~~---......... -- 11-rrTTTirTTTTTTrrrrrrr..,.,-,rrrrrrrTTT-rn-rrr-rrnrrrin-,-,n-,-,rrr,"TTT""il Figure 6-28. Reflex dilation after cervical sympathectomy (A) and after transcction of the brainstem rostral to the colliculi (B). Pupillograms of two cats without anesthesia. The sensory stimuli (arrows) were squeezing the cats' tails. A: Five days after lcftsi_ded preg_anglionic sympa_thectomy the normal pupil (solid line) dilated quickly and extensively, the sympathectomized pupil (broken line) slowly and inextensively. B: Two weeks after deccrebrati?n b_etween the.mesencephalon and ~he diencephalon both pupils dilated sluggishly to the sensory stimulus. The fast, sympathetic component of the reaction was abolished bilaterally even though the peripheral sympathetic chain was unimpaired on both ides. The parasympathetic-inhibitory component of the reaction-was preserved. (From I.E. Loewenfeld, Documenta ophthaf., 12 [1958):185) 370 / Table 6-20. - YEAR 1 52 1855} 185 [. Anatomy and Physiology Experiments proving that the pupillodilator center must be located rostral to the pons AUTHOR SPECIES Budg:e rabbit Schiff SECTION AT Cl STIMULATED C4-5 post. roots Tl-T3 1867 Chaveau Salkowsky frog, gu ineapig rabbit, cat, dog rabbit I donke;):1: rabbit 169 Nawalichin rabbit Schiff & Foa Bochfontaine Fran~o is-Franck Luchsinger dog: dog,cat dog,cat cat, goai rabbit C 1 or medulla upper cervical above medulla Cl cat cat, goat rabbit dog dog cai above Cl 1861 --1 74 1876 1 7 18 0 -1--1- T-r 1 3 -1--51 6 Tiiwim Guillebeau & Luchsinger Bechterew Kalsclianowslct Kowalcwsky 193 Nawrocki & Przybylski ~ Braunstein 1 94 1 94 1 95 Langendorff Steil Bechterew 1907 Trend lenburg Bumke ~ Bach 1909 & Langendorff - hem isection of medulla or rostral cord Cl-C3 T5-Ti:'l Cl-2 or C5-6 Cl 2 or C5-6 rostral to Cl cord Cl below colliculi cerv. cord or medulla hemisection C3-4 transection C3-4 - Tl-T3 sensory m Ioot asEliyxia cord below transection sensory (oody) asphyxia Trendelenburg & Bumke 1912 Karplus & Kreidl 191 Karplus & Kreidl 1925 McDowall Wang &al. 1932 ~ Byrne 1935 Bain &al. 1935 1936 1936 1937 1937 Bremer Bremer Claes Chen & al. Harper & al. no response reduced clIIation dilation no response dilation dilation cat cat,rabbit C3-4 above medulla C~-3 hemisection cerv. cord transection sensory below cut sensory below cut brain peripheral end of cut cord cat cord hemiseciion below pons cat hemisection, medulla no response no response clilation dilation miosis 1 enhanced by sympaclilation thectomy dilation no response dilation ipsilateral miosis ? high cervical cord cai,rabbit above CB sensory sensory (body) (Iace) - cat,rabbit dog,monkey cat cat cat cat hemisection below medulla cord or medulla cord hemiseciion cooling or cuiiing upper cervical cord cervical cord below colliculi cord or medulla cervical cord cat cat cat cat,dog cat below colliculi below medulla below colliculi medulla partial cord transection sciatic sciatic sciatic 5tli nerve visceral sensory (body) brain sciatic vagus, splanchnic nerve sensory (head) cord above transection brain or olfactory acoustic internal capsule caudal surface or cut visceral sensory cat cat below colliculi partial cord transection brain above cut sciatic or splanchnic caudal to 3rd n. nucleus sensory high cervical transection below colliculi below colliculi high bulbar transection midpontine sciatic brain air blown in nose reticular system or sensory above cut darkness cat cat Claes I rarris 1944} 1946 1946 1949 1953 1962 Keller Kuntz &Richins Sachs & al. Rossi &Steilanon Bonvallet cat,dog, monkei cat cat, dog, monkey cat cat 1963 King & al. cat pretrigeminal emotional excitement nerves -- - ---+ - cat,dog - ----- + no response scnsorv /head) or asphyxia any sensory nerve sensory (body) sensory (face) + dilation sciatic - * no response Cl cord - dilation cat 1939 1944 & al. miosis dilation no response d1Iahon dilation no res12onse dilation , pe rs is ting after sympathectomy no response dilation no res122nse dilation sensory nerves (body) cortex sensory ( body) asphyxia sensory ( body) , after strychnine crural nerve brachlal plexus, after strychnine sensory (body) brain senRory aoove cut sensory below cut brain anemia, or dyspnoea sensory above cut dyspnoea or poisons 1909 PUPILLARY REACTIONS miosis, enhanced by sympathectomy dilation no response clilation m iosis , enhanced by sympa thectom):'. dilation ipsilateral miosis, but R-L after bilat. svmpathectomv no response dilation no response slow dilafion, no NM or PF no res12onse dilation no response no response dilation dilation dilation dilation dilation dilation no response unless lateral cord was saved dilation no dilation unless lateral cord was saved no response no response slow dilation no response slow clilation without NM or PF slow dilation, no NM or PF ,-=--- - -- --+ - ---- - - ,_ + -- - ------ --- --- - -- - - 6. Reflex Dilation Table 6-21. The effect of forebrain lesions on pupillary size and reflex dil~tion - Schiff & Foa 18 5 Brown-Sequard Katschanowski YEAR 1874 --1 75 SPECIES AND LOCATION OF LESION AUTHOR 194 Bechterew & Mislawski Braunstein 1895 Bechterew 1891 dog: removed brain rostral to corp. striatum ?: damage to brain surface dog: destruction of colliculi transection at mccluilary level dog: transection caudal to thalamus cat,dog: ~ Levinsohn 1904 Bach & Meyer 1904 1908 1909 Woodworth & Sherring!on Bach Trcndelenburg Bumke & 1910 Karplus & Kreidl 1912 Karplus 1913 1914 1914 Schrotten bach Karrr1us & Kreidl Ffc• er 1916 1918 1920 1924 1924 1925 1925 Schrottenbach Kar2lus & Kreidl Dusser de Barenne Amsler Dresel Cannon & Britton Gozzano 1926 Spiegel & Kakeshita Lewy Nishimura 1927 1927 1928} 1929 1928 1929 1930 1931 1933 1934 & Kreidl Bard Spiegel Fulton & Ingraham Ihzuka Schaltenbrand Cobb Byrne ten Cate ? = species / 371 & cortical extirpation (chronic) aog: c!amage in area or 3rd ventricle dog:, cat, monkeJ: cortical extirEation cat: removal of one hemisehere cat: removal of both hemiseheres or ?: chronic removal of hemispheres thalamenceehalon cat: removal of one hcmis2here cat: removal of both hemiseheres cat,rabbit,dog, monkey: removal of one hemisehere unilateral cortical ablation bilateral hemispherectomy cat: removal of both hemiseheres cat: removal of hipothalamus cat: removal of both hemispheres after transection of 3rd nerve rabbit: lesion in ventral thalamus monke:z::: removal of both hemiseheres cat, monkey: lesion in medial thalamic area rabbit: subthalamic region cat: cooling or removal of colliculi cat: removal of both hemispheres dog: acute decortication dog: removal of rorebrain cat: removal of frontal lobes cat: removal of colliculi, dorsal midbrain & ventral grey cat I guinea )2ig: decortication damage to diencephalon ?: "coreus Lu:z::sii" cat: removal of both hemispheres cat: section from superior colliculi to mammillarv bodies cat: removal of colliculi & midbrain tectum cat: separation of hypothalamus from forcbrain b;J:'.ventral stab wound ?: removal of both hemispheres removal cat: cat: diencephalic lesions removal ot entire neo,eallium removal: 01 acoustic cortex of neocortex (see bibliography); OCULAR EFFECTS sensory dilation nerves - miosis 1 2tosis I enophthalmos 2upil dilation preserved reactions abolished sympathetic effects abolished cortex cortex sciatic sensory nerves - - sensory nerves sensory nerves sensory stimulation sensory nerves sensory nerves sciatic sciatic sciatic tactile NM = retraction exaggerated reactions of pupil, NM, and palpebral fissures miosis , enop!itlialmos inconstant I fleeting s~eath. deficit dilation no reseonse in "pseudoexaggerated responses affective state" dilation no reseonse small, fleeting ipsilateral roiosis sliglit iesilateral miosis anisocoria due to previous cord hemisection 2ersisted maximal dilation with PF & NM no res122nse maximal dilation with widening of PF and retraction of NM miosis, ptosis, enophthalmos dilation sensory defective sciatic sciatic - 8th nerve miosis, ptosis, enophtha!mos maximal ailation witn PF & NM miosis submaximal dilation miosis sham rage with maximal dilation dilation dilation submaximal dilation no response transient Horner's dilation slight handling sham rage with maximal pain dilation mild handling sham rage with maximal aua:Itory oilation mild sensory sensory sciatic auditory auditory - - cat: not known from abstract STIMULATION sciatic sensory acoustic of nictitating ipsilateral dilation miosis & PF dilation dilation and ptosis no response sliam rage with cfilation no response membrane; PF = widening of palpebral Section means total transection unless otherwise indicated. The column * represents the following: +=the author believed Budge•s center the site of reflex transmission for alferent impulses from the body to the pupil; - = the author believed the reflex center to be located rostral to Budge' s center. NM = nictitating membrane; PF = palpebral fissures ; C 1, C2, etc. , cervical spinal segments; Tl, T2, etc., thoracic spinal segments; above= the cut was made rostral to the site named; below= the cut was made caudal to the site named. Note that sensory impulses from the body could not reach the eye directly via Budgc's cilio-spinal center: the pupils did not respond at all after transections of the rostral cord or the medulla, pons, or midbrain caudal to the Edinger-Westphal nucleus. Stimulation of areas above such lesions as well as asphyxia, intoxications, or general stress continued to dilate the pupil, but the movement was slow and incomplete, and not accompanied by retraction of the nictitating membrane or widening of the palpebral fissure Hemisections of the rostral cord or lower brain stem interrupted the efferent sympathetic path to the ipsilateral eye and hence rendered the pupil smaller than the pupil on the other side, and its sensory reflex dilation became slow and small. fissure. 372 / Table 6-21 YEAR I. Anatomy and Physiology (continued) AUTHOR 1935} 1936 Bremer 1935 1936 1935 l\Iettler & al. Spiegel & Scala Claes 1937 1937 1937 1937 1937 Barris Chen & al. Garcia & KiQfer Karelus Rioch & Brenner STIMULATION OCULAR EFFECTS transection caudal to midbrain transection rostral to midbrain dog: decortication of mesencephalic grey cat: destruction rostral to 3ra n. nucleus cat: transection removal ol' colliculi removal of rostral cortex cat: bilateral rostral to midbrain dog: decerebration dog: thalamic lesions cat: decortication + removal of colliculi cat, rat, oppossum, guinea pig: cerebral ablation,leaving basal ganglia and rhinencephalon intact sensory snesor:y sensor:y sensory (bod:y} sensory sciatic (tail} cat: cortical lesions monkey: destruction of "corpus Lu:ysii" clog: small tbalamic lesions bilateral cortical lesions cat: cat: removal of rostral hemispheres sensory pain no response slow dilation dilation dilation miosis pupils normal catale2tic cats with suonormal an. slow, submaximal dilation m10s1s, pfos1s, enoplillialmos dilation same as Bard's cats but less marked: pupil dilation with PF and M, plus conjugate deviation of eyes & head awa:y from stimulus dilation miosis, ptosis 1ps1latcra1 m1os1S, ptoSlS pu12ils, NM normal exaggerated reactions of pupils with NM retraction and widening of PF iosilateral ptosis, miosis, enophibal. mio sis, somnolence, cataJ.e2s:y ipsilateral miosis maximal ai1ation without rage maximal clilation, rage with sympathetic mass discharges normal R=L c!Ilation slow, submaximaI clilation slow, submaximal dilation slow I submaximal dilation savage attacks with dilation sham rage with maximal dilation dilation with rage-like faciovocal activity dilation, but cats were placid and hyporeactive to adequate stimuli mild sensory maximal mild sensor:y cutaneous mild sensory maximal dilation with rage attacks dilation with defensive res22nse dilation with rage reactions \esilateral central Horner's transient miosis reduced attack responses without ,eueillar,'l'. dilation Horner's syndrome Horner's ipsi :>> contralateral transient iJ2silateral Homer's ipsilateral Horner's SPECIES AND LOCATION OF LESION cat*: Schwarcz Shinosaki Kiprer ~ Magoun l\Iagoun & Ranson 193 1937 1937 193 1970 Kennard Abrahams & al. Glusman & Roizin Carmel Sano Keating & al. lesions dog 1 cat: thalamic cat: hyQQthalamic lesions cat: unilateral removal of neocortex cat: removal of frontal .12ole damage to hippocampal-iornix system I sc2tal or amygdaloid lesions cat: cortical leg area, unilateral cat in narcosis : removal of colliculi iransection rostral to midbrain acute removal of cortex cat: ventro-medial hy.EQthalamic nucleus cat: removal of frontal cortex cat: diencephalic and rostral midbrain lesion except for olfactory cat: decortication tubercle, pyriform lobe, Ammon's horn, and midline cortex additional removal of midline cortex, am,'l'.gdala, hi22ocam2us cingulate ablation cat: bilateral above h:yQQthalamus cat: decercbration hypothalamic nucleus cat: ventromedial ( ererubral) man: subt'Eiaiamotomy man: subthalamotomy : amygdaloid complex reptiles 1970 1970 1972 Kim & Buscher Kim & Umbach Schiffter & Pohl man: man: man: 1939 Garcin & KiJ2fer ~ Ranson 1940 1940 & Magoun Girndi & Evers Spiegel & Scala 19-10 1944 Ury & Oldberg Bodes Harris, & Magoun 1944 19-15 1946 Wheailev Kennard Kelly & al. ~ Bard & Mountcastle 1955 1960 1960 1966 1966 cat*: Bremer' s "cerveau isole" - - sensor:y sensory - - mild sensory - - mild sensory mild sensory sensory to leg sciatic, s2Ianchnic sciatic, s2lanchnic sciatic, selanchnic mild sensor:y mild sensory pain - sensory were used by many others; the cortex normally inhibited subcortical structures. Karplus and .Kreidl (1910) found that pupillodilator and other sympathetic effects of hypothalamic stimulation were enhanced some weeks after ablation of the cortex; and this convinced them that the hypothalamus contained the reflex centers for these reactions, and not merely descending fiber tracts with cell bodies in the cerebral hemispheres. Chronic conditions of irritability after cerebral lesions (with maximal mydriasis) were studied intensively during the following decades (Cannon and Britton, 1925; Bard, 1928-1929; and many later workers; see Chapter 9). Fairly small lesionsespecially in parts of the phylogenetically old - subthalamotomy (ventromedial} subthalamotomy subthalamotomy fornix-amygdaloid area preparations nerves nerves these papers dilation with sham rage are not added to this Table; see Chapter 9• "transitional cortex" of the rhinencephalonwere found to give rise to various states of emotional excitement, with characteristic patterns of an aggressive or defensive nature. 