Chapter 10: Reflex Integration: Pupillary Consequences

CHAPTER 10 Reflex Integration: Pupillary Consequences CONTENTS I. Fatigue and Arousal ................. A. Summary . ...................... B. Appearance ..................... 1. Pupillary "Fatigue Waves" . ........ (a) Appearance in Healthy Subjects .. (b) Chronic Fatigue ............. (c) Diurnal Changes . ............ 2. Light Reflex Changes ............ C. Mechanisms ..................... 1. Mechanism of "Fatigue Waves" of Pupillary Size . ................. (a) Sympathetic Excitation and Deficit .................... (b) Modulation of Parasympathetic Outflow ................... (c) Central Nervous Integration . .... 2. Mechanism of Small, Rapid Pupillary Oscillations ................... 3. Mechanism of Light Reflex Changes .. (a) Sympathetic Innervation ....... 480 480 482 482 482 483 485 486 490 490 491 491 492 492 493 493 (b) Central Nervous Integration . .... (c) Afferent Factors in Light Reflex Fatigue ................... D. Significance of Pupillary Fatigue Changes ....................... II. Development and Aging ............... A. Summary . ...................... B. Appearance ..................... 1. Pupil Size .................... 2. Reactions to Light .............. (a) Strong, Long-lasting Light Stimuli ................... (b) Short or Weak Light Stimuli .... (c) Longitudinal Age Changes ...... 3. Pupillary Dilation ............... C. Mechanisms . .................... 1. The Iris . . . . . . . . . . . . . . . . . ..... 2. Sympathetic Deficit . ............. 3. Central Inhibition . .............. D. Significance of These Changes ........ 493 494 496 498 498 499 499 500 502 503 503 503 505 505 513 514 515 I. Fatigue and Arousal A. Summary It is surprising how little work has been done on the pupillary signs of fatigue and of arousal, since these states are with us constantly throughout life. Much more often than any disease, a state of tiredness, or weariness, dulls our existence: it robs our vitality and sense of well-being, muddles our mind, and poisons our emotions. And characteristic pupiJlary changes are faithful mirrors of the degree of tiredness present at any given time. Work on "pupillary fatigue changes" has become somewhat confused by an ambiguous terminology. The word "fatigue" is used for a number of very different phenomena by physiologists, psychologists, physicists, and the general population, so that often no one knows what "fatigue" is supposed to be. And for the pupil, the reduction of reactions that is found upon repeated stimulation is called "reflex fatigue" by some and "adaptation" or "habituation" by others. Disputes about pupillary fatigue changes usually have arisen merely because different authors using a given term meant different phenomena. Yet everyone knows just what is meant when we say, "I am weary"; "I am sleepy"; "I am tired." It is that kind of fatigue that causes changes in pupillary movements. And, in addition, there are reflex changes under the influence of repeated stimuli. These 480 two events interact: the pupillary effects of tiredness and of repeated stimulation are additive, while arousal and rest counteract the effects of series of light stimuli. In summary, the following points must be remembered in research upon the pupil. (1) The earmark of pupillary "fatigue changes" is inconstancy. When a healthy, alert individual sits in darkness, looking at a distant, dim fixation light, the pupils are large and quiet; and they may remain so for long periods if the person remains mentally active (Figure 10-1). But with increasing boredom alertness wanes and sleepiness increases; and together with the slack posture, the drooping lids and nodding head, the pupils become smaller and unsteady. Waves of pupillary dilation accompany periods of spontaneous arousal and fade with deepening drowsiness until, at the time immediately preceding sleep, the pupils are quite small (Figures 10-2 to 10-6). (2) Pharmacologic experiments as well as clinical lesions and (in animals) neurosurgical procedures have shown that the pupillary "fatigue waves" take their origin from fluctuating degrees of central nervous integration. The efferent mechanisms are (a) decrease of sympathetic discharges and of inhibitory influences upon the parasympathetic sphincter nucleus during periods of 10. Reflex Integration: Pupillary Consequences leepine ; and (b) increa e of the e functions during arou al ( ee Figure 10-17). (3) Light reflexe elicited during uch periods of gradual drifting into Jeep are uperimpo ed upon this shifting ba eline of central nervou integration; anddepending on the equilibrium of force active at each given moment-they differ in extent, peed, and timeamplitude pattern from one moment to the next. The more alert the individual, the better integrated the reflex; and the clo er to leep the le extensive. This decrement of the light reflexe goe hand in hand with changes in the hape of the reaction . The reflex forms that accompany pupillary "fatigue wave " are identical to those recorded in patient with le ion in the sympathetic and central inhibitory neuron . But, in contrast to these patients, tired people have uch responses only fleetingly: as soon a their draw ines gives way to arou al, or is overcome by a good night sleep, extensive, well-integrated reflexe are re tared (Figures 10-4 and 10-9 to 10-12). (4) Repeated timulation of the eye with light flashes too long and too clo ely spaced to allow full redilation of the pupil brings about the ame equence of reflex deficits observed under the influence of fatigue, even when the subject is not tired. But the disintegration of the reflexes occurs faster (and their restoration upon psycho ensory stimulation i le complete) in tired than in well-rested people. (5) Illnes , a chronic lack of adequate sleep, or other stress exacerbate the pupillary fatigue ign , just as they render the individual more weary than would be expected under the given circum tance . And during old •-~ :~--=-A 5--- 481 age, also, sympathetic and central inhibitory discharges weaken. These age changes gradually become irreversible, so that "fatigue shapes" of the light reflex tend to become permanent features with advancing years (see below). (6) In small animals and children, in contrast, the same reflex components are stronger than they are in healthy adults. And again, when normal, adult persons are subjected to acute mental or emotional stress, their pupils also are large and their light reflexes are inhibited. The exaggerated sympathetic and central inhibitory forces, however, do not last, and the reactions revert to normal as the individual calms down. Excited mental patients and hyperactive, hyperexcitable people sometimes cannot relax, and their pupils show signs of excitement constantly, without adequate cause. Repeated light stimulation in such individuals may result in increased extent and smoothness of the reflexes. A single healthy person can thus produce the whole range of pupillary phenomena from wide mydriasis with inhibited light reflexes to rniosis with misshapen residual responses. None of these signs can be said to be "normal" or "abnormal" without knowing the age, the experimental conditions, and the subject's physical and mental state. The pupils must be considered pathologic only when their range of reactivity is permanently narrowed so that well-integrated reactions never can be obtained, and when defects or suppression are excessive for the individual's age. When the pupils are used as indicators in physiologic and pharmacologic experiments these factors must be considered. Often they are not, and this, of course, leads to confusion. ~ / - - - .....r--- - . -B ~--~/ ~>-- -~l ➔ 2 ~-c ,II """ 1111 1111 81-7 s 1111.111·1111111 o.,~c.-. mln.-. ' b b Q h - : ... b- 0 7 .,... ' a ~ 5 o.,se( ....... "' 111 1111111 111 "' "' "' "' Figure 10-J. Spontaneou pupillary movement in a healthy 24year-old man. The pupillogram of the right eye are hown. A and C were original records. In B, the time axi of the graph was compressed in the following manner: the pupillary diameter at the beginning of each ucces ive econd was taken from the original record, and was plotted as a ingle measurement (small rectangles); ixty uch measurement thu how the pupillary movements """ "' """"' "' "' "'"" "'"' "' ""~ "' that occurr~d within each minute. A; Normal light reflex; B: Diameter dun~g the fifth to ninth minute in darkness. The pupil was l~rge and quiet. The subject was not tired, and was able to con~mue t~e test for more than 2 hours without remarkable changes 1~ pup11lary behavior. C: Slow (a) and fast (b) pupillary oscillat1ons of small extent (see text). (From 0. Lowenstein, R. Feinberg, and I.E. Loewenfeld, Invest. Ophthal., 2 ll963]:138) 482 I I. Anatomy and Physiology B. Appearance 1. Pupillary "Fatigue Waves" (a) Appearance in Healthy Subjects With the development of infrared-sensitive recording devices it has become possible to study pupillary movements in darkness over extended periods. Such records show the following. When healthy, adult persons sit in the dark, looking at a distant fixation point such as a dim red light, the pupils are relatively large and quite stable in size. They are, however, seldom entirely immobile. When they are observed for some time, two kinds of spontaneous movements can be seen: first, slow tides of gradual dilations and contractions, lasting from about 4 to 40 seconds and measuring up to about half a millimeter in extent (a in Figure 10-1,C); and second, occasional little dips a third of a millimeter or so in amplitude and about a second in duration (b in Figure 10-1,C). These movements are always symmetric on the two sides, and they do not coincide with the respiratory movements or with the pulse, as has been claimed in the literature. If the subjects keep themselves occupied mentallyfor example, by working out a problem, or by trying to remember a sequence of events-or if they are entertained by conversation, this state of quiet wakefulness can be maintained for hours. But if they sit in the dark without such mental stimulation and with nothing to do, they will, sooner or later, become drowsy; and simultaneously their pupils become smaller and begin to oscillate (Figure 10-2). Together with the deepening waves of sudden, spontaneous awakening and gradual slipping into a doze, the pupils will enlarge rapidly, then recontract slowly in an uneven, wavering decline. The more tired the subjects are on the day of examination, and the less they resist their growing lethargy, the shorter the initial period of mydriasis and the steeper and more frequent the following oscillations. Soon the spontaneous periods of arousal become short and less and less 7f-'J:---.,..."""'--------------~----✓-""""---~ 71----~----------------------1 ' • B-------...:.JL. • ___ 't _:_+1~,-,,,1 5t-----------------_..J'-------4 2 7 6 Sl-------------~-1;•\J\.1"\1"-~\:---rr-n---, ~ D------------------~~ t C 5 61----!;--'1.t'\.-/---------+f-'i-ca,----j--\~------j ,.. 13 " 't ..... -- 31----------------------~7 f: ._ E minutes_. t £::3 f 2 ~ls 15 /6 min.Figure 10-2. Pupillary "fatigue waves." ln each line, the diameter of the subject's right pupil was plotted as the ordinate by the same method described for Figure 10-1. A: Record obtained from a normal, alert 24-year-old man. The pupils showed only little activity after many minutes in darkness. The graph shows the movements between the twelfth and sixteenth minute of the experiment. B to D: Pupillary movements of a healthy but very tired 38year-old man. Less than 3 minutes after the beginning of the test the pupils began to become smaller. During the following minutes extensive, irregular waves of pupillary contraction and dilation appeared as the subject repeatedly drifted toward sleep and roused himself spontaneously (lines B and C). Finally, the periods of arousal became shorter and shorter and less and less complete. Immediately before he fell asleep, the pupils were very small (end of line D). (From 0. Lowenstein and I.E. Loewenfeld,Ann/s N. Y Acad. Sci., 117 [1964):142) Figure 10-3. Pupillary "fatigue waves" in an extremely tired normal subject. The right pupil's movements were plotted as described for Figure 10-1. The subject, a 38-year-old man, was very tired after a strenuous series of lecture trips. In addition, he had come down with a slight cold on the day of examination. After an initial period of wakefulness, he became drowsy. His pupils began to fluctuate wildly over a large range, in successive waves of spontaneous arousal and following decline (a in A). Shortly after the twelfth minute of the test he fell asleep, and was awakened by a sudden, loud sound (arrows in B). The pupils dilated extensively, but recontracted soon, as again he drifted toward sleep (fifteenth minute, line C). A second sound stimulus was followed by conversation (starting at X) which kept him awake during the remainder of the test. (From 0. Lowenstein, R. Feinberg, I.E. Loewenfeld, Invest. Ophthal., 2 [1963]:138) 10. Reflex Integration: Pupillary Consequences complete, and eventually they cease altogether: the pupils become quite small, and the subjects fall asleep. At any time during this development a psychosensory stimulus such as a sudden ound, touch, pain, conversation, etc., restores the waking condition. The pupils dilate and their "fatigue wave " are abolished. Depending upon the type and the intensity of the stimulus, mydriasis with steady pupils can be maintained for some time (Figure 10-3). We have found the same waves of sleepiness with intermittent arousals, paralleled 'by pupillary oscillations, in all the mammals we have studied, and have had fun observing them in a variety of species in the zoo. They are especially impressive in monkeys, who under ordinary daytime circumstances are extremely active animals. When they are sitting in a box with their extremities and head 7 - 10 II -- -- _ ...~ 5 -- ~ -~/~"--- -- ------l - - 31-1-.--1---------1 -~ff--i " 2 s min.- Figure 10-4. Spontaneous pupillary movements in healthy, young, but tired identical twins. A and B were identical twin brothers. They had just graduated from dental school some weeks before. On the day of examination they were tired because until very late the previous night, they had packed their bags preparatory Lo leaving for army service overseas. The tests were done in immediate succession, al 10:30 A.M. for A and at 11:30 for B. Al and Bl: The eyes were in darkness except for the framed intervals marked 1,when the right eye was expo ed to I-second light flashes of about 15-foot-candle intensity. The large arrows S indicate the times of presentation of sensory stimuli (sudden sound). Note the close similarity in the reaction pattern of the two brothers. In A2 and 82 the time axis of the graphs was compressed in the manner described for Figure 10-1. At the beginning of each record, the right eye had been adapted to the timulating light for 1 minute. The first measurement shows the pupillary diameter at the moment this light was turned off. After the initial dilation in darkness, the pupils began to oscillate (a). Within the following minutes these oscillations became increa ingly frequent and extensive, and, beginning with the sixth minute of the test, repeated sensory stimuli were needed to keep the subjects awake (small arrows s, sound stimuli). Again, the pattern of pupillary behavior was strikingly similar in the two brothers. (From 0. Lowenstein, R. Feinberg, and J.E. Loewenfeld, Invest Ophthal., 2 [1968]:138) 483 prevented from moving by elastic bandages and sponge rubber supports that are not uncomfortable, and when the light is then turned off, they fall asleep with astonishing rapidity. And even when they have been awakened by a loud sound such as a cap-pistol shot they again drift off into slumber within seconds. Apparently monkeys are unable to keep themselves awake by spontaneous mental activity, as human subjects do, at least for some time. (b) Chronic Fatigue In these times of tenseness and of high-pressure activity many people habitually fail to sleep sufficiently, and it is easy for anyone to find a number of acquaintances who are chronically tired. Although they have no neurologic defect, it is difficult for them to stay awake over an extended period when they are not engaged in some activity. The pupils of such people have "fatigue waves" to an exaggerated degree. When they are tested as described above, the initial period of wakefulness with large, steady pupils is short; and as their eyelids droop and fixation becomes unsteady, the pupils shift erratically over a wide range. Soon the striated muscle tone relaxes so that the head sinks down unless supported; then the eyelids close, the globe moves upward, and sleep ensues (Table 10-1). Under the same circumstances of life the same person tends to show the same pattern of pupillary fatigue waves in repeated tests; and the traces of identical twins are so similar that they are difficult to tell apart (Figure 10-4). Resistance to outward stress, the need for sleep, and the patterns of falling asleep are deeply ingrained traits in each personality. The particular pattern shown by a given person under a given set of conditions changes, however, when the physiologic state is altered, for example, by a period of sustained stress or by some general disease. During such states of reduced vitality, the subject's exaggerated general tiredness is paralleled by exaggerated pupillary fatigue waves (Figures 10-3, 10-5, and 10-6,A). And as the individual recovers and normal strength returns, the excessive pupillary signs of fatigue are wiped away (Figure 106,B). Old age also exacerbates fatigue reactions of the pupils. Old people's pupils on the average are smaller than those of younger people. The periods of full alertness are shorter, those of tiredness with fluctuating pupil movements more frequent, and the change from wakefulness to drowsiness more sudden than they were in the same individuals when they were young (see below). In all stages of life there are, however, marked individual variations. Some people are tense and highstrung. They rarely relax. They are on the go all the time and wear out their friends and relatives with their hyperactivity. During the pupil test, while sitting in darkness, they can hardly wait to get up again and move around; and they are busy planning what they will do next. Their pupils remain widely dilated and do not oscillate. Others are easily fatigued. Though they sleep 8 mz=~-=------ I Table 10-1. - Pupillary signs of fatigue, and related phenomena YEAR AUTHOR * 1906 1922 1923 1924 1924 1926 1927 Kutner Pietruski Kleitman Guglianetti Hess Lowenstein Lowenstein & Wes!J:!hal Kleitman Simonson & Hebenstreit Lowenstein Guerra Jores p p p 1929 1930 --- 1933 1935 1935 1935} 1936 1937 1941 1942} 1943 1942 1948 1948 1948 Lowenstein - YEAR Ace p p 1951} 1952 1953 p p 1953 1956 w p 1957 1957 1957 1959 1959 1961 P,W (24 h} p (~ ,Ace P,V Lowenstein & Friedman Del Zo:e:eo Morone Simonson & Brozek(a&b) p 1961 1961} 1962 1963 1963 1964 1964 PV p FFF, V,P 1979 p --1979 p -- 1979 1979 1982 p p P,E 18h 1983 * YEAR p DBring & Schaefers OOring & Schaefers Lowenstein & Loewenfeld Busch & Wacholder Rossi Edwards & Li:EJ22ld Breinin Kleitman Rossi Graf Morone Lowenstein & Loewenfeld Scholander Dureman & Scholandcr Lowenstein & al Tiedt Berlucci & al Elul & Marchiafava 1951 Halsted Bartley ADDITIONS 1964 Lowenstein, Kawabata & Loewenfel!:! --1966 Loewenfeld 1969 Lowenstein & Loewenfeld 1972 Loewenfeld 1976 Utsumi, Ishikawa & Kimura AUTHOR 1950 1964 (24h} 1965 1966 p p 1969 FFF 1969 p 1969 1969 0 EOM p 1969 1970 1970 1970 1970 p 1970 p 1971 (P) p w p p 1972 1972 P (24h) P,EOM 1973 1974 Ace Frankenberg _(gekko} Karlsen & Sli Lavie Loewenfeld Kollar its, Lehman & Gillin Kollarits & Gillin 1983 24h P p ---1984 P {10h) ---1986 p p 1984} 1986 p AUTHOR * Lowenstein & Loewenfeld Borgman Voloshin & Bonvallet Berggren & \Wlinder Bonvallet & Voloshin Buren Yoss, Moyer & Ogle Yoss (a 1 b,c} Bobo &Bonvallet Bonvallet & Bobo Yoss Yoss, Moyer & Hollenhorst Yoss & al Simonson Bonvallet & Bobo Geacintov & Peavler Knopp & al Daly & Yoss p P (24h} P,Acc Ace P,Acc Ace P** P** P,Acc P** P** P** PW P 1 Acc p p P** Pressman &al. Pressman & al. Pressman, DiPhillipo &Fry p Loewenfeld p P,A p In Column*, P means pupil (as secondary consideration when in brackets); 24h, 18h, 10h means daily rhythm, observed over the time periods stated; ** = further descriptions of Yoss and co-workers' work is given in Chapter 37. A = ageing vs fatigue; Ace = accommodation vs fatigue; E = endocrine mechanisms; EOM = extraocular muscles vs fatigue; FFF = flicker fusion tests vs fatigue, and O = other tests; W = work phys iology, and V = visual fatigue. See Table 9- 7 for literature Table 10-2. YEAR concerned and arousal as related to brain stimulation. Experiments on diurnal pupillary changes AUTHOR SUBJECTS --1950 D~ring & Schaefers 6 1963 Tiedt 7 1965 Borgmann 9 --- with sleep Ex* --3h --? --- 2h TOTAL TIME 1-(7) d** 72 h ? PUPIL SIZE EXTENT max min max 8AM 2-5AM - night day day night 1976 Utsumi& Ishikawa 4 1979 Lavie 8 --- 8AM --- --- --- 3h 18 h 6AM 15m 10 h 75-125 m rhythms --- LIGHT REFLEXES night --night SPEED min - max - night 3-6PM day day 2-8PM 6AM min midnight night --6AM 75-125 rhythms ID 2-8PM light reflexes not in phase with diameter Ex* = examined at intervals given in this column; **=four subjects 1- 2 days, one each 2 - 3 days, and one 7 days; h =hour; d = day; m =minutes; TOTAL TIME = total time of observation; max = maximal, min= minimal, and - = not stated; ? = not clear from text. Note the small numbers of subjects and the short periods of observation, which may explain the inconsistency of results among authors. Utsumi and Ishikawa discussed the large inter-personal variations observed, and possible relations to diurnal changes in biochemical (endocrine) systems. In their own subjects blood cortisol levels parallelled the pupillary changes. For Utsumi & Ishikawa, read Utsumi, Ishikawa and Kimura. 