Chapter 40: Glaucoma

CHAPTER 40 Glaucoma CONTENTS A. Summary ......................... 1396 B. Treatment of Glaucoma with Autonomic Drugs ........................... 1397 1. Historical Background: Eserine and Pilocarpine . . . . . . . . . . . . . . . . . . . . . . 1397 2. Other Drugs . . . . . . . . . . . . . . . . . . . . . 1398 C. Mydriasis during Glaucomatous Attacks ... 1403 D. Pupillary Behavior Outside of Acute Glaucomatous Attacks ................ 1409 E. Nervous Influences (Experimental and Clinical Findings) ................... 1. Peripheral Nerves ................. (a) The Fifth Nerve . ............... (b) The Third Nerve ............... (c) Sympathetic Nerves ............. 2. The Central Nervous System . ......... F. Conclusion ........................ 1410 1410 1410 1411 1412 1412 1418 A. Summary The complex and ever-expanding research on intraocular pressure regulation exceeds our field of competence. The present chapter therefore is limited to a description of work done over the last century in which the pupil were directly involved. These studies were partly practical, that i , they dealt with miotic or other drug u ed for glaucoma therapy; and partly they were concerned with theories about a possible influence of pupillary movements upon the intraocular pressure, or the rever e; or with the effects of peripheral or of central nervou mechanisms. (1) Ever since the discovery of the beneficial effects of eserine and of pilocarpine in some types of glaucoma, a very large number of publications dealt with relations between mydriasis or miosis and the intraocular pressure, and with pharmacologic mechanisms and potency of various drugs. Not only miotics but also anticholinergic drugs, adrenergic agonists and blockers (both alpha and beta), and other substances were used. Most of these drugs were given topically, and a few systemically. These publications are collected in Tables 40-1 and 40-2. (2) Since acute attacks of high intraocular pressure are accompanied by mydriasis, some authors thought that both the pupillary dilation and the increased pressure were due to pathologic sympathetic discharges. But interruption of the sympathetic nerve does not prevent the pressure-related mydriasis, which was later found to be due chiefly to ischemia of the retina and of the iris sphincter muscle. (3) Cutting the fifth nerve or stimulating its distal stump causes sharp rises of intraocular pressure, together with miosis, vasodilation, and a breakdown of the blood-aqueous barrier. These effects, occurring especially strongly in rabbits, are mediated by local release of prostaglandins and of other biochemically active substances, and are unrelated to the autonomic innervation of the eye. (4) Stimulation of the third nerve raises the intraocular pressure, mostly by pressure of the contracting 1396 extraocular muscles upon the globe. In addition, strong innervation of the ciliary muscle with forward-bulging of the lens can play a role in eyes with shallow anterior chamber angles by pushing the iris root forward and by thus occluding the angle. (5) Stimulating the sympathetic nerves to the eye also increases the intraocular pressure, and cutting the sympathetic nerves leads to a transient fall of ocular pressure. These effects are due chiefly to contraction of the extraocular smooth muscles; vasomotor, secretory, and other mechanisms also play a role. The details of all these events, and possible interactions of several mechanisms as well as secondary consequences, are far from explained to date. The same is true for central nervous influences upon intraocular pressure regulation. (6) The pupils of glaucoma patients (outside of acute attacks of high intraocular pressure, and in the absence of severe visual loss or of iris pathology) contract briskly to light, but the reflex pattern indicates poor central inhibition of the pupillo-constrictor nucleus. Similar reactions were brought about in monkeys by experimental lesions rostral to the midbrain. In addition, there is clear experimental evidence that central (diencephalic) stimulation can cause both rises and falls of intraocular pressure, together with or without pupillary, vasomotor, or other autonomic effects. But the search for a "center" for intraocular pressure regulation remained fruitless: no localized group of neurons or fiber tracts specifically related to the intraocular pressure were found. This is, no doubt, partly because of technical difficulties encountered in all experiments of this nature. But the entire concept of discrete "centers" for the regulation of autonomic functions has not withstood the test of time. These questions are discussed in Chapter 9. (7) Aside from the important role of the pupils in drug studies on the eye, the most useful clinical pupillary test for patients with glaucoma is the "swinging flashlight test" or other maneuvers to demonstrate early loss of retinal function, before permanent damage has developed. 40. Glaucoma / 1397 B. Treatment of Glaucoma with 1. Historical Background: E erine and Pilocarpine utonomic Drug filtrati n ( out fl . . ) of the ecreted eye fluid. Cal a bar . tretc h • t h e m t ~ar~ the _center of the pupil. The ucc of the m d1~at1 n will principally depend on For more than a century glaucoma ha been treated wheth_er th _c ntract1on of the iri i forceful enough to with the cholinergic drugs phy o tigmine ( rine) and draw 1t. p npheral p rtion away from the cornea and pilocarpine. The early hi tory of the e drug i d crib d thereb , t r open the channel of outflow for th; in Chapter 14. Their role in glaucoma th r p wa dammed-back ular fluid ... ' described by Kronfeld in hi delightful hi tory £ erine " eb r' conclu. ion (in I 76) wa that Calabar and Pilocarpine: Our JOO-Year-Old Allie:' When e erin e tra t, or it. principal on. tituent, e erine, wa a mo t and pilocarpine arrived on the cene the phthalm I giu. cful drug. Hi. v ry detail d article appeared in Graefe' cal world was very much under the influen e f lbr ht rc/111fi,.r Ophthalm~l~gre everal month after Ludwig van Graefe's earth-shaking di covery that acut inflamLaqu ur. fir t. preliminary c mmunication entitled 'A matory glaucoma, until then an ine capabl blinding nev therap utic indicati n for phy o tigmine ' in which disease, could be cured by iridectomy (v n raefe, 'a defin'.t ?r ~ f the el ated ten ion' foliowing re1857). The results of thi op ration were o triking! p at d m·t11lat1on. of an aqueou olution of 0.3 per beneficial that the mere thought f any n n ·urgical cent or 0.5 p r ent ph . tigmine wa reported to have treatment met with under tandable r i tan e. Thi urrcd in a. of glauc ma implex and 1 ca e of resistance applied also to glaucoma implc , in e on e ndal) glaucoma. 1 Graefe, up to the time of hi death in J 70, rec m"Ludwig Laqueur (1 39-1909), a native of ile ia mended and practiced iridectomy in noninflammatory rman ) and earl pupil f von Graefe, held licen e glaucomas." pra tice mcdicin and medical faculty po ition b th Eserine is an alkaloid derived fr m th alabar b an: in crman, and in ranee. After the war of 1 70-1 71 "The first studies of the ocular effect f the dru ,; ere th• rman go ernment app inted him to a profe ordone, independently, by the then- ry- ung II . ~ip .it the bilingual ni er ity in tra bourg. There, Robertson in Edinburgh, and by the om what Ider n without kn " I dg f eber· work, Laqueur b gan to Graefe in Berlin, the re ult appearing in print in I 63. u. c c. cnnc in human glaucoma in March 1 76. Hi These early studies ... centered ar und th effect. f b<,crvati n. were publi. hed in full in the ft-quoted topically applied Calabar extract n the pupil and articl ' bcr tr pin und Phy o tigmin und ihre accommodation in normal eye of olunteer . Thee tabirkung n auf den intra cularen Druck,' which aplishment_of e_ffectiveand largely nontoxic do age pr ed pear din raefe' Archil•fiir Ophthalmologie during the ~o be ~u1te simple. Thi paved the way for clini al trial. latter part of 1 77. The article contain the fir t clear-cut m which the Calabar extract clearly dem n trated it de cription of the action of e erine in bringing about the usefulness as a miotic. From what appear to bee ten i e . ub. idenc and non-recurrence of attack of acute 0 ?servations in cases of glaucoma, on Graefe recoginflammat ry glauc ma. Thi would have b en a theranized o~Iy _the miotic effect of the drug which h i und p utic triumph of the fir t order if the ophthalmological beneficial. m that it facilitated iridectomy. . . . pparworld had not been o much under the influence of the ently he did not observe a drop in pre ur and ub idunqu tionable ucce of iridectomy in acute inflammaence of an attack as the re ult of admini tration of tory glaucoma. Laqueur wa under that influence and, Calabar e~tract, although its u e b came part f hi· therei re, a igned very much le importance to hi pre-operative routine. di c ery than it de erved: E erine i not intended to "The first systematic study of the effect f extract of take the place of iridectomy; e erine i only intended to Calabar on the intraocular pre ure apparent! wa create more favorable condition by making the operaundertaken by Adolph Weber (1 76) th • f a I . , e pioneer o ti n ea ier. • a~atton tonometry. • .. After topical admini tration ? . a abar extract to animal eye Weber' t n met r md1cated a rise m • pressure m • the v1treou '. chamb r and . 1. Weber aid the e experiment were begun in 1 69, and a very mark~d drop in pressure in the anterior eght mea urement of relative pre ure in the anterior and m~nt. • •.• With regard to ad mini tration of alabar p terior egment of the globe were done in 1867. Weber's ex rac~ m glaucoma, Weber (1877) made th laconic paper wa publi hed in 1 76 purred by the hort communication f Laqueur' which Weber' friend and pupil E. Meyer in rmar that he had used the drug 'with ucce in ome Pari aw and ent po tha te to Weber, offering to upport orrn_sof t~e. disease,' but he went into con iderable Weber' priority. Weber mentioned thi but made the point tta1l ~xplammg the effect of the drug: 'The mechanical that he did not wi h to imply that Laqueur had known of his 1 th ;~:~: t~ [ ~ pathogenesis of] a whole group of glaucopre iou effort : "To av id all mi understanding I want to expre clearly that it i far from me to think that Laqueur had th :r e displacement of the attachment of the iri on any knowledge of my ob ervation , but that I place particular su~t iary body towa rd the periphery of the cornea to value upon hi communication and the correctne of the an extent that the wh 0 I • overlaid b · · . e pectmate ligament i b ervation becau e I am convinced that they were made y ms which thereby obstruct the proce of entirely independently from mine." f~ 1398 / V. Pupillary Pathology: Pupillary Signs in Various Diseases "With regard to eserine in glaucoma simplex, Laqueur wa certain of pres ure drop in some cases. With only his finger erving a measuring tool he expres ed himself with under tandable reservation: 'My experiences with eserine are not numerous enough and do not concern a ufficient number of fresh ca es to allow a final judgement regarding the value of the drug in glaucoma implex.' "Between Laqueur' fir t and econd communication Weber once more expressed his opinion regarding e erine and added a highly significant remark about pilocarpine (1 77): 'Calabar is a very potent drug which in the beginning, without any doubt, rai e the vitreou pressure. Therefore I want to recommend the greatest caution in u ing the drug in glaucoma. Under the influence of Calabar visual field loss may occur in portion which eem to be in a state of torpor in dim light, but function quite well in bright light. Much more warmly I would like to recommend the u e of pilocarpine for the pre- and post-operative treatment of the glaucomas. This drug i a happy combination of a blood ve el relaxant and timulant of both phincter ( of the iri and of the muscle fibers around the major arterial circle). I live in hopes 1) that in ome of the chronic simple glaucomas pilocarpine will take the place of iridectomy and 2) that in many others pilocarpine will erve to make up for the insufficient effect of the operation.' "Laqueur and Weber opened the door for the clinical u e of pilocarpine and eserine in ophthalmology. The pure alkaloid in uitable vehicles became readily available. A miotics, that is, before operations for glaucoma and at the end of cataract operations, in rotation with atropine to break posterior synechiae, and for the reduction of peripheral iris prolapses, the two drugs oon e tablished their place in the armamentarium of the ophthalmologist." The concept of the usefulness of eserine and pilocarpine for long-term treatment of glaucoma was established more gradually. The development of accurate tools for tonometry (von Graefe, 1862; Weber, 1867; and especially Schi0z, 1908); progress in perimetry (Bj~rrum, 1889); and the availability of cocaine as an effective surface anesthetic (1884) made it possible to do careful, long-term observations on well-matched groups of patients with glaucoma (Zentmayer and Posey, 1895; Posey, 1914; and many later authors). These studies showed conclusively that, in Kronfeld's words, "Through the conscientious and systematic use of pilocarpine and eserine, the visual status-peripheral and central--of patients with glaucoma simplex could be maintained at the initial level for periods ranging from 5 to 15 years." The history of eserine and of pilocarpine has been one of most brilliant success. These two drugs have been used during the century since Weber's and Laqueur's time for the relief of many millions of glaucoma patients throughout the world. A large number of ot_her chol_inergic substances also have been used, both direct-actmg ones like pilocarpine and anti-cholinesterase drugs like eserine. Some