3. The Role of the Cortex These findings indicated that the motor center for the sympathetic part of pupillary reflex dilation was located in the hypothalamus: when this region of the brainstem was damaged, the reaction was lost; and when it remained intact, maximal mydriasis could be evoked by mild sensory stimuli, together with mass discharges to all sympathetically innervated organs. This was still possible after the cerebral hemispheres had been destroyed 6. Reflex Dilation or disconnected from the diencephalon. It should be remarked, however, that these facts fail to prove that in the intact individual the cortex plays no role in sympathetic pupillary reflex responses, or that normally these reactions are transmitted from the afferent path and thalamus to the hypothalamus, as is today widely believed. As discussed in more detail in Chapter 9, I think that the hypothalamic nuclei represent a cerebral motor center for the expression of emotional states but that normally they are called into action by more complex neuronal circuits; and that for complete, integrated responses of conscious mammals, appropriate to the environmental conditions, participation of the cortex is essential. As regards the pupil, the following points should be mentioned. (1) Karplus and Kreidl's discovery that the electric excitability of the hypothalamus remains undisturbed, and is, indeed, enhanced by degeneration of the corticofugal fiber system, merely proves that the descending pupillodilator pathway has a cell station in the hypothalamus. But it does not answer the question of whether the hypothalamic efferent neurons normally receive impulses directly from the thalamus ( or other high brainstem sites) or indirectly by way of thalamo-cortical connections. As is the case for the sympathetic neurons of Budge's center after transection of the upper cervical cord, the hypothalamic neurons, deprived of their cortical connections, are likely to become sensitive to normally ineffective stimuli; and direct thalamic-hypothalamic transmission may thus become possible. (2) Electric stimulation of various cortical areas in awake animals readily evokes fast, sympathetic pupillary 373 dilation (Figures 6-26,B and D and 6-29, and Table 6-22). The cortex is thus able to bring about sympathetic discharges. But this reaction (just like the fast, sympathetic component of dilation to sensory stimuli) is abolished abruptly as soon as the individual falls asleep, comes under the influence of anesthesia, or is in pathologic coma. This happens long before electric excitability of the hypothalamus and of its efferent connections is depressed (see above, and Figures 6-26,A and C and 6-27). (3) Spontaneous thoughts and emotions that require cortical function can elicit sympathetic mydriasis as easily as can sensory stimuli. In fact (as has been mentioned already), the pupillodilator influence of a given sensory stimulus is closely linked to the mental and emotional change it causes: similar stimuli may elicit a mild response at one time but a violent reaction at another time when the person or animal is taken by surprise or frightened. Clearly, it is the change in consciousness produced by the stimulus rather than its sensory quality as such that determines the amplitude of the reaction. [n conclusion, then, the motor center for the sympathetic component of pupillary reflex dilation is situated in the hypothalamus. When the forebrain is removed or disconnected from the diencephalon, subcortical transmission from the afferent path and thalamus or reticular formation to the hypothalamus apparently can take place. But under normal conditions in intact, awake individuals this probably does not occur; and the impulses probably run partly or entirely by way of the cortex to the hypothalamic efferent center. I. Descending Sympathetic Connections From the hypothalamus, the pupillary dilator pathways descend throughout the brainstem and cervical cord to synapse with preganglionic sympathetic neurons at the C8 to T2 level. The course of these fibers has not been studied in detail until recent decades, and different locations have been assumed. Beattie (1932) thought the fibers probably descended in the posterior longitudinal bundle; Hunsicker and Spiegel said that they ran in the central grey of the pons and midbrain; Crouch and Elliott (1936) said they ran in the lateral tegmentum; and according to Magoun, Ranson, and Hetherington (1938), hypothalamic descending connections were distributed in a "wide area in the central tegmental region." In 1939, Wang and Ranson said there was an "extensive reactive region" in the brainstem for pupillary dilation; and Lyle (1954) thought the sympathetic fibers were located in the central grey matter of the brainstem, the dorsal longitudinal fasciculus, and the reticular formation. This uncertainty about the course of the sympathetic tract has impeded clear thinking about clinical conditions. For example, under the influence of Merritt and Moore's dogmatic statements (1933) / to the Cervical Spinal Cord it is today still widely believed that the rniosis in the Argyll Robertson syndrome is due to interruption of the descending sympathetic fibers in the midbrain. These authors claimed that the sympathetic fibers ran in the central grey or close to it at the level of the Edinger-Westphal nucleus, so that both parasympathetic and sympathetic deficit would result from small, medially situated lesions at that site. In reality, however, the sympathetic fibers run laterally at the level of the rostral midbrain, as will be described presently. Experiments on the descending sympathetic connections were often complicated by the fact that the pupillary dilation due to inhibition of the sphincter nucleus and dilation caused by sympathetic action were confused with each other. Further, in the brainstem and spinal cord, a great many afferent and efferent pathways (in addition to nuclear masses) are crammed into a small area. The earlier experiments usually were done with relatively large electrodes; and strong currents were used that could easily stray to nearby afferent paths. Such afferent stimulation could then produce sympathetic activity by reflex and, in addition, could inhibit the 374 / I. Anatomy and Physiology Table 6-22. - YEAR The mechanism of pupillary dilation upon cortical stimulation AUTHOR 1 70 Fritsch& Hitzig 17'-l Schiff & Foa 1876 Bochfontaine 1876 Ferrier _1_7_ Luciani & Tamburini Bessau 179 1 79 Luciani & ---Tamb~ini Katschanows • 15 ....!filrr._ Frans;ois-Franck 18 7 Mislawski -1-Beevor & Horsley 18 8 Horsley & Schaefer --1889 Ferrier 1889 Schaefer 1890 Ferrier 1890 Munk 190 Obregia ~ Bechterew & Mislawski ~ Braunstein 1895 Bechterew 1895 Bianchi 1897 Beohterew 1900 Beohterew 1900 Parsons 1900 Stewart 1901 Parsons 1901 Stewart 1902 Levinsohn 1904 Parsons 1907 Piltz 1910 Kar2lus & Kreidl 1911 Bechterew ~ Karplus & Kreidl 1916 Scbrottenbach 1917 LeY!on 1922 Brown ~ Karalus & Krcidl 1929 Bar 1931 Friedberg 1932 Wang &al. 1933 Hunsicker & Spiegel 1936 Hoff & Green Crouch &Thompson Smith Spiegel & Hunsicker ~ Clark & Ward 1937 Masserman 1937 Rioch & Brenner 1939 Claes 1939 Crouch &Thom:eson Ur;y & Oldberg 1940 1941 Smith 1942 Hodes & Magoun 1936 1936 1936 1945 1945 1946 1946 1948 Hess & BrUgger Smith Siebens &Woolsley Ward & Reed Crawford & al. SPECIES AREA STIMULATED dog cat,dog dog monkey dog,cat, monkey cat cortex cortex convex surface of the brain frontal eye iield monkey dog,cat dog,cat dog,cat monkey different cortex angular - --- points on ihe convex brain surface and cingular gyri, 2nd external TUS ii 1a1:moid~us s X + + + + ---E + --+-- --- + --+---+- monkey monke;y cat,monkey dog dog frontal e;ye fielct, su2ras;ylvian convolution strong stimuli from all points horizontal limb of 2recentral gyrus frontal eye field; marginal convolution near genu of corpus callosum temporal lobe various sites (not specified) frontal eye fields cortex (area unspecified) parietal ( sensori-motor) area dog sigmoid gyrus cat 1 dog dog dog,monkey dog,monl<ey monke;y dog,cat dog dog,cat, monkey dog dog,cat,monkey cat, dog I monkey rabbit I cat, dog oat monke;y oat rabbit a2es monkey cat,monkey oat cat cat (dial) sigmoid r;yrus rostral sigmoid gyrus frontal cortex IrontaI cortex frontal pole; frontal eye :fields mesial brain surface near cruciate sulcus cortex (unspecified site) pre-splenial, coronal, anterior suprasylvian convolutions and mesial surface of cruciate sulcus cruciate g;yrus ( anterior central gy:rus) precentral sulcus, angular gyrus as lxifore; and posterior su2ra-sylvian convolution convexity of hemis2herc frontal polo angular gyrus, rostral to 8_ylvian fissure frontal cortex frontal pole rostral eye fields superior frontal convolution frontal cortex areas concerned with eye movements cortex sigmoid gyrus cat cortex cat, monkey, chim:eanzee cat monkey gyrus proreus and sigmoid gyrus in cats; precentral and cingulate gyri in monke;ys frontal cortex ( sigmoid gyrus) frontal lobe, medial to inf. preoentral sulcus cat cortex + cat cat cat cat cat cat monkey cat (urethane, cbloralose) cat monkey cat (nembutal) monkey chimpanzee anterior suorasvlvian e:vrus anterior sigmoid gyrus olfactory tubercle, pyriform lobe rostral cortex anterior sigmoid cortex rostral cruciate sulcus, gyrus eroreus cingulate r;yrus , area 24 of Brodman ant. sigmoid, coronal gyrus proreus, genualis; and orbital gyri (mesial surface) gyrus genualis and suboallosus rostral cingulate gyrus mesial surface, rostraI to cruciate sulcus area 8 frontal eye fields + + + monkey + ---+ + ---+ ---++ ---+ ---+ + + + + --+-+ + + + + + + + ---+-- + + + + + --+---- + + --+ --+ + ---+ + + + + --- + + + + + ~ -*-- --- * ----- ---* ------*---* -*-* -*---*-- ----- ------*-----*-- -----------*--------------* --*--N-- --------*-----------------*-- ---N ---* ----* Because of the well-known depressive effect of anesthetics upon the cortex, most of these experiments were done with only curare and local infiltration of the wound, analgesia (morphine), or light anesthesia with volatile agents • All these animals showed sympathetic pupillary and other reactions ( + in column S). A few who did not were under the influence of non-volatile anesthetics (Nin column X); E in that column means that the animals had generalized epileptic seizures; and* in column X indicates that they showed a syndrome composed of relatively slow pupillary dilation together with conjugate eye movements away from the stimulated side, sometimes with head turning. 6. Reflex Dilation Table 6-22 YEAR 194 (continued) SPECIES AUTHOR Mettler ~ Rasmussen 1948 1949 1949 1950 1950 1951 1951 1951 1951 1951 & Penfield Ward Kaada & al. Sachs &al. Akert & al. JeITerson Akert &al. Gastaut & al. Hess & al. Hoff & al. Kaada cingulate cortex cingulate gyrus temEoral lobe, insula, orEitaI surface, orbital gyri, ant. perforated substance cingulate ana oroital cortex cingulate gyrus, Brodman' s area ~4 cin!;%atc and orbital cortex am_yg aloici com12lex orbital and cins:!!late cortex anterior sigmoid g.z:Ei rhinencephalon, best for cat= sup. limbic gyrus near gyrus cinguli; monkey = cephalad to genu of corpus callosum cingulate cortex amygdaloid, hippo campus, stria terminalis, fornix, habenula gyrus proreus, genualis, subcallosus arcuate gyrus medialis am.z:gdaloid comElex 1 hiE~camEus Walker's area 13; Brodmann's area6 1 8 1 9 1 13 1 24 sigmoid gyrus, rostral to cruciate fissure ( area 8 in man); ant. pyriform, orbital, ectosylvian, ant. composite & sylvian gyri cingulate cortex (see Figures 6- 26 and 6-31A )-cingulate cortex ant. limbic and orbito-frontal cortex am_ygdaloid com12lex amygdaloid complex am.z:gdaioid complex am.l:':gdaloid complex am_ygdaloid com12lex amygdaloid cortex 1952 Wilson cat (dial) monkey cat 1 dog monker dog 1953-} 1957 1955 1963 1970 1970 1972 1970 1972 (nembutaI) (awake) Loewenfeld cat Hess & Akert Hilton & Zbrozyna Bonvallet & Bobo Bobo & Bonvallet Bonvallet & Bobo Keating & al. Kim &al. cat cat cat cat cat re12tile man rostral Figure 6-29. Cortical landmarks in the forebrain of the cat (areas mentioned in Table 6-22). (From J.W. Ward and S.L. Clark,]. comp. Neural., 63 [1935]:49) 6, 8, 9, ru1d 24 to precentral X + monke.z: {dial) monke.z: {narcosis) cat, dog, monkey cat monke.l:': cat cat cat cat primates , dogs , cats ( dial) cat cat 1953 s areas Gastaul Morin &al. Koikegami & Yoshida Okinaka & al. ---- ---* AREA STIMULATED monke.z: man 1952 1952 1953 375 / gyrus, mostly area 6 + + -+---+ -+-+ + + --++ --- * ---- -- -- ---- --N --+ -,_ + -- ---i-r + --++ ---- -+ -- -+-+ + + + -+--+--+-- ----w--- -- -- ----- 376 / I. Anatomy and Physiology Venlr. lha,..{am,c n.udeu.s and. mcdi.al ler,.ni.scus:ucleus c:et\lralis cent.nun. medi.anum) eamen.la,..l fteld. H ., (Forel) uc°klJ..5ruber ublhalamu: rv.deus (½5) ub.slanha. n½ra Suy.a~mil lar~ COtnrt\1.851.