484 10. Reflex Integration: Pupillary Consequences (c) Diurnal Changes Off and on it ha been said that the pupils show diurnal change , and this is true enough. But the generalizations that they are larger (or smaller) and more active (or le o) during the day than during the night arc as meaningles as any other flat statement about the pupil. The few studies about this ubject we could find were i~adequate both in numbers of subjects studied and in time of observation; and it i therefore not surprising that the re ults were diametrically opposed (Table 10-2). 1 But even if they had been more elaborate, they . I. Two more recent paper , one by Utsumi, Ishikawa and Kimura ( 1976) and the other by Lavie ( I 979), are not included here. ~ 2 I 1$~ ---~-A ·I , 1 1 z -1 1 485 still must of necessity have given distorted answers, since individuals awakened at various times during the night can hardly be equated to those spending their nights peacefully sleeping. The neurologic mechanisms of sleep and wakefulness have been discussed in Chapter 9. The pupillary phenomena that accompany these states are well known. Pupillary size parallels the changing levels of central nervous integration: the more aroused the subject, the larger the pupils; and the deeper the sleep, the smaller. In fact, the tightening miosis observed when "desynchronized REM sleep" develops from "slow-wave synchronized sleep" was instrumental in the realization that-despite th-e activated EEG-"desynchronized sleep" is deeper than "slow-wave sleep." During the waking hours of the day, also, as has been seen, the pupillary size is at all times linked to the momentary level of wakefulness and of mental and emotional stimulation. And everyone knows full well that these can differ during different time of day, and at the same times on different days, depending upon a great many external and internal conditions . Besides these, different people have different habitual patterns of diurnal sleepiness. Ogden Nash described to 11 hour every night they barely manage to get through the working day; and their favorite sport is no~zing in front of the televi ion creen. During the pupil test they droop off quickly, and large fatigue waves of their pupils accompany the ups and downs of their dro~ ~ state. Such " leepy normal" people' pupils and their lifestyle approach those of pathologic sleepines as described in Chapter 37 ( ee Figure 10-7). 1 / rn ~ ; -fu~Bfr==,-~ 3 -- -- z ,--;- ,- l - i o.,stt .... 7 C ::Bl I ,. s stc.- ,. IS ,s .,s •o b--b ·t 7 :--B2 sec.... \,.... / - ~ s ,o IS 1• ,. 2J lJ .. •o - .. ...... .. 9 a 7 ~- b ,5 ,.tB3 3 <: / V\./""'o. V /"'i./ \.I • ... : •' ,,, ,. ,. sec.~igure l~-5. Spontaneou p~pillary movement in a chronically tired subJect. Record of the right pupil are shown (original pupillograms). Both the time and amplilude axes were reduced to halfsize in Bl to 83, because of the large extent and long duration of these move~ents. The subject, a 3 -year-old woman, had been healthy un!Il some weeks before the te ·t, when she had had extensive abdominal surgery. After the operation she was always tired, and slept several hour more per day than she had done before. At the beginning of the test she was alert, and both her pupillary dian:ieter and her ~ight reflexes w~re normal for her age (line A). During the first minute of the fatigue te t, the pupil remained large and stable (line BI). oon, however, irregular fluctuations ,. .. JO ------ .. --...... \ 4"0 ~ -..,. a --.i"H.-"--. a.ppeared, and the ~mall, fast dips associated with imperfect fixation became more frequent (bin line B2, during the eighth minute of the test). Thereafter, both types of pupillary oscillations became e~aggerated. :be pupils dilated and constricted in extensive waves, m parallel with frequent periods of extreme drow iness and subsequen~ arou~al (BJ, recorded during the sixteenth minute ~f the_t~st). This sub~ect was myopic, and her pupillary contractions sharpened the unage of the dim red fixation point which was out of focus when her pupils were large. She therefore could ob~e'"".eher own pupillary movements, and relate them to her subJect1ve state. (From 0. Lowenstein, R. Feinberg I.E. Loewenfelcl Invest. Ophrhal., 2 [ I 963): 138) ' ' 486 / I. Anatomy and Physiology how ' sleep is like a bashful maiden" who lets the late-awake-late-sleeping man wait and wait, while on the opposite side of the globe, where people have to get up, "she lingers." Other, more fortunate individuals proclaim the virtue of their "early to bed and early to rise" sleep-waking pattern that is so useful to chickens. Obviously, diurnal pupillary changes cannot be expected to be the same in these different groups of the population. Twenty-four-hour and other rhythmic cycles are, of course, common in many systems; and I do not wish to create the impression that I deny the existence of such variations for the pupil. However, as explained here, there are many factors that can modify or override them in the busy life of man. 0 We found, in experiments on hundreds of normal subjects, on thousands of patients with various diseases, and in longitudinal studies on ourselves and others over more than four decades that pupillary size and reaction patterns alway~ parallel the degree of arousal or of fatigue; and that they agree with the subjective sensations connected with these states: if the person feels tired, the pupils show fatigue signs; and if the person feels wide-awake, they do not. This is true in the morning, at noon, and at night. In fact, we are convinced that someone who says he is tired but has large, quiet pupils for more than 10 or 15 minutes while sitting in the dark with nothing to do is not telling the truth. 2. Light Reflex Changes In a given person a series of light stimuli rarely elicits a series of uniform light reflexes. For each combination of stimulus parameters, the pupillary system requires a minimal time to regain the pre-stimulatory equilibrium of sympathetic, parasympathetic, and central inhibitory forces. If the intervals between light flashes are too short to allow this recovery, the stimuli will interact: from reaction to reaction the neural balance will shift; and consequently the reflexes will change in extent, in speed, and in their time-amplitude pattern (Figure 10-8). 2. 5~-=-==--------------------~ 5 A ' ~ <., ~ ::, . 't .... "' <:, I:: ::, II 10 8 "' .... <> <: B 14 ~7 E6 ~ 13 12 10 II e 9 "Units ,,. min.- 13 6 B IS Figure 10-6. Spontaneous pupillary oscillations in a chronically tired subject. The record was obtained from the same subject as in Figure 10-5, 2 weeks later (Al to A4) and 2 years later (B). Intermittent periods of irregular pupillary movements first appeared during the second minute of observation (Al). They became more frequent and extensive with time, until finally the subject no longer could rouse herself, and the test had to be discontinued (twelfth minute, line A4). Note that the pupillary fatigue waves are not related to lid-close reactions (indicated by dots): in complete darkness, spontaneous closing of the eyelids is not accompanied by pupillary contraction, except at the moment of falling asleep (last lid closure in A4 of this record). Two years later, the effects of the operation had been overcome completely. The subject felt well and was no longer chronically tired. The record shows no irregular pupillary movements (twelfth to fifteenth minutes shown in B), and the subject was able to continue a series of similar experiments for several hours. (From 0. Lowenstein, R. Feinberg, and I.E. Loewenfeld, Invest. Ophthal., 2 [1963):138) 7 - - 14 4 2 3 Sleepy - - - Severe i !!; of sleep " - - - ~~~o_l_t- Mild i MoTte 13 12 t 1 1 II Figure 10-7. Limits of pathologic somnolence and "sleepy normal" population. In A the distribution curve is drawn for hours of sleep per night in a general population. Patients with pathologic sleepiness are on the extreme left (11 hours or more). Boutlines the border area between "sleepy normal" and pathologic somnolence (see Chapter 37). (From R. Yoss, Mayo Clin. Proc., 45 [1970):426) 10. Reflex Integration: Pupillary Consequences Ju ta for the pupillary diameter, the mo t important factor for fatigue change of the pupillary light reflex is the phy iologic and mental tate of the individual at the time the te t i done. A a per on become leepy, reflex fatigue, that i th decrement of functi n brought on by repeated timulation, i uperimpo ed upon the pontaneou fatigue wave of pupillary ize: reflex fatigue i greatly exaggerated in tired people during the downward drift from vigilance to leep; and it i rever ed when the ubject awakens and the pupil enlarge (Figure 10- to 10-11). This unsteadine of the reflexe that alternate between deterioration and pontaneou improvement is a mo t eharacteri tic indicator of tiredne a distinct from permanent reAe deficit due to di ease or in old age. Individual variation in degree and in time pattern of leepine and wakefulne also are reflected by the pupillary movement . ChronicaJly tired people have light reAexe that deteriorate quickly upon repeated timulation; and psychosensory stimuli improve them (Figure 10-10 A). In contrast hyperactive, ten e people have reflexes that are spontaneou ly inhibited. After repeated light stimulation thi inhibition lessens, and smoother, more exten ive reflexe are observed, while p ycho en ory timulation tend to uppress the reaction even further (Figure 10-12,A). And again, the normal aging proces reduce central 9--------------------~ al-, --~~~==-~~-------------I 71-11 6--v1 ---:l-:-"', -----==-= - >\ -· ..\,- -•-----,--:--==···· Ill ---:-:.: ..!... .. I ··-- ~\\ ~,, ~!':<-··· :.;__ ___ "7°" s-,----1--\~,,---Jl--------~ ~. ' {(,:• \\ 4-----1--\ t 31 E• I _••_•~I--•!~~---~ Light E 2 .!----1..-,H-.-,! seconds--. ,...., '-t.···"--------------l ~-· '· !n-! r-r! ! TT!1+rnn-r-rTTT1rTr-rTTTI'TTTTTTI"TTrrrn"TTT......., 0 1 2 3 4 Figure 10-8. Pupillary reflex fatigue in a per n who wa not tired. The ubject was a healthy, alert 19-year-old girl. After 6 minutes in darkne her pupil were large. ix I- econd light flashes of medium inten ity ( LSfoot-candle ) were given, with 3-second dark inteival . The first, econd, third, and ixth reactions are hown (marked I to VI). ote the light decrement of reflex amplitude and the hift in timing of the light reflexe : the early phase of the contraction movement decrea ed I markedly than the later phase. Peak contraction peed wa enhanced from 6.05 to 7.2 mm/ econd from the fir I to the la t re pon e. _j / 487 inhibition of the ligh! re~~x, togeth~r ~~t? th_e decline in general exc1tab1hty: reflex ~nh1b1t1on1s powerful in children an? young anu~rnls. T~ey have large pupils and vanable, rather mextens1ve light reflexes that are easily blocked by psychosensory stimulation (Figure 10-10,C). ~d oI~,re?ple with smaller pupils have more dtstmct fatigue shapes" of the light reflex than do younger ones under the same experimental conditions (see below). Light stimuli of different intensities, durations,_ and frequencies produce different degrees of reflex fatigue, as can be seen in the following experiments. -The reflex fatigue shown in Figures 10-8 to 10-10 was brought about by moderately bright ("standard") 1-second light flashes, presented at a 4-second rate. Under these conditions the pupils were unable to recover their full diameter between each reaction and the next; and consequently they became smaller after repeated stimuli. With sufficient numbers of such lights (and in the absence of psychosensory stimulation to restore mydriasis) the reflexes can be reduced to virtual extinction. -Reactions to shorter light stimuli of the same standard intensity and rate are more resistant to progressive reflex fatigue, since the effects of each light are more quickly overcome. In contrast, very bright light flashes, or prolongation of those of moderate intensity, will rapidly drive the pupils below their linear range of movement into miosis, and repeated stimuli will then elicit only small responses. -Dim light flashes do not cause reflex fatigue at all, since the influence of the first flash upon the retina and the pupillomotor system has faded to insignificance before the next one is presented. In wide-awake people such reactions therefore can remain uniform for long periods; and in tired people they merely reflect the ups and downs of the spontaneous pupillary fatigue waves upon which they are superimposed: during the declining phases of these waves they are facilitated; and during the ascending phases they are suppressed (Figure 10-13). In general, their amplitude is larger in calm than in excited individuals. 2 -Diffuse background illumination also affects the pupils differently in tense, hyperexcitable people than it does in those who are calm or tired. The higher the level of arousal, the less effective is a given intensity of such background light; and the more tired a person, the more extensively will the pupils contract to the same light (Figure 10-14). And again, the light reflexes will be enhanced in excited people by diffuse background illumination, while they will be markedly depressed in those who are tired (Figures 10-15 and 10-16). 2. However, at the bottom of the valleys of fatigue waves, or when_ the pupils are tested with the subject near sleep, the reactions to weak stimuli may decrease. 488 / I. Anatomy and Physiology 21 ,,"" - --a 7' ~ b =:? a - I 3't 7 , 6 - t5 E If E 3 '"";---=-==• a 7' / -- "Ill,. b / a Ill o.,s~c....... Figure 10-9. Light reflexes in a tired man. The record was obtained from a healthy but extremely tired 35-year-old man. He had worked throughout the night and had been awake for 32 hours at the time of the test. As he gradually drifted toward sleep, his pupils became smaller and smaller. The light reflexes became les and les extensive and showed a variety of time-amplitude -A 8 7 6 5 4 3 2 ·- ---~ -2- ------1 ······---✓-!---;,':::r:::::::::::: ,,,_ _3_ l::-:-- 7 6 5 4 t~ E E <Q; vE w;g~ -- C: 2 -~ -0 time in 0. 1 sec. ➔ -,-1----l -----1 patterns: square, w- and v-shaped. Finally the pupils had become quite small and hardly responded to light (thirty-fourth reaction). At that time the subject was awakened by a sudden, loud sound (arrow). The pupils dilated rapidly and reacted well to the following light flashes. (From 0. Lowenstein and I.E. Loewenfeld, Annis. N.Y. Acad. Sci., 117 [1964]:142) Figure 10-10. Influence of sleepiness and of excitement in a monkey (A), man (B), and rat (C). a, darkness; b, light stimuli of IS-foot-candle intensity. Because of the differences in ocular size, the horizontal corneal diameter (from limbus to limbus) was used for each species as enlarging factor for the ordinate of these records. The pupillograms show the reactions of one eye (solid lines). The dotted line in A represents the width of the monkey's palpebral fissure. The sudden, deep dips in this line are eyeblinks. A: As the monkey (macaca mulatta) gradually fell asleep, his lids drooped and his pupils contracted. The light reflexes that were superimposed on this movement deteriorated quickly. B: In a very tired human subject the tenth light reflex measured less than a millimeter in extent and was square-shaped. A sudden sound stimulus (arrow) aroused the subject and restored the light reflex. C: A rat was frightened by sensory stimuli that were applied between three successive light stimuli (shouting and blowing into the animal's face). The pupils became very large and the light reflexes were suppressed. 10. Reflex Integration: Pupillary Consequences / 489 7 j =, -- = ~ 6 "Ii J· 1 1 'l. ... f 111111111111 11111 111 11111 Tl TTT l: num6er oF light ~c'tlons 7 .----,.,-,-1'11 nu.mMr l,1111111111111111111111 i---L- ililTTTTTT Figure 10-1 I. Effects of general fatigue upon pupillary diameter and light reflexes. The records were obtained from a healthy 24year-old medical student. A, before and B, after a tiring day in a busy clinic. In A, seventy-three, and in B, seventy-six, consecutive light reflexes were recorded (light flashes of I-second duration, 15-foot-candle intensity, with 3-second dark-inteivals). The top lines (solid) show pupillary diameter at the beginning of each light reflex, and the bottom lines (broken), the amplitude of the corresponding light reflexes (both in mm). The small broken vertical lines mark off consecutive fatigue waves of the record. Note how the subject's natural rhythm of pupillary dilations and contractions, and of the parallel ups and downs in reflex amplitude was deepened and accelerated when he was tired. (From 0. Lowenstein and I.E. Loewenfeld,J. nerv. ment. Dis., 115 (1952]:121) OF l<ght reeu'tio,t4' Figure 10-12. Light reflex and psychosensory effects in tense (A) and in tired subjects (B, C). A: The subject was a 27-year-old man. From early childhood he had always been hyperactive. In school and later at work he was the leader who got things started (though not always finished). He slept only about 5 to 6 hours each night without feeling tired, and usually was busy with several projects at once. His tenseness and impatience made him somewhat trying to his friends and family. His first light reflex was inhibited, with shorter than normal contraction time. The fourth contraction had increased extent and speed, but a sen ory stimulus (sudden sound, at s) reversed this development, and the fifth reaction was inextensive, with premature redilation. B: The subject was a 32-yearold resident physician. He worked extremely hard at the hospital and had three small children at home. He seldom got enough sleep and was usually tired. Pupillary reflex fatigue was marked, leaving the tenth response inextensive and square-shaped. The sound stimulus elicited a strong reflex dilation and a fully recovered eleventh light reflex. C: The subject was a very tired 25-yearold fourth-year medical student who had crammed for weeks for final examinations. During the twenty-fourth light stimulus he was almost asleep, and his light reflex was reduced to a shallow w. A sudden, loud sound directly before the twenty-fifth light completely blocked the light reflex, but 4 seconds later, after the dilation movement had been completed, a good reaction was obtained. (From 0. Lowenstein and I.E. Loewenfeld,J. nerv. ment. Dis., 115 [1952]:121) 490 / I. Anatomy and Physiology C. Mechanisms important that the physiologic responses to acute, catastrophic stress should not be confused with the events that take place as a person gradually tires during a working day; for when a slight or moderate degree of stre s elicits a given physiologic mechanism, more intense tress need not only evoke more of the same respon e: additional, entirely different mechanisms may come into play (see, for example, "Humoral Mechanisms" in Chapter 6). The fatigue dealt with here also differs from that measured in experiments on physical endurance, as in ' work physiology," or in ports, in which signs such as accumulation of waste products in muscle, consumption of oxygen, depletion of tissue stores of glycogen and 1. Mechanism of "Fatigue Waves" of Pupillary Size The spontaneous pupillary oscillations described here are found in human subjects when- the day's ordinary wear and tear makes them feel tired. This kind of fatigue differs from the exhaustion of experimental animals under the influence of severe, acute stress, such as long hour of running on a treadmill uphill, or swimming, or being everely chilled for protracted period . These conditions bring about an outpouring of epinephrine, hypertrophy of the adrenal gland , and other chemical and anatomic changes. Such extreme conditions rarely play a role in civilized human life. After all, we are not caught on a ledge on the Eiger north wall every day. [t is Figure 10-13. Enhancement and suppression of low intensity light reflexes. The solid line represents the right pupil, the broken line the left pupil. The eyes were in darkness except for the period framed at Ir., when the right eye was exposed to dim light (intensity about 2 log units above the subject's scotopic visual threshold). First line: The subject was a 38-year-old healthy but very tired man. After the first light reflex he gradually fell asleep. During this time the contraction to light was enhanced and redilation after the light stimulus was absent. At the end of the third light stimulus the subject clo ed his eyes (ccc). Second line: Shortly before the fourth light stimulus he was awakened by a verbal stimulus ("wake up!"). The pupils dilated vigorously, and the reaction to the fourth light stimulus was suppressed. The fifth stimulus elicited a normal reflex. (From 0. Lowenstein and I.E. Loewenfeld, Amer. J. Ophthal., 48 [1959]:87; published with permission of The American Joumal of Ophthalmology, 0 The Ophthalmic Publishing Company) "'I "'lt------+---1------1 6 1-------1 s -------- t ,,1----.s~= -- =_=-_=_~=:; -- ----=---- £:3 E~~--nrrrmTTITTmmcrrlrrTTTTTmmnrnTTTITmmfnmrrnl-=n~~~~~~ o.,.s~c.