publications about these and other drugs u ed to study intraocular pressure mechanisms, or to treat glaucoma, are collected in Tables 40-1 and 40-2. These tables contain only work we came across without a special search and are, of course, far from complete. They are included solely to serve as a key to some of the pertinent literature and to show the gradually shifting trend of thought over this long time. 2. Other Drugs Cocaine, as already mentioned, played a revolutionary role in ophthalmology because of its anesthetic property. This wonderful drug allowed eye surgery to be performed quietly and meticulously, without pain. And the inaccurate e timates of intraocular pressure by trans-palpebral finger pressure could be replaced by corneal measurements, done with precise instruments. It is fortunate that the mydriasis elicited by cocaine does not abolish the light reflex and yields readily to eserine and pilocarpine, so that the usefulness of cocaine in glaucoma was not marred by the development of acute attacks of increased intraocular pressure. Anti-cholinergic drugs such as atropine, eupthalmine, and so forth, did trigger acute glaucomatous attacks. ln patients with narrow angles and shallow anterior chambers these effects were largely mechanical, a already described by Weber: during mydriasis the peripheral iris blocked the corneo-scleral angle and hence the outflow channel of aqueous through the trabecular meshwork and canal of Schlemm; and conversely, energetic miosis pulled the iris taut so that its peripheral tissue was dragged away from the chamber angle. Because of these effects some authors held the pupil size as such solely responsible for the pressure-raising action of mydriatics and the pressure-lowering action of miotics (Table 40-3). But others pointed out that in glaucomatous eyes with deep anterior chambers and open angles the cholinergic miotics still could decrease intraocular pressure, and that attacks of glaucoma occasionally were triggered by mydriatics without blockage of the angle. Curdy (1923) saw lowering of the intraocular pressure in iridectomized eyes; and Vannas found that miotics dropped the pressure of rabbit eyes that had been iridectomized even more effectively than in the normal fellow eyes. The pupil size as such therefore could not be solely responsible for the pressure changes. Other actions of cholinergic drugs that had been discovered since the mid-1800s also could alter the intraocular pressure: contraction of the ciliary muscle (with secondary effects on the trabecular meshwork); dilation of intraocular vessels; secretory effects on the ciliary body; or improved outflow of aqueous. In fact, the ability to bring about intraocular pressure changes was not limited to cholinergic drugs; adrenaline, noradrenaline, and other adrenergic substances, as well as sympatholytic drugs, had 40. Glaucoma Table40-1. YEARI Autonomic drugs used in the treatment of glaucoma and ,·n SUBJECT AUTHOR 1876:1 uiqueur, 1877 Vllliams 1878 rdltzke 1885 flUger 1885 ,rmai~ac ,rneker 1887 1887 Laqueur 1895 uivagna 1895 Zentmayer & Posey 1897 Bietti 1897 LJlVal!:na ""I898"~ro 1899 ,.7etwood Aiken -Weber effects STUDIED of eserine YEAR in glaucoma eserine in ,,.laucoma oilocarnine Jaborandi: eXQ. on dogs &rabbits mydriaties & miotics vs. IOP coeame 1n glaucoma eserme, J2ilocareine, cocaine, atroE!ine eserine, atroeine etiocaq~ine in glaucoma miotic treatment in glaucoma 1iiBl> - arecoline arecoline holocaine in glaucoma bromoh;)'.drate in glaucoma in glaucoma as anesthetic arecoline as miotic in glaucoma 1900 1901 1900 1900 1903 1905 1910 1911 Knapp attacks Maximoff Wessely Ring Wessely Gronholm Knape 1911 1914 Tolz~ski Posey arecoline in glaucoma 12ressure lowering effect of SUQrarenin attack of t IOP after euQhthalmine effects of adrenaline (IOP ♦ ,Eu[!ilf_) ___ eserine in glaucoma atropme, ellect on ant. chamber eserine, metabolism and vessels dionine (biphasic effects) long-term glaucoma treatment with eilocarpine history & mechanism ol caiaEiar 6ean p1Iocarp1ne m glaucoma vs. iris cysts Sharp Vo~ Knaoo Koller Schoenberg Curdy Accardi Schoenberg Zunz Accardi Cerker Frankowska Puscarill: & Cerker Accardi Hamburger Passow Thiel ""I9W Sca!Zitti 191J 19W 1921 1921 1922 1923 1924 1924 ~ --rM5 --rM5 1925 1925 1926 1926 1926 1926 of 1' IOP after aclrenahne 1n euphthalmine glaucoma miotics & ml:'.driatics in s:Iaucoma & miotics in ,,-Iauc. Id. Koller l mydriatics eserine in intact & sympatnectomizeo eye thyroicl extract ( IOP slightI:i(J, QUQiI !! ) adrenaline m;)'.driasis vs s:laucoma eserine +, 1928 1928 1928 1928 1929 )929 1929 insuline ( QUJ2il IO Pt in large doses) Qilocar12ine in glaucoma eserine on QUJ2il & IOP of normal eye subconjunctival pilocarpine in glaucoma hl:'.J22Ehyseal extracts (EUQilf, IOP !! ) glaucosan droQS in glaucoma B):'.stemic atroEinic & cholinergic drugs erc:otamine treatment in glaucoma hypophysin in rabbits (local, 0 enectJ IV --+miosis & hl:'.))OtOn):'. BaCl alone (pupil+, IOPf); with aclrcnaline QUEilt I IOP½ ~ilocareine ~ionine ( eth):'.I morQlime ! eilocarpine' cocaine-aclrcnaline adrenaline in normal ere aminoglaucosan (histamine) in glaucoma [!h):'.SOStigmine KC! vs. intraocular eressure 1930 pilocarpine vs. BP in ciliari veins eplieclrinc: pueiis +, IOP -· O; blood flow+ Qilocar12ine C[,!hedrine in normal el:'.e & in glaucoma Qh):'.SOStigmine caffeine t IOP in glaucoma rut not in normal eie ciliary body extract: IOP-t, P+in rabbits 1928 vom Hofe Mazzola Salvati Serr Une:erer Castresana Graf & Scheer de Jaeger 1929 Korobova & Samojla~ ""T929 Orr 1929 Samoilov 1929 Sergijewa 1929 Vog! 1929 Wegner ( d. Bistis) Bellavia ~ Bruno Veil Yata Yonkman Hamoorger Kikai 1931 Rumanomiclo 19:iT ViBaret &al 1932 Fischer 1930 1930 19 JO 1931 19:Jl 1932 vom Hofe 1932 1932 1932 1932 1932 Kin Larsson Linksz Rossi Sziisz Vannas Ve1nRven Ferrari 1932 1932 1933 srnephrine in rclaucoma eEfieOrine &;ei""ocareine in norm.&~c. s:Iaucosan ( P:t) & aminoglaucosan ! ) eserine side-effects of aminoe:laucosan eserinc: effect on blood-agueous barrier subconjunctival ergotoxine· ex.in rabbits 1-methylacetylcholine (mecholyl); exp. eserine, pilocarpine, adrenaJine, histamine, atro12ine, sco~la~ine, _ACh _ "Tenosin" (Bayer)~ tyramrne, histamine & sugar ( Pt IOP•hn glaucoma I _ atroeine: s~culations on effect m glaucoma eserine vs. intraocular vessels (ex12) adrenaline, eserine vs glaucoma (cx12) vasodilator drugs in normal & glaucoma atropine, scopolamine vs. e:laucoma _ miotics & m:t:driatics I aniridia in rab_b1ts l dor):'.l IV in cat &rabbit & isolated SQhinctcr hypophyseal extract ( P ♦ !OP = 0) 1933 1933} 1934 "Iii3'r AUTHOR Wetzlich Diike-E@cr 1934 1934 1934 1934 1935 1935 1935 1935 1936 1936 1937 Galeazzi van Heuven Howell Kawabata Cavaniglia Fontana Miloro Rossi Argouchevitch Wilenkin Myerson & Thau 1937 1937 1938 Post Streiff Baratta 1938 1938 1939 1939 1939 Rea Schmidt Clarke Terliskeli Weekers &al. Mverson & Thau SchlaeQEi Beach & Holt Fricdenwald ,Jona 0' Brien & Swan Stacrkle Schmidt Clarke Gesell& Hansen ~ 1942 Kull 0' Brien & Swan 1942 1942 Su!@r ..ll:!.L Hess Morano 1943 1943 Swan Uhler 1943 Kravitz 1944 Krome@ 1944 Lebensohn 1946 Leopold& 1946 Comroe McDonald 1946 Scholz 1946 Scholz & Wallen 1946 Vidal &al. 1946 van D:t:ke 1947 Marr _ll!il_ Owens & Woods 1947 Rodin 1947 v. Sallmann & 1947 Dillon Schmeltzer 1947 Simonelli 1947 Su,zar DFP 1947 Wcekers 1947 Esente 1948 Fanta 1948 Fontana 1948 Grant 1948 1948 Leopol~J'mroe Perri l9'f8 Schmeltzer 1948 Brllnlng 1949 Christenson & 1949 Swan Dun(,!h):'. 1949 Feldman 1949 Givner & 1949 Graubard Glees & 1949 Wuerstenberg Pasca 1949 1949 Rokitskaya 1399 • experiment on intraocular pre ur Manola 1940 1940 1941 1941 1941 1941 1941 1941 1942 / SUBJECT STUDIED insullne: P•, 10Pt with large doa,,a coca1ne-adrenaline,1op in glaucoma , subcut. morphine HOP an glaucoma cnuune, m~scartne, pllocarpme, a1rop1ne, homatropme, hyoscmamine, eucatropln , ergotamine, eumydlne, euphthalmln , eserine {mechanism of action l carbamino.i::l choline (action) pilocarplne ( slde--eiiects In glaucoma i eoine•nmr•ne n. ~""" ~ and 12ue,11& IOP vs drugs, normal" g•~•coma 121 ca~ne G't or weaker 1n glaucoma carbac~l!iiclo!:l:'.11, dinical ~r,ence do!:;)'.l in g ucoma treatment prosturmlne cllnlcal exoer,ence JV novocalne: no drop in IOP carbamino~i clioline f;;;o!)·I, ac(on IOP & Pects ol c lmergic adreoerglc drugs neosvnepfirine eoineolirine cllntcal s~tro12an in normal & guwcoma eye "simpamina 11 (l>eta--plieny l-1&0propy Iamine ) , mydriatlc with no IOP effect eserlnel 21locare1ne! a[ro~1ne Uexl J insulin shock ( Pt , IOP • ) mecliolyl 1 12rosh~lne m glaucoma [rea[m. syntropan 2'1'· adrenanne as myar1auc ln g1aucoma, & with atroeine to loosen synech,ae furmetlilde - act10n, e~[all~on !OP 12!!St. h~f,hl:'.seal extracts 1n ra661ts attaclc aucoma iHer myar1ahcs car bachol (iloryl) tn gliiicoma !di S;)'.mE!';tliom1mehcs ! ,·a&0press1n I dor:z'.I in glaucoma physostigmine, pllocarp1ne vs 1rls cyala ver1tol !s.i::r6!;8~m1mehc I: £710P-+-dory!, mec ly , Xcli -mec Ism In gliiic. car6acliol in ,zlaucoma erostigmine ind\laucoma treatment carbachol tn g ucoma trea[men[ g:~coma arra[K 1iiclucOO~- myar1ahco =-:nalin cl~lon c ''sympaDiicolonii"-ocular ellects oi prostlgmlne jn.r.i carliacOOI 1n pe[rolafiim ( Rllu~i5ffil'. rr. J furmetliide Ii other mlotlcs m glaucoma carbachol in glaucoma treatment g:on1osco~~{s. m1ohcs 1n ~Iliil."Oiim DF P In g coma treatment ! e oi ... DFP In glaucoma treatment DFP In glaucoma treatmen! ur ..- (exp m raoons1 D1e_., ( exp In norma1 man 1 car6acliol autonomic drugs used !ii oeli[hiimolUJ<Y DFP in chronic daucorna furmethide, pilocarpine eserine I mston- I tn o DFP (exp In rabbits): euecta on anter1or SCs;!!!ent caelllarlea mlotlcs: visual l1elds~{1,liucoma tr.! erostis;!!!lne in glaucoma tr. DFP ln glaucoma DFP in glaucoma furmethide 1 cserine, Dt P, In ~aucoma Eilocar12ine: mloaia VB IOP [n c-uarea erostil,!!!ine - ellect on pupils aiid :£1:!Jtl TEEP vs. glaucoma IM morphln~ pupila and !OP no preHuri! i!f1Rf1Sf"'"~~~•.miotics: ctlecta on ~211 lonv"'an mlntacol {n. r. l adrenergic blockers In glaucoma trenl- -- e;i;:;tts of mlotica jglaucoma lzother} ~edrlne I adrenaline IV pontoeaine In glaucoma: no drop In IOP rut relief of J?!!n y mintacol In glaucomatau {ormoca,n (ital. ancau,cllc) • nonx:amc &!!thi:u· !l!! eff~t on !OP furamon vs. retinal eocma In gi:auco - 1400 V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 40-1 YEAR 19-19 1949 1949 1949 1949 1950 1950 1950 1950 1950 mo 1950 1950 1950 1950 1950 1950 1951 1951 1951 1951 1951 1951 1952 1952 1952 1952 Lco[!Qld Mikaelvan Niedermeier Poliak& Volkov 1952 LaRocca 1952 1952 Savae2v Weekers Weinstein 1953 1953 1953 1953 1953 1953 1954 1954°" Abraham Aus:!!stinsson BonavolonUl Rizzo Savinich v. Sallmann & al. Agarwal Bayo &de la Peria Gcrcwitz Hallerman Hofmann Junghannss Lieb Morrison (a) 1952 1952 1954 1%4 1954 1954 1954 1954 1954 1954 1955 1955 1955 1955 I I Neuschwander Posner ClarK& Dug!@n Delong& Scheie D'Ermo Duke-Elder & Goldsmith Eidelman 1952 1952 1952 1951 1951 I AUTHOR Scheie Swan Thiel Vintserovitch Wirth Ameral Filho Anderson Bayo &de la Pena Bloomfield & llaimovici Dietz &al Grant lluerkamp & Was:!!er Leoe2ld Marr li:Grob Moreu-Gonzalez Moacyrde As:!!iar Mullen & Leo[!Qld Newell &al. Waj£!er von Beuningen Hoorens & Piette KnUeffer Lehrlnger 1951 1 (continued) (b) " Swan Weekers & al. Christini & Fiorini Funder Gitller & Pillat Jirkov & al. 1955 Mody & Koenen 1955 1955 1955 Pau Quintcri lliZZini 1955 Straub & Conrads -- SUBJECT STUDIED YEAR symposium on medical tr. of glaucoma e:te cuccts ol various c ,~ ine esters mintacol in glaucoma furamon in glaucoma mintacol (ohosphacol) in glaucoma miotics & m.l:'.driatics ( surve.l:'. ol literaq adrenaline, cocaine, scoe2laminc in gl. direct-acting synthetic parasympathomimetics {ex2erimental l IV dibenamine in chronic simple glaucoma hypophiseal extracts TEPP rn glaucoma rnintacol (phosphacol) - actions on pupil and on !OP surve.i:: of lit. on ocular eharmacolog.i:: TEPP in chronic glaucoma DFP, mintacol, dihydro-ergotamine in glaucoma mintacoI in glaucoma treatment hvdrogenated erwt alkaloids in glaucoma IV ctibenamine tor acute congestive glauc. dibenamine in glaucoma antihistaminic drug (n.r.) acute glaucoma attack precipitated b,l:'.m.l:'.driatics and blocked b,l:'.miotics physostigmine, pilocarpine, proserin, carba.cholin (rabbits and glaucoma) mydriatics and miotics in glaucoma dibenamine, midazolines, bcnzodioxanes .i::ohimbine, ergot alkaloids (e~ &clin.) dibenamine in flaucoma mintacoI: pupi~and IOP (n.r.) dor:tl in glaucoma treatment mintacol (n.r.) mintacol, floro2!J:'.l, doryl in glaucoma new miotic "miotisal"-similar to mintacol summa!:Y'. on autonomic drugs erostigmine & erozerin in glaucoma oiridosti(Tffline - effects on ouoil & IOP benzosullate ol trimethyl furfuryl ammonium in glaucoma retinal detachment in DFT-tr. apnacic eve ehosehacol 1 miotic & antiglaucoma drug eserine 1 DFP - mode of action ganglion blockers & anesthetics vs. pilocareine, escrine, adrenaline,mechol,l:'.l "floroe!J:'.l" (DFP) (n.r. l rnintacol - enz:tme studies !PI ,IOPi ) cortisone: no effect in normal & glaucoma 'lisostina" in normal and glaucoma ehenamine (Russian drug) adrenaline I noradrenaline (ex2. on cats) s~eathol,l:'.tic dru~s- effects on glauc. mioticol (DFP-li , diisopropyl paranitro phenyl phosphate) in glaucoma m1otic cysts in glaucoma eves (12 of 349) iris changes alter 1ong-1.0rm m1maco1 noradrenaline in oehthalmolog:y eustigmine ( neostigmine) in glaucoma various drugs on P, IOP, ocular vessels stabdily ol p,lo, ncost,gmine, esermc, and DFP mccholyl· drug eassage of glaucoma drugs (exe.) DFP and miotic C)!'.Sts eeineehrine, miotics in glaucoma adrenaline in glaucoma (novocaine block of nerves) miotic cysts al'ter mintacol in glaucoma dcmecarium bromide ( BC 48) in glauc. ettects 01 pilo & adrenaline alter ergotoxine propantheline bromide in normal and glaucomatous C)!'