<.1l: -+----:ruber I,,f,mdi.bu.lar recess Su.blhalarn.ic n.w:lws of Lu.!is loleral ~ni.cu.late bod~ ci.N!!reum ---In fundi.b\LL.1.1,,_ Figure 6-30. Transverse section of the human diencephalon through the habenular region and infundibulum (Weigert myelin stain). The place indicated by Karplus and Kreidl is shown by the cross. (From O.S. Strong and A. Elwyn, Human Neuroanatomy, 3d ed. [Baltimore: Williams and Wilkins, 1953]) Edinger-Westphal nucleus, also by reflex or by way of the brainstem reticular core. Unless the brainstem or cord was transected rostral to the stimulated point, such inadvertent afferent stimulation could not be ruled out with certainty. led to maximal mydriasis (see Tables 25-11 and 25-12 and Figures 25-15 to 25-18). Lewy had stimulated efferent fibers coming from the area described by Karplus and Kreidl, and many later workers have obtained pupillary dilation and other sympathetic effects from this part of the descending path. In fact, the active hypothalamic region extends more rostrally than Karplus and Kreidl had thought, as was demonstrated by a large number of subsequent experiments (Table 6-19 and Figure 6-31). At first, there was much discussion about the location of reactive points in specific hypothalamic nucJei; but this search yielded no consistent results and later gave way to a concept of general areas (Ranson and Magoun, 1939). Some workers described a rostro-caudal functional division in the hypothalamus, with rostral parasympathetic and caudal sympathetic representation, while others maintained that there were medio-lateral differences in responsiveness. It appears fairly well established that, for oculosympathetic reactions, the medial (paraventricular) hypothalamic area is responsive only rostrally and caudally, with a silent portion interposed. In this middle part, lateral stimulation is effective (Ranson and Magoun, 1933; Elliot, 1936; Kabat, Magoun and Ranson, 1936; Kabat, 1936; Ectors, 1937; Ectors, Brookens, and Gerard 1938; and many later authors). 1. Historical Background Toward the turn of the century, pupillary dilation due to brain stimuli was well known; and several authors remarked that the oculosympathetic fibers must run laterally in the cord, since fairly large cord lesions did not prevent the reactions as long as the lateral funiculus remained intact (Kowalewski, 1886; Mislawsky, 1886; Parsons, 1901; Bechterew, 1908). Karplus and Kreidl (1909 and later) said that the fibers for the oculopupillary reactions took their origin from the caudolateral part of the hypothalamus. A responsive area "S" was located "medio-dorsal to the basis pedunculi" or "next to the dorso-mcdial corner of the basis pedunculi." Later workers (Lewy, 1927; Shinosakj, 1929; and others) understood this to mean the subthaJamic nucleus of Luys, but Karplus took pointed exception to these statements (1927, 1937; see Figure 6-30). Lewy was really not all that far off the mark, since it was found later that lesions in the subthalamic area caused ocular sympathetic deficit and that stimulation 6. Reflex Dilation It should be cautioned that these statements refer to anesthetized animals. Without anesthesia, electric stimulation in this busy area can evoke activity by exciting centripetal or centrifugal fiber paths, or both, with many possible indirect effects. Since synaptic transmission to the hypothalamic pupillodilator neurons is blocked by anesthesia, reactions of anesthetized animals give a clearer picture of the arrangement of efferent elements than do reactions of conscious animals. 2. The Main Descending Sympathetic Tract There is good agreement among four recent detailed investigations about the principal descending ocuJosym- A1 -~---+--~ - corpus cotfosum sut>drlor collicullu ~~A~:::s;;;;;;;:;:~:b,J6,,'1/:r'1:::,:':s -pitteol body .,_C:_;:::: _-_-------=~:':,t::.rr:,::•ur• t":1<-'\.'<,------cf~-===-- 1 011,.,-ior cammlssur• / 377 pathetic tract (Kerr and Brown, 1964; Koss and Wang, 1972; Loewy et al., 1973; Saper et al., 1976). From its hypothalamic origin this path runs caudally by way of the subthalamic-prerubral area. At the level of the mammilJary bodies it begins to shift laterally, just dorsal to the substantia nigra. At the level of the superior colliculi it is concentrated in the ventrolateral tegmentum; and it then continues ventrolaterally throughout the remaining brainstem. As it progresses caudally, it occupies (in cats) a more and more superficial position, just dorsolateral to the pyramidal tract (Figure 6-32). In the human brain the sympathetic fibers are located more dorsally in the medulla because, as pointed out by Loewy, Araujo, and Kerr, the inferior olivary nucleus is more developed in the human medulla than in cats, and occupies the ventral area. In the cervical cord the oculopupillary fibers travel directly beneath the pia in the lateral funiculus, near the insertion zone of the dentate ligament. At the C8 to T2 segments, they abruptly dip into the substance of the cord and travel mesially to synapse with the preganglionic sympathetic neurons in the intermediolateral cell column (Figure 6-33,B). . •• •• ~----...-'------~- mommlllary bodf•s p4t11Uory •fa/Ir opllc ch1asm Figure 6-31. Areas in the central neivous system furnishing pupillomotor impulses upon electric stimulation (experiments on cats). Al: Midsagittal diagram, showing a basal diencephalic area DI (hypothalamus), and a dorsal area D2 which includes the dorsal hypothalamus and ventral thalamus. C is a mesial cortical area just rostral to the corpus callosum (cingulate cortex). A2 and A3: The diagrams show pupillary reactions obtained in twenty five cats in chloralose anesthesia. The symbols mean: open circle, no response; narrow block oval, pupillary constriction; solid triangle, slow pupillary dilation without retraction of the nictitating membranes (parasympathetic inhibition), and solid square, fast pupillary dilation with retraction of the nictitating membrane (sympathetic excitation). The cortical area C was stimulated in six cats both in anesthesia and later, in the awake animals, with permanently implanted electrodes. During anesthesia only the slow, incomplete pupillary dilation without retraction of the nictitating membrane was obtained (parasympathetic inhibition). In awake animals the reactions resembled those provoked by strong psychosensory stimulation: fast pupillary dilation, retraction of nictitating membranes, and all associated sympathetic signs. (From O. Lowenstein,Ann. d'Oculist., 188 (1955):981) A B C D E t B: Diagram of a midsagittal section of the cat's diencephalon. The vertical lines A to F indicate planes of transverse sections (not shown). The animals were anesthetized. Electric stimulation of the area outlined by the line of crosses resulted in dilation of the sympa~he~tomized pupil, that is, parasympathetic inhibition. Sympathetic discharges were obtained only from a smaller area in the h~pothalamus, namely, dilation of the parasympathectomized pupil (area enclosed by dash-dot lines); retraction of the nictitating membrane (dotted line); and piloerection (broken line). The symbols mean: A, Sylvian aqueduct; Ac, anterior commissure; CC, corpus callosum; CG, mesencephalic grey; CSC, commissure of the superior col lieu Ii; F, fornix; H, habenular nucleus· ICol inferior collicu_lus; MI, massa intermedia; OC, optic chias:n; PC, posterior comm1ssure; SC, uperior colliculus; 3V, third ventricle; III, third nerve. (From R. Hodes and H.W. Magoun,J. comp. Neurol. 76 [1942):461) ' 378 / I. Anatomy and Physiology Figure 6-32. Sympathetic efferent path in the brainstem and spinal cord (experiments on cats). 1. mid-hypothalamus 2. hypothalamus level of mammlllary 3. rostral at bodies diencephallcmesencephalic border zone mldbrain hindbrain superior at level of colllculus 4. mldbrain at level of superior colliculus medulla 5. mesencephalic-pontine border at level of Inferior colllculus spinal at 6. pons at level of superior olive 7. rostral medulla at level of medial vestibular nucleus 8. medulla at level of inf. olivary nucleus 9. caudal medulla A: Results of stimulation experiment[ in anesthetized cats. Crosssections of the brainstem are shown at 3-mm intervals. The symbols indicate points that yielded pupillary dilation and retraction of the nictitating membrane. These reactions were purely sympathetic-efferent because the parasympathetic short ciliary nerves had been cut beforehand in the orbit. To improve the pupil's mechanical range for dilation, I% phy ostigmine had been instilled into the eye. The main descending sympathetic path is shown at the left. The thalamus was unresponsive because of the anesthesia. In the hypothalamus the most reactive area was dorsomedial to the columns of the fornix (level 1). In the caudal hypothalamic area the excitable field moved laterally (level 2). It then de- cord to T2 ca scended to the mesencephalic reticular formation just dorsal to the substantia nigra (level 3) and the ventrolateral tegmentum (level 4). It continued in a ventrolateral course throughout the remaining brainstem (levels 6 to 8). In addition to this main lateral tract, an active sympathetic area was found in the ponto-medullary midline (levels 5 to 8, marked by the ascending broken arrows; see text). (Slightly modified from M.C. Koss and S.C. Wang, Amer. J. Physiol., 222 [1972]:900) 8: Microelectrodc stimulation and fiber degeneration studies were done lo trace the lateral sympathetic tract from the hypothalamus to the cervicothoraeic spinal cord. Note the good agreement with Koss and Wang's results throughout the brainstem. In the spinal cord the sympathetic tract was found to occupy a superficial position in the ventrolateral funiculus (see also Figure 6-33). Pupillary dilations were also obtained from the ponto-mesencephalie midline, but these results were interpreted as parasympathetic-inhibitory because the animals had been sympathectomized (see text and Figure 6-34). (Slightly modified from A.D. Loewy, J.C. Araujo, and F.W.L. Kerr, Brain Res., 60 [1973J:65) C: A descending lateral sympathetic tract was marked by silver staining after injections of radioactive proteins into the hypothalamus. The silver grains found caudal to the injection thus indicate the position of uninterrupted long fibers. The arrow in the medullary section shows the location of the descending tract. At the spinal level, fibers dipped into the cord. There was a heavy ipsilateral and slight contralateral representation of fibers (see also Figure 6-33). (Slightly modified from C.B. Saper, A.D. Loewy, and W.M. Cowan,BrainRes., 117 [19761:305) 6. Reflex Dilation The sympathetic pathways in the brainstem and spinal cord are much more tightly concentrated than had been realized. For example, Kerr and Brown showed that a large response could be much reduced or lost by shifting the tip of their microelectrodes a mere fraction of a millimeter (Figure 6-33,A and C). Until recently it was generally believed that the descending sympathetic fiber tract had one or several relays between the hypothalamus and the spinal cord. But Saper and his collaborators (1976) have demonstrated that direct fibers run this entire course without interruption. These authors were able to label hypothalamic neurons by injecting horseradish peroxidase into the lateral spinal cord; and conversely, they could follow the transport of radioactively labelled proteins from the hypothalamic area to terminal fiber branches in the intermediolateral cell column of the spinal cord (Figure 6-32,C). Whether these long-fibered neurons serve the pupil or different sympathetic functions is, of course, unknown. / 379 stimulation of the opposite cortex continued to produce bilateral mydriasis. In regard to subcortical pathways, Karplus and Kreidl (1912) undertook a series of hemisection and stimulation experiments and found that dilation of both pupils could be obtained by unilateral stimulation as far caudal as the lower cervical cord. Transections of the cord or brainstem cephalad to the stimulated point did not interfere with these bilateral responses. Karplus and Kreidl therefore concluded that the sympathetic path underwent partial crossing at the C8 to T2 levels of the cord. Later workers confirmed this; and Loewy, Araujo, and Kerr (1973) found degenerating nerve fibrils in the dorsal commissure of the spinal ..,...--~·'. -~ /•~?~:-- ifg}t~~--:-·-~.. _·~-•)k-- :c-.,.,_ ,i},,·,:;.;i_,:.. ... 3. Location of Commissural Fibers It had been noticed from the start that unilateral brain stimulation often caused bilateral mydriasis. At what level do the efferent discharges reach the opposite side? Table 6-23,A shows that opinions varied widely. Karplus and Kreidl (1910) and later authors established that there was no decussation between the cortex and the hypothalamus: after their hypothalamic area "S" was destroyed, pupillary dilation upon cortical stimulation on the side of the lesion was abolished, while / .,,'$=~ -.;l!:4._{,i;,~ ·-· ~ '~•-. ·-1 A ~,;~-::~~--~-~- • t.l~fi!f?'~, ---:~ti, Pyr 1/t.....,.. 1mm L..-J Tr dilation vasoconstriction veslcoconstrictlon B Figure 6-33. Descending sympathetic fibers in the caudal brainstem and spinal cord. A: The ventral surface of the medulla was exposed to stimulation with microelectrodes in 4 cats. Stimulation of the pyramidal tract (6 to 9 volts, 1 millisecond, 60 Hz) produced no change in blood pressure, bladder pressure, or pupil size. Stimulation of a zone 0.50 to 0.75 mm lateral to the edge of the pyramidal tract resulted in bilateral pupillary dilation. Increases in blood pressure (up to 50 mm Hg) were obtained from an area 2 mm lateral to the pyramidal tract; and increases in bladder pressure again further lateral, as indicated. (From AD. Loewy, J.C. Araujo, and F.W.L. Kerr, Brain Res., 60 [1973):65) B: At the spinal levels C8 to T2 the pupillary fibers dip into the cord substance and synapse with neurons in the intermediolateral cell column. Stimulation at higher levels elicits bilateral pupillary dilation; and after lesions in the lateral pupillodilator tract. degenerating nerve fibers were seen to cross the midline in the dorsal commissure of the spinal cord. 9 c---------1 Br---;::==============---------l 7 ,-11-------1--------~ 6r--1----=,,-.--...::=::---------I C: Pupillograms of depth stimulation of the cord (nine cats). The electrode was located at the CS level, 1 mm anterior to the dentale insertion. Trace a was obtained from the surface of the cord (solid line), and traces b, c, and d, at 0.25 mm steps below a. The reaction decreased rapidly, and at position d, 1 mm below the surface of the cord, it was negligible. (Band C from F.W.L. Kerr and J.E. Brown, Arch. Neural., Chicago, 10 [ 1964]:262; c, 1964, American Medical Association) 5 4 3 +2 E It--:=:/ 4 ~~~~~~~~~~~~~~%~~~-=r-_=_=_=j !:.....sec.