- qt-- .. ------------- 8 •••••• •• ,-------------------------~-·················--·············· ---~- ---------;;.--i •U e t5 ~-<---------1 '--------~--------~ 'I- ~3r~~-~~------'~--' ~2 ....... . .....~1····--······························· -..... -~ ---;;;-,--'------- ...... ____ __ __ ,_---~'-;~------'--_-_-_'_,_-_'_'_-_,_-_-_-~~----------~ sec~ Figure 10-14. Effect of dim, steady illumination in three normal subjects. At a the subjects had been adapted to darkness for 30 minutes. During the time beginning at the arrow, both eyes were exposed to dim, steady, blue-green light of about 4.5-log intensity above the subjects' scotopic visual threshold. A (dotted line): The subject, a 22-year-old woman, was in good health but often felt tense and irritable for days, without apparent reason. She had difficulties falling asleep at night. Even during lengthy pupillary fatigue tests she never became drowsy. When the dim light was turned on, the pupils contracted but almost at once began to redilate, with shallow oscillations. After 2 minutes of adaptation to the light they had returned to nearly their dark-adapted condition. B (solid line): The subject was a normal, well-rested 24-year-old woman who had a calm, well-adjusted personality. Her pupils contracted more extensively to the dim light than those of subject A. They did not escape the effects of the stimulus. but redilated slowly and partially. C (broken line): The subject, a 36-year-old man, was generally healthy but was always tired because he seldom slept more than 5 hours a night in order to satisfy the demands of a family, a strenuous full-time job and additional evening studies. During pupillographic fatigue tests he usually fell asleep after about 10 minutes unless kept awake by conversation. His pupils contracted extensively to the dim light. The light-induced oscillations were vigorous and sustained, and the pupils failed to redilate to a substantial degree upon adaptation to the light. (From 0. Lowenstein and LE. Loewenfeld, Amer. J. Ophthal., 51 [1961):644; published with permission of The American Journal of Ophthalmology, c The Ophthalmic Publishing Company) 10. Reflex Integration: Pupillary Consequences other ub tance and other biochemical change are dominant feature . While u tained phy ical effort ta,ces the capacity of the body and one of it biologic con equence eventually will be tiredne , a runner who ha just cracked the 4-minute mile may be winded, but he is not about to fall a leep. The decrea e of contractility of isolated mu cles or the dimini hed output of trenuou physical work after repeated effort are not the ame kind of fatigue we experience when we ay ' I am tired" after a long monotonou day in the factory or office. This wearine need not be a ociated with muscular fatigue or other ign of phy ical tre • and it can be abolished from one moment to the next by p ycho ensory stimulation: whiJe we are drifting into lethargy, a thunderclap an unexpected plea ant or unpleasant event that touche our emotions, or a udden idea that stimulates our imagination can in tantly reverse the proces : alertnes i re tared and it may be maintained for a long time. Pupillary fatigue waves are thus associated with that kind of tiredne that normally lead to sleep and not directly with other phy ical or mental consequences of activity. What is the mechanism of the low, large waves of pupillary dilation and con triction that accompany the waves of somnolence and of arou al in tired people? (a) Sympathetic Excitation and Deficit Mydriasis often was thought of as due entirely to sympathetic activity, originating in the caudal hypothalamus; and miosis to lo s of ympathetic innervation and consequent preponderance of para ympathetic tone. But central integrative proce e re ult in reciprocal as ocia- I 491 tion of active sympathetic with inhibitory parasympathetic mechanisms or the reverse. This is true for any kind of pupillary dilation or contraction movement, and it is true for the pupillary fatigue waves as well. The sympathetic nerves serve as efferent pathway for these oscillations· but they are not alone responsible for them. This can be proven by interrupting the cervical sympathetic chain, or by paralyzing the dilator muscle with sympatholytic drugs. These measures reduce the amplitude of pupiJlary fatigue waves, as seen in Figure 10-17,B: as the pupils contract in the sleepy person, the difference between the sympatheticaJly denervated and the normal pupil becomes smaller, and during arousals it becomes enlarged. In addition, the spontaneous pupillary dilations of fatigue waves are slowed down on the sympathectomized side just as are those elicited by psychosensory stimuli (s in Figure 10-17,B). However, the pupillary fatigue waves are far from abolished by sympathetic denervation; and their rhythm, when compared to the normal pupil, is not modified. (b) Modulation of Parasympathetic Outflow These residual oscillations after sympathetic denervation must be transmitted by changes of activity in the only other efferent pupillary path, that is, by alterations of parasympathetic outflow to the sphincter muscle. It is easy to prove that this assumption is correct: paralysis of the sphincter muscle by lesions or by atropinic drug reduces the extent and speed of pupillary fatigue waves, again without affecting the rhythm of contraction and enlargement as such (Figure 10-17,A). A t 6 ~ 5 t ,, ~~~llllllll!!Diilll!lll!IIWIIlllllllI!miiimJtmnmmllWl!I!IIlllllllIIlllwimmliamllWl!I!IIl• 7 -✓---------1 ~3 ~2mai-n-r+rrrn-~~~~~~~~ 0.1sec. ➔ Figure 10-15. Reflexe elicited by 1- econd light fia he in three normal subject ( ame ubjects a in Figure 10-14). At a the eye had been in darkne for 6 minute . During the time framed at b they were exposed to the tandard 15-foot-candle light. ompared to the reflex of ubject B, that of was light! inhibited, and that of C slightly depre ed. (From 0. Lowen tein and I.E. Loewenfeld, Amer. J. Ophthal., 51 (1961):644; publi hed with permi ion of The American Jou ma/ of Ophthalmology. The Ophthalmic Publi hing ompany) F_igure 10-1~- Effec_tof a_daptation to dim illumination upon pup11laryreaction lo bright hght (same subjects as in Figures 10-14 ~nd _10-15). At a b~th e~es were in darkness (upper solid lines) or m dim blue-g_reen 11l~mmat1on ~lower broken lines). During the l-second periods b, light stimuli of 15-foot-candle intensity were presented to the nght eye. The adapting light was the same used m the exp~rimenl of Fi~ure 10-14. In the tense, excitable subject ~• the pup_1lwas only shghtly smaller after adaptation to the dim lig_htth~n It had been i~1darkness, and the reflex elicited by the bn~ht light flash was slightly enhanced by this background illumination. In the well-rested, calm subject B the difference between t~e p~p1llary diameters in darkness and after adaptation to the di_mlight was greater than in subject A, and the light reflex was slightly ~educed after light-adaptation. In the fatigable subject c adaptation to the ~im lig~t had a profoundly depressing effect ' upon bot~ the pup11lary diameter and the light reflex. (From o. l.ow~nste1_nand I._E.Loew~nfold,Amer. J. Ophthal., 51 [1961]: 644), published with perm1ss1on of The American Journal of Ophthalmology, e The Ophthalmic Publishing Company) 492 I l. Anatomy and Physiology (c) Central Nervous Integration Both sympathetic and parasympathetic nerve , cooperating in reciprocal fashion a they do in all pupillary movements, thu constitute the efferent path for fatigue oscillations. When either path i interrupted, the fatigue waves are reduced; and when both of them are eliminated the pupil arc fixed. But neither of them i re pon ible for the rhythm of the e o cillation , which continue unchanged in the ab ence of either one. The fatigue waves cea e when a period of leep ha re tored the brain' capacity to maintain a teady equilibrium of wakefulne (Figure 10-18). And irnilarly, centrally acting drug uch a caffeine or amphetamine aboli h them together with all other physiologic sign and ubjective feeling of tirednes (Figure 10-17,C and D). The fatigue wave of the pupil thus have their origin in the un teady, variable level of central nervou integra- l ---V ,.. r-------.....r II 10 12 2. Mechanism of Small, Rapid Pupillary Oscillations The irregularly occurring, small dips in pupillary size often seen in the records of sleepy people (Figures 10-1 and 10-5) have a different mechanism. They closely resemble small light reflexes in their configuration and timing; and further, they arc absent in excited individuals who e light reflexes are inhibited; and they are abolished by conjunctival instillation of atropinic drugs. _,... s tion in tired people. During gradual failure of the brain's arou al y tern sympathetic discharges to the iris wane; and simultaneously, parasympathetic firing accelerates, due to reduced inhibition of the Edinger-Westphal nucleus; and in rever e, spontaneous or reactive increases in arousal enhance the sympathetic outflow and strengthen the inhibition of the Edinger-Westphal nucleu . While the brain of tired people hover between wakefulness and leep, such spontaneous arousal reactions alternate with gradual reductions of the level of con ciousnes , until sensory, mental, and emotional stimulation or the individual s will to stay awake, come to the re cue and restore a state of vigilance; or until lethargy grows irresistible and leads to sleep. ll 0 min.-. 71 71---------------------------1 b -~~f~ ts D _ !::~------------------------~ f:: 11 12 __ ......................... .................................... ...__..._..... 13 ,_ _...,_;.__.....,, ............ _._ 3 2 .. t 3- 21. Figure 10-l 7. Effects of drugs on pupillary fatigue waves. Three experiments are shown, done on three different, tired subjects. A, a 51-year-old man; B, a 21-year-old man; C and D, a 38-year-old woman. In A, the parasympathetic inneivation of the right eye (dotted upper line) was abolished by two drops of0.5% cyclopentolate, instilled into the conjunctiva] sac an hour before. In B, the sympathetic neives to the left eye (cros ed lower line) were depleted by two drops of 5% guanethidine (lsmelin) that had been instilled the previous day. Note that in both experiment the fatigue waves of the treated eye were reduced in extent while their basic rhythm remained the ame as in the untreated eye. In C, no drug was given. The subject was tested in the evening. after a 13hour working day that had been preceded by only 3 ½ hours of sleep. Since she made no attempt to stay awake, she fell asleep at the end of the eleventh minute of the test (last lid closure, marked by a dot). At this time, 10 mg of Benzedrine were given orally. One hour later the ubject felt wide awake and slightly tense and excited. The pupillary fatigue wave had vanished. D hows the record between the eleventh and the fifteenth minute of the test. (From 0. Lowenstein, R. Feinberg, I.E. Loewenfeld, Invest. Ophthal., 2 l 1963]:138) I B i1 L,__ ,__ ,________ Omin.- .,____ _,_._,_ 2 3 Figure 10-18. Pupillary fatigue waves relieved by sleep. Two experiments were done on the same normal subject, a 72-year-old man. At the beginning of each record the right eye had been adapted to a standard 15-foot-candle light for 2 minutes. The graph begins at "light-off." A: At 6:00 P.M. the subject was tired and his pupils started to oscillate directly after the first redilation in darkness. Beginning after the second minute of the test, repeated sensory stimuli were needed to keep him awake (sudden sound, marked by black triangles). During the sixth minute (not shown) these lost their effectiveness, and the subject was unable to keep awake. The experiment was stopped. I le was given an opportunity to rest and slept for an hour. B: At 8:00 P.M. he felt well. His subjective sensations of tiredness and the pupillary fatigue waves were gone. (From 0. Lowenstein, H. Kawabata, and I.E. Loewenfeld,Amer. J. Ophthal., 57 [1964]:569; published with permission of The American Jou ma I of Ophthalmology, The Ophthalmic Publishing Company) 10. Reflex Integration: Pupillary Consequences From our ob ervation and e pecially from experiments on our elve with the far fixation point thrown out of f~cus by weak plu len e , enabling u to ee our own ~up1llary movement by their effect upon the blurred image of the far fixation light, we think the following ~appen . When a per on grow leepy it become 1~creasingly difficult to maintain teady fixation upon the distant fixation light; and at interval the ubject becomes aware of having drifted off the mark. A mall, corrective eye movement i invariably followed by one of these little dip in pupil ize. We think thi i due to light stimulation of the dark-adapted retina a the image of the dim red fixation target i wept aero it toward the fovea. Ogle and co-worker (1964) have recorded imilar small pupillary movement when the image of the far point was moved on the retina by pri m ( ee Chapter 5). 3. Mechanism of Light Reflex Changes (a) Sympathetic Innervation A wa the case for the fatigue waves of pupillary ize fatigue pattern of the light reflex were a cribed to defect of ympathetic innervation (see Lowen tein, 1937). Thi view agreed with a number of phy iologic finding . For example, Orbeli, in 1924, found that the gastrocnemiu mu cle of the frog, fatigued after repeated contraction due to electric tirnulation of the seventh to ninth pinal nerve reacted with renewed vigor when the ympathetic nerve upply of the leg was timulated; and Maibach ob erved (1928) that the ame improvement of the contraction could be produced by adding adrenaline to the bath in which the mu cle wa immer ed. Hunter (1925), after depriving one wing of bird of its . ympathetic innervation, aw that thi wing fatigued more readily than did the normal one during prolonged flight; and oate and Tige (1928) had similar re ult with goat and dog : after extirpation of one lumbar mpathetic trunk the ga trocnemiu and anterior tibial mu cle fatigued sooner on the operated than on the normal ide. Hunter (1932), recording action potentials from corre ponding mu de of the normal 1 Figure 10-19. Reflex fatigue and ympathetic innervation. and A1 : Pupillogram and peed curve. of the first, second. and fourth of a erie of light reflexe (normal man). The extent of contractions decrea ed lightly, and the reflex shape was m dified. shown by the speed curve in ', there as an early bur t of c ntraction peed in the econd reflex, foll wed by rapid deceleration, o that a relatively large part of the c ntraction occurred in the early pha e of the reflex. The e feature were even more marked in the fourth reaction. B' and B': First .. econd, and fourth light reflexes of a young, leepy cat who. e left eye had been ympathectomized ome day before. The fir. t reflex of the pupil on the operated ide (broken line) howed an early. increa ed peak of contraction speed. compared to the reaction on the normal side. Upon repeated timulation, the difference between the cat' normal and ympathectomized pupil ' reflexe. faded away. (From O. Lowen tein and J.E. Loewenfeld, J. nm. ment. Dis., 115 ( 1952): 1) / 493 and the sympathectomized leg of d~cereb~ate frogs, found, upon bilaterally equal st1mulat10n, weaker discharges of lower frequency and shorter duration on the sympathectomized than on the normal side (for more experimental evidence, see Cannon, 1915, 1953; Simonson, 1971). All experiments indicated that sympathetic denervation increased the fatiguability of skeletal muscles while sympathetic stimulation counteracted the fatigue. The decrease in extent of pupillary light reflexes upon repeated stimulation, and their subsequent recovery upon psychosensory stimulation, resembled these effects; and further, psychosensory reflex dilation of the pupil, which had this beneficial influence upon the flagging light reflexes, derived most of its amplitude from sympathetic activation. In addition, the early change in the shape of light reflexes due to repeated stimulation ( or during general fatigue) resembled that seen after cervical sympathetic denervation (Figure 10-19): the contraction was slightly accelerated, compared to that of the fir ·t reflex; a higher peak of contraction speed was reached earlier and was then quickly lost, so that a relatively large part of the contraction movement occurred during the early phase of the reflex, and only a little occurred later. In fact, after a number of reactions, the sympathectomized and the normal pupil reacted quite alike, indicating that the sympathetic influence upon the reaction on the normal side must have faded away as a result of the reflex fatigue. (b) Central Nervous Integration The idea that decreased and increased sympathetic efferent discharges, respectively, played a role in the !:~ ! • 1=-~1- --~--~2 ~ ~ - --- llght --- Ilg ht 4 494 I l. Anatomy and Physiology production of light reflex changes during fatigue and arou al was therefore quite correct. However, as for the fatigue wave of the pupil, this was only part of the story. With deepening lethargy (or more numerous light stimuli) the reflcxe continued to disintegrate and reflex hape appeared that were not accounted for by peripheral ympathetic deficit alone: quare- haped, or flat wor v-shaped reactions, and sluggi h remnants, as een in Figure 10-9. Some of the e reflex shapes were encountered a permanent defects in monkey with electrolytic le ions in the hypothalamus and in the diencephalicmesencephalic area ro tral to the third nerve nucleus (Figure 10-20). Such lesion interrupt inhibitory impul e to the para ympathetic Edinger-Westphal nucleu from more rostrally located areas; and conversely, electric stimulation in the same rostral areas activates inhibitory impul es and can block the light reflex. The ame mechanism i responsible for the tight mio i in Jeep, in anesthesia, and in decerebrate animal : it i due to vigorous firing of the pupilloconstrictor neuron when they are relea ed from inhibition. This ha been proven by many investigators, as described in Chapter 9. In fact, the experiments of Figure 9-25 demon trate that peripheral adrenergic impulses to the dilator mu cle play only a minor role in the modulation of the light reflex: while supramaximal stimulation of the peripheral sympathetic chain inhibits light reflexes only lightly, low-intensity brainstem stimuli block them as completely in a normal as in a sympathetically denervated eye. 3 Both the fatigue waves and the alterations of the light reflex in tired people thus derive from the same central mechanisms that are responsible for the miosis in sleep and uncon ciousness, and conversely, the mydriasis in emotional excitement. The only difference is that the manifestations of tiredness and of arousal are variable and incomplete. Pupillary fatigue signs are signs of sleepiness, not of the exhaustion that follows strenuous activity. Sleepiness and the associated pupillary oscillations often follow but need not follow previous effort, as demonstrated by patients with excessive daytime sleepiness and normally by animals like cats. 3. In the past, we used to refer to the central inhibito'!' component of reflex integration ~s the "_central symgathet1c system." Later we abandoned th~s term m favor of centr~central inhibition," since we realized that the pharmacolog1c nature of the system was unknown. "Sympathetic" may, ~owever, have been less inappropriate than we then thought, sm~e Dahlstrom and co-workers (1964) found a rich noradrenerg1c network of nerve endings spun around the neurons _of the Edinger-Westphal nucleus of rats. Recent pharmacolog1c work by Koss and his co-workers (1976, _1980,_ 19~1? 