.CS oeilon ! s.l:'.meathol,l:'.tic) effects mintacol, clinical experience cITect of serpasil sleep on P, IOP & retinal arter.l:'. eressure miotic cysts after long-term tr. with various miotics for glaucoma AUTHOR SUBJECT STUDIED Weber neoserin in glaucoma Weekers & al. adrenaline, noradrenaline, aleudrine, Weekers & (beta-agonist), isoproterenol in glauc. 1955 Lavergne retinal detachment, provoked by DFP 1955 luwf-e;'iin-;;-;;'str;e:\'in='----l--:g:::an=g"'li"'o-=n'bc,I-:-o-=-cr:-k.,,&,..h"':t"'d,..,e"'r,..g""in,..,~e-xp-. ~m_m_an ___ , 7i=-----l-';D!':F::'· P~-=cl;--,i"'n:"ic:::.;ac;.l.:::e:..:xe.ec::e:::r-=.ie"n-'-'c"-'e'-"'"""'---"'!..!!=!...._--I 1956 i-C;::;-"'e=nta:':'-:n=n 7 isc-,-tccenc:.s,-e-n---l~D;;;F=-P=-(,..m""1;:· 1956t-C;:;;'-hr o=t;.:ic=cy...os::::t:.1::sc:::).o..:..::=c:::....------I &Swan 1956 Funamoto ilo neos ne hrine vs. pressure on globe 1956 I ·F~u='na:::'m=oito=-----I.J:!!'7ili:o'-',-'c='o:'n:':;to~m",i..t"'1e=::;,;::;im:::,.,i~a:,.,i!'..n::..:v::.:s::.:::::e~re;s;:s::.u:. I 1956 Msc""e=-re=-w~it-=z=-----l..<m:..:;oio'--!t~ic=c.l:'.:..:s:ct;:;s:..::;.;O.:cn.=n:..:o:::r::.:m::::a~l;,c::.:.l:'.c..e:...:s::.,)= 7jt""·m:':'ac..:.... 7bc:..:.:.:on:...j;;_u<..n:::c"'ti'--v'--'a:;.:l l 956 l7'Ki"'·tc:a ____ l ..:s=u '--'a"'tr:..:oc::p::;:in=e'--",(LCr::..:ab;:.-;bt..,i~ts~) ----I 1956 17u7:· c::';b~&~P,;:;i-:::r::-c;:-h--+::p;;'is=lo='=c:'::a~r'=p'i:in:':e::..:,:..:.e='. s:-:ec:rciin':-'.e'!-,:::.;:c;.ar~ba;;._c;:h:::o~I=-, L,dr:-o=ry--I.--=z-, mestinon, prostigmine, DFP, HEPP, TIPP TEPP I mintacol in normal human e.l:'.e 1956 t-.,M;:a:-;-t-,,.su-:-kar:-:-----l-,I"'O;,;P;,:._=-r=-a+is....;ie.:n::.:g::.:s=u::,.b:cs;.ta"'n:...c;.:e:cs:.:i:c:n=c~SF~(;::e=x __ I 1956 Paul & tranquillizers & ganglion blockers:thoraLeo.J22ld zine, reserpine, pentolinium tartrate 1956 I ·u-=e.-lio ..... 1,,.Ct-,&,---a ... 1.---l---,T"'E""P="P---m~1-o-s1,.,_s_v_s-"--v.;..is-u,..a~1-e~r~re-c~t-s-----· I 1956 1 Ustimenko "P)rroehos" (Russian miotic) in glaucoma 1957 ·c="'"ro~u~z~e'°'t=---·l-:-dc=e~m-=e-=c=a=r=iu~m-b"'r=o=m=1cc·d'°'e'-===-'--="---"=====---• 1957 D}rmschitz enocaryinc in glaucoma 1957 Gartner & tIOP after cyclopentolate, epinephrine, Billet earedrine in glaucomatous e.l:'.es 1957 Gougnard demecarium bromide (BC48) in glaucoma ..,1..,,9-=-5=-7-l-:'H,-r-u~by'-------Iglaucoma attacks after diagnostic mydriasis 1957 Ieroschewsky DFP, mintacol, dibcnamine, diamox, sulfanilamid D, hyder!b,in in glaucoma tr. 1957 Janes & atropine and DFPCalkins vessels 1957 Leopold & echothiopate iodide 217 -Ml (thiophosphanil Gold quarternary come2und) in glaucoma 1957 Leydhecker & al. mintacol plus prostigmine 1957 Manzitti & Illlotic,an my riat1cs in ocu ar Paris therae:t ( text ) demecarium bromide in glaucoma 1957 Miller & al. 1957 Morrison Eilocarpine 1 carbachol 1 mechol:tl 1957 drug treatment in glaucoma Ourgaud 1957 Palich-Szant6 new miotic "ortho" in ophth. practice cyciog.i::1: only 1 in 800 cases had t IOP 1958 Barkman mydriatics after cataract surgery to 1957 Weisel & erevent flattening of anterior chamber Swan miotics vs. outflow laucoma 1958 Becker 1958 Filatov ~ilocarpine, 1-15 in glaucoma emccarium bromide - effects in patients 1958 Gerhard & with glaucoma Kettler pilocarpine (pupil size vs. glaucoma) 1958 Lavrentieva epinephrine, phenylephrmc, 1soproternoI 1958 Lee m glaucoma pilocarpine, arecoline, &other choliner1958 Riker ic dru s text "armin" (anticholinergic), p osp aco , 1958 Ustimenko eilo I in normal & glaucomatous eyes prolonged miotic treatment in glaucoma Weekers & 1958 Gustin iris changes & !)ermanent miosis pilocarpine, eserine, phosphacoI, horn Zbarskii 1958 atropine vs. dark-adaptation in laucoma 1959 Abraham 1ri ocvc 1tis ue to miotic tr. (g aucoma) 1959 •-Be="'c~k,..e-r-,.-&_a...,l-.--•-e..,c"ho--t,.,.h"'"io-e--a:-::te.,....,&.,,.rec--:v"'e--r--s,.,a.,..I.,,6""y.,,P"'2""A-nr.M. 1959 Bozzoni & "opilon" ( sympatholytic) & Pilocarpine in Longo normal & glaucomatous eyes 1959 1_D~r::::an'.!:c::::e~:...::;a::;r:.:r::.....__ 1_..;;d;;;e;::m;:e:.:c:.:ar=-;ciu::m:::,.:b:.:r;.:o:.:m1::;·;::d:.:c...;m;::..:n:.:o:.:r:.:m:;a=I=--& __ 1 1959 Garner & al. 2% 1- eeinephrme in glaucoma 1 1959 i -;,G=ia-"-r=d"'i~n1,..· "'&---l-p-i'ho~sp,..h.-o..,l~in-e...,..iod-..i'de,....,.in~g,.lauc,--c,-o_m_a=------Paliaga treatment 1959 Janes & Abraham miotic iridocyclitis in glaucoma l 95 9 l-"-Le=o=-l"'d"'&.,;=a..,.l=. -'--l---,b-,-lo-od-,--c,-ho,..l,,.i-ne~s'-ct-e-ra_s_c~in.,.__n_or_m_a.,..l..,,&_g.,,lr:-a-uc-. -- 1 1959 Merdzhanov & physostigmine, p1locarpme - unusual Bankov reactions in glaucoma 1959 Pasino &Pisano miotics - effect on outflow iac11ity 1959 Pillat & Gittler mishaes with tosmilen treatment 7e-, --I 1960 1-c"-"a"'m=-bcci=-ag"""g=i=&~~-i-~m=i:---'n-:-ta-C~'O-'sl-, ~p.,..ho_s_p',h-o ...l.,..in_c_1.,.._ o.,,d~1d.,..e-,-es_e_r~1""n Bottino dor:tl, Eilo 1 carbachol, demecarium br. - ocular rigidicy in normal & glauc. eyes 1960 Drance phospholine iodide ( 217 MI) in long-term 1 1960 ~D.c.r~an_c_e....,,.&'C"a:-r,--r=---•-....,.tr::---'. ~071 -=c-.:-h-=-roc--:n::-,1--=-c--s::-,1-=m=--'p:-,l--=-e--g"l"'au"'c"'·o'"'m=-a=-~ 1960 Langham & adrenaline sensitivity alter denervabon Ta,l:'.lor 0:0 P, exp. on rabbits & cats ) · 1960 Miller demecarium bromide: iris cysts 7at,..,i-on---,.,,.t,-,c--r_e,..y--ec'i-cro..,,,-ps,,.....,cc--:x=p:-.-r--l 196 o 1-"MU=ll:,;:e..::cr~&-a'l-. --• -~i.-o_-c_o_nc-e--n--,t-r 1960 Montaldi pi ocarpine vs visua ie 7t1r::cccs"ic::n-g::,Ir=ac:-u-::-co::-:m=a----------, 1960 •-p='"'a-'-a-'--n-o-n--,i----l·-':m-=--i'-=0 1960 Priestley & al. pilocarpine, eucatropine, cyclopentolate, phenylcphrine, ephedrine, epinephrine, paredrine 1955 l 955 e 40. Glaucoma Table 40-1 YEAR AUTHOR Andrcani 1961 Andreeva 1961 1961 1961 1961 1961 1961 Becker & al. Bruix Castr~n & Pohjola Coyle &al. Frank& Leonard Korecz Krjci & Kraus 1961 KUckle 1961 1961 1961 1961 Kutscheva Sa.man Sharts & sliulpina Wcekers & al. 1962 1962 1962 B!iriny Oosterhuis Sadakovsky & 0 • a Bonomi & DiComite Catalino & al Pearce Eakins 1963 1963 1963 1963 1963 1963 1963 1963 1964 1964 1964 1964 1964 1964 1964 1964 1964 1964 1964 1964 1964 1964 1965 Eichler & Farah Fenton & Schwartz Macri Smith & al. Swegmark Aasved Black & al. Bonomi Bron di Comite Daniele & Diotallcvi Davanger Dorian & Schirmer Eakins & Eakins Ferfilfain Gn!ldiger & Mrrui Macri 1965 Sears & Sherk Velicky Bonomi & Comite Kristensen 1965 1965 Langham Langhof 1965 1965 Larynkhina Levene & Friedman Lowe Mosta[a & al. de Roetth & al. 1965 1965 1965 1966 1966 1966 Alfonso & al . Boles Carenini &Orzalesi DiComitc 1966 Ellis 1966 1966 1966 Langham & Fraser Hiscox & McCullough Lemke Leopold 1966 1966 Scars Scars & al. 1966 1401 (continued) 1961 1961 / SUBJECT STUDIED YEAR AUTHOR R658 (antichol.) mydriatic, notIOP in normal human c c & rabbits "neomorin" (Bulgarian mydriatic), no t IOP in normal human eye epinephrine in open-angle glaucoma "tonilon"- antic ho 1. - treatment of glauc. mydriacyl: notIOP in children &adults pho spholine iod idc in tr. of glaucoma echothiopate "pyropos' 1 (Russian miotic) "sintostigmin" ( Czech miotic) & pilocarpine in treatment of glaucoma guanethidinc (ismelin) -effect in normal & glaucomatous eyes guanethidine (ismelin) in glaucoma reseffiine (pupil &IOP-t in rabbits) din ( Soviet m iotic ) effects of various sympathomimetic amines in normal & glaucomatous eyes ilocar ine vs. aqueous outflow in monkey) guanethi ine (ismelin) on P IOP 1966 1966 1966 1966 Srivastava Stein Tarkkanen & Karjalaincn Wahl & Tyner Wcekers & al. 1967 Awasthy & al. synthetic adrenaline-like drug filanetbidine, mechanism on IOP in rabbit e ects of homatropine on IOP and outflow facility of normal & glaucomatous eyes adrenaline, noradrenaline, 1soproterenol (exp. on rabbits) cholinesterase & anhcholmesterase dru s 2 pilocarpine (time course ) in norma an glaucomatous eyes iris vasoconstriction with antiglauc. drugs in cats pilocarpine =ethidine, epinephrlile lil glaucoma tr. renaline in glaucoma tr. (iOP+ ) beta-adrenergic blockade reserpine, brcty lium, etc. sympathetic block in rabbit eyes guanethidine - effect on IOP BW467 C60 (sympatholytic) in rabbits mydriatics & miotics in iridectomized glaucoma eyes pilocarpine in normal &glaucoma eyes guanethid1I1e - mechamsm, compared to adrenergic drugs, on P & IOP adrener ic effects on aqu. outflow e T PP (IOPtin rabbits ) isoprenalin (beta-adrenergic )- effect on outflow facility in rabbits I-epinephrine, 1-arterenol, d, 1-isoprote renol, pilo, eserine, DFP, demecarium br. - effects on iris arteries of cats (constr.) trabecular effect of noradrenaline rabbit coffeinc, homatropine as provocative test reserpine, xylocholine, guanethidine, brelium & BW 467C60 in rabbits pigment release & IOP by mydriatics:EPPY, demccarium br., mintacol, adrenaline bitartrate 1 synephrine) in glaucoma adrenergic drugs after sympathectomy (exp) ismelin & 1-adrenaline -d-bitartrate in tr. of glaucoma demecarium br. in 4 normal & 24 lauc. pilocarpine and phospholine iodide in glaucoma attack oft IOP by phenylephrine in glaucoma atropine 1 neosynephrine blood cholinesterase - effect of phospholine iodide in normal & in glaucoma patients guanethidine - normal human eyes cataract formation in long-term treatment with pilocarpine, phospholine iodide guanethidine, BW 467-C60, reserpine, bretylium xylocholine in rabbits systemic effects of ocular anticholinesterase treatment (CNS, gastro-int., respiratory) pupil & IOP after pregangl. sympathectomy i of systemic cholinesterase on treatment with cchothiopate in glaucoma patients mydriatics & miotics in Fuchs's with glauc. cholinergic drugs & anticholiesterases in ~laucoma therapy (summary ) norepinep rine content o iris body after cervical ci iary sympathectomy (rabbit) 1966 1967 1967 1967 Baranfu Tregu-va 1968 Waitzman & King Castren & al. Langham & Carmel Siebeck & Oiila6i 1969 1969 1969 Bron Bronson & al. Kramer & Potts 1969 1969 1969 Langham & al. LiQSOn &al. Makabe 1969 Payer Turner 1968 1968 1969 1969 1969 1970 1970 1970 1970 1971 1971 1971 1971 1971 1971 1971 1972 1972 1972 1972 1972 Waitzman Willets Havener Hiatt &al. Leaders & al. Tost & Kuntsch Harris Langham & al. Holland Leaders & Fortenberr,l'. Lorenzetti Newsome & al. Sawada &al. Falter & Thompson Harris 1972 Harris Holland Jahnke & Thumm Lerman 1972 Podja & al. 1972 Podos & al. 1972 Matsushita & Kondo Spaeth & Vacharal Tsukahara 1972 1972 1973 Bekauri & al. 1973 1973 Halasa & Rutkowsk Holland & Wei 1973 1973 1973 Imazumi & al. Lamble Langham & al, 1973 1973 1973 1973 1973 1974 1974 1874 1974 1974 1974 Leaders Neufeld & al . Neuman & Floru Hutkowski & al. Salem & Ellison Benson Chrai & al. Eisleld Floru Havener Jablonski SUBJECTS STUDIED J2hysostigmine epitrate ( epinephrine borate) in glaucoma cataract format.ion in Jong-term glaucoma tr.: pilo, dcmccarium br., phospholine iod. blc-od choli nestcrase on cchothiopate tr. in normal & glaucoma patients norsynephrine, phenylephrine, isoproterenol, epine,ehrine, noreein. in glaucoma tr. oral glycerol, diamox, eserine, pilo drops in acute glaucoma pilocarpine effect on outflow ( monke,l'.s) adrenergic & S.)'.mpatholytic drugs on P & IOP prostaglandins in ant. chamber oi rabbit & cat - miosis &+ IOP guanethidine, pilocarpine in ~Iaucoma protripty line epinephrine ("EPPIJ") & IOP guanetfi,drne vs. agucous secretion l!iIOP lens opacities from OF P tr. in man H3-norepinephrine uptake in cats vs. exp. symeathectomy adrenergic drugs vs. pupil & IOP echothiopate, pralidoxime "mydrial" on homatropine, pilocarpine, outflow in glaucoma phospholine iodide pupt!, toP vs guanethldine, thymoxanune, & other sympathomimetic or -lytic drugs prostaglandin, norepineohrin ( exn. rabbits) pilocarpine, I-epinephrine on P, IOP & ouU!ow ocular pharmaco o!!Y ( ~k ! srstemic anticho :inergic ~gs topical efienylethyl ammes in rabbits 1- glaucosan and neosynephrme m treatment of glaucoma echothio12ate iodide: erlect on oufilow lac1!1!:,ji neosyncphrine, norepinephrine, isoproterenol, orotrintvlene on !OP & pupil 6-hydrox,. aopamine & adrenaline in glaucoma effect of L 84~ on IOP & pupil in monkeys IOP+, eu,rl no effect) groups o symp. amines- effect on pupil and intraocular pressure dccamethasone I steroid l & vehicles (exp.) "ubretict" ( anticholineslerasc) 1 £ guanethidine phenylcphrinc, to relieve miosis in pilocarpine-treatcd glaucomatous eyes echothiopate 6-hydroxy dopamine, epinephrine in glauc. clonidine, pilocarpine vs. IOP and pueil size prolonged-release pledgelets for glaucoma treatment ( piloca!Einc ) inactivation of pilocarpine by serum (gl. and normal) pilocarpine treatment with soft contact lenses retrobulbar anesthesia and pilocarpine for glaucoma surgery atropine as ,erovocative glaucoma test 6 hydroxy dopamine- anatomic & physiologic effects (12upil & IOP ) adrenal & hypophyseal hormones - effect on ~pils & IOP in ex15:riments on rabbi ts thymoxamine in angle c osurc glaucoma 6-hydroxy dopamine to enhance effects of adrenaline in glaucoma treatment 11 ,daumarin", carbachol, nilo in glauc.tr. adrenaline bitartrate: ouoil & IOP in rabbit epinephrine, norcpinephrine a1tero1.- or,Bblockade : IOP and pupil in rabbits ~lymcr release systems for glaucoma tr. epineplirinc, norepinephrine oonzoctamrnc ( seaahve !: pupil &:IDP oc.-adrenergic blockers in glaucoma eeinephrine bitartrate vs. IOJ:5 corneal penetration or autonomic drugs corneal oenetration ol pilocarpme (ra66itsj clonidine 1 /8 <,:,in o-laucoma "sulnirid" lantinsvchotic\ in glaucoma ocular pharmacolog;.)'