-- 380 Table 6-23. / I. Anatomy and Physiology Crossing fibers in the descending sympathetic pathway . A LOCATION OF CROSSING FIBERS- VARIOUS VIEWS - YEAR AUTHOR 1900 Parsons 1901 Parsons 1909 Karplus & Kreidl 1910 Karplus & Kreidl 1912 Karplus & Kreidl 1916 Schrottenbach ""I92"4 Parsons 1930 Shigematsu 1932 Beattie 1933 1937 1937 1939 1939 1951 1953 1964 1973 Ranson & Magoun Chen & al, Shinosaki Harrison & al. Ranson & Magoun Ban &al. Koikegami & Yoshida Kerr &Brown Locwy &al. SPECIES OPINIONS ABOUT THE LEVEL OF CROSSING OF SYMPATHETIC cat cat there are no crossing fibers in the corpus callosum (bad cut it without effect) the descending s_ymi2athetic tibers ;erobabl_y cross at the level ot the thalamic nuclei cat the sympathetic cat there cat some sympathetic rabbit cat cat cat there are no crossing sym:eathetic fibers between the cortex and the hypothalamus probably the fibers cross "after passing through the the cerebral pedunculus" crossing occurs 2robabl;y in the s2inal cord at the level oi Budge's center the descending fibers probably decussate between the subthalamus and the midbrain tegmentum cat cat cat YEAR AUTHOR 1900} Parsons 1901 1901 Stewart 1904 Parsons 1909 Karplus & Kreidl 1916 Schrottenbach 1927 Lewy 1929 Shinosaki Shigematsu 1930 1936 Crouch & Elliott 1936 Miller 1937 Karplus 1937 Shigematsu --- 1939 and the hypothalamus at the caudal end of the cervical cord perhaps rabbit cat,dog, monkey cat cat some of the svmoathetic fibers mav cross in the suoramammillary commissure believed in the existence of crossing sympathetic fibers (partial) above the midbrain the descending s_ymi2athetic tract crosses ;2artl:y at the level of Budge' s center the descending sympathetic path crosses partly at the level of the cilio-spinal cord some of the sympathetic IPSILATERAL fibers OR PREDOMINANTLY cross in the supramammillary CONTRALATERAL commissure MYDRIASIS UPON BRAIN SPECIES STIMULATED AREA cat cortex, dog cat cortex near cruciate sulcus cortex especially mesial surface i;esi < contralateral bilateral I sometimes cat postero-lateral slightly cat cat cat cat cortex: "frontal pole" "corpus Luys ii 11 "cori2us subthalamicus" "co!:QUS Lu_ysii" 1 lateral hypothalamus far lateral hypothalamus caudate nucleus hypothalamus "cor2us Luysii", weak DC ''cor2us Luysii", far lateral i2silateral onl:y "strictl_y unilateral" mostlt iesilatcral with DC currents sometimes onl:y i2silateral usually R=L, sometimes ipsi > contralateral i]2silateral onl:y iJ2Si < contralateral slightl_y iJ2Si < contralateral bilateral mydriasis bilateral miosis cortex usually bilateral but 1 monkey ipsilateral from sigmoid gyrus R=L ipsi > confralateral bilateral '6ut not always symmetric "i2s ilateral I contralateral I or bilateral" bilaterall_y s_ymmetric first ipsilateral, and 1-2 seconds later contralateral also ipsi > contralateral ipsi< contralateral cat cat cat cat Hess cat 1951 1964 1966 1967 Ban &al. S2iegel & al. Bure~ova & al. Nashold & Gills rabbit man rat man 1973 Kalyanaraman man --- cross between the cortex cat cat,dog, monkey 1939 fibers fiber decussation located caudal to the basis pedunculi cat Crouch & Thompson --- is no sympathetic is probably the descending s_ym:eathctic fibers must be located caudal to the mammillary bodies some of the s_ymi2athetic fibers ,erobably cross oeiow C2 the decussating fibers probably are located in the upper and lower end of the ciliospinal cord decussating fibers are :erobabl_y :eartl_y in the brain stem and :2artly below C7 B. REPORTS OF PREDOMINANTLY STIMULATION - fiber decussation PATH especially mesial PUPIL LARY DILATION surface hypothalamus posterior hypothalamus lateral hypotlialamus "lateral h_y12othalamic nucleus 11 Forel' s field chemical, thalamus especially thalamus & subthalamus, Forel's field hypothalamus, dorsal hypothalamus , ventral bilateral, sometimes ipsi <contralateral ipsi < contralateraI ipsi < contralateral 6. Reflex Dilation cord of cats whose sympathetic path had been destroyed in the medulla. It should be noted, however, that it would be an exaggeration to refer to these crossing fibers as a "hemidecussation," since unilateral lesions rostral to the cervicothoracic cord result in pronounced sympathetic deficit on the side of the lesion only. This clearly would be impossible if there were extensive hemidecussation of the sympathetic path below the lesion, at the CS to T2 level. Foerster and Gagel (1932) observed ipsilateral Homer's syndrome after high cervical ventrolateral chordotomies; and oculosympathetic deficit has been well known as one of the earmarks of lateral medullary-pontine infarcts, (for example, in Wallenberg's syndrome). Later, small thalamic, hypothalamic, and subthalamic lesions were found to also bring about ipsilateral sympathetic deficit (see Chapters 25 and 44). Lesions were placed stereotactically in animals as well as in the human brainstem (for the relief of intractable pain and for certain motor and psychiatric disorders). Some of these patients acquired an ipsilateral Homer's syndrome, together with vasomotor and sudomotor defects reaching all the way down to the toes on the operated side (see Figures 25-16 and 25-17). The vasomotor and sudomotor fibers as well as those for the orbital smooth muscles must descend in the brainstem close to the pupillary tract, since lesions at different levels bring about disturbances of these systems together with the pupillary defect. It has been known for a long time (Kowalewski, 1886; Karplus and Kreidl, 1912), and has been our experience also, that the ocular signs that follow such rostral cord or brainstem lesions are not as complete as those due to interruption of the cervical sympathetic nerve. For example, cocaine often is still able to enlarge the affected pupil, although usually not as much as on the normal side. This has been thought to be due to a more diffuse arrangement of the descending pupillodilator fibers in the brainstem and cord, compared to the tightly packed fiber bundle of the cervical sympathetic chain. However, the descending path (as just described) is far more concentrated than had been believed. It thus may well be that the residual sympathetic innervation still found after brainstem damage is furnished by the crossing fibers in the cervicothoracic cord. Whether these are the only crossed fibers in the descending sympathetic system, or whether some fibers run to the other side at more rostral levels, is not known. It should be kept in mind, however, that phylogenetically old systems tend to decussate at caudal levels and newer systems more rostrally; and that usually no additional hemidecussations develop in a fiber tract after an old one has been established. ln any case, the fact that interruptions of the descending sympathetic pathways as far rostrally as the subthalamic area result in the clinical appearance of a unilateral Homer's syndrome shows that the crossed contingent-at no matter what levelmust be small: the deficit on the side of the lesion is / 381 much more pronounced than that possibly caused by loss of some crossed elements, and consequently, a crossed defect is not obvious clinically. Conversely, the sparing of a small crossed contingent of fibers from the healthy side is so slight as to require drug tests to be demonstrated. In contrast, experimental stimulation of the hypothalamus or the descending sympathetic tract is sharply focused and powerful, so that marked pupillary dilation can occur in both eyes even though only few crossed fibers are stimulated. Some authors reported that they had seen dilation in the ipsilateral eye alone, especially when the stimuli were delivered to the lateral hypothalamic area. Spiegel (1927) went so far as to say that any response of the opposite pupil was proof of stray stimulation to that side. Others, in contrast, described greater responses of the beterolateral than of the ipsilateral pupil, at least in some areas and to some forms of stimulation (Table 6-23,B). These statements should be viewed with suspicion. Anyone who has done such experiments is aware of a number of artifacts that can bring about unusual reactions. One difficulty is the close proximity of the stimulated area to the optic tract, the efferent third nerve, and the postganglionic sympathetic fibers in their intracranial course. Co-stimulation of the optic tract will add bilateral pupilloconstriction (predominantly contralateral in cats) to the dilation movement, and this will tend to cancel dilation movements. Stray currents to postganglionic sympathetic fibers will enhance the ipsilateral mydriasis while excitation of the third nerve will reduce it. 4. Additional Pupillary Dilator Pathways in the Brain stem (a) Lateral Elements In the experiments of Koss and Wang (1972) on the descending pupillodilator tract, all reactions were purely sympathetic-efferent, since the short ciliary nerves to both eyes had been divided previously, thereby interrupting the parasympathetic outflow to the iris. Since Loewy, Araujo, and Kerr had not done this, their experiments revealed pupillary dilations upon stimulation of the lateral pupillodilator path even after the peripheral sympathetic chain had been cut (Figure 6-34). In addition to activation of efferent sympathetic discharges, inhibition of the Edinger-Westphal nucleus was thus induced by the stimuli. The authors explained this finding by assuming that afferent pupillodilator fibers may run together with the efferent tract. These afferent fibers were thought to be concerned especially with mydriasis due to noxious stimuli. It was stressed that the lateral ( descending) pupillodilator path runs next to the ( ascending) spinothalamic tract, all the way from the rostral midbrain to the spinal cord. The question of whether the assumed afferent pupillodilator fibers belonged, in fact, to the spinothalamic tract or whether they were a separate pathway was left open. 382 / I. Anatomy and Physiology For reasons already discussed (see "The Afferent Path," above) I take exception to the term "pupillodilator fibers' as used here. This is not mere quibbling, since basic anatomic concepts are involved. As used here, "pupillodilator fibers for noxious stimuli" implies that specialized sensory fibers for the conduction of pain ascend from the body to the midbrain, and that their specific function is to enlarge the pupil by inhibiting the Edinger-Westphal nucleus. Other "afferent pupillodilator tracts" have been described before, for somatic or for autonomic afferent impulses. But from an anatomic viewpoint, simple economy makes it appear unlikely that space could be occupied by different types of afferent connections for the pupil in the small and crowded area of the midbrain tegmentum. And from a physiologic viewpoint there appears no reason to assume multiple afferent input to the Edinger-Westphal nucleus for different kinds of sensory stimuli. This small group of visceral neurons serves a phylogenetically old, rather primitive function that is unconscious and involuntary. And pupillary reflex dilation is always part of a general arousal response affecting all autonomic and somatic motor functions. In my opinion, the close proximity of the descending sympathetic and the spinothalamic tracts in the lateral brainstem, as described by Loewy, Araujo, and Kerr, would suggest that stray stimulation to this important afferent tract is likely to be conducted to the thalamus and the reticular formation of the brainstem, from whence it can reach the Edinger-Westphal nucleus just like any other afferent message. (b) Medial Elements Koss and Wang obtained (in 1 mm L-..J A1 I Pupillomotor•o tract Sub Ni i - 9 ____ 9V~__, 8 A2 ~ 6V t t ,I' 6 0~ .. 0 o :HlllJ• 00 ~ 4 ~ ~ • • •• .... O : O ... 0 .. :::::: 0 : 0 0 '-•o • CONTRALATERAL (NORMAL) .,.?• 3 ..J.-"""-..,__....................... e,JJUJJ• •~,:u,, .tt~ 0 0 ~ 0 ., o ,.~"' 0 o ef'"' 1 o,,: .,i'• 0 Figure 6-34. Pupillary dilation of the lateral pupillodilator tract, before and after cervical sympathectomy on the opposite side. A: Stimulation of the tract (marked by small hatched area and arrow in A') in anesthetized, intact cats caused strong pupillary dilation, somewhat more extensive on the ipsilateral than on the other side (A2). B: The peripheral sympathetic chain had been divided on the side contralateral to the stimulating electrode. Compared with the movement shown in A 2 the contralateral dilation was reduced, but a sizeable residual reaction still remained (B 2). In cats decere- ... 0 0 •••oo ..... 