1984, 1985, ~98~) also indicates that the central pup1llary mh1b1tory mechanism 1s mono-adrenergic (probably n~repinep_hrine)_wher:1 elicited ~y afferent and by medullary reticular _s11mulat10?;for hypothalamic stimuli a non-mono-adrenerg1c mechanism appears to play a role (Koss, Gherezghiher and omura, 1984). House cats that do not go out hunting spend nearly three-quarters of their day asleep. And when they awaken they do not engage in strenuous activity. They eat; they groom; they take leisurely walks to the screen porch or the window, and may even watch outside movements for a while or play. But soon they recline for their next nap; and as they approach the edge of sleep, their pupils are small and unsteady, and have reduced, sluggish reactions to changes in light. (c) Afferent Factors in Light Reflex Fatigue A number of authors have denied the existence of central nervou pupillary fatigue with disintegration of the light reflex (Clippers, in the 1950s, and others). In their opinion the reflex changes observed upon repetitive stimulation were caused by retinal adaptation to the stimuli and consequent weakening of the effectiveness of further light flashes. In general, however, sensory adaptation plays only a small role in reflex changes upon repeated stimulation. As mentioned already, the effects of weak, short stimuli tend to fade away during the dark-intervals between stimuli, so that series of reflexes elicited by weak light fail to show progressive decrement of effectiveness. ()./J'e<!.- Figure 10-20. Effect of hypothalamic lesion on light reflexes in a monkey. A: Light reflexes in a normal monkey (macaca ~,ulatta!. Note the variability of the extent and shape of the_reactions w_h1ch is typical for normal monkeys, and is associated with changes m excitement from one minute to the next. B: Same monkey after an electrolytic lesion had been placed in the caudal hypothalam_ic area. Extent and pattern of the light reflexes had become uniform, although reflex dilation, elicited by a sudden sound (arrow) was not impaired. (From 0. Lowenstein and I.E. Loewenfe_ldArch . . Neural. PJychiat., Chicago, 64 [1950]:341;e 1950, American Medical Association) 10. Reflex Integration: Pupillary Consequences E o.af - - CD E 0.6, i .s: 0.4f C, - ::i 0.21 .2 0 ! I ~ o.af _2 0 5! u - - • CD 0.4! .,_ -I I - C 0.2i 0 - o o! rllrL11TlII ® J • T- I (j) I 7 I \ 1 \ " J ...... --.,, ... ~ \ 5 \ I F 6--. - -~~\ 6 @ ® about 5°), intensity slightly more than 1 log unit above the subject's visual threshold. The reactions varied irregularly. This was true for the first reactions of different series as much as for reflexes within series. I -1· Q➔ .. ,rfT,r ® L.1,,_ll !rJ,Jn l11,r11,'1 Figure 10-21. Amplitude of light reflexe elicited b weak timuli (35-year-old n rmal ubject). The c lumn. indicate reflex amplitude (in mm) of contraction. 10 1- econd light fla he , pre ented in erie often ( erie. numbered). Fla~h interval were 3 econd in duration. hite light "--.J u~d. cenirall fixated (retinal area 8 ® II lrlrrlrlJI lrrlfl,JTT l, ITrLTl1'1lLrrLT,l 9 l 0 ® ® 495 The development of a smaller entrance pupil due to increasing tiredness similarly fails to play a noticeable part in the development of reflex changes when bright light is used: even switching the stimulus from a normal eye to an atropinized fellow eye with a widely dilated pupil does not alter amplitude or shape of the reflexes (Figure 10-22). Steady background illumination that (as described above) can have profound effects upon the light reflex elicited by bright, intermittent light (Figure 10-16) does not owe this capacity to adaptation of the retina, since illumination of the opposite, nonstimulated eye has identical results, as shown in Figure 10-23. The dim background light, reaching either eye, appears to counteract central inhibition of the light reflex. This is the reason for the facilitatory effect of background light for light reflexes of tense, excited people, and its detrimental effect in tired people whose central inhibitory function is weak to begin with. hen, C r e ampl , ten erie of ten reflexes each t dim light ar recorded in healthy alert ubject , the variati n bet~ een the fir t reflexes of each erie · are a wide a the ariation between th t n r flexe. within each erie (Figure 10-21); and witching the timulu from a previou_ ly timulated e e to the other e within uch ene h n ffect. In the lo'>'-medium range of timulus inten ity adaptation d play a role. The first rea ti n f each erie tend to be the large tone , and th reaction impro e when the timulus is itched fr m the previou Iy timulated ide to the other. For reaction to bright light, again, adaptation pla no role: for the e reactions the capacity of the pupillomotor tern i the limiting factor and the . timuli are trong enough to allow ome I of afferent effectivene without material change in the reflexe . - / ,~ , ,, , __,. ' ~ \ \ ~ llllllllllii I .,,., ''\\ \ _____ ',, ~ IITTTTT 111111111111111111111111111 ----, ' .,,., .,,.~ ---- ~ ,, , i-" Ill II I I I I I I 111111111 I I Ill II II I 111111 I I I I I I I I II 11111 () I Fi~ure ~0-22.. R _le of entranc~ p~p1l i r reaction to moderately bnght light um_uh.:ne. ub~ect nght pupil large and fixed becau e of preVl0U in ullau n f three dr p f I% homatrop· hydrobromide ( _lid line ). Th . left pupil w normal {broken me line ). ta, the nght ·c "-a llmulated through the normal pu- pil, and at b the l~ft eye was stimulated through the dilated pupil. Ther~ w~s no noticeable difference between the reactions of the functioning pupil. (From I.E. Loewenfeld, von Graefes Arch. Ophth al., 157 L1956]:628) 496 I I. Anatomy and Physiology Figure 10-23. Effect of dim illumination of the contralateral eye upon pupillary light reflexes. A shows the method used for unilateral light adaptation: a 3-volt flashlight bulb was clipped onto a black eye patch (b) with a central hole (c). In back of the bulb (that was visible through the hole) a reflector, made of crumpled aluminum foil (stippled area) was attached to the eyepatch with black masking tape. No light was allowed to escape from the eyepatch lamp, which was attached to the patient's face with black masking tape so that the contralateral eye remained in darkness. Two adapting intensities were used in these experiments. For the weaker one the voltage to the lamp was adjusted by rheostat so that the filament of the flashlight bulb just began to glow a dark orange. The subject saw many dim, intersecting orange circles of light which filled the entire visual field; they were the entoptic images of the highlights formed by the crumpled aluminum foil. For the higher intensity, the filament burned orange-yellow. B: Three experiments were done on the same person, a healthy 24-year-old woman. The eye-patch lamp was fastened to her right eye, and the pupillary movements of the left eye were recorded. Solid line: Reflexes to three consecutive IS-foot-candle light flashes, presented to the left eye after 30 minutes in darkness. At the end of these reactions, the dimmer eye-patch illumination was turned on for 2 minutes. Broken line: The left pupil had become about 1.2 mm smaller than it had been without the controlateral light. ]ts first light reflex was slightly enhanced, compared to the reaction when both eyes had been in darkness. Dotted line: The brighter eyepatch light made the pupil even smaller, and now all light reflexes were fast but of reduced extent. Note that the effect of repeated stimulation of the left eye was similar to that of dim contralateral illumination: the third light reflex in darkness (solid line) was similar to the first one with the dim eye-patch light (broken line); and the third reaction with dim contralateral light resembled the first with the brighter eye-patch light (dotted line). (From 0. Lowenstein, and I.E. Loewenfeld, Amer. J. Ophthal., 5 I [1961]:644; published with permission of The American Journal of Ophthalmology, c The Ophthalmic Publishing Company) D. Significance of Pupillary Fatigue Changes We cannot measure fatigue .... A subject's simple statement that he is fatigued is ... much more reliable than any measurement yet suggested in this symposium. (G. Wald, 1939 session of the Advisory Committee on Visual Fatigue, National Research Council, Washington D.C.) Fatigue is one of the commonest complaints of man. Not only does it lie in wait for us after a busy day: it may trip us up earlier, causing errors and accidents at work, impatience and quarrels with associates, and motor crashes on the way home. It lengthens the period of debility after an illness; and some unfortunate individuals almost never are able to emerge from its shadow, their lives a dreary, unending battle against overwhelming tiredness. Every clinician sees such cases; and it is important to distinguish between fatigue as expression of organic dysfunction and similar complaints without physical foundation, voiced by patients who are mentally depressed. How can these different conditions be told apart, and what distinguishes physiologic from pathologic fatigue? Concerning the first of these questions, the literature abounds in statements saying that fatigue cannot be measured. And yet the pupillary signs just described are accurate and objective indicators of tiredness. We have often wondered why they are used so seldom in clinical and experimental work on fatigue. Both the fatigue waves of pupillary size and the associated reflex fatigue upon repeated stimulation are involuntary and unconscious, so that they cannot be produced deliberately; and best of all, running records can be obtained (in light or in total darkness) without touching the subject. These show the slightest fluctuations in alertness from each moment to the next, from day to day, from week to week and over longer periods. Sadness, disgust, anger, and other negative emotions do not produce them; and pupillary fatigue signs are not found in depressed patients unless they are, in addition, really tired (see Chapter 45). As to the difference between physiologic and pathologic fatigue, we think the definition of the term in everyday usage provides a clue. According to the 1960 edition of Webster's New International Dictionary, the general meaning of the word is "weariness from labor or exertion, exhaustion of strength, loss of power due to continued work but removable by rest." The fundamental aspect of "normal fatigue" that distinguishes it from impairment is, thus, its temporary, reversible nature. But the patients in Figure 10-24 were always tired. Their condition of exhaustion was not preceded by activity, and it was not removable by rest. Their fatigue was, thus, pathologic. As is usual in life, things are, however, not always as clear-cut as in these cases. There are many people who are not acutely or chronically ill but who fatigue more ) LO.Reflex Integration: Pupillary Consequences 497 usuaJiy from youth, suffer from devastating daytime sleepiness without any known infectious, degenerative, or other disease. When excessive fatigue is part of an acute illness it is reversible insofar as it disappears when the disease has been overcome. This type of fatigue is a physiologic accompaniment of the disease. While indicating the presence of a pathologic state-and hence sometimes important as an early warning signal-it is itself neither "normal" nor "abnormal." It is no more correct to consider all fatigue pathologic than to regard all heat production abnormal because a rise in temperature accompanies disease. In healthy people fatigue can serve a regulatory function by telling the individual it is time to rest. Its beneficial or detrimental aspects depend entirely on its intensity, as related to the circumstances under which it occurs. When it is preceded by prolonged activity and removed by rest, it is part of the normal homeostatic cycle. When unprovoked by activity, tormenting in intensity, and oppressive by increased frequency it makes every effort seem an unbearable burden, and prevents the individual from leading a normal life, it is pathologic. quickly than they should, that is, they become tired after activity that does not lead to the same degree of weariness in most healthy people. Where, then, should the line be drawn between physiologic and pathologic fatigue? Aside from patients with excessive somnolence due to acute or chronic medical conditions (infectious, toxic, traumatic, endocrine, or neurologic), three main groups of people make up the vast army of the chronically tired: (1) Those who are tired because of habitual lack of adequate rest. This may be caused by (conscious or unconscious) overwork or other forms of burning the candle at both ends; to a naturally greater need for sleep than can be fitted into a socially acceptable time schedule ("long-sleeping normal")· to acute or prolonged stressful conditions of life; or to sleep-disturbing conditions such as sleep apnoea and sleep-induced myoclonus; (2) Persons under the influence of various drugs, either self-administered or prescribed (alcohol sedatives and narcotics, tranquillizers, anti-hypertensive drugs, etc.); and (3) Patients with sleep disorders like narcolepsy who, Figure 10-24. Pupillary movements in pathologically tired patients. A: Three years before examination the patient, a 16-yearold boy, had been a passenger on a school bus that collided with a truck. He lost consciousness and was ·oporous during the next 4 days. He was difficult to rouse and disoriented and excited when aroused. When left alone, he immediately lapsed back to sleep. Skull X-rays and a neurological examination were normal, but the EEG was diffusely abnormal. more on the right than on the left ide. Since the accident he complained of constant, overwhelming fatigue. Hi sleep wa restless, and he had headaches and wa forgetful and unable lo learn. While he had been a good student before the accident, he now had to force himself to keep awake in class, was too tired to follow the teaching, and invariably fell asleep after some time. On examination he was tense, restless and jittery. His movements were slow and circumstantial. I !is knee jerks were hyperactive (L > R), and there was a slight central seventh nerve paresis on the left side. The EEG showed paroxysmal diencephalic dysfunction with spike potentials at the anterior temporal and the car lobe electrode . Vision was normal except for total loss of convergence for near, without exophoria. He was sent to the laboratory becau e the school psychologist had diagnosed his tiredness as mental depre sion. The pupil test, done in the morning, showed that he wa unable to maintain alertness. After 2 minutes his pupils began 10 oscillate (A2), and after 3 minutes he began to fall asleep (A3). B: The patient, a 36-year-old man, had been suffering from multiple sclerosis for the preceding 5 years, with everal bouts of paralysis of the left upper and lower extremities, diplopia, and paresthesias, inter persed with almost complete remissions. About a year before his first attack he had begun to feel constantly tired; and thi fatigue continued since, even during the periods of remission. No amount of rest seemed to help, and he felt even more tired when he awoke in the morning than at bedtime. Hi pupillary movements expressed a state of extreme fatigue: the light reflexes were quite normal during moments of alertness, but they deteriorated within seconds. When the patient at quietly in darknes , hi pupils fluctuated wildly, and almost from the beginning of the te I repeated sensory stimuli were needed to keep him awake ( ound timuli at s). (From O. Lowenstein, R. Feinberg, and I.E. Loewenfeld, Invest. Ophthal., 2 [ J 963J:138) / s 6 -- BI - I 5 - - -- 2 ,------1 - ------ 6 -3-,--------1 - --t----------l 't 3 l 2 o.,sec.6 8 s '+ ' 3 2 l \. - ✓• / l 5 '+ t 3 f2 f I min:--- -' - 3_ 498 I I. Anatomy and Physiology II. Development and Aging The causes of our dissolution are either inward, or outward: the inward are borne with us, abide with us dailie, and accompanie us even to the grave. The outward doe spring and rise from without, compas e us on every side, and though a man may keepe himselfe from some few, yet there are an infinite number besides, which cannot be avoyded. (Laurentius, 1599) A. Summary A fundamental property born with us i mortality: it is the price of our existence as individuals. An early period of growth and maturation is followed by gradual decline that eventually will lead to death even in the absence of obvious disea e. Age changes begin long before the acknowledged period of senescence; and they continue steadily, at different rates for different tissues, and more quickly in species with a short than in those with a long life span. The "normal tate" is thus not a fixed set of qualities but merely the condition appropriate to each given age. And to evaluate pathology, the normally expected age curve of each function must be kept in mind. It ha been known for a very long time that the pupils of infants and of old people are smaller than those of older children and of the young adult. But how much smaller? What is the configuration of the "normal age curve" of pupillary size? How are the pupillary movements affected? And what are the probable mechanisms of these changes? These questions are discussed in the following pages. As children grow from birth, their pupils grow also. They are largest between puberty and the attainment of maturity, that is, from about 12 to 20 years of age; and then they decline in size linearly, decade after decade until old age, when the curve flattens out slightly. Several factors are responsible for these changes, both in infancy and with advancing years. The small pupils in early childhood usually are attributed to tardy growth of the dilator muscle that is said to require from several months to a year or two after birth until it can function effectively. This is not true. The pupils of newborn babies-and even of premature infants with birth weights just compatible with lifedilate strongly to phenylephrine, a directly acting alphaadrenergic agonist. The dilator muscle thus appears to function well when its anatomic appearance still suggests immaturity. The smallness of the entire eye of infants is one of the reasons why their pupils are so small: it limits the absolute pupillary size o,,tainable even under the influence of mydriatic drugs. A further factor in premature and very young babies is incomplete 9 +--+---+--+---+--1----+--+--+---+--+---+--+----+--+--+----ic------+----1 3 ~---1---1----l---l----l---+---l--+---l---"-+---1-=---+---1--t----;-1r-"--r.