. (3rd Eel. or text) guanethidine with phenylephrine & epincphrine for mydriasis in glaucoma 1402 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 40-1 YEAT! (continued) AUTHOR 1974 1974} 1974 1974 1974 Lambie Langham Langham & Diggs Macri & C:evario Mapstone 1974 1974 Piltz &al. Thornburn 1974 1975 Thumm &Jahnke Bonomi & Steindler Kriglsfein 1975 1975 1975 1975 Kriglstein & Langham Ross & Drance Yoshida 1975 Seidenhamel 1975 1976 1976 1976 1976 TI76"" Talo & -Allenr (fn~'t/f m Birmingham & al. Harbin & al. Kabak & al. Katz & al 1976 Kondrat~va 1976 Langham & Kriglstein 1976 1976 Mehta Shannon & al. 1977 1977 Azuma & al. Di Tizio & al. 1977 Gwin & al. 1977 Francois 1977 Ulsumi & Nishida Langham & Palewicz 1977 1977 & al. Dawson &al. SU13JECT STUDIED YEAR AUTllOH ewncehrinc P cnoxylX'nznmine, propranolol, isoprotc-reno! vs. !OP in normal mammals oilocarpine eficcts on aqueous lormation thymoxaminc + pilocarpinc or phenylephrine + piocaroine in closed-angle glaucoma areclidine, pilocan>ine rexn. on glaucoma single dose of pilocarpine vs. oufITow lacility in the human eve clonidine-effect on pupil size and IOP pindolol (beta-blocker) miosis and drop ol intraocular eressure bet hanidine sulfate, adrenaline b<>rale on !OP of rabbits IOP & pupil effects of repeated closes of adrenaline summarv on adrenergie influences on !OP pharmacokinetics of pupil to pilocarpine & troeicamide isoproterenol ( d & dl isomers) on LOP of rabbits and in glaucoma 1977 Stodmcister 1977 1978 197 Zimmerman & Kaufman 13rubaker & Trautman Fran!,OiS & a.I. Gwin &al. 197 1978 1978 .Johnson & a I. Smith & al. Macri &Cevario 197 197 Tsuchisakn & Takase Wand & Grant 1979 1979 1979 Birmingham& al. Goldberg & al. Kleiper & al. 1979 Kohn & al. amilript~linc and nortriet~line clonidine effects on eueil & IOP (rabbits) infusion of eilo in normal eyes (method) dipival eeineehrine dieival eeineehrine versus IOP timolol (beta-blocker):iJOP in normal human volunteers miotic & hypotensive effects of various eilocaryine solutions epinephrine, phenoxybenzamine, propranolol-effects on !OP & QUQil of rabbits subconjunctival injection of eilocareine dopamine (rabbits), guanethidine, alphablockers, and halo2eridol dipival epinephrineeffect on IOP guanethidine & oxyprenolol lor open-angle glaucoma pilocarpine in glaueomatous beagles (pupil and IOP) carbachol, pilocarpine, aceclidine vs. inlraocular structures dipival 1978 SUB,JECT STUDIED 1979 Mishima 1 79 1979 1979 Romanova & Abak-umova Smith &al \Vaitzman & al. &al. 19 0 Goldberg & al. 19 0 Keren & Treister 1980 1981 Nagataki & Mishima Zimmermann &al Hoyng & Dake 1981 Mapstone 1981 Moro &al. 1981 Nerlo & Wielunska 19 0 epinephrine noradrenalinevs. IOP & pupils; phenoxybenzamine vs. outflow res is lance vision in people who had smoked marijuana for 10 years : nothing much efficacy of stabilized pilocarpine for long-term 1,Iaucoma therney timolol for glaucoma: drop in JOP without p,millary effect timolol: decreased !OP without pupil lary effect ·oe pine (drops vs. ocusert) epinephrine, I -epinephrine, ~ p in normal and glaucomatous beagles: nupil dilation and drop in JOP timolol lor glaucoma treatment efiicacy of flocarpinc in oil dopamine, ydroxyamphctaminc * phenylephrine versus !OP pilocarpine ( ocuserl) in glaucoma thymoxaminc in diagnosis of openangle glaucoma infusion of eilocaq~ine oilocaroine gel vs. drops in glaucoma adjuvants (vehicles) interacting with drugs dipival epinephrine vs. I-epinephrine in glaucoma treatment adrenergic drugs- effects in norma 1 and i,Jaucoma eve pilocarpine eilocar2inc droes versus oeusert prostaglandins & norepinephrine vs. eupil, IOP, &cervical symeathcctoml:'. dipivefrin (dipival epinephrine), comeared to eeineehrine & DFP ( +) isomers of aceclidine & pilocaroine pharmacokinetics of drugs instilled into the human e):'.e timolol, dipival epinephrine, N- demeth):lated carbachol guanethidine & adrenaline drops for filaucoma treatment piocarpine-phenylephrine (vs. nicrment release 5-6-dihydrotryptamine & serotonin vs. eueil and IOP (rabbit) methyl cellulose & carbachol in glaucoma patients: miosis but no effect on IOP ADDITIONS 1970 Kronfeld 1971 Hepler 1973 Jaworowska & Mosczynska Kowalewska Rubin &al. 1973 & Frank 1975 Flom &al. Frankelson & al. Trueblood & al. 1976} 1976 1979 lle2ler &al. Ile2ler & Petrus Cozanitis & al. 1979 1978 Green Saari & al. 1978 Schoenwald &al. Goldberg & al. 1975 ~ 1980 1980 Ohrstrom & Pandolfi Saheb &al. 1980 Spaeth 1980 lovely summary on eserine and pilocarpine marijuana-smoking suggested lo lower IOP in glaucoma 2atients effect of polish drug "POR-6" on pupil and on intra-ocular pressure release of pilocarpine from collagen-gel and -film ! in vitro) marijuana-smoking to lower IOP in "laucoma epinephrine & methyl amines, and adrenergic ~tentialor on 12upil and IOP drug contact time was increased when drugs were used in stic~ vehicles rc~rt on effect of marijuana-smoking on 2u2il and IOP in glaucoma eatients effect of i.m. atropine and glycopyrrolate on eueil and IOP short summar):'. on marijuana and the ei:e pilocarpine in oily solutions and in polyvinyl alcohol 2% pilocarpine in different gel vehicles (rabbit eyes) interaction of timolol and epinephrine on eupil and IOP effect of oral and ol topical beta blockers with toeical eeineehrine on 2ueil and !OP comparison of effect of thymoxamine (none) & of pilocarpine for shallowing of anterior chamber effect of autonomic drugs on pupil & !OP after dcxamclhasone-lrcatment effect of tranylcypromine on adult rabbit 2u2il and IOP timolol maleate vs. IPO & pupillarv functions 1981 effect ol Ol.-1 and"'-~ adrenoceptor agonists 1982 on ouoil and IOP I rabbit) topical 9 - 30% demethylated carbachol: 1982 Kitazawa & miosis in glaucoma ei:es I but no change IOP Shirato compared thymoxamine & pilocarpine as rever Saheb & al. 1982 sers of 2henyleehrine-induced ID):driasis blocker) Silvestrini & al. effect of dapiprazole (ol-adrencrgic 1982 on rabbit pu2il & IOP ! local and systemic) bioavailability vs. pH of pilocarpine in human 1982 Sugaya &al. eves effect of topicald.-adr. agents on pupil & IOP 1983 Mittag enect o! rociverine (spasmolytic) on pupil, Pardin & 1983 IOP 1 & angle (none) Sae2nati "timolol update": report of meeting with 9 Zimmerman 1983 other authors narticioaline:) complex effects of aminotelralin compounds Burke, Chang 1984 on eu2ils (dilated) and on IOP !+) of rabbit & Poller Ilou , 11'1iya,.aki ethylene vinyl alcohol copolymer matrix vs. 1984 Eilocareine-relcase & Takada effects of 1-norepincphrine & racemic erythro Langham 1984 -methvl noreninenhrine on rabbit eve danger off !OP after 2. 5% phenylephrinc 01 Shaw& Lewis 1986 1% troeicamide in open angle glaucomn legal implications of pupillar_y dilation by 1986 L;):'.nch drugs for optometrists Alexander & 1987} Schollcs 1981 Hoyng & van A12hen Kirkham & al. Innemee & a I. 40. Glaucoma Table 40-2. / 1403 Drugs used in the study or treatment of glaucoma ANTICHOLINERGIC ~ -Atropine - Homatropine - Scooolamine - Hvoscinamine - Eucatrooine - Euohthalmine ◄ - Cvclooentolate - Mydriacyl - Syntropan - Propantheline Bromide , - Eumydrin CHOLINERGIC (anti~holinesterases) ,? Phvsostigmine - Neostigmine {eustigmine , prostigmine, proeserine) - Pvridostigmine ( mestinon \ - Phosphacol ( mintacol) - Phospholine Iodide ◄ ( echothiopate) - Demecarium Bromide ( BC 48, tosmilen) - DFP - TEPP , - Mioticol CHOLINERGIC ( direct-acting) / - Pilocarpine (iaborandi) - Arecoline - Aceclidine ( glaucostat\ - Choline - Carbachol * ( carbaminoyl choline, dorll, carbocholine) ◄ - Methacholine (mecholyl, methyl acetvlcholine) - Furamon ( furmethide) - Benzamon - Muscatine * Carbachol also has nerve terminals. of the adrenergic extracts" include mediators . . See Table 40 - 1. ADRENERGIC ( agonists and potentiators ) / - Eoineohrine (adrenaline, glaucosan) - Noradrenaline - S~ephrine - Neos~e2lirine (Elienlleplirine) . - Aleudrine (iso2roterenol, beta-~omst} - E2hedrine - T,yramine - Paredrine ( hldroxl-a.m2hetamine) - Cocaine** - Am2hetamine } CNS effects - Caffeine , - Clonidine SYMPATHOLYTIC / - Erg:otoxine - Dibenamine - Guanethidine {ismelin) - Bethanidine - Thrmoxamine ( 02ilon) "< - Reser2ine (Se!:J2asil) - Timolol (beta-blocker) - Pindolol (beta-blocker) - 6-hydroxy-dopamine (chemical sympathectomy) ' BODY EXTRACTS *** - Thl!:oid extracts - Insuline - Hvnonhyseal extracts - Ciliarl bodl extracts { - Prostaglandins - Histamine (aminogiaucosaI) ANESTHETICS - Cocaine - Novocaine - Dionine (ethyl morphine) ( a seaative) { - Benzoctamine - Thorazine (a tranquillizer) some indirect effect by slight release of acetylcholine from the ** Cocaine is not an adrenergic drug but potentiates the effects transmitter, noradrenaline. *** Substances listed under "body all those naturally produced by the body except the natural such effects. What was more, adrenergic drugs did not always raise the intraocular pressure, as might have been inferred from the difference of their mechanism, compared with that of cholinergic drugs: adrenergic drugs also could lower the pressure. These facts all contributed to a growing number of theories about normal and pathologic ocular pressure reactions. They also opened new approaches for therapy, especially in recent years when beta-adrenergic agonists and antagonists became available, allowing new ways to modify vasomotor and other sympathetically innervated mechanisms (Tables 40-1 and 40-2). C. Mydriasis during Glaucomatous Attacks Since mydriasis is associated with increased intraocular pressure in acute glaucomatous attacks, some authors assumed that the pressure rise and the dilated pupil were both caused by sympathetic stimulation. However, interruption of th~ sympathetic pathways at various levels failed to prevent the pressure-related mydriasis (Tyner and Scheie, 1953; Charles and Hamasaki, 1973). Further, the enlarged pupil in such eyes with high pressure has, at best, feeble reactions to cocaine (Christini and Fiorini, 1955; Lawrentieva, 1958; Rutkowski and Thompson, 1972), indicating loss rather than increased sympathetic activity. Besides, sympa- thetic stimulation does not cause marked reduction of the reactions to light and near vision, a prominent feature of the enlarged pupil during glaucomatous attacks. Could the pressure rise and mydriasis, then, be due to deficiency of parasympathetic stimulation of the eye? This also was unlikely, as shown by various experiments. (1) Cutting the third nerve was followed by mydriasis but by no ocular pressure change (in rabbits; Greaves and Perkins, 1953), or by an acute, transient pressure drop, not a rise (in dogs; Thomas, 1964). 1404 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 40-3. YEAR 1860 1867 1883} 1885 1898 1910 1928 1929 1932 1932 The direct effect of intraocular pressure on pupil size, or the reverse AUTHOR Kugel AdamUk H<Htzke Hess & Heine Grtlnholm Serr Korobova & Samojlov Kin Vannas EFFECTS* ** YEAR AUTHOR IOP -2u2il 2u2il -IOP pupil -IOP + 0 1947 Matteucci Cerusi + 1951 Ace pupil 2u2il pupil + -10P -IOP -roP -!OP pupil -IOP 2ue1I --+IDP + + 0 + 1958 1962 0 1933} 1934 1934 Wetzlich pupil --+IOP + Kawabata + 1941 Sugar pupil -IOP in glaucoma only pupil --+IOP in acute glaucoma 1944 Lowenstein & Schoenberg pupil -+!OP 1953 1957 + 0 1963 1963 1964 1970 1972 EFFECTS* intramural nerve damage--+ ouoil &IOP Duke-Elder & pupil --+IOP in acute glaucoma Goldsmith ~er &Scheie 10P --+ pupil Dymshiz 2upil --+ IOP !OP--+ 2u2il Lavrentieva IOP -pupil !OP -+pupil Saman (anoxia) Christensen & pupil -IOP Pearce in glaucoma Jaeger & al IOP -euEil Loewenfeld IOP --+2ueil IOP -+pupil Charles & Hamasaki (interru2ted blood flow) IOP -pupil Rutkowski & (interrupted blood flow) Thompson ** & + + + 0 + + + + + + + + EFFECTS*: IOP pupil means a direct effect of high intraocular pressure upon the pupil, and pupil IOP means a direct effect of pupil size upon the intraocular pressure (normal reactions, unless specified otherwise) . Ace -IOP mean a direct effect of accommodation upon the intraocular pressure. In columns **, 0 means the author denied a direct effect, and+ means the author saw or assumed a direct effect. -OTE: These are only a few examples from a vastly more extensive literature. (2) Stimulating the third neive intracranially failed to affect the ocular pressure when the extraocular muscles has been paralyzed by decamethonium iodide, even though good miosis resulted (Greaves and Perkins, 1953). (3) Cutting the third nerve, or retrobulbar blocking of the short ciliary nerves, dilated the pupil but did not interefere with its ability to contract to locally instilled pilocarpine, while raising the intraocular pressure prevented (or reversed) the pilocarpine-induced miosis (Tyner and Scheie, 1953; Charles and Hamasaki, 1970). The sphincter muscle of the pressurized eye thus was unable to respond to direct cholinergic stimulation. In fact, under the influence of high intraocular pressure the iris sphincter of dogs refused to constrict even to the powerful muscle-stimulating action of calcium ions (Tyner and Scheie, 1953). Jaeger, Weeks, and Duane (1963) raised the intraocular pressure in one eye of human volunteers by means of transparent plethysmographic goggles while the pupils and the retinal arteriolar tree of the pressurized eye were obseived. After 15 to 45 seconds of pressure about 5 to 15 millimeter Hg above the systolic level of the ophthalmic artery, vision was blacked out, and (direct and consensual) light reflexes no longer could be elicited from the pressurized eye, while stimulation of the normal eye and near vision still contracted both pupils. The failure of light stimulation in the pressurized eye was thus caused to a large degree by retinal ischemia. In addition, the pupil of the pressurized eye dilated, so that it became larger than its normal fellow pupil. The authors considered that this enlargement was also due to loss of afferent conduction. But uncomplicated damage to the retina or optic nerve on one side (like unilateral darkness in normal people) does not lead to anisocoria (see Chapter 17). Further, it is well known that the enlarged pupil in acute glaucomatous attacks responds less actively than does the normal pupil to light and to near vision (Figure 40-1). The above-mentioned failure of