00 0 0 00 •• L....l-....,ji-...1,.....1....:.L.. 0 0 0 0 aD 0 o" 0 0 oe o• oe o_., 0 o., :" 0 o: 2 7 IPSILATERAL (NORMAL) '?, 0 0 00 e oo • §- q, ':, o~ 5 •• •• e ~ ,,,,, G1' ~ 0 0 0 0 0 B -.: 0 0 0 0 ~ C( IPSILAlERAL (NORMAL) 0 2 2 ~•• -..,.. -~ •• CONTRALATERAL ••• (SYMPATHETIC CHAIN CUT) 4 Time, 6 8 10 12 14 seconds brated between the stimulated point and the more rostral Edinger-Westphal nucleus such residual reactions were not obtained, since the decerebration blocked the path for ascending inhibitory impulses to the pupilloconstrictor nucleus. The reduction of the contralateral pupil's responses from A to B demonstrates the effectiveness of the sympathetic fibers that decussate caudal to the stimulated point (see text). (Slightly modified from A.D. Loewy, J.C. Araujo, and F.W.L. Kerr, Brain Res., 60 [1973]: 65) 6. Reflex Dilation cats) bilateral ympathetic pupillary dilation with retraction of the nictitating membrane upon electric stimulation of a medial area tretching from the colliculi to the inferior olive (Figure 6-32 A, levels 5 to 8). The reactive area wa not a de cending path ince sympathetic activity could not be evoked below the olivary level. Further, tran ection of the brainstem rostral to the stimulating electrode reduced the responses and raised their thre hold, indicating that part of the fibers must ascend toward the midbrain or higher. Since, further, the reaction per i ted when an additional midline lesion was placed caudal to the electrodes, the remaining impul es mu t have been conducted to the ciliospinal cord by laterally directed fibers. Loewy, Araujo, and Kerr al o found pupillary dilation from thi midline area· but they said it was due to inhibition of the Edinger-Westphal nucleus, since it persisted after the peripheral sympathetic nerves were cut bilaterally. The apparent di crepancy between the results of / 383 these two groups of investigators is easily resolved when the conditions of their respective experiments are kept in mind. Both sympathetic efferent and parasympathetic inhibitory reactions were elicited by the stimuli. Koss and Wang obtained sympathetic reactions only because they had interrupted the parasympathetic nerve supply to the iris beforehand. And Loewy and co-workers saw the inhibitory influence alone, having cut the sympathetic chains. These workers said that sympathectomy did not materially reduce the reactions, but since they had cut both sympathetic chains, and the experiments were done on different cats and in different experiments, their results with and without sympathectomy could not be compared with any degree of accuracy. l think that the midline area stimulated in these experiments was part of the ponto-medullary reticular system, since Bonvallet and co-workers, and many others, have obtained both sympathetic activation and parasympathetic inhibition from that area (see Chapter 9). J. Hu moral Mechanisms for Pupillary Dilation In the previous sections of this chapter we have traced the reflex pathways for pupillary dilation in response to psychosensory stimulation and have discussed the central nervous integration of this movement. It is composed of two coordinated factors, namely, sympathetic excitation of the pupillary dilator muscle and inhibition of parasympathetic outflow to the sphincter muscle at the level of the oculomotor nucleus. An additional kind of pupillary dilation remains to be considered. 1. Discovery of "Paradoxical" Pupillary Dilation Pourfour du Petit in 1727 in his report to the Acadcmie de Science said that a few days after he had cut the vago-sympathetic nerve in the neck of dogs, the paralytic signs began to fade. Cruishank (1795) made the same observation: 3 weeks after the vago-sympathetic trunk in dogs had been divided, the eyes had returned almost to normal. Cruishank thought the nerve had regenerated. Budge (1852) added the observation that this regression of signs occurred sooner and more completely when the superior cervical ganglion had been removed than when the iris had been decentralized by cutting the cervical chain in the neck: when this nerve was divided on one side and the sympathetic ganglion excised on the other in the same animal, the pupil on the ganglionectomized side at first was smaller than the one with the preganglionic lesion. But this relation was soon reversed: 24 hours after the operation the denervated pupil had become larger than the decentralized one. In addition, both pupils slowly became larger than they had been immediately postoperatively, and gradually they almost regained their normal size. Budge thought that the pupillary sphincter muscle, deprived of its normal antagonist, had adjusted to the new situation by relaxing slightly. In 1867, Griinhagen, in an experimental protocol, described a kitten whose superior cervical ganglion had been removed 6 days before. When the animal was asphyxiated, the pupil on the side of the lesion became larger than the normal one. Griinhagen did not comment on this finding, but Schiff, who in the same year had made a similar discovery, thought that the excitability of the sympathetic nerve endings may have become enhanced when the sympathetic nerve impulses that normally reached them were eliminated by the lesion. In the following years, similar observations were reported. A number of authors described experiments in which the eye, some time after removal of the superior cervical ganglion, had not only lost all signs of sympathetic paralysis but, on the contrary, showed signs of extreme sympathetic irritation when the animal was subjected to anoxia, asphyxia, ether or chloroform narcosis, or sensory or emotional stimuli. The same pupillary behavior occurred at the moment of death, or when intravenous injections of adrenal extracts were given. Around the turn of the century, the phenomenon suddenly attracted a great deal of attention. Kowalewski (1886) and Langendorff (1900) named it the "paradoxical" pupillary dilation, expressing by this term their astonishment at seeing a pupil dilate supernormally without its proper nerve supply. The interest aroused by this phenomenon was well justified. In fact, these observations opened the way for a whole new chapter in physiologic thinking. The iris here reacted to naturally occurring chemical stimuli, not to electric currents. Shortly before 1900, Oliver and Schafer (1894, J 895) had described the effects upon· the cardiovascular and other systems of intravenous injections with extracts of 384 / \ I. Anatomy and Physiology adrenal medulla; and soon afterward, as already mentioned, it was found that the sympathetically denervated iris responded especiaIJy well to this substance. Lewandowsky (1898) and Langley (1901) concluded that the effect must be exerted upon the dilator muscle cells themselves and that these must become supersensitive to adrenaline when they had lost their sympathetic nerve supply. EJliott (1904, 1905), in a large, systematic study, confirmed Langley's earlier impression that only muscles that had once been innervated by sympathetic nerves showed these re ponses, while those controlled by somatic motor nerves and by the cranio-sacral (parasympathetic) division of the autonomic nervous system did not. EIJiott (1904) said that the close similarity of the effects of stimulation of sympathetic nerves and those of adrenal extract "suggests that sympathetic axons cannot excite the peripheral tissue except in the presence, and perhaps through the agency, of the adrenaline or its immediate precursor secreted by the sympathetic .... But since adrenaline does not evoke any reaction from muscle that has at no time of its life been innervated by the sympathetic, the point at which the stimulus of the chemical excitant is received, and transformed into what may cause the change of tension of the muscle fibre, is perhaps a mechanism developed out of the muscle cell in response to its union with the synapsing sympathetic fibre, the function of which is to transform the nervous impulse. Adrenaline might then be the chemical stimulant liberated on each occasion when an impulse arrives at the periphery." As early as 1901 Langley had remarked upon the differential effects of adrenaline on different tissues, that is, it had no effect on parasympatheticaJly innervated organs, an excitatory effect on those stimulated by sympathetic nerves, and an inhibitory effect on those inhibited by sympathetic nerves; and he had thought these diverse actions would be best explained by the existence of intrinsic differences between the effector cells themselves rather than between different types of innervation. In 1902 to 1905 Anderson had discovered the corollary of these findings, namely, supersensitivity to some bloodborne substance of the pupillary sphincter after interference with its autonomic nerve supply. Langley (1906, 1907, 1908, 1909) elaborated upon these results. He suggested the general principle that the effector cells contained "receptive substances" that interacted at the synapse with the chemical product of nerve stimulation (and with various drugs), and that determined the occurrence and the type of the response (sympathetic or parasympathetic, excitatory or inhibitory). More than half a century elapsed until the tremendous importance of this idea was fully realized. The thought that autonomic and somatic nerve trans20. In modern texts, Loewi is usually credited with having found the chemical nature of nerve transmission as such. While this is not true, his experiment was so convincing that it gave the needed boost to the general acceptance of the idea. mission required a chemical mediator at the synapse was discussed during the following decade. That it was true was demonstrated dramatically by 0. Loewi's experiments with frog hearts in 1921.20 Another important development that grew from the work with adrenal extracts was the recognition of the role played by the sympathetic-adrenal system for the maintenance of a state of bodily equilibrium under conditions of stress (Cannon and his school, 1911 and later). Many studies on these and other aspects of sympathetic innervation were done by a large number of authors during the following decades (Table 6-24). The mechanism responsible for "paradoxical" pupillary dilation was discussed for a long time. Budge's idea of a reciprocal loss of sphincter tone-a reasonable suggestion in his time-did not agree with the finding that "paradoxical" dilation could still occur after the sphincter was paralyzed by atropine. Nevertheless, it kept surfacing later; and occasionally it was expanded into complicated systems in which various "centers" in the hypothalamus, cervical cord, or midbrain were said to lose or to regain their "independence" and increase or decrease their "tone" (for example, Hufschmid and Rummel, 1949; Seitz, 1953). Other explanations for the unexpected mydriasis in sympathetically denervated eyes included (1) irritation of nerve endings due to the lesion, (2) permanent contracture of the dilator after denervation, (3) loss of inhibitory nerves from the superior cervical ganglion, and ( 4) increased blood flow to the dilator muscle, or increased permeability of its vessels, allowing greater than normal concentrations of humoral substances to reach the muscle (Poos, 1935, 1949; and others). All these theories had to be discarded for one or several reasons (Chapter 11). 2. The Concept of Denervation Supersensitivity As already mentioned, Lewandowsky (1898) first proposed the theory that denervated sympathetic effector muscles become supersensitive to chemical substances carried in the blood, such as adrenaline. In the following years the presence of physiologically liberated adrenergic substances in the blood, and their increase under conditions of stress, became firmly established. Anderson's finding of "paradoxical" pupillary constriction after parasympathetic lesions broadened the concept of supersensitivity, and it was recognized as a general principle: removal of the final autonomic neuron and, though less so, "decentralization," that is, interruption of the preganglionic neuron, led to reactions to a given stimulus of lower threshold and longer duration than on the normal side. Both natural transmitters and some drugs could elicit such enhanced effects. These facts became widely known during the 1920s and 1930s (see Cannon's [1939] and Cannon and Rosenblueth's [1949] summaries of this fascinating field). But the exact mechanism of "denervation supersensitivity," that is, the reason why denervated and decentralized effectors 6. Reflex Dilation Table 6-24. - YEAR 1 94} 1895 1897 1 98 189 1898 1899 1901 1903 1904 1905 1905 1905 1907} 190 1907} 1908 1908 1909 1909 1910 1911 1911 1912 1912 1914 1914 1916 / 385 The sympathetic and adrenal systemsthat affect the pupil: Literature reviewed AUTHOR Oliver & Schllier Velich Lewandowsky Radziejewski Schultz Boruttau Langley Anderson Elliott Elliott Wessely Tuclcett P* --- -- •----:;:+ + + + I----:;=- -- ++ + + Loewi Schur & Wiesel Waterman & Smit Kahn Schultz Frohlich & Loewi Cannon & Hoskins Cannon & De la Paz Dale & Laidlaw Elliott Cannon Loewy Githens 1916 Stewart & Rogoff 1916 Stewart & al. 1917 Githens 1917 Joseph 1917 Stewart & Rogoff ( abc) 1919 Kellaway 1921 Cannon & Rap2ort 1921 Cannon & Uridil 1923 Hartman & Hartman 1923 Hartman & al. 1923 Koclama 1923"" Stewart & Rogoff 1923 Trendelenoorg 19.!4 Cannon &al. 1924 Jendrassik 1924 Karelus ~ Kodama ( a&b) ~ Lepehne & Schlossberg ~ Mc Carrison ~ Sliimidzu ""°"i92"5 Boshamer 1925 Cannon & Britton Langley ""°"i92"5 1925 McDowall ~ Poos 1925 Sugarawa + + -- + ----- 1926 1926 )926 1927 1927 1927 1927 1927 1928 1927 ~ 192 192 ~ 1928 1929 1930 7:93o + + ~ - 1931 ----rfill - 1931 - ---1931 + 1932 + 1932 - + + -++ + -+- -- + AUTHOR YEAR 1931 Kahn 1932 1932 1933 )933 1933 1933 1933 Poos Cannon Poos Rylant Rylant & Demoor Sugarawa cannon Tinel & al. KUltz Kellaway Lanz Mazzola Ungercr Cannon &al. Cannon (a&b) Finkelman Koppfuyi & Lieberson Bacq Cannon & Bacq Kumanomido v. buler & Gaddum Foerster & al. Yonkman Cannon Duel Rosenblueth Sato Schlossberg Bacq Cannon & Rosenblueth Feld berg & Mintz Hinsey & Cutting Pak & Tang Rosenblueth & Rioch Velhagen CatteII & aL Feldberg & Gaddum Feldberg & al. Freeman & aI. Rosenblueth & Cannon Rosenblueth & Morison Ungar & Zeliony Asher Brown & Feldberg Cannon & Rosenblueth Freeman Grant Itikawa Liu Liu & Rosenblueth Bodo & Benaglia -- + ~ -- ----rror -- - + + -+- -- - -- -- -- -+- --+ 1933 1934 ----rror 1934 1934 1934 ~ 1935 ~ + -+- 1935 + + 1935 1935 + 1935 1935 - + + - 1935 1936 P* + + Miller ---rm- 1932 --- - + - --+- + + -- -+ - + + --- - ---- + -- -- -+- -- + + -- --+- --- + + - + -+- --- - - -- + - + - + - YEAR AUTHOR Cannon & Rosenblueth 1936 Itikawa Loewi 1936 )936 Partington Rosenblueth & 1936 Camion White & 1936 Oklebcrry Cannon & 1937 Rosenblueth 1937 Chang Cozzoli 1937 Frommel & 1937 Zimmct Heinbecker 1937 ~ Luco Meyerson & 1937 Thau ~ Simeone ~ Wright & al. Bender 1938 Cannon 1938 Grant & 1938 Pearson 1938 Linksz 1938 Heath 1938 Hinsey & Philli2s 1938 Luco & Liss:fk 1938 MacIntosh Ryu 1938 1938 Shen (a&b) 1938 Simeone & al. ~ Cannon Cannon & 1939 Liss:fk 1939 Clark & Ravent6s 1939 Darrow & Gellhorn 1939 Drake &al. 1939 Hins~ &al. Liss(a&b) 1939 1939 Marazzi (a&b) 1939 Ryu 1939 Saeger Simeone & 1939 Maes ~ Simmon & Sheehan ---1940 Feldman & al. 1940 neath & Geiter 19-10 neath & Sachs ~ Jarcho & Boot 1940 KlOEP Romanova7:Mo Bochon ---1940 Sachs & Ileath ~ Scbupfcr (a&b) 1940 Weinstein & Bender 1941 Bean & Bohr 1941 Cleg:horn & al. 1941 Drake & Thicnes 1936 -- - -- + 1941 P* -- -- -- - -- + + -- + + + -- + -- - -- -+- - + -- YEAR 1941 ~ 1942 1942 1943 1943 ~ ~ 1945 ~ 1946 1947 ~ 1948 ~ 1948 1948 194 -- 1948 -- + 194 ~ ~ + - --- - + + -- - 1950 1950 1950 1950 + + -- -+ + --- - + --+ + - -+- -- + + + -- 1950 1951 + --- 1949 ~ + + -- -+- ~ + + + 1951 1951 1951 1951 1951 1951 1951 ~ 1952 1952 1952 1952 1952 1952 1952 1953 1953 1953 AUTHOR Hoagland Le Compte Sachs & Heath Kojma Weinstein & Bender Ekstrom & al. L. Hess Langworthy & Ortega Levinson & Essex Gellhorn & Levin von Euler Hillarp Mc Dowall Raab & Maes Ahlguist -Mtrom (n.r.) Hortling Jaffe (a&b) Morone & Andreani Nickerson & Goodman de Vissher & al. Wormser Burn & Hutcheon Cannon & Rosenblueth Jaffe Nagakura von Euler lless & Koella Kirgis & Pearce Lowenstein & Loewenfeld Rovatti & Morone Burn & Robinson Emmelin & 1\luren JJokfclt von Euler (a&b) Kaindl & von Euler Lund Tripod Tum Suden & al. Wien & Mason Boros & Takats Burn & Robinson von Euler & Hellner Forst & Deininger Koella & Ruegg Lundberg Sciuto Angenent Burn & Phil2ot von Euler & Folkow -P* - -- -- + + + ---+ -- + + ---- - + -- ---+-- + ---+- --?