--lr----t 2 +--+--1----+-+---l--t---l--t---l--t---l--+---l--+---lr--t---lr----t +1 E £:0 0 S 10 11ears-+- 15 20 25 30 3S ~O Figure 10-25. Pupillary size in darkness (1,263 subjects of the population survey). The pupil camera used for this survey is described in Chapter 15 (Loewenfeld and Rosskothen, 1974). The examinations consisted in series of infrared flash photographs, exposed either in darkness (data for this Figure), or at the end of bright, white light flashes (data for Figures 10-29 to 10-31). The "darkness" pictures were taken after 3 minutes of adaptation, preceded by not less than 15 minutes in moderate room illumination. According to previous studies this suffices to reach nearly full ~5 so 55 60 bS 10 75 80 IS ,o dark-adapted pupillary diameter. Longer adapting periods were not practicable, and in many subjects they do not lead to further pupillary enlargement because sleepiness ensues. The subjects for this graph were chosen at random. For each subject the average pupil size was used, (R + L)/2. The ordinate shows horizontal pupil diameters in mm, the abscissa age in years. Note the wide scatter among individuals, and the obvious age trend. (From I.E. Loewenfeld, in Topics in Neuro-Ophtha/mology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979)) 10. Reflex Integration: Pupillary Consequences development of peripheral adrenergic transmission, as demonstrated by absent or inextensive pupillary dilations to the indirectly acting syrnpathomimetic drugs tyramine and hydroxy-amphetamine. Probably the most important cause of miosis in small children is, however, immaturity of the brain and consequently low levels of mental and emotional activity as well as their pupillomotor concomitants, sympathetic discharges and central inhibition of the parasympathetic sphincter nucleus. ' Senile miosis" has been blamed most often on atrophic iris changes and on a defective sympathetic nerve supply. However, the age-related decline in pupillary size begins shortly after full growth and maturation have been reached, long before senile iris atrophy occurs; and further, this decline continues gradually over a great many years while pupillary movements continue briskly. The gradual loss of pupillary size can therefore not be attributed to iris atrophy, at least not for ages below the sixth or seventh decade. A defective pupillodilator system also cannot be a prominent cause of the miosis, since pupillary dilations to sensory stimuli and to cocaine are not impaired until advanced age, and even then not to a marked degree; and further, the dilator muscle does not become thinner with age. The chief cause of the developing miosis with advancing age is progressively decreasing central inhibition of the sphincter nucleus. The age curve for the pupilJary light reflex parallels that for pupillary size only partly. Children between the ages of about 3 and 13 years often have large pupils, and yet their light reflexes are relatively inextensive, since / 499 they are blocked at the Edinger-Westphal nucleus by strong emotional factors. This inhibition can be overcome by longer, more intensive light stimuli. In these children and young adults long-lasting, bright illumination will therefore elicit much more extensive light reflexes than will short or weak light flashes. The exact opposite is true for older people: when prolonged, bright light is used, their small initial pupillary size (in darkness) limits the amplitude of the reflexes, while reactions to weak or to short light flashes-that do not require much mechanical range-hold up well until the end of the sixth decade of life. Beyond this, anatomic changes in the iris begin to contribute noticeably to deterioration of the light reflexes, so that they tend to flatten somewhat, more so with rapid than with slow rates of stimulation. The time-amplitude patterns of pupillary light reflexes of old people resemble those shown by younger people under the influence of tiredness or of repetitive stimulation (see above). But the reflex changes due to fatigue are only fleeting, and the reactions can be restored by rest or by psychosensory stimulation. In contrast, those due to age are permanent. Interpersonal differences in pupillary size and reactivity are marked at any age, so that no flat statement can be made about the "normal" pupil. Knowledge about the average age trend in healthy populations does, however, provide a background for the evaluation of individual cases; and for the assessment of pupillary physiology and pathology the "normal age curve" must therefore be kept in mind. B. Appearance 1. Pupil Size As already mentioned in other chapters of this book, the "physiologic pupillary diameter" has been much talked about in a general way. Some said it runs between 3 and 5 millimeters; others said that it is larger; others again that it is smaller. All these statements are worthless because the conditions of examination varied between studies, and often they were not specified. The structure of the iris in different people is not entirely alike, so that there are built-in differences in pupil size and in the range of physiologic movements. In addition, fatigue, emotional stress, and other factors vary. Even under stable conditions, any normal person's pupils can therefore fluctuate over a wide range. How can we, then, construct an age curve, and how meaningful is the information for a given patient? In answer to the first question, it is obvious that large numbers are required. The usual "control group" of twenty subjects or so simply will not do, no matter how elaborate the statistical analysis. For this reason we were not satisfied with the data available in the literature, and conducted a population survey in our laboratory at Columbia University during the years 1969 to 1972. The following description of the age curve from 6 to 100 years is largely based on this material (Figures 10-25 and 10-26). For smaller children we have only limited experience, and have therefore not drawn the curve in Figures 10-25 and 10-26 below age 6. Considering the rapid growth in infancy and early childhood, together with inaccuracies concerning the true age at birth, much larger numbers are needed to arrive at an age curve in this early range that we would regard as reliable. A provisional curve is shown in Figure 10-27, because these children were at least examined in darkness with the same in~trument, in the same place, and by the same examiners. As can be seen, the age groups above 6 years agree well with the population survey of Figures 10-25 and 10-26. But as a warning to those who are satisfied by statistics based upon small numbers, be it recorded here that when the 216 children of Figure l 0-27 were grouped in alphabetical order, the first 30 were girls, while the final count was 109 girls and 107 boys. The ~tatistical probability of this happening by chance is_very s~all, and_yet it happened, just as there are wmners m lottenes, against overwhelming odds. 500 / I. Anatomy and Physiology L J J I J J iI r1 u" f As seen in Figure 10-25, the pupillary diameter shows wide catter among individuals at all ages. Nevertheless, an age trend can be discerned; and it becomes quite clear when measurements of groups of subjects are averaged (Figure 10-26). During the first decade of Life the pupils grow larger with age. During the next decade the curve rounds a gradual peak; and then a steady decline begins and continues over the remaining life span. 4 Previously published age curves of pupillary diameter, obtained with objective methods, run fairly well parallel to our curve (Figure 10-28). It will be noted that our values in general were slightly smaller than those found by others. There are many possible reasons for this, such as differences in the populations studied, the duration of dark adaptation, the distance of fixation, or the degree of effort demanded of the subjects. The _,., agreement in the slopes of all recorded data, and the difference between these and the results of studies without objective records, are, however, I 1'0TAL J471 plain. Ht 6-l I fHI I 1t9 I ht3 1 b:; I 11 I 73 t ·1 6 I ao l. l. L l. Li Ii IJ 2. Reactions to Light Figure 10-26. Pupil diameter and width of palpebral fissure in 1,470 ubjects. The subject were chosen at random. The left cale and black circles represent millimeter of horizontal pupillary diameter ( haded area); the right scale and white circle how palpebral fi sure, also in millimeters. For each individual the right-eye and left-eye mea urement were averaged (see Figure 10-25). U ·ing the individual data of Figure 10-25, age groups were averaged, as noted along the ab cis a. For each age group the number of subjects i indicated along the abscissa by number. Note that smaller age step were taken for children than for adult , because of the relatively rapid growth period. (From I.E. Loewenfeld, in Topics in Neuro-Ophthalmology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979]) Figure 10-27. Horizontal pupillary diameters in a group of216 healthy children. The same methods were used as in Figures 10-25 and 10-26. The ordinate shows pupillary diameter (in mm). The small dot show data for individual children, and the large circled dots represent averages for the age gropus bracketed along the abscissa (numbers of children in each group given). Note the wide catter among individuals at all ages, and the average age trend. It has been known for many decades that the amplitude and the pattern of pupillary light reflexes arc related to pupillary size. The reflexes tend to grow larger from birth to adolescence and then smaller again after a peak at about 12 to 20 years (Figure 10-29). This age-dependent early increase and later loss of reflex amplitude is partly due to mechanical limitations of the iris: all other features being equal, smaller pupils have more difficulty than larger pupils in constricting under the influence of light or other stimuli. This self-evident relation between beginning conditions (at rest) and the amplitude of movements is found in many other motor systems also. It has been given the high-flown name of "law of initial values," and a vast literature has accumulated about it. For the pupils this "law," however, does not always hold true: when the pupils are dilated because the subject is tense or excited, the light reflexes-far from being especially largeare inhibited and therefore less extensive than when the pupils are smaller because the individual is calm, as described above. 4. The loss of pupillary size (in darkness) measures about 0.4 millimeter per decade from ages 20 to 60. The broken line and white circles in Figure 10-26 show that the width of the palpcbral fissures also first increases and later decreases. This curve is less steep than that for the pupils, and its peak is maintained until the mid-30s. In our tests the subjects were asked to keep their eyes open and to continue looking at the fixation spot. This appeal to voluntary innervation may have influenced the curve for the lid. The far fixation spot was chosen to be 15 degrees above horizontal in order to elicit co-contraction of the levator palpebrae with the superior rectus. With straight-ahead gaze the lid measurements would have been smaller. 10. Reflex Integration: Pupillary Consequences Bl 7 -l +-, I •, /' .......... ......... ~ "· .......... ~~:;,~ / !! ~I:; I :-...... '~~·¼_ / '~-~~,"' ·"·~.e><:""~~, 5- W ~ ~~""' =b=&=- : SciLz, 1957 (208); ;S -$--$-, Birren&al, O 4- ··•···········•···•: 1950(222); -+-•-•-+-: g ------: Locwcnfeld; ~ 3 .......... C} •, -....._ $ "-.. "-.. "'- hd, 3 min. dark ·, 1-1--1-1--1--1-1--1--1--1--1--1--1--1--1--1--1--1~1--I----! o AGE t~ "$ +. vd, 90secsdark j u ♦---1-: ' " hd, 60 min. dark Borgmann, 1972 (136); hd, 15 min. dark Kndlecova &al, 1958 (453); hd, 15 min. dark Trcndelenburg, 1943 ~ 501 /8-~~~~ ~":~♦- // 6-1 / 9L~C- °r ~ C\I ~ .--,~~ ,s, oo 7 7 r-1 i ~ ~ C'JC-1 cn ! '-=t' m "11 a, ~ m i i ! ! ! ! C'?M,q'~U':ltt')C.O(OC-r,:- "l:tf ~ C> ! -.:t- ~ en. l ".!+ Figure 10-28. Age curve for pupillary diameters in darkness, published by various authors. The number of subjects in each report is given in parentheses in the key; hd, horizontal diameter; vd, vertical diameter. The duration of dark-adaptation is noted for each report. Birren and co-workers ( 1950) and Seitz ( J957) used mean values of flash photographs with white photoflashcs; we used average values and infrared flashes; Borgmann measured the pupils with the Lowenstein-Loewenfeld infrared pupillo&>raph (mean values); Kadlecova and co-workers measured pupil sizes on the screen of an infrared-sensitive image converter (mean values). Trendelenburg's data were based on observations without objective measurement. (From I.E. Loewenfeld, in Topics in NeuroOpl,thalmology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979]) Figure 10-29. Pupillary diameter and light reflex amplitude among 1,402 individuals of different ages. The same methods and population were used as in Figure 10-26. ln 68 people of that group light reflex amplitude could not be tabulated because of incomplete records (mostly blinks in one or more pictures of the light reflex series). The stimuli were bright white light flashes, as described in Chapter 15. For each subject, contractions in response to stimulation of the right eye and of the left eye were averaged, and the right and left pupil sizes also were averaged, so that each individual's result is the average of four measurements. A shows amplitude of pupillary contractions at the end of 3 seconds of stimulation, and B, at the end of 1 second of stimulation. The black circles and solid lines show average reflex amplitude, and the vertical bars indicate the normal range. The top of each bar represents reflex amplitude not exceeded by 98% of the individuals in the particular age group; and the bottom of each bar shows reflex amplitude reached by all but 4.9% of the individuals in that age group. The average pupillary diameter (taken from Figure 10-26) is al o shown (broken line and right scale). Age groups (in years) and numbers of individuals in each of these are indicated along the abscissa. Note the early growth period of the responses. For the contractions to 3-second light stimuli this is followed by a two-humped decline. The early part of this decrease probably is due mainly to the loss of pupil size in darkness, since the extensive contractions require a large mechanical range (A). The smaller contractions that occur during the fir t second of light do not need as large a range, and they hold up well until the end of the sixth decade of life, when they also decrease (B). 502 / I. Anatomy and Physiology The age curve for light reflexes elicited by strong light stimuli of several econds' duration differs from that of reaction to short or to weak light flashes. For this reason the two kind of response will be described separately. (a) Strong, Long.lasting Light Stimuli For reactions to powerful, prolonged light stimuli the starting diameter of the pupil in darkness is directly related to the exten ivenes of the light reflexes. This relation is linear in older people with weak reflex inhibition; and there i relatively little individual scatter in such popula- al 143 CHILDREN A 6 -I 8 YOUNGER THAN 11 YEARS . 7- I • . • . • • •• .. . ••• ! •··••···· ◄ =UP TO ll YEARS ----=40 . . ....•...: /-;:/• ...... ... . . . .·=-i ... . ...,.. ............ ::• • . • . . . .... ~41.-,.• • ........ ... ..• ___.!,--" . i :. .... _....-. • • • .,. • • • .... .·:. ... . • tion groups (Figure 10-30,B). In animals, children, and excited mental patients, however, strong reflex inhibition may or may not be present at any time, as just mentioned. And consequently, there is marked scatter among individuals, and even among reactions of a single individual from one time to the next (Figure 10-30,A). Further, the relation between pupil size and reflex amplitude usually is not linear in such groups. In other words since the pupils are inhibited they react less extensively than would be the case if the beginning pupil size alone dictated the amplitude of the responses. The inhibition was strongest and most variable in the young- 1 A 7 - )I .... ,; • • I 4- I . I ,,,."' -~ ..···/ • •• :: 6 -, __ ----- s5 ; -I I l L_I ____ •__,_____ ,_____ ,_ 5 -I = 30 - 39 YEARS -49 YEARS - -- - ······• .. ,-•• t·"'-::•:;;;/ :✓ I , ' i ~4 • •• 3 t:l 3 § 0 1 CONTRACTION 2 TO LIGHT 3 p. 4 in mm ( 3 second light flashes) -1~---------1-----1----12 0 3 4 7 -, ,J 6- -•-•-I B ]I LI ~ ......... 93 PERSONS 60-69 YEARS OLD =50-59YEARS 1 = 60 - 69 YEARS = 70 - 79 YEARS .. 4 - ~ ii: :::, p.. ~1-----1-----1-----11 0 CONTRACTION 2 TO LIGHT 3 4 in mm ( 3 second light flashes) 0 CONTRACTION Figure 10-30. Relation between pupil size and reflex amplitude (3-second light flashes). The same methods were used as in Figures 10-25 and 10-29 (individuals from the population suivey). Pupillary diameter was plotted (in mm) against extensiveness of the light reflexes (also in mm). Each individual subject is indicated by a dot (average of right and left eyes). The lines are mean cuive . Note the linear relation between diameter and reflex amplitude in the group of old people (B), and the slight interpersonal scatter among them, compared to the wide scatter and relative inextensiveness of the reflexes in young children (A). (From I.E. Loewenfeld, in Topics in Neuro-Ophthalmology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979]) TO LIGHT in mm. ( 3 second light flashes) Figure 10-31. Relation between pupil size and light reflex amplitude among different age groups. Mean cuives were derived for the different age groups, as in Figure 10-30 (see key). For a given pupil diameter (thin broken lines, at 5.4 mm in A and at 5.0 mm in B) the light reflexes were less extensive in children than in adults (compare the dotted line with the broken and solid lines in A). And again, the 30- to 39-year-old group in A had less ample contractions at the same starting diameter than did the 40- to 49-yearold group. The 40- to 49- (A) and the 50- to 59-year-old groups (B) were almost identical. From then on, the trend reversed: for a given starting diameter older subjects reacted slightly less extensively to light than did younger subjects (compare solid line with broken and dash-dot lines in B). (From I.E. Loewenfeld, in Topics in Neuro-Ophthalmology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979)) 10. Reflex Integration: Pupillary Consequences est children used for the population survey ( ages 5 to 6). It decreased with age, and played no material role in age groups beyond 40 years. Except for a limited mechanical range, brought about by the decreasing pupil size, there is no apparent deterioration of reactivity until past middle age. In fact, for a given beginning size (in darkness) the light reflexes of middle-aged people are faster and more extensive than those of children and young adults with pupils of the same diameter in darkness (Figure 10-31,A). This tendency reverses only for age groups above 60 years. Among these-at a given pupil diameter in darknessthe light reflexes of older eyes have slightly less extent than do those of younger groups (Figure 10-31,B). (b) Short or Weak Light Stimuli The reflexes evoked by short (or by weak) light flashes-requiring less mechanical range than do those caused by long (or by strong) stimulation-are relatively insensitive to the age-related decline in pupil size: such reflexes have a relatively flat age curve until well into the seventh decade of life (Figure 10-29,B), while the reactions to long light flashes begin to decline much earlier (Figure 10-29,A), as just mentioned. In children, also, the early part of the light reflex, that is, the contraction that occurs within the first second of stimulation, is relatively regular, and can be well preserved even when the later part of the contraction is suppressed by emotional factors. In young children with a short attention span and quick changes of mood this may occur from one moment to the next and vanish as rapidly, so that the pupils show characteristically variable W- and V-reflex shapes under the influence of series of short light stimuli / 503 (Figures 10-32 and 10-33,A and C). Strong, bilateral light flashes, or longer-lasting stimuli, can overcome this block, and extensive reactions may then emerge ( see B in Figure 10-33). The light reflexes of older children usually are Jess inhibited than those of younger ones, and they are therefore usually larger, smoother, and Jess erratic from one reaction to the next (Figure 10-32 and D and E in Figure 10-33). (c) Longitudinal Age Changes When single individuals are followed over long periods of time, the same sequence of age changes is run through that is shown by subject groups of increasing age: the pupils of a single child growing up have an early growth period and later decline in size. While the child is small, it has typically inhibited, irregular reflexes. As it matures, the reactions become extensive and regular (Figure 10-33). On the descending branch of life, also, the reduction in size and the shift in reflex shape exhibited by the pupils of older population groups from decade to decade are paralleled in single individuals as they grow old (Figure 10-34). 3. Pupillary Dilation Except for patients with iris atrophy, the pupillary dilations to sudden interruptions of light and to psychosensory stimulation are active in older people, and they may be extensive. Similarly, healthy old eyes show vigorous pupillary dilations to mydriatic drugs. For example, the pupils of the 82-year-old mother in Figure 10-34 dilated fully to conjunctiva) application of 0.1 % hydroxyamphetamine. Both the mother's and the daughter's pupils climbed up to 9.1 millimeters (in darkness) 1 8 J--::±---:-1-------1 7 6 5 t4 . 3 ~ 2 0.1 sec. ➔ Figure 10-32. Pupillary reactions to light of children at different ages. Pupillograms of three girls, 6½ (A), 8 (B) and 11 years old (C). Their pupils reacted characteristically for their ages. The smallest girl's light reflexes were strongly inhibited, with reduced reflexes of variable V- and W-form. A sudden sound stimulus, given after the fourth light flash (arrow), suppressed the fifth light reflex even more; but as the child calmed down, her pupils became smaller, and the sixth light reflex improved. The older children showed similar tendencies but to a less marked degree with increasing age. (From I.E. Loewenfeld, in Topics in Neuro-Ophthalmology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979]) 504 / I. Anatomy and Physiology 8 7~ -- 6,--51-A4 3 2 -~ -- 8 7>-- P\J_ 6 54 3 ,__ 2 7-= ~ ✓---- - -\- / ~ lr+I s 1-D4 3 --c--- -\ f'J / l.r. -\ ' .I' - / ""' 2 \ 6-E~ 5 1'>../ 4 3 1.r. E 2 E 0. 