pilocarpine and of calcium ions to maintain miosis in the presence of high intraocular pressure also indicates malfunction of the sphincter muscle. The nature of this defect was studied further by Charles and Hamasaki (1970; in owl monkeys); and by Rutkowski and Thompson (1972; in man). When the pressure of the monkey eye was raised above the diastolic ophthalmic artery pressure via a cannula in the anterior chamber or in the vitreous, the pupil became large and resistant to miotics; and india ink, injected into the arterial circulation, failed to enter the iris vessels. When the blood pressure was subsequently raised by systemic injections of epinephrine, the iris was again perfused with blood, and pupillary contractions were re-established. Rutkowski and Thompson performed fluorescein angiography in normal volunteers while the intraocular pressure was raised with a semiautomated suction cup ophthalmodynanometer. As shown in Figure 40-2,B, no fluorescein entered the iris when the pressure was elevated above the diastolic ophthalmic artery pressure, and the pupil dilated. Three seconds after the pressure was released, the iris vessels had begun to fill with blood; perfusion was back to normal (while the pupil had recontracted) 15 seconds after the end of pressure. When the intraocular pressure was raised even higher, above the systolic ophthalmic artery pressure, the mydriasis was more pronounced (line C in Figure 40-2). Pupillograms, recorded while the intraocular pressure was raised, revealed both afferent and 40. Glaucoma sphincter muscle deficit in the pressurized eye: when the normal eye was exposed to light, the pupil in the pressurized eye constricted less extensively than did the normal pupil, and it began to redilate while the light continued and while the normal pupil maintained contraction ( defective sphincter action, b in Figure 40-3,A). Further, pilocarpine-induced miosis was lost when the intraocular pressure was raised. (Figure 40-3,B). And the dilator muscle also failed to act normally in the pressurized eye (Figure 40-3,C). These experiments prove that increased intraocular pressure shuts off the blood flow to the iris muscles. The resulting ischemia causes pupillary dilation because of impaired sphincter muscle function. The dilator muscle also does not behave normally in the pressurized eye. This loss usually is overshadowed by the coincident sphincter deficit. But after bilateral treatment with an anti-cholinergic drug (that paralyzes both sphincter muscles), the decreased dilator function in the pressurized eye, compared to the normal eye, can / 1405 be seen clearly (Figure 40-3,C). This dilator defect appears less severe and less long-lasting than the decreased sphincter function. Iris perfusion apparently stops at intraocular pressures slightly above the diastolic ophthalmic artery pressure. This confirms that the intravascular pressure is lower in the iris than it is in the choroid and retina (see Chapter 1). Rutkowski and Thompson suggested that this fact may account for the "paradox" sometimes seen in angle-closure glaucoma, that is, pupillary dysfunction with preservation of retinal function. Rutkowski and Thompson said that the increased mydriasis which occurred when the intraocular pressure was raised further, that is, above the systolic ophthalmic artery pressure, was difficult to explain on the basis of ischemia alone, since the blood flow had already stopped at the lower level. They thought that some additional (still unknown) detrimental factor may result from such high pressures. (Could this be pressure on ciliary nerve fibers or endings?) 7 6 5 4 3 7 6 5 4 3 2 7 6 5 4 E 3 E 2 t Figure 40-1. Mydriasis in incipient attack of glaucoma. The patient, a 51-year-old housewife, complained of pains around her right eye as well as in her head, chest, abdomen, and legs. Exhaustive neurological and medical workups were entirely negative except that her right pupil (solid lines) was enlarged and reacted poorly to light and to near vision. The pupillogram showed loss of central inhibition, with a small left pupil (broken lines) that reacted to light with quare-shaped reflexes. The right pupil was enlarged and both its contraction and its dilation movements were reduced. But the reflex pattern was the same as on the left side. The contractions were not sluggish, as they are in cases with efferent parasympathetic deficit, and the dilations also were normal in timing, though not in extent. These pupillary findings suggested impairment of the iris muscles. Both the patient's father and brother had glaucoma, and she herself had had previous attacks of "smoky vision" with pain and redness in both eyes. These had been treated with eye drops. Ophthalmological examination showed best vision as 20/100 on the right and 20/40 on the left side. with intraocular pressure of 22 mm Hg on the right and 16 mm on the left side. The ophthalmologist advised the patient to use 1% pilocarpine for IO days. But during the following night the patient was admitted to the hospital on an emergency basis with an acute attack of glaucoma in her right eye. Iridencleisis was performed, and tension was maintained at 20 mm OU on 2% pilocarpine OU during the following year, with corrected vision 20/25 OU. 1406 A. / V. Pupillary Pathology: Pupillary Signs in Various Diseases No Pressure 0 B. 20 28 53 65 56 mm. Pressure 0 C. 16 47 50 85 mm. Pressure 0 47 50 Figure 40-2. Influence of high intraocular pressure on iris angiograms. Three experiments on the same normal person are shown. The numbers indicate seconds after the fluorescein injections. Line A shows normal filling of iris vessels within 28 seconds. In line B fluorescein was injected at time zero while the intraocular pressure was held at 56 mm Hg (the diastolic ophthalmic artery pressure was 39 mm Hg). Forty-seven seconds later no fluorescein had entered the iris vessels, and the pupil had become slightly larger; 50 seconds after the injection the pressure was released (arrow); and 3 seconds later some of the iris vessels had filled with 52 78 blood, while the pupil was still dilated. During the sixty-fifth second the pupil had recontracted and circulation had recovered fully. In the experiment of line C the intraocular pressure was raised to 85 mm Hg, above the systolic ophthalmic artery pressure (70 mm Hg). The pupillary dilation was more extensive than in experiment A, and refilling of the iris vessels after release of pressure occurred more slowly. (From P.C. Rutkowski and H.S. Thompson,Arch. Ophthal, Chicago, 87 [1972]:25; e 1972, American Medical Association) 40. Glaucoma A ---. I.; Light In Light In Normal Eye Pressurized Eye ~ B 4 ~ qi, .... 7 .... I.; ~ ~---- -Pressurized Eye -Normal Eye ~ 2 0 33 ~~ o[ 1 11.: §- ~ 7 10 41 39 37 35 SecondsAfter Occlusion 20 30 s /Pressf'eOff Pressure Storied ~ ~ ., 0 40 Time (sec) - Pressurized Eye - Normal Eye ---1 20 30 Time(sec) 40 50 ized eye began before the systolic artery pressure was reached: the pupil enlarged 0.8 mm during 15 second of pressure. Upon release of pressure, the mydriasis increased slightly before it was followed by complete recovery of iris sphincter function during the next 15 second . C: Both pupils were large becau e I% tropicamide had been instilled into both eyes before the experiment. One eye was pressurized to 82 mm Hg (systolic ophthalmic artery pressure 71 mm Hg). A ignificant miosis occurred in the pre surized eye 15 seconds after the intraocular pressure was raised. It remained quite constant during 35 seconds of pre surization. A sudden sound (marked S) was followed by further pupil dilation in the normal but not in the pressurized eye. Complete recovery of iris dilator function occurred 2 seconds after the pressure ended. The dark area along the absci sa shows the pressure-induced change in anisocoria (in mm). Figure 40-3. Effect of increased intraocular pre sure upon pupillary movements. Three pupillograms were recorded of the same subject's reactions. (From P.C. Rutkowski and H.S. Thompson, Arch. Ophthal, Chicago, 87 [1972]:25; 0 1972, American Medical Association) A: Pressure was maintained at 82 mm Hg (I I mm above the systolic ophthalmic artery pressure). During the time shown by the shaded areas a the light stimulus was placed on the pressurized eye, with poor afferent function. During the time shown by the clear area b the light was shifted to the normal opposite eye. The increased output of the good retina caused both pupils to contract. The movement was less extensive and less well sustained in the pressurized than in the normal eye. B: Both pupils were small because 2% pilocarpine had been instilled in each eye previously. One eye was pressurized lo 82 mm Hg (systolic ophthalmic artery pressure 75 mm Hg). Mydriasis in the pre ur- Figure 40-4. Pupillary reactions of four patient~ with primary open-angle glaucoma. The records show the first, fourth, and fifth light reflexes for each case. Between the fourth and fifth lights a sudden loud sound stimulus was presented. Lines A to D are pupillograms of four patients with glaucoma, and line E shows the reactions of a 35-year-old normal subject (for comparison). Note the patients' monotonously square reaction forms, well-developed reflex dilation, and failure of producing a normal light reflex after the sound stimulus. Patients A, B and D had equal pupils. Patient Chad an (unrelated) Homer's syndrome on the right side (solid line). Note the defective psychosensory dilation in that eye. (From 0. Lowenstein,Arch. Ophthal., Chicago, 55 [1956]:356; o 1956, American Medical Association) 6 5 G;-1--:---+-------+--,1-----1---+------j I ----·=-,---If---------\ t ------- ... 5 E: y E: .s 3 .I. ~5 ~ ¥1----+---~~'----------l J31---t-:-'.:--+-------+---+-----+---1----_j q_ Figure 40-5. Darkness reflex in normal individual and in glaucoma. The solid line shows the darkness reflex of a 48-year-old man with primary open-angle glaucoma and the dotted line that of an age-matched normal subject. Note the relatively small pupil size, the well-preserved dilation in darkness, and the poor redilation after the contraction induced by reappearance of light in the patient. 1407 ~ <:5~s '"::::: >:::: lCl ...__-.;: ~ ~ _<:::, ~ 3 c:s-....:. ~ 9 ~ Pressure Started Full Occlusion JPressure Off / 2 Time light in 0.1 second - li9ht light 53 A 40 I 46 38 34 A =syphi Iis of the A B = non-specific B C D E F G H C. N. S. infections of C. N.S. C = multiple sclerosis D = traumatic brain lesion E = postcancussion F = space syndrome taking processes K J G = degenerative p Q R 0 H = cerebral arteriosclerosis M = non-specific psychoses I = paralysis ogitans N =psychoneuroses O P =cerebral autonomic attacks = endogenous nervousness disorders of C. N. S. J = diabetes K = hyperthyroidism mel litus (sch izophrenio l (manic-depressive z Q = glaucoma L = essential hypertension R =experimental subject ·....: 0.) J A= syphilis of the C.N.S. B = non-specific infections of C. N .S. C = multiple sclerosis D = traumatic brain lesion E = postconcussion syndrome F = space taking processes G = degenerative disorders of C. N. S. 0 M N = para Iysis agitans J = diabetes mellitus K = hyperthyroidism I 1~.1 P Q =nan-specific psychoses H = cerebral arteriosclerosis R (schizophrenia =1 (manic-depressive= l = psychoneuroses O = cerebral autonomic attacks P = endogenous nervousness L = essential hypertension Figure 40-6. Relative frequency of central inhibitory loss in patients with different diseases (A through R, as marked in the key). The height of each column shows how much more (or less) frequently central inhibitory deficit was found in each patient group, compared with the frequency in the total (unselected) patient population of 1,800 cases (I, marked by black horizontal line). In A, the central syndrome was in its "pure" form, that is, no other pupillary sign was present. In B, the central inhibitory deficit was 1408 K L M1 Q = glaucoma R =experimental subject combined with other pupillary pathology, especially midbrain signs. In A, the average age of each patient group is indicated (in years) above the corresponding column. Note that "pure" central inhibitory loss occurred more often in glaucoma than in any other patient group, while "mixed" (central inhibitory plus other) pathology was rare in glaucoma. The opposite was true among patients with cerebral arteriosclero is. 40. Glaucoma / 1409 D. PupillaryBehaviorOutside of Acute GlaucomatousAttacks There is agreement among clinicians that the pupils of patients with primary open-angle glaucoma-outside of acute attacks of raised intraocular pressure, and in the absence of marked visual loss-constrict briskly to light and to near vision. In 1944 Lowenstein and Schoenberg recorded pupillary reflexes of such patients with the motion picture pupillograph. These records revealed signs of poor central inhibition in virtually all cases. Nicolato (1943), Marucci and Marone (1945), Citroni (1955), and Matteucci (1956), who also recorded pupillary reflexes in patients with glaucoma, obtained the same result: all pupillograms showed the same stereotyped features, different among patients only by degree: a relatively small pupillary size in darkness; abrupt, square-shaped light reflexes; well-preserved reflex dilation; poor or absent reintegration of the light reflex shapes under the influence of psychosensory stimulation; good darkdilations; and feeble redilations after the contractions that followed the reappearance of light after the dark interval (Figures 40-4 and 40-5). These records indicated that central inhibition of the pupilloconstrictor nucleus was weak in patients with primary simple glaucoma. Because of these constant findings, and because the diencephalic area of the rostral brainstem was known to be involved in the regulation of a great many autonomic functions (see Chapter 9), Lowenstein and Schoenberg suspected that the same area might contain clements related to intraocular pressure regulation. Others disagreed with this conclusion (for example, Weekers and Gustin, 1958). They pointed out that normal pupils also become smaller with age. In addition, prolonged treatment with miotics may lead to structural changes in the iris and a 10 9 tendency toward permanent miosis. However, the reflex shape found so consistently in the glaucoma group by Lowenstein and Schoenberg was not one that results from iris damage. To the contrary, the peak contraction speed tended to be at least as high as it is in normal reflexes of the same amplitude. And further, squareshaped light reflexes were encountered as distinctly in the clinically normal eye as in the affected eye of patients with unilateral glaucoma, with or without miotic treatment. 