--+- --+ + -+ + + + + -- + -+- - + --- + + --- + -- --- - - -+- -- -+-+- - + -- -- + -- + - --++ -,- - In column P*, + means the pupil (or iris) was used as test object. This was often but not always true for fundamental work on the adrenergic and adrenal systems, in which other indicators were used (nictitating membrane, gut, blood vessels, etc.). This work is included because it affected the understanding of these mechanisms and hence the functions of the iris also. It will be noted that this Table is not up to date. It was drawn up in 1979, mostly as a key for literature dealing with adrenergic mechanisms. I did not continue it because recent work is readily available from the Surgeon General's and other computer lists. 386 / I. Anatomy and Physiology Table 6-24 (continued) YEAR AUTHOR 1953 1953 1953 1954 1954 Golding-Wood Rueirir & Hess von Sallmann & al Burn & Phileot Burn & Trendclenbu rg Celander von Euler Folkow & von Euler Furchgott Ilolzbauer & Vo~ Koelle Lieb Paasonen & al. 1954 1954 1954 1954 1954 1954 1954 1954 1954 1955 1955 1955 1955 Page Brewin & al. Eccles Hoffman Lowenstein & Loewenfeld 1955 Ruegg !a&b) 1955 Seitz (a&b) 1955 Selye 1956 Emrnelin & Stromblad 1956 Folkow & Hamberger 1956 KUbler & Ruegg 1956 Moore &al. 1956 Nickerson 1956 Owe-Larsson 1956 Roddie & al. 1956 Roth baller 1956 Sigg & Schneider 1957 Burn & Rand 1957 Loewen1'eld 1957 l\Iishima 1957 Nelson & Gellhorn 195 Ahlquist 195 Bowman &al, 1958 Burn &Rand (a&b) 1958 von Euler & Lishajko 1958 1\luschoil & Vogt 1958 Walter 1958 Wescoe 1959 Bertler & Rosengren 1959 Burn & Rand (ab) 1959 Burn &al. 1959 Davis & Greene 1959 Hillar12 1959 Schotz & Page 1960 Burn & Rand 1960 Eldred & al. 1960 Emmelin 1960 von Euler 1960 Fleming & Trendelenburg --1960 Gatling 1960 Hillare 1960 Innes ~ Johnson &Sellers P* + + + + + ---- - -- -- +- + + + -- -- - + - YEAR 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 1960 + -+- + + ---+ -- -- + + -- - + + + + + ? -- - --- + - -- - 1960 1961 1961 1961 1961 1961 1961 1961 1962 1962 1962 1962 1963 1963 1963 1963 1963 1963 1963 1963 1963 1963 1963 1963 1964 1964 1964 1964 1964 1964 1964 1964 1964 1964 1964 T9G4 1964 1964 AUTHOR Kllrki & al. Koein Kuntzman & seectors Langham & Tarlor Loewcnfeld Marler Maxwell & al. Mayer Mc earthy & Shideman Mirkin & Cervoni Orleans &al. Siegel & aJ. Seectors & al, Swinyard & al, Tabachnick Titus & al. Trendelenburg & Fleming Whitby & al, Bennett & al. Burn (a&b) Emmelin & Engstrom Guth & Bailey Haertig & al. Marley Saman Ahlquist van Alehen & al. Falck Marley Bhagat & Shielcman van Alehen & al. Caust & Pritchard Lowenstein & al. Elfvin Eranko llam6crger & al. Orlov Reinert Sears & Sherk Smith Trendelenburg Angelakos Csillik Dahlstrom & Fuxe De Robertis Dorian & Schirmer Fuxe &Gunne Hamberger & al. Hillarp & Malmfors La.ties & Jacobowitz Malmfors Nickerson Nilsson Norberg Norberg & Hamberger - P* -- + + + -- --- -- - - -- - - + + + + + + -- + + + + + + -- -- ---- - -- ++ + -- + + -- -+ --+ + + + -- + -- -- --+ YEAR AUTHOR 1964 1964 1964 1964 1964 Richardson SchaCJ2J2i & Koella Sears & Sherk Takats (a&b) Thoenen & al, 7:964 Vogt ~ van A1J2hen& al. 1965 AndE!n 1965 Burn &Rand 1965 Csillik& Koelle ~ Ehinger & Falck Erllnko & 1965 Rllis!l.nen 1965 Freundt 1965 Fuxc & Sedvall 1965 Hamberger & al. 1965 Hillare & al 1965 Ilokfelt& Nilsson """""I965"Iversen & al• ~ Jacobowitz & Koelle Langham 1965 1965 Malmfors (a&b) 1965 Malmfors & Sachs (a&b) 1965 Nickerson 7965 Oono 1965 Sjoh.-vist & al. 1965 Udenfriend 1966 AndE!n & Henning 1966 Corrodi & al. 1966 Dahlstrom & I-Jaggendal 1966 De Groat & Volle 1966 DeRobertis ~ Ehinger (a-d) 1966 Ehinger & Falck ~ Ehinger & al. 1966 Ehinger & GustafssonSporrong 1966 Erllnk<l & R1lis1!.nen von Euler 1966 ~ Gunne & Lewander 1966 uaefli &al. ~ Hokfelt ~ Langer & Trendelenburg 1966 Langham & Fraser 1966 Laties & Jacobowitz 1966 Richardson 1966 Robson 1966 Schae211i & al . ~ Sears &al. 1966 Smith ~ Stj!lrne Trendelenburg 1966 Ehinger ------rITTi7 1967 Hamberger & ~ ~ Malmfors l!okfelt Iversen P* + + + -+ ---+ + + + -- + + ? - YEAR Langer &al. Langham & Weinstein 1967 Sears & Gillis ~ Becker & Kreutzer --rm,g- rrnlaelt ]968 Iwamura & al. 196 Kitazawa & Langham 196 Langham & Carmel ~ Lutz 19!1 196 19!1 1969 1969 1969 1969 1969 1969 + + + --+- 1969 1969 1969 1969 1969 1969 ? -----+ -- + -- ++ + -+ -- - -- 1969 1969 1969 1969 1969 1969 1969 1969 1969 1969 1969 1969 1970 1970 1970 1970 1970 1970 1970 + + 1970 - 1971 + 1971 1971 1971 1971 + + --1971 + + 1971 - 1971 --+- 1971 __ ?_ --- 1971 1971 -+- 1972 + -- - AUTHOR 1967 1967 1972 Oehl Saman Schae02i Black &al. Calnes & SJ2iers Christ & Nishi Ehinger & al. Geltzer Hllggendal & Malmfors Heuster & al. !Tokfelt Jonsson & al. Knyihar & al. Kramer & Potts Langer & Trendelen burg Lind & Turner Miller & Lewis Nisida & Sears /a&b Patil Posner Scars Singer & Bcr Spiers & Calne ~iers Staflovil'. Ungerstedt & al. Waitzman de ChamJ2lain & al. Cole & Rundle (a&b) Ebinger & al. Ehinger & Falck Lind & Shinebourne Riley & Moyer Treister & B.franv Van Orden & al. Bevan-Jones & Lind de Chamelain de Champlain & Nadeau Farnebo &al. Farnebo & Hamberger Farnebo & Lindbrink Goldschmidt & Schlumpf Graham & Aghajanian Holland Lind &al. Malmfors & von :Euler Consolo &al. Holland P* + + + + + + + + + + + + + + + --- _+ __ + + + ? + - + + ,....±.__ + _+ __ + + + -,--=-+ + + + + + + + + + + + --+ + -+ -+ -+ --+ + ? + + 6. Reflex Dilation Table 6-24 ~ 1972 1972 1972 1972" 1972 1972 1972" 1972 1972 1973 1973 1973 1973 / 387 (continued) AUTHOR Kramer & Potts Langham & Diggs Laties Lauber & al. Neufeld & al. Richardson Sachs &Jonsson Thoenen & al. Tsukahara Carpel & Calina Farnebo & Hamberger J-Jedqvist Holland & Wei (abc) - P* + + -+- -+- + + _?_ -+-+ + --+ YEAR AUTHOR P* 1973 1973 Ivens & al. Kitazawa & llorie 1973 I.amble 1973 LanJ.ham & al. 1973 -Ne eld &al. 1973 Radius & Langham ~ Salem & Ellison 1974 Iversen & al. 1974 Lambie 1974 Langham & Diggs 1974 Laties 1974 Navon & Lanari 1974 Neuield & Sears + ? + + -- - + --+ -+- + + + + + would react so exten iveJy, remained obscure until recent times. Some features of this phenomenon are still unfolding today. However, the e discussions far surpass the subject of pupillary reflex dilation. They have been summarized in Chapter 11. 3. Appearance of "Paradoxical" Pupillary Dilation As just mentioned, small doses of adrenaline, injected intravenously in animals with one sympatheticaJly denervated eye, cause the supersensitive pupil to dilate widely, while the le s en itive normal pupil remains unaffected. With large doses, the normal pupil may enlarge a little, but the dencrvated iris always responds much more extensively and for a longer time (Figure 6-35). The pupil on the side of the lesion enlarges also in response to adrenergic substances instilled into the conjunctiva] sac. This reaction has been used for many decades as a diagnostic test to verify the existence of a suspected lesion within the peripheral sympathetic path. Under the influence of psychosensory or of central nervous stimulation, the denervated pupil at first dilates more slowly than the normal pupil, since it has lost the fast sympathetic reflex component. But it continues to enlarge while the normal pupil recontracts. With sufficiently energetic stimuli the pupil on the side of the lesion therefore becomes the larger of the two and can remain so for protracted periods (Figure 6-36). Because of the similarity of this movement to that produced by intravenous adrenaline, the "paradoxical" reactions to various forms of stress were thought to be caused by adrenaline, released into the blood by the adrenal glands. Soon it was found, however, that "paradoxical" pupiJlary dilation, as well a supernormal responses of other denervated effectors, was not abolished after adrenalectomy, after adrenal denervation, or when the return of blood from the lower body to the heart (and hence to the head) was stopped (Table 6-25). Some mediator for "paradoxical" reactions under these condi- - YEAR 1974 1975 1975 ~ ~ 1975 1975 ~ """'f975 1975 ~ 1975 1976 ~ AUTHOR Takats Burn stock lloefke & al. Iversen & Creese Korkzyn (a&b) La.ties & Lerner Moore & Thurn burg Neufeld & Page Reid Sears Ungerstedt & al. Zeller & al. van AlJ!hen Bauscher & Sears - P* + - + + + -- -+-+- -- + - + + + YEAR AUTHOR 1976 Hill & al. ~ Koss & Rieger Shannon & al. ~ l97f""" Butterfield & Neufeld 1977 Cohen &al. 1977 Koella 1977 Marotta & al. L'l.or & al. 197'f""" 1977 Sharoe & al. L'l.ties & Lerner "'""i97s 1978 Macri & al. 1978 Page & Neufeld 1978 Putkonen & a.I. 1979 Koss 1979 Wa.itzman & al. tions must thus come from a source other than the adrenal medulla. And indeed, two potential adrenergic sources were discovered: (1) Besides the chromaffine cells in the adrenal medulla, there were patches of chromaffine tissue scattered widely in sympathetically innervated organs. Though individual islands of such tissue were not large, their combined output could be expected to be considerable (see, however, below); and (2), some of the adrenergic mediator released by sympathetic nerve endings could "spill over" into the blood when sympathetic nerves were strongly stimulated. Until the 1940s the chemical identity of this sympathetic nervous mediator remained unknown. As late as 1945 0. Loewi flatly stated that it was adrenaline. Cannon and his group, and others, however, had noticed important differences in the actions of adrenaline and of sympathetic stimulation ever since the 1920s (Table 6-25); and Cannon had therefore named the substance released by adrenergic nerves "sympathfo," avoiding a premature chemical term. A likely candidate for the role of this mediator seemed to be the methylated form of adrenaline, noradrenaline, and this was proven beyond doubt by von Euler in 1946. For several decades these two auxiliary sources for humoral adrenergic substances were generally considered insignificant, compared to the massive outpouring of adrenaline from the adrenal glands under conditions 21 of stress. Sympathin was said merely to help adrenaline in the adjustment of bodily equilibrium under such conditions. . 21. Many authors, _andespecially Selye in many publicat10ns, strongly emphasized the adrenal mechanism and reinforce~ t~~ idea of its_foremost importance, so that "stress r~act1on became virtually synonymous with "adrenal discharge" for many readers. Surgeons denervated the adrenal glands on the basi_sof this theory in the hope of controlling vascular hypertension,but the results were disappointing. - P* + + + -- - - - + + + -- - + -- ___±__ + 388 / I. Anatomy and Physiology ,_ r 9e-A 7 9'-B ........_ I I 7 6 --- I .. r • ........... I 6 5 ---------- 5'=1__} 't ·-- ------------------------------32 3'-' 2 ' ........._ I I • 0 ~ 0 IO 10 "" ,0 so ... --- -------------,. ... - -------... - ... •• I •o IO - _,,,,, ;;.__e 0 0 20 " I 8 I 7 -,r,\ '__\ ,',-, ' 5 3~1-t~~-- I: E0 I ~ sec.- ' •• IOO .. o ............ ........... "" 6 .. to "-.: I 9 ,o ............ / IO so 30 .. __ ,, JO ---.., ... .. -----_____ ________ ..,..,,,. ~ . 50 ... TO 10 ... Figure 6-35. "Paradoxical" pupillary dilation in response to intravenous injections of adrenergic mediators. Pupillograms of a cat in nembutaJ anesthesia, 5 weeks after the right superior cervical ganglion had been removed. The solid lines represent the right pupi.1, the broken lines the left (normal) pupil. Note the contracted time axis in these graphs, compared to the usual pupillograms, used because of the long duration of these reactions. In experiments A and B, I ccm of saline containing 3 gamma/kg body - ... "" ._,_ ... ------------,.. ........... _________ 120 '"° ""-...... ,so 010 OIO -- ;-~--;;- •20 weight of adrenaline (A) or of noradrenaline (B) was injected into the cat's femoral vein. In experiment C, 20 gamma/kg adrenaline was given in the same way. The arrows indicate the beginning of the injections. The normal pupil failed to respond to the smaller drug doses, and did so only slightly to the large dose. In contrast, the denervated pupil reacted extensively to the weak and maximally to the strong dose. (From J.E. Loewenfeld, Documenta ophthal., 12 [1958]:185) Figure 6-36. Pupillary dilation in response to hypothalamic stimulation after unilateral postganglionic sympathectomy. The same cat was used in two experiments, in nembutal narcosis. Record A was taken I hour after the right superior cervical ganglion had been removed, and records B to D (2 weeks later. In all records, the right pupil is represented by the solid line, the left pupil by the broken line. The arrows show times when electric stimuli were 10 20 14 0 5 delivered to the hypothalamus (2 milliseconds, 4 volts, square waves at 120/second). A: The stimulus elicited fast, complete dila12 _JLz:=-=-tl--./-~::::__--=====------.;;:-.,..__ ____ _, tion of the normal left pupil, and slow, incomplete dilation of the 10 --l_"-===J.✓~1'.!'===========================--::_---::::__c~~ ""' acutely sympathectomized right pupil. B: The normal pupil dis -,I'--_-_-_/-,.'-·~/-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-::._-_-_-_-_-_-::._-_-_-_-_-_-_-_-_-_-_-_-_-_-~--",::.:;~---' lated as it had done 2 weeks before. The syrnpathectomized left - -1-~''=-~ + ✓-,.