1 sec ....... ' A ,-- ~\ ~~-- .,-- \ / \j -47 ~ ~- ~ ./ t-J 1.r. ~ 4 ---- - \.r. l.r. - \r-,.,/ l.r. 3 5 ---- ,-., ·- Figure 10-33. Pupillograms of the same person over a 19-year time pan. The first record was taken when the child was 6½ year old. Her pupils were large for her age. The reactions to light were, however, relatively inexten ive, and they varied in amplitude and shape from one moment to the next (A, with the right eye stimulated). When bilateral, trong light was u ed, the inhibition wa overcome, and a large, well-shaped reflex resulted (B). About 3 month later, the ame reflex pattern wa recorded (C, with the right eye timulated). Nine year after C, when the girl's age was 16 years and 2 month , her pupils were slightly larger in darkness than they had been before, and the reactions had become less in- l.r. ~ I' .... l.r. ~ =-~ 4 5 ----=- -~i--,--,..._ l.r. r~ - 11.r .I --,-~' 1.r.l "" hibited. They now were extensive and regular in shape (D). In E, the reactions were recorded when the subject had reached the age of 25 years and 5 months. Her pupils had become a bit smaller. The contractions to light were large and regular, but redilations after the contractions to light were not quite as vigorous as they had been in D. A psychosensory stimulus (sudden sound, at arrow) enhanced the following light reflex instead of inhibiting it, as it had done before, and as is the case in most small children. (From I.E. Loewenfeld in Topics in Neuro-Ophtha/mology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979J) Figure 10-34. Pupillogram of mother and daughter over 12- and 37-year time spans respectively. For each subject two pupillograms were superimposed (left eyes only), with the solid lines representing the first and the broken lines the second tests. The peak speed of the first contractions in A and Bl is indicated (in millimeters per second). All stimuli were about 15 foot-candle intensity. In A and Bl they lasted l second, and in 82, 5 milliseconds each (marked by small arrows). Line A: The first test (solid line) was recorded in June 1940, when the daughter was 19 years old. Note the slight reflex inhibition, revealed by a relatively low peak peed of contraction and a slight W shape of the first reflex of the series. The later test (broken line) was done in June 1977. With age, the pupils had become smaller and the contraction speed faster, while the amplitude of the first reaction remained roughly the same. The pupil redilated imperfectly after the first contraction, and the second and following reflexes were reduced in extent. Lines Bl and 82: The subject's mother was examined in March 1957, when she was 70 years old, and again in March 1969, at the age of 82. Her vision had remained 20/20 OU. In the first test her reactions resembled those of her daughter's second record, except that her pupils were slightly smaller and the movements somewhat flatter. This trend became more marked during the following years, especially in the reactions to fast driving by short, repeated light flashes (B 2). (From I.E. Loewenfeld, in Topics in Neuro-Ophthalmology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, J979]) t ss \.r. --~ ~ ~ --r-= l.r. \1 t -\_ -3 2 ~ ~ 8 7 ,I l.r. l.r. 2 ~ A ,-,.." -~ -46 45 ~ 8~ F\1 7 6-- - F\ :c -=- I l.r. 1.r. 44 5 i_r '\,. -B ,.,,, - ...,-. .,,,,--· \ l.r. -- --- -4 3 i'I l.r. - - -2 '\I L-LL.1.1.ll.l.WUJ.L.L.U.U.U.U..U..U..U. 0.1 sec.~ .......................................... ~ ...............-~-~- JO. Reflex Integration: Pupillary Consequences Table 10-3. 61-65 66-70 71-75 76-80 15 25 37 54 36 9 3 6.6 7.2 7.2 7.3 7.2 7.3 7.0 46-50 51-55 56-60 NUMBER OF CASES 5 12 7.8 7.2 A VE RAGE PUPIL DIAMETER (mm) A VE RAGE AGE OF PATIENTS FOLLOWING DRUGS From Lange, 505 Pupil sizes reached under the influence of mydriatic drugs AGE (YEARS) 1. 2. 3. 4. / --- WITH FULL PUPIL Scopolamine alone ................ Scopolamine plus glaucosan ............ Glaucosan alone ...................... Glaucosan plus scopolamine ............ DILATION ••••••· · · · · ••••••• •• • •••• ••••••• 81-85 IN RESPONSE 67 69 73 67 years years years years 86-90 OF THE 7 months 1954 hour after two drops of this drug were instilled. Lange (1954), Kadlecova and Pcleska ( 1958), and Borthnc and Davanger (1971) had similar findings (Table l 0-3). More recently Korczyn and co-worker (1976) observed significantly less peak mydriasis after instillation of 5% hydroxy-amphetamine among 15 subjects aged 63 to 75 years (6.96 ± 0.66 millimeters) than among 23 subjects aged 17 to 20 years (8.17 ± 0.82 millimeters), although the druginduced increase in pupil diameter was about the same in the young and the old groups (1.80 ± 0.21 and 1.88 ± 0.22, respectively). Cocaine (5%) enlarged the pupils of the young group slightly more than those of the old (1.85 ± 0.24 and 1.48 ± 0.22, respectively); and both the old and the young subjects reached maximal mydriasis after 10% phenylcphrine, that i , the drug-induced increase in pupil size was greater in the old than in the young. The authors concluded that "the sympathetic tone is reduced in old age . . . due to degeneration or to functional inactivity." While this may be true to a limited extent, we do not believe this mechanism to be a major cause of the small pupil size in old eyes. Korczyn's tests were done in room light rather than in darkness; and the marked loss of central inhibition of the pupilloconstrictor nucleus must have rendered the miotic effectiveness of this light more potent in the old than in the young. This also would explain the differences in mydriatic actions of cocaine, hydroxyamphetamine, and phenylephrine. Among these three drugs, cocaine blocks the light reflex least, hydroxyamphetamine slightly more, and phenylephrinc in 10% solutions almost totally. We did not include reflex dilations in our population survey because the stimuli are hard to quantify. Many reasons contribute to differences in reactions to a given sensory stimulus among children, mature adult, and old people. For example, a sharp, cracking noise made by a toy pistol is heard more loudly in youth than in old age. It is more interesting and exciting to children than to adults; and its effectiveness depends at any age upon the interpretation given to the event by the subject; and this is related to a great many factors of each individual's life experience. It is, in our opinion, probable that average age curves of a large population will reveal psychosensory reactions to be reduced with age. The point here is that in healthy eyes this reduction is not as great as is the decline in pupillary size shown in Figures 10-25 to 10-27. C. Mechanisms What causes the reduction of pupillary size and reactivity with age? And why arc infants' pupils so small? 1. The Iris Most often senile iris change arc said to be responsible for the miosis in old age, while the small pupils of infants are said to be cau ed by slow growth of the pupillary dilator muscle (Duke-Elder, and many others). Thi muscle is said to require months or even a year or two after birth to develop sufficiently to become functional. This is not true; and it i , indeed, an odd idea that this most primitive of all mammalian muscles should need so much time to become able to contract. It can, in fact, be demonstrated that the human dilator muscle is able to function well before the normal time of birth, since premature children down to tiny sizes have extensive pupillary dilations to direct-acting alpha-adrenergic drugs (Figures 10-35 and 10-36,A). The drug-induced mydriasis of these children cannot be due to inhibition of the pupillary sphincter, for such inhibition is effected by means of beta-adrenergic receptors; and further, pupils already enlarged by paralyzing the sphincter with atropinic drugs show very marked additional dilations upon subsequent instillation of alpha-adrenergic drugs (Figure 10-35). According to Carpel and Kalina (1973) these infants' pupils are able to dilate to 90% of the corneal diameter 506 / I. Anatomy and Physiology under combined cyclopentolate and phenylephrine treatment, that is, more than is possible in older children or in adults. I do not think this indicate that the dilator is more powerful at such an early stage than it is later in life. But it work must be easier because of the yet scantily developed stromal connective tissue. Similarly, the rat's pupil dilates ca ily in darkness to about 90% of limbus size. Thi al o is likely to be due to the extreme thinne s of the troma in these animals. One factor for the smallness of newborn babies' pupils is the mall ize of the entire eye: while relative to corneal ize the pupil can enlarge extensively to drugs, the ab olute ize are till smaller than they arc when the globe is fully grown. However, compared to the total body the eye is far advanced in its development at the time of birth: while body weight increases about twentyfold from birth to adulthood the ocular volume grows only about three times as large a it is at birth, and the ocular diameter not even twice a much (Table 10-4 and Figure 10-37). The anterior segment of the eye, especially, is relatively very large at birth, and it grows more A 100 -- 95 quickly than any other portion of the globe (Figures 10-38 and 10-39). The cornea reaches virtually it full adult diameter within the second year of life (Figure 10-40, 10-41, and 10-45). This is important for the pupil, since the iris root inserts behind the scleral limbus, so that the diameter of the cornea is closely related to the outside (ciliary) diameter of the iris. Considering this, it can be seen that during early childhood the pupil is smaller than the size of the cornea-and presumably the iris diameter-would impose (see the thin double arrow in Figure 10-4l); and when the growing pupil size is plotted a a percentage of limbus diameter, the pupil can be seen to grow more slowly than does the cornea (and probably the periphery of the iris diaphragm). The thickness of the dilator muscle also reaches full size earlier than does the pupillary diameter (see Rother and Leutert, 1966). The small ocular size of very small children is thus a contributing factor for the early miosis; but there must be, in addition, some neural mechanism still incomplete at birth (see below). Regarding iris changes in older persons, Whytt said Pupil diameter [] ~ after cyclopentolate after eye lopentola le and phenylephrine B 100 90 85 85 q_, q_, .._ .._ 80 q_, q_, I:: 75 . I:) 80 \... t 't) [] after cyclopentolate cyclopentolate E:221and phenylephrine ~ after 95 10 90 ~ Pupil diameter \... 75 't) 70 70 :-::::~ q_, §- ~ 65 Q.._ 65 (3 60 6 55 55 ~1600 Birth weight (grams) Figure 10-35. Drug-induced mydriasis in premature infants. In A, the children were grouped by birth weight. Their pupils were mea urcd 30 minutes after conjunctiva I instillation of 3 drops of l % cyclopentolate, a parasympatholytic drug (stippled areas); and 30 minutes after additional instillation of three drops of 10% phenylephrine, a direct-acting adrenergic drug. (This is a very large dose of this powerful adrenergic agonist. No ill effects developed among Carpel and Kalina's children, but France and France (J 973) warned that such instillations may result in violent rises of blood pressure with possible cerebral hemorrhages. We believe 10% phenylephrine an excessive dose at any age, and have, as have others, observed detrimental effects to the iris after its use. Further, in dose-response tests on ten healthy adult subjects, there was not one whose pupils did not dilate fully after instilla- 7.5 8.0 Corneal diameter (mm) tion of three drops of l % phenylephrine. Since 2.5% solutions are again available for ophthalmic use, we think 10% solutions should be stored on a very high shelf that requires an extension ladder to reach.) Note the extensive dilation to phenylephrine, far in excess of that due to sphincter paralysis. In B, the children were grouped by corneal diameter. Even the least mature infants with the smallest corneae bad vigorous mydriatic responses to phenylephrine; and when expressed as percent of corneal diameter, all of them could dilate their pupils to 90% of corneal size. This is more than is possible at later ages. (From E.F. Carpel and R.E. Kalina, Amer. J. Ophthal., 75 [ 1973]:988; published by permission of The American Joumal of Ophthalmology, 0 The Ophthalmic Publishing Company) lO. Reflex Integration: Pupillary Consequences as early as 1751 that "the muscle fibers of the iris lose somewhat of their contractile power." Others thought that an atrophic stroma with increased connective tissue and hyaline degeneration, especially around the pupil edge and between the sphincter muscle strands, or stiff, sclerotic iris vessels, hindered pupillary dilation and thus brought about "senile miosis" with rigid pupils, and distorted pupils as well. The posterior iris leaf also could be damaged in old eyes: degeneration of the dilator muscle was found in some old eyes; and patchy defects in the posterior pigment epithelium were seen on transillumination of the globe (Fuchs, 1885; Meller, 1904; Seefelder, 1909; Axenfeld, 1911; Attias, 1912; Hohmann, 1912; and many others; see Chapter 16 and Table 10-5). Vogt and co-workers (1935, 1939) found senile pigment degeneration near the pupil edge exactly alike in identical twins but much less similar among fraternal twins, indicating that the time of onset and the degree of destruction were determined genetically, and were not due simply to the "wear and tear" of a lifetime of pupillary movements. 11,0 A o/oMYORIASIS TO So/,PHENYLEPHRINE x 140 AT 30 MINUTES 120 100 r = 0, 034 not significant X 80 n = 30 X X •• • 60 4() X 20 -100 -60 -80 -40 -20 TERM 20 GESTATIONAL AGE IN DAYS B 40 60 80 100 / 507 But senile iris degeneration does not begin before the age of 40, while pupil size begins to decline much earlier, and the pupil then continues to contract steadily over the following decades. This makes it difficult to blame the miosis on senile iris changes. The light reflexes of most people, further, remain brisk well into late middle age. This, and extensive responses to mydriatic drugs often found in healthy old eyes, as shown in Table 10-3, would be impossible if the iris muscles were unable to contract forcefully, or if age-related pathology in other iris tissues rendered these contractions ineffective. Further, Rother and Leutert found no decrease in the thickness of the dilator muscle with increasing age. Changes in pupil shape such as ragged pupil edges are found in many old eyes with miosis, but this is not always true: the pupils can be round and smooth in advanced old age, while moth-eaten pupil margins are common also in young people with large pupils that move freely (see Figure 16-6). Destruction of iris tissue therefore cannot be the main cause of the age-related decrease in pupillary size. However, iris changes do take place with age; and they probably contribute to reduced pupillary mobility, as witnessed by the fairly abrupt drop in the age curve of light reflex amplitude for short light flashes after 60 years of age (Figure 10-29,B)· and by the decreasing light reflex amplitudes at a given pupil diameter during the late decades of life (Figure 10-31,B).5 In addition, there are subtle defects of pupillary movements in older subjects that probably are due to increased stiffness of the iris. These are: -the slightly prolonged latent periods of the light reflex in old people, even when the light stimulus is very bright so that the delay cannot be blamed on decreased afferent conduction (Feinberg and Podolak, 1965); -the reduced peak speeds of contraction observed in old people's light reflexes; and 5. See Leutert, 1966, Rother and Leutert, 1966, and Morone and co-workers, 1971, for more recent anatomic electron-microscopic, and histochemical work on age-related iris changes. 1oor o/, MYDRIASIS TO lo/, HYDROXYAMPHETAMINE AT 30 MINUTES 80 X r = 0 • 5 25 Cp < 0 , 01 ) n X 60 = 27 X X X X -100 -20 -80 X 80 40 60 GESTATIONALAGE IN DAYS TE RM x 20 Figure l0-36. Relation between gestational age and pupillary dilation to adrenergic drugs. Each cross represents a different infant (measurements from flash photographs). The line in B is best fit calculated by the method of least squares. A: Thirty infants, 30 minutes after conjunctiva! instillation of one drop of 5% phenylephrine. All children reacted, and there was no significant relation between age and pupillary reactions. B: Twenty-seven infants, 30 minutes after instillation of I% hydroxy-amphetamine. The youngest children failed to respond, and the reactions of those who did were related to age. (From N. Lind, E.S. Shinebourne, P. Turner, and D. Cottom, Pediatrics,47 [ 197IJ:I 05; reproduced by permission) 100 508 / I. Anatomy and Physiology ~ /~ I (left f 22-, f scale) Ocular Diameter In mm .,..-"§_Sj ,,' '-.. ~---.;e---~------·l"'-~~:-- 3::i-----~I;:: ~,,~~:--r~-i"- 2of r----------- ■ / _...-"2_sll !I I ..-,-~~ I /'7-- 18- •----< • 16~ E I E .: -, 14- ...--•· ~ Ocular Volume (relatlve scale) ; II .••+•• e ., L• __ ~ ... at•··~ "' :a :5 G J,7 3,5 J,J "' J, I ii! ... ,.. "" < " >.7 ... 0 0 ;:: e; Q 1-5-1 ~ 4 6 8 +7SE I-I -~-H 1---1-=-l--=:I.::::::-1=1 1-0-.- 1-c=--- : 12 l s ! ::, "' 0 "' I:: > 0 "' i: "' ., "" :,,: >,J !! 6 ,g 1 - ai 1 !4 14 ~ GI 16 18 1 J.:_i ~ 20 16,5 I.S,.S & u:sc·m OF \1TREOUS ( mean values or hflblea 1-6 days old. and 1692 children 1-13 ycau old) _,., ,.s t within successive age groups, calculated from Weiss's individual measurements. The dotted line with crosses represents body weight (relative scale on the right). Body weight increased by a factor of 20 from birth to adulthood but the ocular values increased much less (about 3½ times for ocular volume and J½ times for diameter). 16,0 M 12 z: t: J10:i:i ~ ~ i ~ &!-8 ~ __ ,__ ,_,_,_,Jo B old, and 468 cltlldret1 6 month11 to 13 ycn.r.e old) I I 2 .?! 10 OFPTI-I OF Ar-.TERIOR CltAMUt;R (averages or 80 babies 1-5 day1:1 114 -I~ I -·····-·• Figure 10-37. Growth rate of human ocular volume, ocular diameter, and body weight. The curves were plotted from averages of data published by L. Weis (A11at./-/efte, 8 [1897):191). Ocular diameter is shown by the broken line and dots (left scale, in mm) and ocular volume by the solid line and squares (relative scale to the right)- The thin horizontal broken lines mark off variations El •• Body Weight ( relatlva scale _....+-·-- .._.,-•t; 0 2 AGE IN YEARS ! - i16 11 ;1-.•··· ... I ~;':•4 .; 10 - ~-~· weight at birth s L~-t~~'!!!!~,-,_,_,_,_,_, A 20 ,.,.-f 12 - -1 :'. _....••••••• at birth .--+·---· • i... 1I ,._ (rightvolume ordinate) _,..--.:+-- 0 ■ I ~ 15,0 1.:,.s 14,0 13,5 ,, 13,0 12,.S 12,0 ,/ ------- .... ,,l ,I' 11,.S 10 JI ,, IJ ,. 11,0 10,5 AGE IN YF.AJtS 10,0 Figure 10-38. Growth curves of human anterior chamber depth, vitreous length, and lens thickness in the human eye. A: Average depth of the anterior chamber from measurements of 80 babies, J to 5 days old and 468 children from 6 months to 13 years old. B: Growth of vitreal length (mean values for 160 babies, l to 5 days old and for 1,692 children, l to 13 years old). (A and B from J.S. Larsen,Acta ophtha/., Kbh., 49 [1971]:239 and 441) C: Average thinning of the lens in 80 mature newborn babies and 381 children, 6 months to 13 years old. (Curve drawn from data given by J.S. Larsen (Acta ophtha/., Kbh., 49 (1971]:427). The measurements A and B were slightly smaller for girls than for boys, but there was no significant sex difference in the lens measurements. 10 AGE IN yf;AHS 11 12 13 " Table 10-4. Po tnatal growth and development: Literature reviewed Asdell CIIIEF SUBJECT OF STUDY according to Baker, 1897, noted that infants' eics are almost al wars blue growth (almost none) of the cornea from birth_to age 70 !2,( cliildren, newliorn to 5 years old: all hadullighdt_refl~xcs d volume /see Figure 10-37\ growth curves from age O to 20 vears for oc ar iame er an . e!:!2rlr done work on eueil size of 300 chj)drcn, _most of them sick · dsl O b ld t see the dilator m newborn mfants accordmg to Re cou dno . bo n cats· during the first week of life, cocaine and adrenaline were stimulation by light and by rugs m new r , ineffective, while eserine and atroQine wQrked . . . . the pupils dilated to 5. 