2 From the point of view of pupillary reactions, unilateral pathology was never found. Nicolato (1943), Sano (1956), Matteucci (1956), and Lawrentieva ( 1958) had the same experience. The patients with glaucoma were indeed older than many other patient groups used in our statistics on 1,800 cases (average age 53.4 years); and other older groupssuch as patients with cerebral arteriosclerosis or with Parkinson's disease-also showed a high incidence of central inhibitory loss. Weekers and Gustin's objection that the glaucoma patients' age might be responsible for their pupillary deficit is therefore justified. But the glaucoma group differed from all others in the severity and the purity of their central inhibitory syndrome. Glaucoma patients showed marked central inhibitory deficit more often than all other patient groups, while moderate central inhibitory deficit occurred no more often than in the total group of eighteen hundred cases. And glaucoma patients had the central inhibitory syndrome with outstanding frequency in its "pure" form, that is, without additional pupillary pathology of any kind (Figure 40-6,A and Table 40-4). The "mixed" pupil 2. A minimum of 3 days without drugs was allowed prior to the pu pillary tests. I i I t: !I rn 6 E-< z >"< 5 g:: < Pi ~ 0 ~ ~ :g 4 3 2 1 i I I i i ~ z 0 20 30 40 50 60 70 80 AGE IN YEARS ➔ Figure 40-7. Age of 74 patients with primary open-angle glaucoma. The average age of patients examined pupillographically was 53 years, the median age 52 years. The distribution is shown in the graph. 1410 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 40-4. Pupillary defects in 74 patients with primary simple glaucoma PUPIL PATHOLOGY Normal pupils Fatifil!e signs onli ~central \ mild inhibition_ marked "Dazzling" 2attern w or v-shaQes Consensual deficit _ +:earaslmEathetic outflow _-tslm:eathetic outflow Ar!Q'.11Robertson slndrome §.eastic mio sis Tonic pupil 18()() UNSELECTED 8.6% 19.0% 24.3% 27.3% 2.5% 4.6% 10.8% 11.0% 6.9% 3.5% 3.5% 2.9% CASES 74 GLAUCOMA 0 2 18 54 1 2 8 8 4 0 2 0 (0.0%} (2. 7%} (24.3%} (73.0%) (1.3%) ,2. 7ll!-1 {10.8'.zii} ll0.8%1 (5.4%} (0.0%} f 2 ,2ll!-\ (0.0%) Note that all pupillary syndromes except those of central inhibitory deficit were found less often among the glaucoma patients than among the unselected clinic population ( 1800 cases). syndrome, that is, central inhibitory weakness plus other pupillary signs, occurred rarely in patients with glaucoma (Figure 40-6,B). In this respect cerebral arteriosclerosis showed the opposite trend. Patients with cerebral arteriosclerosis were the oldest group of all ( average age 66.1 years), but they showed the "pure" central inhibitory dysfunction only 1.7 times as often as the total patient group of eighteen hundred, while the frequency was more than 5 times that in the total clinical group when central inhibitory defects were associated with additional pupillary pathology, especially midbrain signs (Figure 40-6,A and B). While the average age of seventy-four glaucoma patients examined by Lowenstein and Schoenberg was 53.4 years, a good many individual patients were considerably younger (Figure 40-7), and yet their pupils all had central inhibitory deficit. This is not the case in normal populations until a much more advanced age. In other words, many of the glaucoma patients showed this sign prematurely. This was not true for the patients with cerebral arteriosclerosis, whose average age was 66.1 years. Age alone therefore did not seem to account for the pupillary changes in the glaucoma group; and Lowenstein and Schoenberg concluded that a special proneness toward loss of central inhibition of the pupilloconstrictor nucleus appeared to exist in patients with primary simple glaucoma. E. Nervous Influences (Experimental and Clinical Findings) 1. Peripheral Nerves Theories about nervous regulation of intraocular pressure arose from these basic thoughts: first, it is difficult to imagine the functions of a complex physiologic system, which requires a narrow range of homeostatic control despite constant, severe stress upon it, to be operated solely by peripheral organs, without some sort of regulatory mechanism; and second, for virtually all bodily functions-both voluntary and autonomicthe nervous system plays this regulatory role. (a) The Fifth Nerve Ever since Magendie succeeded in sectioning the fifth nerve in living rabbits (1824) the intense miosis with ocular hyperemia caused by the operation was remarked upon (see Table 11 in Chapter 6). These signs were found to be accompanied by sharp rises of intraocular pressure, with breakdown of the blood-aqueous barrier and spilling of protein into the aqueous fluid. At first, impairment of the sympathetic pupillodilator and vasoconstrictor fibers that reach the eye by way of the ophthalmic fifth nerve was held responsible for these reactions. But sympathectomy brought on much milder pupillary and vasomotor deficits, a slight fall rather than a rise of intraocular pressure, and no breakdown of the blood-aqueous barrier. Moreover, mechanical or electric stimulation of the fifth nerve had the same effects as lesions, even when the sympathetic fibers had been eliminated by removing the superior cervical ganglion some days beforehand, leading to degeneration of the postganglionic nerves. And often the intraocular pressure rose in both eyes after unilateral nerve stimuli. These facts could be explained by assuming that the fifth nerve sent afferent messages to its nucleus in the brainstem, which then could activate the pupillary and vasomotor changes reflexly; and indeed, ciliary nerve action potentials were recorded upon raising the intraocular pressure in rabbits, cats, and monkeys (Dieter, 1940; Tower, 1940; von Sallmann et al., 1958; Perkins, 1961; see Table 40-5). Perkins stressed, however, that these nerves fired only in response to fairly rapid changes in intraocular pressure, and that there were no sustained discharges that could be assumed to signal information to the brain about the (static) level of intraocular pressure. And further, stimulation of the central stump of the divided fifth nerve failed to produce pupillary, vasomotor, or intraocular pressure responses, 40. Glaucoma / Table 40-5. 1870 1870 1878 1900 1900 1902 1903 1904 1905 1906 1910 1910 1912 1915 1920 1924 1925 * + + A + - ++ - + a+ + Holtzke von Schulten Jonnesco Hess & Heine Jonnesco Zimmermann Angelucci Grunert Herbet Lagrange & Pachon* Mohr Schmid-Rim2ler Jonnesco & Floresco Leber* Henderson & Starling Medow Lodato* Gronholm Stock* Krauss Rochat* Rollet Hartmann Bourquin -- ,_-s 50 30 von Graefe Haffmans AdamUk Wegner AdamUk von Hippel & Grllnhagen Adamtik Dobrowsk:y: Eulenburg & Guttman 1855 1861 1866 1866 1867 1868 1883} 1885 1884 1897 1898 1899 1899 1900 1900 1900 1900 The influence of peripheral nerves upon the pupil and intraocular pressure: Literature reviewed AUTHOR YEAR 1411 + - -+ - -+ - - + + 7i. + - + - + + + + - -+ * - ++ - + - + - + + - + - + A- + + + + + -+ YEAR AUTHOR s 50 30 -+ 1927 Bailliart 1927} Magitot + 1929 1928 Scarlett + + 1929 Bistis 1929 Korobova & A Samojloff + 1929 Tessier + 1929 Thiel@ + 1929 Weekers (d) 1932 A Kin 1932 + Linksz + 1936 Jaensch + 1940 Dieter + 1940 Tower 1943 Nicolato + 1944 Lowenstein & + Schoenbe:r:g_ 1944 Vidal & + Malbran* 1947 Matteucci & + + Carusi 1949} Schmerl & G + 1950 Steinber~ 1951 Davson & + (+) Matchett 1952 Greaves & + Perkins 1952 Mawas + 1952 Weinstein 1953 Greaves & + Perkins 1953 Miller* ,_+ 1953 Tyner & + Scheie '+ 1953 Weinstein 1954 Agarwal + 1955 Christini & + + Fiorini =cited - -- - + - -- - - - - - - - - + a -- a + - - YEAR 1955 1955 1955 1956 1957 1958 1958 1958 1960 1960 1960 1960 1960 1961 1962 1962 1962 1963 1964 1964 1965 1966 1966 1967 1969 1969 1970 1970 1970 Jabonero Linner & Prijot Weinstein Gros & al. Perkins Gloster & Greaves Lowenstein v. Sallmann & al. Galin Krishna Langham & Ta:y:lor v. Nordheim &Nelemans Sears & Bar:fov Perkins Barany Miller Saman Swegmark Eakins & Eakins Thomas Langham Casey Paterson Waitznan &King Kramer & Potts Waitzman Charles & Hamasaki Treister & Barany Tornqvist via other authors; + = nerve influence studied; G = ciliary ganglion; (+) =related indirectly; ration of nerve endings; A = accommodation. In the colums, 5o means fifth nerve, 3o third nerve, nerves; (d) = the author spoke in discussion. while stimulation of the peripheral nerve stump did so readily. Obviously, these reactions must be elicited by antidromic impulses transmitted by the fifth nerve to the effectors. As described in more detail in Chapter 6, the mechanism of these reactions was recognized more than a century after their original discovery; and it is important in ocular pathology because it is involved in the ocular reactions to various forms of injury. These are not mediated by autonomic nerves but by local release of prostaglandins and of other biologically active substances. And the miosis which occurs in response to fifth nerve stimulation, together with vasodilation and increased intraocular pressure, has nothing to do with the usual physiologic pupillary movements. (b) The Third Nerve Since instillation of cholinergic drugs like eserine and pilocarpine into the conjunctiva} sac is so effective in lowering the intraocular pressure of glaucomatous eyes, it was suggested that the parasympathetic nervous system might play a role in the control of - -s 50 30 AUTHOR +* ~ + + G .±.. -+ -+ - + + + + + + + + + -+ -+ - + - - + -+ -- + -+ + - -+ + -+ - -+ - + - + + - + + +* = degene and S,sympathetic intraocular pressure: in addition to the well-known mechanical effect of pulling the iris root away from the corneo-scleral angle, parasympathetic stimulation might affect aqueous production, alter local blood flow and vascular pressure, or improve the outflow facility of aqueous fluid through the trabecular meshwork, canal of Schlemm, and aqueous veins (Table 40-5). Contraction of the extraocular muscles-by voluntary innervation or experimentally by electric stimulation of the nerve-indeed raised the intraocular pressure, and cutting the third nerve, or paralyzing the muscles with curare or similar drugs dropped the pressure. Intense accommodation over some minutes also tended to increase the intraocular pressure as well as pressure in the aqueous veins. Korobova and Samoiloff (1929) suggested that this was brought on by contractions of the ciliary muscle which might cause engorgement of the ciliary processes by interfering with the outflow of blood. Ciliary body congestion associated with externally visible congestion-as in weeping or flushing of the face 1412 / V. Pupillary Pathology: Pupillary Signs in Various Diseases due to emotional excitement, coryza, or surgery about the head-can precipitate intraocular pressure rises in eyes with shallow chamber angles (Sugar, 1941). Further, Sugar observed foward movement of the ciliary zone of the iris when accommodation was induced in the fellow eye. This movement of the iris root decreased the anterior chamber depth and was important in ocular pre ure reactions of individuals with shallow chamber angle. . In four presbyopic acute glaucoma patients and forty normal individuals 15 to 83 years old, a gonio copic contact lens was placed on one eye, an_d the subject was asked to look at an object (a pnnted word) held about 12 inches from the other eye. A spherical reading glass of 4.0 diopters was placed in front of the reading eye. The chamber angle of the eye covered with the gonioscopic lens wa ob erved while the reading glass was removed from the reading eye. After a slight lag period the ciliary zone of the iris was seen to move forward. Simultaneously, the subject described the sensation of accommodation. This forward movement of the iris root and the consequent decrease in anterior chamber depth was largest in young people. A ide from these effects of muscle contractions the parasympathetic innervation of the eye appeared to have little influence upon the intraocular pressure, since Greaves and Perkins (as already mentioned) no longer could produce pressure changes by stimulating the third nerve once the extraocular muscles had been paralyzed with drugs; and paralysis or pharmacologic blockade of the third nerve had no more effect upon glaucomatous than upon normal eyes. in (c) Sympathetic Nerves Many authors thought the sympathetic nervous system was responsible for intraocular pressure regulation. Clinically, pupillary dilation accompanied the attacks of high intraocular pressure, and at the end of an attack the pressure and the mydriasis subsided together. Experimentally, anesthetic block or surgical interruption of the sympathetic pathways as well as systemic or local use of sympatholytic drugs brought on slight ocular hypotony, while stimulating the sympathetic nerve raised the pressure. Glaucoma came to be considered by many to be due to pathologic irritation of the ocular sympathetic nerve supply, or to a general state of "sympathicotonia." This belief was strong enough to prompt resort to surgical sympathectomy