✓-/-/'--_-_-_-_-_::_-_-_::_-_-_-_-_-_-_-_::_-_::_-_::_-_::_-_-_-_-_-_-_-_-_-_-_-_-_::_-_-_-_::~_=t-t ~ pupil had become super ensitive to circulating adrenergic mediators. It also began to enlarge as it had done before; but after 1.8 --,~-:/E 2 : seconds, the movement accelerated (see small broken vertical line); and the sympathetically denervated pupil continued to en-512- _!!_c====5=:z::::=s1;;:0~====·=·==~::-=::'."°===========25:j large while the normal pupil already recontracted. The dener1:_~~i!,,..,,'---;;::------~---"'-........ ....... - ....... - ....... ----D-------1 vated pupil therefore became "paradoxically" larger than the normal one. C and D: Short hypothalamic stimuli of the same voltage 1-,cc,--_-_-_..::._ '_s....... ~ 6- 1---- ----- ---::_ caused less extensive reactions, but the "paradoxical" dilation still ji 4 -----"--=---=--=--=--=i'=--=--=--=--=--=--=--=--=--=--:::.-:::.-:::.-:::.-:::.-:::.-:::.j occurred. The moment of acceleration was about the same in all 2~: /4,-reactions, since it depended on the animal's circulation time, not 5 10 0 0 on the extensiveness of the reactions. (From I.E. Loewenfeld, seconds __. Documenta ophthal., 12 [1958]:185) = t :-=i I .............. ~ := =- ;::::===~t================j ~~--- 6. Reflex Dilation Table 6-25. AUTHOR 1911} 1911 Cannon & Hoskins Cannon & La Paz --rm--Dale & 1921 1921 1922 1922 1923 Laidlaw Elliott Stewart & Rogoff Cannon & Uridil Loewi Hartman & al. Brinkman & Van Dam Kodama 1923 Griffith ~ Kodama 1924 1921j 1926 1927 Jendrassik McDowall Kahn Rylant 1927"" Rylant & Demoor 192 Brinkman & van Dam 192 Houssa.l:' & al. ~ Kiltz ~ Lanz 1930 SPECIE ADRE AL I 'FLUENCE RULED OUT BY STIMULUS INDICATOR* cat tying adrenalectomy; aorta and vena cava asphyxia inhibition injections cat cat, dog actrcna1ectomy; occlusion of abdominal aorta adrenalectomy adrenalectomy; adrenal denervation cat adrenalectomy frog cat iris asphyxia iris "pd" of supersensitive iris isolated heart aorcnaiecto my fright shm. nerves to the liver; sensory & emotional stim. accelerator nerves pain stimuli frog isolated accelerator inhibition dog,cat, rabbit cat, rabbit dog,cat, rabbit rabbit cat Irog cat,dog, rabbit cat,dog, rabbit stopping adrenal blood now adrenalcctomy frog dog frog frog heart adrenalectomy adrenalectomy tying adrenal vessels iso Iatecl heart blood taken from donors' hearts blood taken from donors' aorta blood taken from donors' aorta adrenal dcmedullation isolated heart isolated heart nerves nerves nerves acceleration accelerator nerves inhibition morphine injection accelerator nerves accelerator nerves accelerator nerves sup, cervical ganglion st. piloerectors to tail and nerves to smooth muscles struggle, excitement adrenalectomy 1933 Bacq cat adrenalectomy; denervation adrenalectomy 1933 Brooks cat adrenalectomy sciatic 1933 Cannon & Rosenblueth cat adrenalecto my accelerator 1934 Cattell & al. cat adrenalectomy st. sympathetic strand submaxillary gland 1934 Rosenbluetb .....,J..Morison_ cat cat adrenalectom.l:' adrenalectomy accelerator nerves sciatic, accelerator adrenalectomy sciatic nerve adrenalectomy ligation of adrenal vessels adrenalectomy; adrenal dcnervation st. of peripheral nerves struggle; sensory sensory nerves fright, struggling; st. of accelerator nerves postg. sympathetic fibers adrenal demedullation; cutting s elanchnic nerves isolated heart nclrenalectomy; adrenal denervation aclrenalectom,Y stimulation of peripheral neurons (SCG) adrenalectomy; adrenal demedullation treadmill; other physical or emotional stress cardiac accelerators activity, cold, hypoglycemia; emotions h,YJ22tbalamus used aqueous of stimulated eye mechanical stimulation of rectum """"f93"5Lm 1935 1935 1936 1936 Liu & cat Rosenblueth Grant &al. rabbit Acheson & al. cat 1936 Bodo & Bcnag:lia Rosenbluetb & Cannon Itakawa cat 1936 1936 Loewi Partington frog cat 1937 1938 Ma£,OUO& al. Luco & Lissak Youmans cat 1936 1938 cat cat cat dog of frog stomach accelerator cat adrenal rise accelerator sensory or emotional st. sensori stimuli ether excitement; anesthesia accelerator nerves asphyxia; hemorrh~e; accelerator nerves cat nerve acceleration of denervated heart; in blood 2ressure acceleration of 2nd frog heart "pd!' of supersensitive iris "pd" of supersensitive iris; blood sugar rise blood sugar rise "pd" od supersensitive iris; blood sugar rise intestinal inhibition "pd" of supersensitive iris acceleration of 2nd frog heart acceleration of 2nd animal's heart, abolished by ergotamine Newton &al Rosenblueth &Cannon 1931 1932 strip "pd" of supersensitive of nicotine isolated heart st. of peripheral adrenalectomy 1931 of intestinal "pd" of supersensitive cat Finkelman rabbit Bacq cat Cannon &Bacc cat 1931 389 The discovery of 'sympathin" (noradrenaline), distinct from adrenaline YEAR 1912 1916 / sensory or emotional stimuli sciatic, hypogastric nerve stimulation nerves to nerves nerves of 2nd animal's of 2nd frog's heart stomach blood sugar rise inhibition of frog stomach acceleration of frog heart; contraction of frog vessels inhibition of frog intestine agueous accelerated frog heart "paradox" responses of supersensitive iris I heart I saliva!)'. glands acceleration of denervated heart contraction of denervated NM and acceleration of denervated heart contraction of denervated NM and acceleration of denervated heart contraction of denervated NM; cardiac acceleration; blood pressure rise contraction of denervated NM and of non -preg!!;ant uterus contraction of opposite denervated nictitating membrane contraction contraction of NM of cocainized NM contraction of denervated NM contraction of dcnervated ear vessels contraction of NM; blood pressure rise heart acceleration; contr. of NM; blood 2ressure rise supersensitive NM (after preganglionic sympathectomy) "pd" of supersensitive iris 2nd frog heart contraction of supersensitive contraction accelerated of sueersensitive frog heart denervated jejunal NM NM loop *: "pd" m Column INDICATOR means the so-called paradoxical dilation of the pupil in a sympathetically denervated eye upon stimulation t~at causes adre_ne~gic substances to_enter t~e general circu_lation; M = nictitating membrane; BP = blood pressure; CO2 = breathing of carbon dioxide; SCG = superior cervical (sympathetic) ganglion. 390 / I. Anatomy and Physiology Table 6-25 (continued) SPECIES YEAR AUTIJOR --- 1939} 1939 1941 1941 1947 1948 1949 :!,950 Cannon & Lissll'.k Lissifk ( a&b) Cleghorn & al LeComete Raab & M:aes Kirgis INDICATOR* STL\.IULUS used extracts of adrenergic frog heart and blood pressure ; supernerve fibers , with & with sensitive iris and NM; uterus out erevious stimulation sciatic nerve; splanchnic nn. adrenalectom;):'.: "pd" of supersensitive )!M; BP rise struggling adrenalectomy denervatca ear vesseis chemical analysis 01 tissues (heart, liver, spleen, muse es, kidney) after ( 1) adrenalectomy, (2) sympathectomy, and (3) both; found fall of adrenei·gic mediator after sympathectomy but not after adrenalectomv without svmoathectomv adrenalectom;):'.: pupil dilation asehyxia; CO2 adrenal demedullation dog cooled by stomach fistula. "pd" 01 supersensitive iris in vitro experiments cat cat,frog cat cat,rabblt cat dog dog Jloorens Nagakura ADREKALI FLUENCE RULED OUT BY & Pearce cat 1946j von Euler & co-workers: 1953 1952-} Loewenfeld cat 1955 adrenalectomv identification timing "pd" of supersensitive anesthesia of noradrenaline of responses as transmitter at sympathetic hypothalamus nerve iris endings "pd" of supersensitive iris (see Fi<mrcs 6 35 36 37 and 38\ 10-+---------------------------------------1 ___________________ ,, A----------,~,,=---------------------------------~ 8+--------------------,,-=---=-~-~-=--------_-_-_-_-_-_- - ---1 s...-------------,,~----------------------------------1 +------------/~-----------------------------------1 :l=I_: 4- 2--i---! ,/-,,/·-"~~~~-=====-~-------=:::::==---=-' ,,,._____________________ __________ ,~'--------==========------::.... 0 0 .~ _______________ ,. __. 14t=========~======~~~~~:::==:=::=::=:::t 12-t----------'l~~---------------------------==-- ----------- / 10- -B------/_,,/--------------------------,,.-,,~,,.,,.~ ..._... _... _-_-_______ _ 8-+---§-----/-//------------------------,-_,_~.,--'-'---------------1 t 6 = - / / ,-'------------------1 .,.,_,_, _________________ ---1 ---: -------------------------------eE 2~-~-----------------------------------~ b 4 ~ ___ ,,/·-"-----------------------1 u 20 seconds---+ Figure 6-37. lntluence of intracarotid injections of adrenaline in 2 cats with bilateral chronic sympathetic denervation. Two cats in nembutal anesthesia, several weeks after bilateral removal of the superior cervical ganglion. The solid lines indicate the right and the broken lines the left pupil in each experiment. The double arrows outline the time of injections of 0.75 ccm or a J :10,000 solution of adrenaline hydrochloride into the left (A) or into the right (B) common carotid artery. Shortly after the beginning of the injection the ipsilateral pupil dilated (latent period 2.1 second in A and J.5 second in B). The contralateral pupil did not enlarge until much later, when adrenaline reached it by way of the general circulation (13 seconds after the beginning of the injection in A and 11 seconds in 8). This long delay of the contralateral reaction proved that no blood reached the opposite eye directly, that is, from the injected artery via the arterial circle of Willis. The differences in timing among cats were due to their individual circulation times; and each cat sbowed the same timing in repeated experiments (not hown here). (From I.E. Loewenfeld, Documenla ophthal., 12 [1958]:185) 6. Reflex Dilation 4. Noradrenaline versus Adrenaline in "Paradoxical" Pupillary Dilation During the early 1950s, when we experimented on this system (see Loewenfeld, 1957 and 1958), the general view in the ophthalmologic and neurologic literature was about as follows. In response to p ychosensory stimulation, the central nervous system brought the sympathetic nervous system into play by means of (cholinergic) preganglionic neurons. These reactions tended to be "mass discharges," and were distributed diffusely to all sympathetic ganglia as well as to the adrenal medulla and other chromaffine tissues (which are homologous to postganglionic adrenergic neurons). Action potentials then travelled down the axons of the postganglionic neurons; and their arrival at the neuroeffector junction evoked release of noradrenaline, which excited the effector cells. In addition (especialJy under conditions of severe stress), the adrenal medulla discharged adrenaline into the circulation; and this substance enhanced and prolonged the reactions to sympathetic nerve activity. After sympathetic denervation, the iris became supersensitive to adrenaline, so that it still was able to respond extensively to psychoscnsory stimuli via the humoral mechanism. Sympathin was not mentioned in this connection, though scattered reports about "paradoxical" ocular effects observed after adrenalcctomy continued to appear in the physiologic literature. One of the features of the "paradoxical" pupil dilation, provoked in awake cats by sensory or emotional stimulation and in anesthetized cats by hypothalamic stimulation, urprised us greatly: pupillographic records demonstrated that the "paradoxical" increase of the dencrvated pupil's diameter usually occurred very quickly. In experiments with anesthesia-and hence a stable baseline-and with hypothalamic stimulation, a sudden acceleration of the dilation movement on the operated side was clearly shown during the second or third second of timulation (Figure 6-36). How could adrenaline, poured out by the adrenal glands into veins, arrive at the eye in so short a time? Pupillary reactions to adrenaline injected into the femoral vein confirmed the obvious fact that substances liberated into veins require (in cats) a minimum of 9 to 12 seconds to reach the eye (the exact time depending upon each animal's circulation time), since the blood, before reaching the arterial system, must complete the heart-lung circuit, containing a capillary bed. Where, then, did the adrenergic substance responsible for "paradoxical' pupillary dilation originate? In our search for a possible source of this mediator, we had to exclude (1) the adrenal glands; (2) all other abdominal organs, for example, the spleen, the liver, or accessory chromaffine tissue in the lower body; and (3) all endocrine glands: all these organs liberate their products into veins, so that they would encounter the long delay of the heart-lung circuit before they could be / 391 sent on their way to the eye. Further, diffusion from tissues near the denervated iris could not be considered because these tissues-just like the iris-had lost their sympathetic nerve supply when the superior cervical ganglion was removed. And diffusion from structures beyond the denervated area could not be expected to reach the eye, at least not within 2 second,. The existence of an unknown set of auxiliary sympathetic nerves which might have been spared by postganglionic cervical sympathectomy could not be assumed, for there arc no such nerves, as discussed above. Besides, a nervous connection tran mitting maximal and sustained mydriasis would never require a latent period as long as 2 seconds. Finally, the possibility that a reflex change in respiration could cause the "paradoxical" phenomenon by shifting the oxygen-carbon dioxide balance of the blood was ruled out by the timing of the response, and by the fact that interruption of blood flow to the head for as long as 15 to 20 seconds failed to affect the supersensitive iris. The only possibility we could think of was that an adrenergic substance, probably noradrenaline, might "spill over" into the arterial circulation when the sympathetic fibers to the cardiovascular system proximal to the denervated territory were excited by the central nervous stimulus. From there it should be possible for blood to reach the eye within 2 seconds, as shown by the timing of "paradoxical" pupil dilation produced by experimental injections of adrenaline into the carotid artery of cat (Figure 6-37). The next point to be proven was that the "paradoxical" pupil dilation elicited by hypothalamic stimulation indeed was missing when the arterial blood flow to the head was stopped during and for a few seconds after the period of stimulation. The experiment of Figure 6-38 showed this to be true. The finding of a circulating adrenergic mediator not accounted for by adrenal discharges was, of course, not new. As already mentioned, such substances had been obtained in many experiments from the blood of animals after stimulation of sympathetic nerves to various organs. They were found also under the influence of physical stress such as anoxia, asphyxia, struggling, or cold, as well as after pain, fright, or other strong emotions· and they had been used to accelerate the heart, inhibit gastrointestinal peristalsis, dilate the pupil, contract blood vessels and the nictitating membrane, and raise the blood sugar of the same or of a second animal (Table 6-25). However, the mediator in these experiments had always been assumed to enter the venous circulation, while we found the "paradoxical" pupillary dilation to occur much too soon to be so explained. The phenomenon comes on rapidly not only after strong stimuli; on the contrary, it is the regular pupillary response to moderate and weak stimuli (Figure 6-36): the "paradoxical" reaction to these stimuli always begins within the second or third second; it always reaches its peak within less than 10 seconds· and the dilation always fades before blood from the veins can 392 / I. Anatomy and Physiology .. see.