5 39 infants, one 7-month premature: all reacted promptly to hght and to pm-prick, mm with atroeine early develoement of the light refiex (nr) d • to 1· ht in newborn dogs with eyes still closed the pupils were large and ~ixed for 1 2 days; goo reactions ig_ and to sensory stimuli then appeared; in other litters the reactions started on the 5th, 6t?, a~d 7th_ day, · · guinea pigs, wi·th eye s open · at bi·rth , alwa,y:s had good reactions to light . and to sensory stimuli at birth poor work on 85 intants a,red 1 month to l year: all reacted to homatroe~e growth curves of the cornea, comeared to bod;):'.weight and leng!h (see Fig!:J:res 10-40, _41, and 45) pupils of premature infants down to 1.5 kg body weight reacted to light, sound, and pam, but showed no spantaneous "eueillari unrest" ( fast oscillations l, though ther did have "hieeu~" ( slower and la~er) difference-threshold of the pupils to light was insensitive in premature and improved to age 6 months to nearadult level 91% of 125 newborn reacted to light, but only ~ to cQnvez:e;!m!:e saw Horner's srndrome in 3 children aged 5 months, 8 rears I and 9 years 202 children 1 day to 3 years old: the pupils grew markedly larger up to the second year, with slower growth thereafter; 'at age 3 they measured 3. 75 to 5 mm in diameter . comearative growth curves of bod:t: weight in man and manv other seecies (see Fifil!re 10-44) Kumnick* pupillary size and reactions Kadlecova &. Pele!lka pupillary diameter brain and skull growth from newborn 1962 Moriarty & Klingman Scharfetter 1966 1966} 1966 Kleinbaum & al Leutert Rother&. Leutert 1966 1968 Parks Rohen & Llltjen de cliiimolain & al Lind&. Shinebourne Lind &.al YEAR AUTHOR Aristotle "'"TI!'f3 Ferge~ Eulenburg: l 97 Weiss 1 9 Pfister 1901 de Vries 190:! Trilxmdeau ? 190-1 Bartels 1909 1910 Magitot Michailow 1922 1926 1926 Richter Kaiser Peiper 1926 Rudder 1932 1933 1937 1946 19541956 1955} 1957 1959 1959 "Ilio 1970} 1971 --1971 'Tsrr- Chaner&Mc Graw Cocchi Schuh Heaton Larsen I II Ill } Lai Matthew Millodot 1973 Carpel & Calina 1973 1973 1974 1975 1975 1975 1977 France &.France Heaton Steven Juberg & al Slater &Findley Sauer& Levinsohn Laor &.al 1977 Romano Korczyn &.Laor ADDITIONS May 1988: Erlinko 1972 1973 Loewenfeld • Roth 1977 1978 --1979 1981 --- 1982 1981 Korczyn, Laor &.Nemet Loewenfeld • Rosales &.al. 1982 Ca2uto &.al. Yurkewicz &.al. Rodinov &al. 1987 19 7 La Roche Pre is &.Noonan and reactions from age 6 to 100 years to light from age 3 to 90 years to age 15 (see Figure 10-45) all reacted 350 children from 7th month gestation ( 1090 gr) to full term: in premature than in full-term children (no useful measurements) delayed regression ot pupillary membrane in children of diabetic mothers 1972 1972 1972 rm'! to light and to sound stimuli to light, but less,and more slowly : inlants were large but immature development of anterior segment, especially vessels, from infancy to 9th decade; plotted thickness of iris epithelium &.of dilator vs. age: sharp growth from 0-6 years, then slow ...rowth to about 18 years ,rrowth of eve and develooment of vision (nr) changes in the trabecular network from birth to age 86 onto,renesis of perioheral adrenergic neurons /see Figure 10-43) au reactea to pneny1epnrme, none w aarenaune, 80 infants from 28th gestational week to 60 days post-term: thus, the dilator muscle was functional at the and none below the 37th week to tyramine or OIi -amphetamine; 2 th week, but release of noradrenaline from sympathetic nerve endings began only after the 35th to 37th the degree of mydriasis to indirect sympathomimetics was related to body weight ( see Fig. week; thereafter, 10-36\ onset of light reflex in peking duck began on 18th day of incubation (67% of incubation time) depth of anterior chamlier (growing) } age curves from O to 14 years, olitained from ultrasound measurelength of vitreous (growing) ments (see Figure 10-38) lens thickness (shrinking) growth of iris and of iris muscles in rats (see Figure 1-11) 2u2ils of 2remature infants down to 910 12:ams bod;):'.weight dilated to 1% homatro2ine pupils were small in the newborn, compared to corneal size, and pigment began to form at about 5 weeks of ag:e; at 5 months, eigmentation was "ve!:l'. striking" premature infants down to the 28th gestational week (800 gr) reacted to light; 28 infants from 800 to 2900 gr showed mydriasis to 1% cyclopentolate up to about 70% of corneal diameter; additional 10% phenylephrine dilated these pupils further, up to 90% of corneal diameter (proportional growth of cornea & pupils; see Fig. 10-35) oointed lo dan,rer of violent blood pressure rise when using ohenylephrine in premature infants develoement of l!ght reflex in wild birds occurs earlier than in the domestic chick the pupils should react briskl;):'. to light and near at birth; used reactions to detect clinical deficit growth curves for inter-canthal distance for normal American black and white children (ages 5-11) the center of the QUQil is not at the line of sight (diagrams of infant and of adult ere; see Fi!?i!!!:e 10 39) !"'orne_r's srndro~e _(va_rious causes) in _children 7 weeks 1 4 months 1 14 months I and 3 14 15 1 and 10 rears old m 12 infants pupil d1lation to phenylephrme was well developed, but reactions to cocaine and to OH-amphetamine were less extensive than in adults ; thought this due to low level of noradrenaline-release suggested (against Laor &.al) that the most important reason for miosis in infancy is the smallness of the eye in answer to Romano, 1977, said they "could find no published work in which the size of the iris was compared in various ages." post-natal development of adrenergic neurons in the superior cervical ganglion of rats /see Fi,rure 1 36) aec~ease 01 central ~ibition_ 01 Uie ouoilloconstrictor neurons from childhood to middle age pupils of premature mfants dilated to 1% tropic amide and 2. 5% or 10% phenylephrine (studied maturity ot retinal vessels) reactions to pilocarpine, phospholine iodide, and atropine: the same in infants and in adult ouPillary dia.m~ter _and reactions to light Erom infancy to age 100 (see Figures 10 25 through 10 33) 8 of 10 low-we1gnt mtants got signiticant blooa pressure rises witn "'·";u phenylepnrme plus u.t>';b trop1camiae ey~ droP§, but not when tro12icamide alone was used "dilation in neonates: a protocol." ( n. r. ) tyrosine hy~roxylase m lhe ce_rv,cal cord and in iris processes developed from 8 -day embryos through the EQSt-hatchmg stage to maturity at 7 months of age /birds) after destruction o_f~5% of rat's SCG neurons by guanethidine treatment in infanc the residual cells and their 2rocesses to the 1r1S grew with age Y' "safety of ocular druITT!in ecdiatrics." ( n. r.) observed prolonged mydriatic effect of tolazolinc in premature infants - hydroxy - a!llphetamm . SCC - superior cervical ganglion; OH -amphetamme our laboratory at the Columbia - Pr sbytcrian Medical Center in New York F?r cmhryologic dcvclnpmenl of the t•y and iris, sec Table 1-12. • (n.r.) not rend by reviewer; *: this work was done in 509 510 / Table 10-5. YEAR --1751 Aging, especially of the eye and iris: Literature reviewed AUTHOR Whytt 1811 173 Wells Ferge ~ Mobius Fudis 1 88 1894 Korbling 1896 Silberkuhl 1898 SchmidtRim2ler 1901 Maradon de Mon!_yel 1901 Straub 1902 Friedman 1902 Maradon de Mon!_yel 1902 Prokopenko 1902 1903 Tange Gutmann 1904 1909 1911} 1913 1911 1912 1912 Meller Seefelder 1912 1912 1918 \ I. Anatomy and Physiology Axenfeld EJ22enstein Attias Hohmann Salzmann Winnaver Fuchs ~ Soewarno 1921 1923 Stein Price ~ Handmann ~ Heyster 1928 Mawas * · Unless otherwise CI-IlEF SUBJECT * loss of contractile power of muscles loss or accommoclative power corneal cliameter from 0 to 73 years miosis in old people age ciianges in t!ie iris age vs. ]2U]2ilancl retraction age vs . "Ehysiologic ]2U]2ilsize" age versus pupil size and mydriatic drugs age versus pathology of pupil size and reactions age vs . refraction & pupil width age cEianges , incl. tlie eye and pu21l shape and reactivity or the pupils in old people no elastic tissue in irises 16-55 years old "normal pupil" versus age iris connective tissue arow1d vessels & between muscle fibers: thickening with age h,y:aline degeneration of iris border hyaline degeneration of iris border age vs . iris holes & hyaline degen. of iris border {Eoor dilation) histologic ocular changes with age hialine & other iris age chan~es age & histologic changes in t-e iris age & histologic changes in the iris age changes in the iris increased tissue rigidity (hyaline changes in conn. tissue between S]2hincter & postterior iris leaf) age-related iris pathology due to occlusion of terminal vessels reduced EUEil difference threshold 2u2illary deficits in old 2eoele degeneration at the 2ueil border age cnanges in the iris atrophic changes in the old iris specified, the results - YEAR AUTHOR 1928 1929 1931 1931 1931 1931 Wollenberg Trantas Critchlei Flower Hesch Wolfrum 1933 1951 Heine Undelt Archangelski & Churgina Ferree & Rand Vogt Favaloro Post Rones Maehara Vog! & al Gardner Riddell Simms Larsson & usterlind Asdell Simms Vasco & Pelellka Birren & al l<adlecova & Peleilka Kadlecova & Schock Miles Riddell 1954 Kumnick 1954 1954 Lange Waardenburg 1934 1935 1935 1935 1935 1937 1938 1939 1939 1940 1942 1942 1943 1946 1946 1947 1948 1948 1950 --1950 CHIEF SUBJECT* age changes in the iris age-related iris changes age-related. neurologic defects duration of Hie in vertel:irates age versus iris pigment and structure anterior layer pigment loss, small, poorly reactive pupils, connective tissue sclerosis, hyaline iris changes QUQildefects versus longevity age versus iris changes age-related post. pigment changes versus rigidi!_y of the QU]2ils euEil size in age versus afferent input senile iris changes in twins senile pupillary defects effectiveness oi mydriatics versus age senile iris changes reduced eueillary dilation in age ocular defects in old twins decreased neurons with age assumed iris color chan!iie with age death rate (age curve) in man senile miosis versus reactions to instilled mydriatics chronology oi aging in man and animals mortali!_y versus aging in man pupillary size and age changes aging & dark-ada2ted pupillary diameter visual threshold versus pupil and dark-adaptation aging versus age J2UEilsize versus flicker fusion fields assumed color change in the iris in middle-aged women {nonsense) pupil size, light reflexes , and psychosensory effect from age 6 to 100 senile miosis and reactivi!_y to mydriatics age versus iris structure pertain to the human eye. NEONATEEYE ADULT EYE Figure 10-39. Diagrams of the newborn and the adult human eye, drawn to scale. Note the relatively large anterior segment and the thick lens of the eye at birth. (From A.M. Slater and J.M. Findley, J. exper. Child Psycho{., 20 [ l 975J:243) JO. Reflex Integration: Pupillary Consequences Table 10-5 - YEAR AUTHOR --- 1957 Seitz 195 } Kadlecova 1959 Pele!lka 1958 Miiake ~ Hitter ~ Rohen 1960 1961 1963 1964 1964 1965 1965 1965 1965 1965 1965 1965 1966 & Weekers& Gustin Leinhos Kadlecova Schofield Purtscher Morone & Battistini Rohen Avanza & Alfonso Eriksson & al Feinberg & Podolak Forsius Kristek Pele§ka Purtscher Leutert age versus reaction time to auditori stimuli (a&b) age versus iris changes human pupil size and dark-adaptation versus age age versus eueillomotor deficits reactions to light & sound at ages 6-100 pupil size in light and dark versus iris tissue changes due to a!ie iris age-changes, especially ar~ophile fibers in the stroma age versus Euei[ clilation in clarlmess age versus pupil dilation to darkness and to cocaine eupil and iris changes versus age senile miosis vs. sehincter rigidi!:J'. iris changes in aging, especially increased eigmentation pupillary age curves in normal eyes and in glaucoma age changes {nr} age vs. eueillomotor dark adaetation ocular age changes (nr} age versus anatomic iris changes age versus YEAR 1935 1943 1950 1969 1969 1977 1976 AUTHOR Ozaki darkness reflex E f = electronmicroscopy; 1969 ,_ 1969 1971 1971 1971 1971 1971 1971 1972 1972 1972 1972 1973 1974 1975 1976 1976 1976 1977 1977 1976 Vegge & Rine:vold Yamanouchi Borthne & Davanger Hiwatari Liakos &Crisp Morone & al Vegge Weale Bernick Borgmann Purtscher Said &Sam ires Okamura & LUtjen-Drecoll RS Smith Pele!lka \Veale Korcz.l:'.n&Laor KorCZ,ln & al Millodot Alexandridis & Manner Saari Korczyn & al OH -amphetamine CHIEF SUBJECT age differences in acoustic pupil reflexes {rabbits) Trendelenage curve of human pupil size {see burg Figure 10 -28) Birren & age curve of human pupil diameter co-workers (see Fi~e 10 -28) Yamanoucbi & iu1trastructural study of age changes al. ; Yamanot in human iris vessels -chi &Hiwatari Ishikawa & IPtJpil after tropicamide decreased with Oono age, but additional phenylephrine caused maximal mydriasis in all age grou1:1s Korczyn & !Oldsubjects had more extensive reac Laor tions to atropine and to cbolinergic drugs than did young subjects CHIEF SUBJECT AUTHOR Mc Cawlei & al 1966 Rother & 1966 Leutert ~ Pele!lka ~ Purtscher 1970 Schttfer & Weale 1973 anatomic iris changes with age age versus pupillary contraction (statement onli} 122sition of iris frill versus age latent periods of light reflex versus age heredi!;l of iris structure age versus euen size and reactions age vs. EUEil size & reactions to light iris cr.):'.pts versus age age changes in iris vessels & stroma (nr) = not read by reviewer; ADDITIONS - pupillary - YEAR CHIEF SUBJECT Birren & Botwinick 1955 lluerkam1:1 1955 Kadlecova & Pele§ka 1955 Morone 1956 Kumnick ~ Kadlecova & Pele!!ka 1957 Magari 1959 511 (continued) 1955 195 / - YEAR 1979 AUTHOR CHIEF SUBJECT --1979 --1981 Yurkewicz 1983 1986 1986 1987 of iris and EM: age versus cellularity thickness of basement membranes a!?,e versus pupil size and reactions age I eueil size I and visual acui!;l age I eupil size & reactions to miotics age, J2UJ2ilsize & reactions to midriatics ocular chromatic aberration vs . age reduced pupil light oscillations due to "muscular & vascular degeneration" in age iris "dense" in children, "atrophic" in age reclucecl dilation to cocaine & OH-amphetamine thought to show "reduced sympathetic tone" =hydroxy-amphetamine. Bourne , Smith & Smith Loewenfeld 193 age vs. eueil reflexes and esichosis iris age changes : posterior epithelium, & other structures dilator EUJ2il dynamics & adaetation versus age anatomic iris changes effects of illumination and age upon the EUJ2illar.l:'.near reflex anatomic changes in the iris versus age { electronmicros COQYl iris vessels versus age {electronmicroscoI!Y} effects of mydriatics versus age EM: thickening of basement membrane and increased collagen fibrils in the ag!ng iris pupil size versus age in normal and in es.l:'.choneurotic individuals EM: iris age changes versus movements age versus iris vessels the a[!ng e.l:'.e (nr} J2UJ2ilsize and reactivi!;l versus age age versus I!U[!il size and reactions a1<e chan1<es of colla1<en in the ant. iris leaf Eupil size in darkness (nr) anatomic iris changes with age (EM) Sekuler & Owsley Smith & Fasler Apt & Henrick Pressman &al. Steinmann &al. & al. influence of age upon the human pupillary light reflex pupillary size and light reflex from infancy to age 10 O {see Figs 10-2 5 through 10 -34 ) in chickens hydroxylase activity in NA-neurons decreased with !!,ge (U[! to 5 years) age changes in pupil size and in accommodation pupillary age changes, related to postural hl'.:E2tension mydriasis to drugs was better in young than in old eves in old people, pupils were smaller when they ':"er_e sleee.l:'. than when they were not dilation to local tropicamide was slower above age 50 than in the young 512 / I. Anatomy and Physiology f 13 • GROWTH OF CORNEA .. . ...i• . .··-,t . ..... . • . . .. . . . . .. ... . . . ... . 0· -~-·---·-----0 ... .-... 0... •. • t .. . r . :. .• . •• . 3 to 4 YEARS • 0 12- 00 ,.., l-'-4 • J I • • f:311- I " ·' ~ H ~ Z 1-1 p:: ~ . ----. • .,,,... 0, C""""' r:z::l ~ ...:i10- 0 •~~RS -, -, • • • ,, •• • , : I : :.,_:~'..,...•.. -, • • i0¢, • '\ • . . . .~. • • ------·. 15 DAYS to 3 MONTHS •. • • •. • - • (:'\ •• •. • t • ~ '-. -~- _l:)· ••••• _..,:._ -T(:j • .. •4:-• . . .... • 2 to 3 YEARS • 6 lo 12 MONTHS • .. • ' • 1 to 2 YEARS • • 5 to 6 YEARS ;':. 1-15 DAYS 9- , ,~· I,: • •• ••• •• ; 1. ~ 81 j, 0 u 41--------~---••---s---~~-~~mwuww: BODY WEIGHT IN KILOGRAMS Figure 10-40. Growth of human corneal diameter, compared with body weight. The curves were drawn from data supplied by J.H. Kaiser, (von Graefes Arch. Ophthal., 116, I [1926):288.) Corneal diameter (in mm) is plotted against body weight (in kg). The dots show measurements for individual children. The circles with dots are averages of age groups, as indicated. Figure 10-41. Relative growth rate of human ocular structures. The curve for ocular diameter was plotted from data published by L. Weiss, (Anal. Hefte, 8 [1897):191), whereby numbers for sagittal, horizontal, and vertical diameters were averaged (solid line and circles). The curve for corneal growth was constructed from measurements supplied by J.H. Kaiser, (von Graefes Arch. Ophthal., l 16, I [1926):288), as dotted line and squares. Pupillary diameter was plotted from data of our population survey as percent of limbus diameter, both horizontal (dash-dot line and triangles). Extent of pupillary contractions at the end of 1 second of bright unilateral light stimulation ( our material) is shown by the broken line and dots. The abscissa shows age in years. Note the rapid growth of the corneal diameter. The outside ( ciliary) iris diameter has about the same size. The pupil reaches peak size much later. This means that the iris ring is much wider in small children than it is later (see thin vertical double arrows). Light reflexes reach peak amplitude even later. Figure 10-42. Reflexes to slow and to fast stimulation rates in an old and a young subject. The pupil records of a 70-year-old man (solid lines) and of a 26-year-old woman (broken lines) were superimposed. In A, three 15-foot-candle, ]-second light stimuli were presented. In B, the stimuli were of the same brightness but they lasted only 5 milliseconds each. They were given at rates of one, two, and three per second, as marked by the small arrows. The old man had unusually large, mobile pupils that reacted every bit as well as those of the young woman as long as the stimulation rate was slow. But at fast rates his pupils were unable to follow the stimuli nearly as well, and his pupillary oscillations were much shallower than those of the young woman. (From I.E. Loewenfeld, in Topics in Neuro-Ophthalmology, H.S. Thompson et al., Eds. [Baltimore: Williams and Wilkins, 1979]) JO. Reflex [ntegration: Pupillary Consequences 2. Sympathetic Deficit Second in popularity among the theories explaining the small pupils in infant and "senile miosi " has been the assumption that the sympathetic nervous system is at fault. . /r!J ♦ ! -I •-~, M-~•-M _,,'" ,m I . I I m 1 &rowth of . ~'fluorescent: g:neurona ; ;!extending ; ~:lowerd cor<! 