for treatment of glaucoma at a time when such surgery carried considerable risk (Jonnesco, 1897, 1899; and others). Local and systemic treatment with sympatholytic drugs, and "chemical sympathectomy," were also used ( ergotamine, guanethidine, and beta-hydroxy dopamine, respectively). However, things turned out to be much more complex. Not only sympathetic deficit but adrenaline and other adrenergic agonists also could lower the intraocular pressure (Wessely, 1900, 1905, and others). And sympathectomy or sympatholytic treatment often failed to drop the pressure effectively. Further, even when the pressure fell, it usually increased again after the initial period; and conversely, upon stimulation of the sympathetic nerve the pressure, after the acute rise, fell distinctly below the resting value. It soon became clear that the rapid rise of intraocular pressure upon sympathetic stimulation was caused mainly by external pressure upon the globe, due to contraction of the extraocular smooth muscles. These reactions continued after the striated extraocular muscles were paralyzed, after the arteries to the head were tied, and even in freshly killed animals, which ruled out participation of the blood supply as a major factor (Adamiik, 1866, 1867; and many later authors). Besides these transient effects of orbital smooth muscle pressure, sympathetic stimulation and paralysis were found to affect the intraocular pressure in a number of ways: by altering the volume of the intraocular vascular bed (via vasoconstriction or vasodilation), and by all mechanisms that increased or decreased the rate of inflow or of outflow of the aqueous humor, such as changes in blood pressure and flow in the arterial or the venous circulation; variations of secretion of the ciliary processes; and changes in the facility of outflow through the trabecular meshwork. The latter effect could not be due to vasomotor actions alone, since treatment with epinephrine improved outflow facility in some cases for weeks or even months after short periods of therapy. It appeared that additional, still unknown kinds of sympathetic nerve function may participate in the reactions. For example, aqueous outflow may be altered secondarily by a decrease of aqueous inflow, or by biochemical changes brought on by the primary effects of sympathetic activity. The difficulty in arriving at clear-cut answers to questions about these mechanisms was not a lack of suggestions but, on the contrary, the large number of possible effects and of interactions of different phenomena that have been considered. 2. The Central Nervous System The same is true to an even greater extent for possible influences of the central nervous system upon the normal and pathologic intraocular pressure. The idea that the central nervous system may be involved in regulation of the intraocular pressure is by no means new. It grew naturally from the realization that stimulation or destruction of peripheral nerves changed the intraocular pressure along with other autonomic and ocular mechanisms. Oculopupillary responses to brain stimulation at various sites were, of course, well-known during the last quarter of the ninteenth century, as were cardiac, vasomotor, respiratory, sudomotor, and other autonomic reactions (see Table 6 in Chapter 9). As early as 1884 von Scholten studied parallel reactions of the intraocular and the intracranial pressure upon sympathetic stimulation; and he observed rises in intraocular pressure together 40. Glaucoma / Table 40-6. findings YEAR Central nervous influence upon pupils and intraocular pressure: Experiments and clinical AUTHOR 1884 1929 1936 1936 v. Schulten Wegner id) Rapisorda stavraky 1938 1944 1947 Licheri Lowenstein & Schoenberg Marucci & Morone Leroy 1949 Lowenstein 1950 Levina 1950 Schmerl & Steinberg 1951 Nagai & al 1945 1952 1953 Tagaki Kutscher & Feuersenger 1954 Cavka 1955 Citroni 1955} Lowenstein 1955 v. Sallmann & Lowenstein --1956 Gloster & Greaves 1956 Paul & Leo~ld 1957 Matteucci 1957 Gloster & Greaves 1957 Itkuta 1958 1958 Gloster & Greaves 1959 1959 Kuchle & Rohrschneidcr Carapancea & Simonescu-Caraoancea Gloster Menna 1959 1972 1973 1974 v. Sallmann Jahnke & Thumm Newman Floru 1959 1413 FINDINGS electric stimulation of rabbits' medulla ~ IOP rise & cerebro-vascular events rise in IOP bv caffeine in glaucoma but not in normal oeoole pupils slightly enlarged; !OP, BP &accomm. amplitude reduced after muscle work pupils & cerebro-vascular changes upon diencephalic stimulation in cats, abolished by transection of brain stem caudal 1/3 of 122ns pupil & !OP chanires due to X-irradiation of sellar region (n .r.) loss of central inhibitory activity in patients with primary simple glaucoma same findings as Lowenstein-Schoenberg ( & Nicolato) 100+ patients with electroshock treatment: mydriasis &tIOP in convulsive phase, return to normal slower for IOP & retinal arter.l:'.eressure than .:ir S.):'.StemicBP same kind of pupil reflex pattern (1944) in monkeys with lesions just rostral to the oculomotor nucleus among 125 patients with CNS disease, 40% had asymmetric !OP, especially those with hyQQthalamic im2airment st. in diencephalon of animals, rostral to hypophysis - pupil dilation & fall of !OP; close to hypophysis, miosis and rise of !OP; injection of water in 3rd ventricle -+ rise of !OP without 2ueillary effect from ventromedial and lateral hypothalamus of anesthetized rabbits, electric st. caused biphasic IOP changes with bilateral mydriasis & exophthalmos; upon repetition, IOP rise decreased and fall increased; some reactions were due to contraction of Mllller' s muscle effects of brain stimulation uoon IOP. orbital smooth muscles & vessels enlarged pupils & reduced IOP after air injection into the 3rd ventricle of nonglaucomatous eatients -+ returned to normal after 2-4 hours eatients after frontal lobotomy same eueillary rel'lex pattern as iouna 6y Nicolato- Lowenstein & Scfioenoorg, etc. responses of systemic blood pressure, intraocular pressure, pupils and cutaneous blood flow to electric stimulation in the diencephalic region of cats ( see text) similar experiments as v. Sallmann & Lowenstein, 1955, with similar results (cats) miosis & IOP fall due to tranquillizers (thorazine, reseroine, pentolinium tartrate) bilateral pupil findings in unilateral e:laucoma /same as Nicolato-Lowenstein etc. l effect of dience2halic stimulation on intraocular 2ressure (cats) electric stimulation of the "sympathetic centre in the midbrain" of rabbits caused rise in aqueous pressure and (less so) of vitrous pressure in cats electric stimulation in the area of rostral column of fornix caused mydriasis, rise in BP, fall in IOP, and occasional contraction of the NM; sympathectomy abolished IOP and NM reactions & reduced mvdriasis but not BP chanire electroshock treatment in rabbits reduced IOP but had no pupillary effects unsupported speculations on mydriasis in glaucoma attacks, including assumptions of "X"-factor, affecting reactivity of brain centers to acetylcholine, and "Y"factor predisposing to glaucoma 11 diencc2halic nervous mechanisms in relation to control of intraocular 2ressure" patient came down with glaucoma & cataracts after thyroidcctomy & parathyroidec tomy; attributed this to "changes in dicncc2halon" summarv on "role of the CNS in regulation of the intraocular oressure" action of clonidine on the 2u2il and IOP action of sedative {Qenzoctamine ) on the eu2il and !OP action of antipsychotic drug ("sulpirid") on the pupil and IOP IOP means intraocular pressure, NM = nictitating membrane. BP, blood pressure; with cerebrovascular responses upon stimulation of the medulla oblongata of rabbits. But since in the latter experiment the stimuli also changed the animals' breathing, and spread to the roots of the fifth and tenth cranial nerves, he thought that the reactions were not significant in regard to intraocular circulatory mechanisms. After the remarkable series of experiments about the effects of lesions and of stimulation in the diencephalon-beginning in the early decades of this century with the work of Bechterew, Karplus and Kreidl, Sachs and (n. r.) = not read by reviewer at time of writing; Horsley, Pfeifer, Schrottenbach; and many others listed in Table 6 of Chapter 9-a central regulatory role of this area over autonomic functions was firmly established. This influence was shown so clearly and so consistently that by the 1940s the hypothalamus was thought of as the "highest cerebral center" for autonomic reflex adjustments. It was thus only natural to assume that the diencephalon might participate in the regulation of the intraocular pressure, together with that of all other autonomic 1414 / V. Pupillary Pathology: Pupillary Signs in Various Diseases effector sy terns. And indeed, diencephalic stimulation in animals elicited intraocular pressure changes, and central stimulants such as caffeine raised the pressure in glaucomatous eye , while fatigue and tranquillizing drugs tended to reduce it. Simarily, during the convulsive pha e of electroshock treatments the intraocular presure rose, together with mydriasis and other signs of central excitation. Patients with cerebral lesionse pecially in the hypothalamus-but without glaucoma were found to have a ymmetric intraocular pressures; and both the pupil and the ocular tension responded to X-irradiation of the sellar region, and to air injections into the third ventricle (Table 40-6). The pupillary reaction patterns found by Nicolato, Lowenstein and Schoenberg, and others-as described above-pointed in the same direction; and these findings agreed well with the results of experiments on animals: stimulation in the thalamu , hypothalamus, and subthalamus of cats, rabbits, and monkeys consistently led to inhibition of the light reflex, while monkeys with lesions just rostral to the oculomotor nucleus-which severed inhibitory central impul e -had the same type of monotonously squarehaped light reflexes as did patients with glaucoma, in tead of the notoriously variable reactions of normal monkeys (Figure 40-8). More extensive lesions, such as tran ection of the brain tern rostral to the oculomotor nucleus, abolished central inhibition altogether and re ulted in tight miosis, as shown by a large number of "cerveau i ole" experiments on cats (see Chapter 9). 7 6 _c-- \ s 'I 3 .2. a. 6 - 1>--B ,,-, ...... ' 3 ~ \ \ a.. JY _,,..~ t \ \.... J II E:3 l. l, 'l..-. J a. a b a 6 l, .r --- \.. _,I a. 1,Y L -- - .-.:.... / ." a. l, / ~ \_ a. ~/" .--."'SI. nr == \ a. b --,,~ ,;-' ,I y -1 I s -.:-11' b .....-- 6~c I ~ i\ -- .~./ 'I- a J[. - \ s .-~ _ '\~I === & .-- \r A During the 1950s experiments were undertaken by a number of research groups to determine possible intraocular pressure effects of diencephalic stimulation in cats or rabbits, as described in Table 40-6. ltkuta (1957) obtained aqueous and vitreous pressure rises upon stimulation of the "sympathetic centre in the midbrain" of rabbits. Since the original text of this publication is unavailable to me at the time of writing, I cannot tell which area of the brainstem was stimulated. While it was not surprising that in such experiments a rise of intraocular pressure should accompany sympathetic mass discharges-with mydriasis, increased systemic blood pressure, contraction of extraocular smooth muscles, and other effects-more discrete, dissociated, and complex reactions were also encountered. Thus, Schmerl and Steinberg observed mydriasis with increased systemic blood pressure but a fall of intraocular pressure; and Nagai et al. found biphasic pressure responses. How could such reactions be brought about? L. von Sallman and Lowenstein (in 1954-55) explored the thalmic-hypothalamic region in cats by simultaneous measurements of the intraocular pressure, systemic blood pressure, and cutaneous blood flow in the ear auricles, and by observation of extraocular movements, lids, nictitating membranes, and pupils (see von Sallmann and Lowenstein, 1955). Gloster and Greaves later did similar experiments (1957, 1958, 1959). The chief results of this work were the following. From a ventral, mostly hypothalamic region (Figure 40-9,A) sympathetic mass discharges were / Ot. - ~ ~ ,.,,.; l, a. o.,~ec.Figure 40-8. Central inhibitory deficit. A, normal record (36year-old woman) of the first, fourth, and fifth light reflexes of a series, with a loud sound interposed between lights (marked by arrow). B, reactions of a monkey (Macaca mulatta), after surgical interruption of the central inhibitory path at the diencephalicmesencephalic border, just rostral to the oculomotor nucleus. Note the square-shaped light reflexes, the good sensory reflex dilation, and the failure of re-integration of the fifth light reflex. C, curve obtained from a 42-year-old man with open-angle glaucoma in the right eye. Note that the pupils of the good eye and of the glaucomatous eye reacted exactly alike. (From 0. Lowenstein, Ann. Oculist., Paris 188 [1955):981) 40. Glaucoma Figure 40-9. Blood pressure and intraocular pressure responses to electric stimulation in cat brains. In A, points were plotted that yielded coordinated blood and intraocular pressure reactions, whereby black, up-pointing triangles indicate rises and white, downpointing triangles falls. ln B, uncoordinated reactions were plotted as follows: black squares, ocular pressure rise with simultaneous rise of blood pressure; black triangles, ocular pressure rise without blood pressure response; black circlel~ no change in ocular pressure with fall of blood pressure; white squares, blood pressure rise with simultaneous fall of intraocular pressure; white triangles, blood pressure rise without ocular pressure effect; white circles, no response of blood pressure with fall of intraocular pressure. The areas outlined by dotted lines in the anatomic diagram C show the (lower) hypothalamic and the (upper) thalamic