- 0 S S Figure 6-38. Influence of arterial occlusion upon "paradoxical" pupillary dilation elicited by hypothalamic stimuli. Cat in nembutal narcosis, 5 weeks after tbe right superior ceivical ganglion had been removed. The solid lines represent the right (deneivated and hypersensitive) pupil, the broken lines the left (normal) pupil. The arrows mark times of hypothalamic stimulation (square-wave pulses, 2 milliseconds, 6 volts, 120/second). Just before this experiment, both vertebral arteries had been tied off by slipknots a few millimeters below their entry into the vertebral canal. Both carotid arteries had been dissected free. During the experiments A and D, the carotid arteries were not touched, but in the cxperi- 0 sec.~ 5 .. .. 10 Figure 6-39. Mechanisms of pupillary dilation: Summary, based on experiments on cats. All records were obtained from individual experiments under different conditions, as described in the text. Solid line: Complete response of the normal pupil to a powerful stimulus (cortical, sensory, or at other central neivous sites in awake cats, and hypothalamic in anesthetized animals). Analysis of this movement reveals the following component mechanisms. Line of crosses: Active inneivation of the dilator muscle by sympathetic impulses. Dotted line: Inhibition of the pupilloconstrictor nucleus. Broken line: Normal reflex dilation to mild stimulation (sensory or central neivous in intact animals). This movement is composed chiefly of the 2 neural mechanisms, that is, sympathetic men ts Band C, they were closed off from 3 seconds before to the end of the reactions. Note the ' paradoxical" reversal of the normal and the deneivated pupils' diameter which occurred when blood was allowed to flow through the arteries but not when the arteries were occluded. The difference was especially notable in C and D because the short stimuli produced submaximal reactions. The small vertical broken lines point out the moments of acceleration of the dilation movement in the deneivated eye in A and D but not in 8 and C. (From I.E. Loewenfeld, Documenta ophthal., 12 (1958]:185) 15 20 25" activation of the dilator muscle and simultaneous inhibition of pupilloconstriction. Dash-cross line: An early wave of adrenergic mediator, probably noradrenaline discharged into the arterial circulation by sympathetic neive endings in the heart and blood vessels distal to (toward the heart) the pulmonary arteries. Dash-dot line: A late wave of adrenergic mediator, probably adrenaline and noradrenaline from the adrenal glands, and perhaps other chromaffine tissue, discharged into veins. This last component is brought into play only under the influence of very strong or prolonged stimulation. (From I.E. Loewenfeld, Documenta ophthal., 12 [1958]: 185) 6. Reflex Dilation have reached the eye. In respon e to very trong timuli, in contrast, there i a econd hump in the pupillary dilation curve at about 9 to 12 econd from the tart of stimulation, indicating the arrival of sub tance probably liberated into vein (Figure 6-39).22 While it appears thu certain that the adrenergic mediator for the early pha e of "paradoxical ' pupillary dilation does not reach the heart from sy temic vein , the area from which it i derived i known by exclu ion only: it cannot be situated in or di tal to the vascular territory sympathetically denervated by removal of the superior cervical ganglion nor proximal beyond the pulmonary capillary bed. Becau e the heart and the great arteries contain a great deal of smooth mu cle tissue richly upplied by a profuse network of adrenergic nerve , we thought it likely that upon sympathetic stimulation of these vascular muscles, noradrenaline i pilled into the arterial blood. The old experiment on frog heart upport the assumption that this indeed occurs (Loewy 1921• Lanz, 1928; Brinkman and van Dam, 1922, 192 • Kiiltz, 1928): upon stimulation of the accelerator nerve , the perfusate from the isolated frog hearts wa able to accelerate the heart, to contract the blood vessels, and to inhibit the stomach of a second frog. In fact, Kiiltz said that in the spring of the year the hearts of rana e. culanta liberated an adrenaline-like substance spontaneously in sizeable amounts. Perfusate introduced into the vena cava of anesthetized frogs and recovered from the aorta 5 minutes later remained active when the heart was emptied at half-hour intervals throughout the day. Similarly, Finkelman (1930) ob erved intestinal inhibition when he trickled fluid from an inte tinal trip that was sympathetically stimulated onto a econd strip. In agreement with these findings in lower pecie , Raab and Maes ( 1947) found the ti sue levels of adrenergic mediator in the heart, liver, and pleen reduced after sympathetic denervation but not after adrenalectomy· and Udenfried and co-workers observed that increased synthesis of catecholamine upon exercise occurred not only in the adrenal gland but also in the brain, pleen, and heart. A second possible area for relea e of noradrenaline not delayed by the pulmonary capillarie may be the broncho-pulmonary veins. We had not thought of thi possibility in 1955. According to von Euler and Lishajko (1958), the larger pulmonary vein contain as much noradrenaline as do the arterie • and further, some of the blood from the bronchial arteries also enters the pulmonary veins, which empty directly into the left ide 22. These number refer to cats, and vary with the individual' circulation time. / 393 of the heart. Lockett (1956) obtained an amine considered "bronchial sympathin" by stimulating the right ~nd left sympathetic chains between the stel!a~e gangho_n and T8 (with the accelerator nerves divided_). This ubstance appeared first in the pulmonary ve1~s an_d resembled noradrenaline in chemical and phys10log1c tests. In summary, then, wherever the source of the adrenergic mediator responsible for the ~arly phase . ~f "paradoxical" pupillary dilation, it arnves at the ms much sooner than would be possible for blood from the general circulation (Figure 6-39). Though it is probable, I do not know whether this early appearance is part of other "paradoxical" reactions of denervated structures normally under sympathetic control. If this should be the case, the importance of this early adrenergic mechanism would be greater than has been suspected in the past. First, as demonstrated by the "paradoxical" pupillary response, the humoral reaction to moderate psychosensory or central nervous stimulation is elicited by the first wave of adrenergic mediator alone. The second hump of the dilation curve, due to adrenergic substances from the adrenal glands or from other organs discharging into veins, appears only under conditions of severe stress. If such adrenal hormones are discharged at all in response to moderate or weak stimuli, they do not reach the eye in sufficient quantity to dilate the supersensitive pupil. These facts indicate that the physiologic role of the fast adrenergic mechanism may be as great or even greater than that of adrenal discharges, since under conditions of civilized life we are exposed to moderate stimuli far more often than to severe ones. Second, in their beautiful review on denervation supersensitivity (1949), Cannon and Rosenblueth said that, normally humoral adrenergic mechanisms "reinforce the effects of nerve impulses from the postganglionic adrenergic fibers on the sundry effectors controlled by the sympathetic neivous system"; and after denervation, the developing supersensitivity to humoral mediators will allow these structures to "respond much as they would have if their nervous control had been intact. ' "Although these organs no longer receive the nerve impulses that elicit their activity in normal circumstances, they may still respond in certain conditions and thus share in some of the general responses of the organism." If one adopts this view, the advantage of speedy arrival of the mediator at the denervated effectors, and of as little dilution as po sible along the way, would be obvious. If this mechanism indeed constitutes a homeostatic adjustment for the loss of sympathetic nerve impulses in a given area, it would work best if the mediator were released from similarly innervated structures nearby. In contrast, it would be inefficient to have to wait a full 10 seconds or more from the time of stimulation until the needed humoral adjustment could begin. 394 / L Anatomy and Physiology H. Conclusions: Integration of Pupillary Dilation Movements Reflex dilation of the pupils is thus not a simple movement but is composed of everal mechanisms which vary in prominence according to conditions (see also Chapter 9). The e can be demonstrated in experimental animal by selective denervation and by using stimuli of different intensity. In the experiments of Figure 6-39 cats were used because reflex dilation in these animals is by far the most dramatic in speed and amplitude, compared to other species (see Figure 6-1). But the same characteristic reflex shape is shown in the reactions of all mammals who have a double set of smooth iris muscles. In birds, the movement is slight and slow, evidently because the dilator muscle i feeble and opposed by a powerful striated sphincter. In lower animals dilation and contraction movements, both at least partly governed by local iris mechanisms, are much slower and more gradual than in mammals (see Chapter 1). In response to sudden sensory or central nervous stimulation of intact, conscious animals ( or hypothalamic stimulation during anesthesia) the pupils dilate rapidly and may reach maximal size. This movement is faster than that brought on by strong stimulation of the sympathetic nerve and is composed of simultaneous sympathetic activation of the dilator muscle and inhibition of the pupilloconstrictor nucleus. These two component mechanisms can be mimicked by electric stimulation of the cervical sympathetic nerve (line of crosses in Figure 6-39) and by sensory stimulation after sympathectomy (dotted line in Figure 6-39). If the stimulus is short and weak, these two neural mechanisms govern the dilation movement, and the pupils reconstrict promptly after the stimulus (broken line in Figure 6-39). But with more intense stimulation the pupil may continue large for a considerable time, because two humoral mechanisms are added to the neurologic events (solid line in Figure 3-39). The fir t of the. e is an early wave of adrenergic mediator which is carried to the eye by the bloodstream within less than 2 seconds after the start of stimulation. This timing rules out any source for the substance beyond the pulmonary capillary bed. It probably i noradrenaline, discharged by sympathetic nerve ending that innervate the pulmonary veins and bronchial ve sels, the heart, and the large arteries below the neck and which reaches the eye directly with arterial blood. The arrival of this substance can be seen in intact animal as a hump of pupillary redilation after an initial contraction that follows the end of the stimulus (solid line in Figure 6-39). It can be shown clearly in animals with chronic sympathetic denervation and consequent adrenergic supersensitivity of the iris (dash-cross line in Figure 6-39). It can be mimicked by intracarotid injections of adrenergic mediators. Under the influence of mild to moderate stimulation this appears to be the only humoral mechanism to bring out "paradoxical" pupillary dilation of the sympathectomized pupil. But in answer to powerful stimuli a second wave of adrenergic mediator arrives at the eye about 12 to 15 seconds after the start of stimulation, with the precise time of on et varying among individuals and between species, according to their circulation time. The normal pupil then shows a second hump in the dilation curve, and it may remain very large for protracted periods. The substance probably is adrenaline and noradrenaline, discharged by the adrenal glands (and possibly other aggregates of chromaffine tissue) into veins. This movement can be mimicked in animals with a sympathetically denervated, supersensitive iris by intravenous injections of adrenergic mediators and related drugs (dash-dot line in Figure 6-39). In contrast to widely held opinion, this second humoral mechanism plays no role in the pupillary responses to all but powerful or prolonged stimulation.