20 - ; ;:f 1 • • i ♦ ~• t "" l _..l (:) f:j + (:) ,5'.t• lii" @:)·, O ,:i + at SCG ~ I • fluoreacence at end organ lO-LorHcentcelle i I I . " C:rapld i I I I I I / ef 0 : I I ; ! I I ji 40- H- terminal ffbera atlll poor In fluorescence, pretermlnal densely fluoreacent adrenerglc ground plexus In Irle well developed 1-··-----,,----·----,,----- GESTATION • •• .. ••••••••••-I•••"••-•••-•(•------,----- CONCEPTION IO 513 [n children the sympathetic nerves were thought to be incompletely developed; and this must be true before birth and shortly thereafter, since indirectly acting adrenergic drugs (tyramine, hydroxyamphetamine) fail to dilate the pupils of premature babies until about 3 weeks before term, and the emerging reactions then increase in step with gestational age (Figure 10-36,B). Lind and co-workers (1970-1971) noted that hydroxyamphetamine caused blanching of the blood vessels around the eye in most premature children whose pupils remained unaffected by the drug. This suggested a difference in functional development of the facial vasomotor and the pupillodilator fibers. The progression line with increasing maturity shown in Figure 10-36,B indicates that this development is still incomplete at birth. This has been found in all animals examined. In rats, for example, sympathetic nerves form mature endings only some time after birth (Figure 10-43). Doubtless each species must have its own timetable, depending upon the degree of maturity of the animal and of the eye at birth. Among mammals, this appears strongly related to the life habits of different species. Thus, animals born in underground nests arc much less well developed at birth than are, for example, ungulates, who are born with open eyes and who are able to walk soon after birth (Figure 10-44). -the poor following of rapid timulation rate in old eye . Fa t pupil o cillation are always relatively shallow in old eye , even when the pupil till are large and react very well to lower form of timulation (Figure 10-42). In ummary then, it appear that after the age of 20 there is progre sive failure of the pupil to dilate in darkne and con equently decrea ed amplitude of the pupillary light reflexe , e pecially to long and powerful timuli. Thi i not due to lo of reactivity a uch but to a dimini hed mechanical range of movement impo ed by the relatively mall pupil ize. The decline begins too early, and for several decade of life the pupillary movements remain too bri k, to be explained by enile iris degeneration. And becau e the pupil of healthy old eyes dilate well to locally in tilled adrenergic drugs, their failure to do o pontancously in darknes must be caused primarily by neural events rather than by structural iris impairment. The latter contribute to senile dysfunction, but much later, and in a relatively minor way. so / 1 - POSTNATAL GROW ~HIN OAYS BIRTH lO 20 -I-30 - - - - 1 J •I• 40 - TIMEIN DAYS Figure 10-43. Development of adrenergic neuron in rats. Rats like man, have immature babie . In Figure 10-44 the relative ' growth rates of man and rat can be een, ote that at birth the adrenergic nerve plexus wa still incomplete (see al o Figure l-36). (Curve drawn from data given by J. de Champlain T Malmfo ' ( •1970]: ) r ' L • 01 son, and C. Sachs, Acta physiol. scand., 80 276 514 / I. Anatomy and Physiology dntgs, which proves that the miosis must be due primarily to cholinergic impulses and not to a defective sympathetic nerve supply. In old age, decrease of sympathetic activity is said to deprive the dilator muscle of its tone. The sphincter muscle would then no longer be effectively opposed, and consequently it would go into contracture. Thus the pupil would become small and sluggish. Sometimes this theory was expanded by assuming that the parasympathetic supply of the pupillary sphincter also deteriorated in old age, leading to "global impairment of autonomic tone" (Lange, 1954; Morone, 1955; and others). We do not believe, however, that sympathetic dysfunction is likely to play such a significant role in the development of miosis in later life. As seen in Figures 10-25 and 10-26, the pupils lose, on the average, about half of their diameter in darkness between the ages of 18 and 65 (3 to 4 millimeter ). This is far in excess of the contraction caused by sympathetic paralysis: in otherwise healthy individuals the pupil on the side of a Homer's syndrome is from about 0.5 to 2.0 millimeters smaller than the good pupil after adaptation to darkness; and in light the two pupils are almost alike in size (see Chapter 25). Further, there are no obvious signs of sympathetic denervation in older subjects: there is no sudomotor or vasomotor paralysis, no sympathetic ptosis, no loss of psychosensory reflex dilation or defective dilation to cocaine. While it is likely that spontaneous firing over the peripheral sympathetic pathways decreases with age, this lessening could at most be partial; it does not appear to be due to marked impairment of the sympathetic neurons; and in any case, it could never account for the much more intense miosis that develops in old age. The sphincter muscle, also, is obviously not deprived of parasympathetic innervation in old people, because the light reflexes usually remain brisk. In addition, the small pupils of old people-in the absence of iris damagedilate well to hydroxy-amphetamine and to atropinic 100 I 80 -, .,,0 ·CD-•-0•-&---&- MAN RHESUlMONKEY -GJ-----e-- HORSE _,;;;• .t.-::;,· ~:=:~ :::~srER 0 ~/ t,·<~/; 50 ..., 8 40 < /// .,0 / // ....,./' / 30 -, 0· .. .•-~•/. >10 A • GJ"s:.•·· .-ll!?-•.✓ ,, • .,, ,,0 § Lief ;, 'I, 10 o --~•-· __,.w~•··· ~• • ,,,. ,/.~-::.-·· -I <!>20 - i>: ,{-·· r.o~r:-· •"' ,,t 1' .. -.:"!i:-:,~•·"'· •• /• • ~ "' ,lj:.-· ,,------ L.•7 _,.----• [;; • ,/ ./ 0 'o ~ / 0.-~/ I I Figure 10-44. Relative growth in different mammalian species. The ordinate shows relative weight of the animals at different times, in percent of adult weight. The abscissa shows age in years and months (for man) and in relative growth time for animals, with 100% the adult body weight. The relative size at birth is related to life habits of the species, not to the absolute size of the animals. The growth rate of primates differs from that of all other species: these remain relatively smaller until puberty, and have a more pronounced "teen-age spurt." (Curves drawn from data supplied by S.A. Asdell,J. Gereontol., 1 (1946):222) ,It'' /• ,." :, !/ • •. -;~ /!"/ 60 _I _I ¥"/'l' ..I ,t:{'1//.~-• 10 - .. As described in Chapter 9, pupillary size and movements are controlled by the reciprocal interplay of the pupilloconstrictor and the pupillodilator neurons in the midbrain and the spinal cord. In response to stimuli that raise the level of arousal, sympathetic discharges increase while parasympathetic discharges decrease. The latter event is due to central (probably adrenergic) inhibitory impulses that impinge upon the sphincter nucleus. At birth the brain weighs less than a quarter of its adult weight. It is still immature, especially the hemispheres, so that not much goes on upstairs, and the infant spends most of its time asleep. The lack of cerebral function contributes to the smallness of the pupils: there is as yet little sympathetic and central inhibitory activity. Within the next decade the brain grows to almost its full adult weight, and the pupils enlarge. By the time of puberty they are as large as they will ever be. This enlargement at first is partly due to growth of the eye and iris, as already mentioned, and to increased central nervous activity, resulting in more active sympathetic and central inhibitory discharges than is present in infancy. It can be seen from Figures 10-37, 10-38, 10-40, 10-41, and 10-45 that the eye, the skull, the brain, and the pupils enlarge steeply in early childhood and-in sharp contrast to the rest of the body-they all have completed most of their growth by the age of 5 or 6. During this time the central inhibitory mechanism becomes very strong. In 4- or 5-year-old children the light 1 90 -I t 3. Central Inhibition RELATIVE GROWTH in%_. 20 30 40 50 60 106 126 70 80 90 100 8 16 18 20 1-1-1-1-1-1-1-1-i-i- AGE t.n MAN (YEARS and MONTHS) 21 41 63 -+ 8 4 14 7 10. Reflex Integration: Pupillary Consequences / 515 above). The fa cinating point is that th~se pupill~ry change resemble those seen in old people m all details. With advancing years there is the same gradual loss of pupil ize, the same relatively accelerate~ c?ntractions to light, and the same incomplete red1lat,.ons. La~er there are the same square-shaped, rather mextens1ve light reflexes, and again later the same slowing of the re idual re ponses. But there is one fundamental difference between the pupils of the old and of the young: when the loss of central nervous reflex integration is due to tiredness, it can be restored by sleep or-from one moment to the next-by p ychosensory stimulation. With increasing age in contrast, this recovery becomes le and le s complete, and consequently old people how pupillary "fatigue signs" permanently, even when they are not tired. Apparently the same structures that develop relatively late in infancy are those that lose their activity early (and reversibly) during fatigue, and also lo e them early (and permanently) during the aging proces . reflexe are much more inhibited than they arc later in life. Con equently they are not a extensive a one would expect con idering the pupillary ize in darknes ; and both the amplitude and the pattern of the reaction vary erratically with the up and down of attention and of emotion during the test (Figure 10-32 and 10-33). A· the individual matures and become capable of maintaining a more even emotional keel, the inhibition le ens, o that the reaction become larger and more regular. They are at their be tin young adult people who are well re ted, alert, and calm: a ynergi tic equilibrium is reached between the dilator, con trictor, and central inhibitory forces, and i expre ed in large, teady pupil with exten ive, mooth light reflexe , a h wn in Figure 10-33,D and E). When the individual however, become tired, the sympathetic and the inhibitory pupillodilator force weaken; and as alertnes fade and lcep approache , the pupils contract and the light reflexe deteriorate ( ee D. Significance of These Changes for them the experimental situation carries far more intere t than it does for grown-ups. Thus babies' pupils tend to be small and older children's pupils large and variably inhibited. Old people's pupils not only tend to be mall in darkness but-due to the weak central inhibition-they usually constrict well to dim light and to diffu e room illumination. When observed clinically in room light therefore, they often are smaller (and their Both practical and theoretical con equence re ult from the e facts. On the practical ide, it i obviou that a description of a patient' pupil a "pupil dilated," "pupils constricted," or "light reflex limited (or not)" will not be meaningful without c n idering the patient' age. Young babies have small eye , and they are u ually sleepy. School children have trong central inhibition; they try (intermittently) to be on their be t behavior; and I CORNEALDIAMETER 1::,, r:::~:~:::5~!==-------------• • sol/ 70-, .,. 0 / 1 / ...................... .-■-•-■-• -•-•-■•-•-••■ •illO f55 _,-•• _... 50., ...... I 0 I II •. , o I I I :320 _ 3 ; - + ~ f Figure 10-45. Relative growth rates of the human skull brain cornea, and J?upil: Th~ ordinate represents percent adul{ value~, and the ab c1 sa time m years. Data for the cornea were supplied by J.H. Kai er (\'On Graefes Arch. Ophthal., 116, I (1926].·288)·, h ~ t. o e. o_rthe brain and skull by J .A. Moriarty and W.O. Kingman (m Clt~ucal. eurology, A.B. Baker. Ed. lNew York: Harper, 1 62]). ~upillary data come from our population survey, with pupillary diameter as percent of limbus diameter (both horizontal). 145 •' o/ 30 - j ./ / '·c;·-.......... t ✓• ..... 750:: 50-, 40- PUPIL PUPIL DIAMETERIn % of IImbua diameter 4-.._· 0 ITlal<lmal _, f !. .......... 7 J ...... _1"° ,. / ? 0 10- ! OL_,_,_,_,_,_,_,_, o 1 2 3 AGE IN YEARS • --+ s e ___ 1 a g ,_1_1_, 10 11 12 --;4~'s, 13 1.;- 516 / I. Anatomy and Physiology reactions worse) than they would prove to be when examined in darkness. We have, in our laboratory over the years, seen a number of such patients who had been subjected to exhaustive series of serologic and other tests in the mistaken belief that they had miotic, fixed pupils, the near relation of the Argyll Robertson syndrome but whose pupil reacted briskly to light after dark-adaptation. Conversely, we have seen excitable young people whose "diJated pupils" had seemed fixed or very sluggish to their phy ician . These patients and their families could have been spared much concern and unneces ary procedures if it had been realized that central inhibition may be powerful in an anxious youngster. After some rea urance the inhibition lessens, and with a series of bright light flashe , extensive reactions are eventually produced. Our generaJ view of the pupils in certain diseases also wa influenced by considering the pupilJary age curve. For example the thought of a "diabetic pupil" had alway elicited the image of a small, sluggish pupiJ. However, many diabetic patients are elderly; and compared to the expected normal age curve" we found the miosis in diabetes not as impressive as we had thought before (see Figure 34-7,A). ln contra t, when we examined 409 patients, chosen at random from the Syphilis Clinic at the Columbia-Presbyterian Medical Center, we were startled to find that more than a third of them (even at relatively young ages) reacted less well to light than the lower ex,treme of the normal range (Figure 31-3). Our opinion of what is a "normal pupil" must be reviewed in the light of these findings. We had, in the past, regarded as "normal" the reaction pattern of the pupils of healthy young adults who were well rested and calm. Deviations from this pattern during fatigue or emotional excitement were considered "physiologic" as long as they could be reversed by rest, by psycho ensory stimulation, or by calming down. But patients who had these types of reactions always, and in whom the well-balanced reaction pattern couJd not be restored, were thought to have "pathologic" pupils. I have no quarrel with this view except that I now think that we were sloppy in using the terms' physiologic" and 'normal ' interchangeably. According to the definitions in Meniam-Webster's New Collegiate Dictionary (6th edition, l 960), "physiologic" means "characteristic of an organ's healthy functioning." It is derived from the Greek wordphysiologia, a combination ofphysis (nature) and logos (discourse). This is distinct from "pathologic," meaning the morbid or diseased condition (from the Greek pathos, meaning suffering). "Normal," in contrast, means "according to, constituting or not deviating from an established norm," and this "norm," or " et standard, model, type or pattern" means "the usual condition, degree, quality or the like; average, or mean of a large group." It appears logical that-depending on the group considered-this need not necessarily mean "healthy," that is, "well, sound, robust, full of strength and vigor and free from signs of disease." Regarding the pupillary signs found in old age, they are "normal" in the sense that they become more and more common, and eventually universal, as we grow old. But J think it is no more "physiologic" to have small, poorly reacting pupils due to age than to have the same deficit due to disease earlier in life: if we accepted the many degenerative changes that befaJI us sooner or later with advancing years as "normal" merely because they Figure 10-46. Age curves for different pupil syndromes. Among 1,881 persons examined in our laboratory within a given time, different pupil syndromes showed different age trends ( ee also the clinical chapters of this book). The ordinate shows relative frequency of age groups (decades) represented among the total group of 1,881 individuals (1), compared to different pupil syndromes. Numbers greater than I show that the particular age group occurred more frequently, and numbers below 1, less frequently, among patients with specific pupil syndromes than among the total group of 1,881. Broken line with crossed quares: increased central inhibition that occurred frequently in children and decreased with age. Broken line with hatched squares: Moderately decreased central inhibition, found most commonly in middle age. Broken line with circles: Markedly decreased central inhibition, which was rare among children and increased with age. Dotted line with black squares: Consensual deficit, which showed no age trend. (From I.E. Loewenfeld, in Die Normale und die Gestorte Pupillenbewegung, E. Dodt and K.E. Schrader, Eds. [Miinchen: J.F. Bergmann, 1973]) 10. Reflex Integration: Pupillary Consequences appear to be inevitable, death itself would be a phy iologic event. And while ene cence and death do have advantage for a pecie in e olutionary term I am not prepared to agree to thi for individual patient . We were not alone in blurring the border between the' physiologic' and the' normal," a witne ed by the fact that the ame dictionary in its 8th edition (1973) enlarged the meaning of' phy iologic" to "characteri tic of an organ's healthy or nomwl functioning" (italics mine). At the ame time the concept of 'normal" was upgraded. Already in 1960 it had worn an air of virtue by the further definition of "regular, natural occurring naturally' and-for u e by psychologi t -' free from mental disorder, not in ane or neurotic" (the la t not ' average' in all group ). But in 1973 the "norm" itself had become not only an 'authoritative tandard' as before, but in addition "a principle of right action, binding upon the member of a group and erving to guide, control or regulate proper and acceptable behavior" (italic mine). In view of not too distant hi tory I find thi flavor of moral approval for the average' -still the accepted synonym~minou . A to (presumably "normal") aging, the dictionary is far le s laudatory in it definition . To age i to grow old. Old may, of cour e, mean merely "having exi ted long" or "advanced far in year in life." But in addition it is de cribed as "having lo t the vigor of youth," a "worn out, infirm, weakened, feeble, or exhau ted," as 'having passed the period of greate t u efulne s." Among the synonym of "aged' are ·'elderly" and "superannuated"-the latter equivalent to 'antiquated,' which, in turn, may lead to 'ob olete, out of date, no longer u ed" and from there to "indi tinct" or ' ab ent.' And true well-being appear combined with age o eldom that special word di tingui h "hale, hearty, wellpreserved" old age from ' enility," meaning "old age or its physical and mental infirmity." Language it elf has thu been haped by our realization of the detrimental change brought about by age. And in peaking of the pupil, it would create confu ion if we simply labelled a per on' imperfect reaction a "normal" without further definition when they conform to the expected age curve. It would, in my opinion, help clear thinking if we made the di tinction between (1) physiologic, that i , condition to be found in the healthy young, and (2) normal according to the patient's age. A given patient' pupillary reflex pattern mu t be evaluated on the background of the known general age trend. For example, ince central inhibition weaken early and will be lo t completely in every per on who live long enough to how thi ign, it hould not be alarming when the inhibition fade at the appropriate time. The same defect found in a child, however, hould alert u to a pathologic proce . Or-in contra t- ince the afferent pathway from the retina, the midbrain neuron , and the para ympathetic fiber in the third nerve do not age early, a fixed or luggi h pupil indicate pathology at any age (Figure 10-46). / 517 The marked interpersonal scatter in the pupilla:J findings of a large healthy popula_tion_is _p~alleled. m many other systems. There are wide md1v1dual variations in the beginning and the rate of progress of the aging process: one person grows and matures more quickly than another; one remains robust and mental!y creative to an advanced age while another becomes frail, or his mental faculties deteriorate before his time. And on this background of innate proneness or resistance to the aging process the outward stresses of life operate to hasten the decline. Among many other theories about the cause of aging, it has been proposed that the process is not an inherent and unavoidable part of life, but is only the result of "wear and tear," of accumulated insults and diseases over a lifetime. This explanation carries with it the hope that elimination of all detrimental factors may greatly lengthen the human life span. The marked increase in life expectancy achieved within the current century appeared to support this view. There are, however, many facts that do not accord with it. 0 Among these, the age curves of functional integrity in many systems-just like the pupillary age curve-begin to decline early, directly after growth and maturation have been completed. These losses, though steadily advancing, often are not acknowledged as part of the aging process. It is, perhaps, disconcerting to look back upon the time when our reflexes were swiftest, our muscles strongest, our endurance greatest, our memory most retentive, and our emotions warmest, and to realize that we have spent these golden moments in high school. Further, age changes may go unrecognized until they have used up the wide safety zone between the perfect and the insufficient. Thus loss of accommodative amplitude begins as early as the decline in pupil size; but usually it goes unnoticed until the last few diopters that allow us to read comfortably nearby are gone. For mental work, a decline in quickness and energy may be compensated for by experience and by discipline; and while we know that a professional boxer aged 30 is handicapped against a younger man, our interests change, and most of us remain quite fit for what we really want to do well into middle age. As a physiologic mechanism, however, modern man has hardly embarked on his career whenunder primitive "natural" conditions-it would have ended in the stomach of some youthful beast. The apparent lengthening of the human life span within this century is mainly statistical, not biologic. It was accomplished by a reduction of infant mortality and the control of some diseases. Beyond this, little has been added to the Biblical three score and ten. And while we have learned to avoid a good many of Laurentius's "outward causes of our dissolution," the "inward" ones yet "abide with us and accompanie us even to the grave." . tn 6._See Yogi's interesting finding about senile iris pathology twms mentioned above.