portions of the diencephalon. From the lower area most stimuli resulted in sympathetic mass discharges; and from the upper area, blood pressure and mtra~cular pressure falls, and many uncoordinated response were obtained. Most stimuli were given 2 mm from the midline and occasional ones 1 or 3 mm from the midline. (From O. Lowenstein,Ann. Oculist., Paris, 88 [1955]:981) 1415 pressure change (Figure 40-10,E and point E in Figure 40-11); or complex reactions of intraocular pressure or of blood pressure could be combined (Figure 40-10,C and point C in Figure 40-11). Simultaneously the pupil could show the fast, full sympathetic type of dilation (Figure 40-10,A and D), or only the slow, incomplete parasympatheticinhibitory type of enlargement, without retraction of the lids or of the nictitating membranes (Figure 40-10,B). Or the pupils, lids, and nictitating membranes would fail to respond altogether (Figure 40-10,C and E). The peripheral blood flow also could correspond with the intraocular responses, such as the marked vasoconstrictions in sympathetic mass discharges, or the equally marked vasodilations during some intraocular pressure falls (as in Figure 40-10,E); or it could remain unaffected (Figure 40-10,B), or could react without corresponding blood pressure or intraocular pressure changes, sometimes even asymmetrically in the two earlobes (Figure 40-10,D). often elicited: steep rises of intraocular pressure were associated with equally prompt and extensive elevations of the systemic blood pressure, with widening of the arterial pulse and constriction of peripheral vessels. The pupils dilated swiftly and completely, the palpebral fissures enlarged, and nictitating membranes were retracted. Such a reaction is shown in Figure 40-10,A, and the particular spot stimulated is marked A in Figure 40-11. Stimulation of a more dorsal (somewhat overlapping) thalamic area yielded coordinated drops in intraocular and blood pressures (Figure 40-9,A) or uncoordinated reactions of all possible kinds (Figure 40-9,B). The intraocular pressure could rise without parallel change in systemic blood pressure, as in the reaction of Figure 40-10,B and point B in Figure 40-11, or even with a simultaneous fall in blood pressure (Figure 40-10,D and point D in Figure 40-11). Or the ocular pressure could fall, with or without a corresponding blood A / B C \i<----- -.il-------~n~-----:;;t;----==~-- . ...... ..__ '---------=--- ,.----'-.. .---r-superior co/lieu/us descending fornlx habenu/ar nucleus pineo/ body posterior comm/ssure massa intermedia anterior commissure mommillory bodies pituitary stolk optic chiosm 1416 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Topographically or pressure falls on mass discharges on two main regions A But there certainly these uncoordinated responses the one hand, and sympathetic the other, were grouped in the and B outlined in Figure 40-9. was no orderly separation of Figure 40-10. Responses to electric stimulation in cat brains. On top of each set of graphs, voltage (V), frequency per second (F) and duration of the stimuli (in seconds) are indicated. Intraocular pre ure (OD, right and OS, left) and blood pres ure were recorded manometrically, in mm Hg. Peripheral blood flow in the ear auricles (AD, right and AS, left) was measured photoelectrically; and pupillary (OD, right and OS, left) as well as nictitating membrane reactions ( M) were observed. In A, a sympathetic ma s di charge is shown, composed of rises of blood and intraocular pressures; vasoconstriction in the ear auricles; fast, complete pupillary dilation; and contraction of the nictitating membranes. In B, the intraocular pressures increased without corresponding reactions of the general blood pressure or the peripheral blood flow. The pupils dilated slowly and submaximally (parasympathetic-inhibitory type of dilation), and the nictitating membrane failed to re pond. C shows complex, uncoordinated reactions of ocular and blood pressure , peripheral vasoconstriction, and failure of pupillary and nictitating membrane reactions. In D, the eye pre sures rose, together with fast and extensive (sympathetic) pupillary dilation and constriction of the nictitating membrane, but with a imultaneous fall of blood pressure and complex reactions of ear blood flow, different on the two sides. In E, exten ive fall of intraocular pres ures occurred without distinct blood pressure reaction, pupillary or nictitating membrane effects but with marked ear vasodilation. (From L. von Sallmann and 0. Lowenstein,Amer. J. Ophthal., 39, II [1955]:ll; published with permission from The American Journal of Ophthalmology, The Ophthalmic Publishing Company.) [A] ! functions: similar responses could be obtained over fairly wide areas; and conversely, stimulation of adjacent points could provoke different-and occasionally completely opposite-effects. Which were the mechanisms responsible for these many different reactions, and how could central nervous events affect the intraocular pressure? In a number of responses, the peripheral mechanism at work was plainly apparent. Thus, in a first type of reactions, extraocular muscle contractions brought on sharp rises of intraocular pressure, with or without associated blood pressure or other effects. These responses had very short latent periods, and they were able to follow stimulation rates much too fast for any but striated muscle systems. Sometimes (but by no means always) these pressure changes coincided with overt movements of the ocular globes. In a second type of responses, extraocular smooth muscle contractions were re ponsible. Though they usually were associated with pupillary and vascular sympathetic effects, they occasionally appeared alone: widening of the palpcbral fissures, retraction of the nictitating membranes, and forward bulging of the globes coincided with extensive rises of intraocular pressure, without noticeable striated muscle or vascular events. These reactions had latent periods of about 0.3 second, and they merged into smooth, continuous reactions at a stimulation rate below 4 per second. Finally, in a third type of reactions, there were no s,1111 6V, 60F, 30Hc. mcnH9 [SJ 00 -zo 15 OS OS 15 10 Blood PreHure 200 100 • .; 0 I. IW''ll'hi ....... a.-1' 100 At ,_.I AC1ice 4.-'t.:.:J~ ..-..-:-:r-..➔+--.:..r.:.,,+.,....,-1,::.:_-_ g: Pupil Actio11 ;..;..-~:...+-...-:.:~:::::::::::::.t:::::::::::::t~:::::::::::.!::t:=:: 10,1: oo- 40. Glaucoma In the first place, the precision of localization of stimulated points is limited. Even sharp, thin electrodes push and bend relatively dense brain structures such as fiber tracts before they penetrate. As shown in Figure 40-11, this results in actual electrode positions that tend to be higher anatomically than the intended positions, defined by the coordinates of the stereotaxic instrument. Further, the brains of individual animals are not exactly alike, so that both rostro-caudal and vertical variations in electrode positions result in different experiments. In addition, the direction and extent of the spread of current through the surrounding brain area depend on tissue conductivity, on the polarity and voltage of currents used, and so forth. Sometimes a slight change in stimulus frequency or intensity suffices to alter or to reverse a response. Second, even the same stimulus at the same site can result in different reactions, depending on initial blood and intraocular pressures, body temperature, or state of contraction of the peripheral vascular bed, and on other (known or unknown) conditions. Further, the results of experiments on anesthetized animals cannot be accepted as certain proof for the existence of a physiologic mechanism that acts similarly under normal conditions. One can never be sure whether the stimulus affects neurons or fibers passing through the stimulated area; whether the stimulus characteris- discernible extraocular striated or smooth muscle contractions. Often the ocular pressure changes were accompanied by extensive blood pressure changes, and the intraocular pressure appeared to ride along with the systemic blood pressure. Some stimuli, however, brought about ocular pressure rises or falls without corresponding blood pressure effects, or even with opposite ocular and blood pressure variations. Often these were accompanied by corresponding reactions of the nearby cutaneous vascular bed of the earlobes, but occasionally these also were missing. These experiments thus showed that diencephalic stimulation can indeed both raise and lower the intraocular pressure; and that several peripheral mechanisms are capable of bringing such changes about. Which of these (or other, not yet demonstrated systems) actually participate in physiologic intraocular pressure regulation remains unknown. Moreover, the experiments also indicated that the concept of diencephalic "centers" for intraocular pressure regulation, as imagined in the 1940s and 1950s, cannot be maintained. While different response types were grouped more or less in main overall areas, no topographic relation could be discovered between specific reactions and identifiable cell groups or fiber tracts. As discussed in Chapter 9, such localization has remained largely unsuccessful in all work on central autonomic representation. Some of the reasons for this failure were merely technical in nature. JIIIM. 4V,to,, 1 Slim 4V, SOF. 30sec mmHf .!]J"1:!l_, if +I I 1417 IOsec. r~ ••Ht , _- . • . -10 ID) j s.... •v. 20,. -... 9oaec. OD OD 00 - , -t I . . -115 OS ~ w,•~ . == .....-: • . . - . ,- -,o 1·; 81Md ,, ..... :_. _ - -200 810od Preuure OS ..., OS -20 -100 .---··-· _ ·, • - ~ _, -t- -200 100 Blood PrtHUrt ♦. ==-•-========-=--o ' ---·-/ --o ~-AD ~L-..1 .. -AS ,._~IMffM Pupil Aetiot1 ~_,...•..,.. __ '_'_r_, __.; ;-: --=;;;;;;;;...;....-------00 -'-----~-----OS [!) D::::.:.:.:.:.:.:.:.:_-_-:.,-_-:.,-_-oD DI NM' Ou+ ... ftJI- ggPupll Action 1418 / V. Pupillary Pathology: Pupillary Signs in Various Diseases tics have any relation to the physiologic action currents; whether the reactions are due to activity of the stimulated structures directly or whether additional circuits in other parts of the brain are activated secondarily; whether the anesthetic suppresses part of the response; or whether inhibitory, compensatory, or other indirect mechanisms modify the result. The same difficulties were encountered in experiments on all autonomic functions, and on the mechanism of sleep and arousal and the higher functions of the brain as well. Here also, stimulation and lesion of the brainstem were effective over wide regions, and yet stimulation or lesions at closely neighboring sites could cause oppo ite effects. This puzzling state of affairs became understandable when it was realized that the brainstem is not composed of series of neatly stacked lower and higher "centers" for the control of various responses. Instead, several biochemically distinct neuronal systems stretch over extensive rostro-caudal areas, and interact with one another as well as with lower and higher systems in the spinal cord and cerebral hemispheres. These facts and the historical development of ideas concerning them are described in Chapter 9 and need not be dwelt upon here. Obviously, new developments since the mid-1950s must be taken into account if new experiments about intraocular pressure mechanisms are to be undertaken. Other biochemical results concerning the effects of various forms of injury upon the pupils, on ciliary body function, on outflow facility, and on other features of intraocular pressure control also must be considered. Some of these are mentioned in Chapter 11 and in other work cited there. F. Conclusion The studies on peripheral and central nervous influences upon the intraocular pressure, though stimulating, have thus not yet resulted in a clear understanding of their role in the maintenance of normal intraocular pressure, or of possible defects in glaucoma. However, analogy with other bodily functions now as in the past makes it difficult to imagine that this complex function should be able to adjust to the constantly changing conditions of life in the absence of neurologic control. For practical purposes miotic and other drug therapy is the most important field in which the pupils are involved. A useful clinical test is the "swinging flashlight" test or other procedures to demonstrate early asymmetry of afferent conduction in glaucoma patients. Such tests sometimes are able to reveal objectively low-grade afferent loss in patients with vague visual complaints before the damage has progressed to the point of obvious and permanent impairment. :~ !J. )0 20 )0 20 3S ,---------,--------,,-..,...-------,---------.35 , 10 = -10 11 Al<'TERI0-POSTERIORCOORDDlATES Figure 40-11. Location of stimulation points in stereotaxic brain stimulation. Electrodes were placed in fourteen cat brains, using the same Horsley-Clarke coordinate (7 mm above and 11 mm rostral to the inter-aural line). The outline drawing of brain structures corresponds to average values, as measured with the Horsley-Clarke instrument in sixteen hemisected cat brains. The crossed broken lines indicate the theoretical position of the coordinate in the "average" brain. The black dots show the actual anatomical location of the electrode tip at this setting in the fourteen individual brains. Note that many of these readings were higher than the target point of the stereotaxic instrument because the electrodes tended to compress the brain tissue and to push it ahead as they were lowered into the brainstem. The area occupied by the actual locations shows the individual variations among cat brains. The points marked A to D were anatomic positions from which the reactions of A to D of Figure 40-10 were obtained. These were located histologically. (From I.E. Loewenfeld and R. Altman,]. Neuropath. exper. Neural., 15 [1956):181)