Brit J Ophthl (1976) 6o, 575 bnorml pupillry responses in mystheni grvis pupillogrphi study TSUM YMZK ND STOSH SHKW From the Deprtment of Ophthlmology, Shool of Mediine, Kitsto University, Kngw, Jpn Disorders of eye movements re frequent in ptients with mystheni grvis (MG), but bnormlities of pupillry responses re less well known Previous investigtors hve exmined pupillry responses in reltively few ptients nd quntittive results hve not been reported (Mnson nd Stern, 965; Ossermn, 958; Bptist nd Souz, 96; Herishnu nd Lvy, 197) Eletroni pupillogrphy enbles one to detet subtle degrees of pupillry bnormlities s well s to quntify pupillry responses Pupillogrphi investigtions hve reently been improved both by using well-ontrolled stimulus (open-loop stimulus) nd by exmining the derivtive urves (veloity nd elertion) of pupillry responses (Meyer, Ogle, Hollenhorst, nd Moyer, 969; Morgn, Hollenhorst, nd Ogle, 1968) By fousing the stimulus light, the dimeter of the light ry n be mde smller thn the smllest size of the pupil (Mxwellin view) Hene, pupillry responses (hnges in the size of the iris perture) will not ffet the stimulus This is lled n open-loop stimulus nd enbles one to ontrol the stimulus preisely We hve investigted pupillry responses in ptients with mystheni grvis nd in norml ontrols both before nd fter edrophonium hloride injetions By using n open-loop stimulus nd mesuring the derivtive urves of pupillry retion with infrred video pupillogrphy (shikw, Nito, nd nb, 97), involvement of pupillry responses in most of our ptients ws demonstrted Methods nd mterils PTENTS ND CONTROL SUBJECTS Seven ptients rnging from i2 to 45 yers of ge with mystheni grvis were exmined Six hd oulr mystheni grvis, nd one hd generlized mystheni Present ddress: lo Dr D Robinson, the Wilmer nstitute, Deprtment of Ophthlmology, Johns Hopkins University, Bltimore, Mrylnd 2125, US ddress for reprints: Dr Stoshi shikw, Deprtment of Ophthlmology, Shool of Mediine, smizodi, Sgmihr City, Kngw, Jpn grvis n eh ptient, the dignosis ws estblished by typil history nd physil findings of musulr wekness nd ftigue The dignosis ws onfirmed eletromyogrphilly by deline in the mplitude of the tion potentil nd by showing improvement in musle strength fter injetion of io mg intrvenous edrophonium hloride either from skeletl musle or from extroulr musle n Tble the linil dt re summrized Only two ptients (nos 5 nd 6) hd been treted with orl ntiholinesterse in the pst, but none ws tking ntiholinesterse medition t the time of the exmintion The sme two ptients hd been treted with orl prednisolone on lternte dys One ptient (no 5) hd hd poor response to prednisolone nd therefore it hd been withdrwn bout one week before mesurement of his pupillry response The other ptient responded well to prednisolone nd ws tking medition t the time of exmintion (prednisolone OO mg/ dy) Five helthy dults were seleted for ontrols with men ge of 25 yers; three of them were given edrophonium injetions RECORDNG OF THE PUPLLRY LGHT RESPONSE The pupillry light response urve ws reorded using eletroni infrred video pupillogrphy (shikw nd others, 197) This system onsisted of n infrredsensitive silion-vidion mer (HTV-N-248), video nlysing system with speilly designed integrted iruits for lulting the pupillry re, nd monitor sope Responses were linerly relted to pupillry re within ±i per ent in the rnge of O-O mm2 nd 5 mm2 System smpling rte ws 6o Both sinusoidl (o25 to 3o ) nd pulse (one seond) stimuli were used The stimuli were presented under open-loop ondition The light soure ws helium neon gs lser with 6328 wve length nd o-8 mm bem dimeter, whih ws less thn the smllest dimeter of the pupil The one-seond pulse stimulus of oo5 mw (bout five log units bove visul threshold) ws delivered through shutter of five-seond intervls The sinusoidl stimulus of zero to o75 mw with vried frequenies of o25 to 3o ws produed by using neutrl density filter, sttionry polroid filter, nd rotting polroid filter in the bem pth Eh subjet ws seted in front of the pupillogrph vidion mer nd the hed ws stedied with hin nd forehed rest fter 5 minutes' drk dpttion, the subjet ws sked to fixte smll red light (2 mm in dimeter) through hlf mirror inserted between the Br J Ophthlmol: first published s 11136/bjo68575 on 1 ugust 1976 Downloded from http://bjobmjom/ on 15 Otober 218 by guest Proteted by opyright
576 Br-itish Journl of Ophthlmology Tble Clinil mnifesttions of mystheni grvis Extroulr Symbols Ptients ge Sex Type of Ptosis musle Pst expressed no (yers) MG involvement tretment in figures 1 12 Mle Oulr Yes Yes None 2 45 Mle Oulr Yes Yes None O 3 42 Mle Oulr Yes Yes None 4 25 Femle Generl Yes Yes None 5 39 Mle Oulr Yes Yes Steroid 6 29 Mle Oulr Yes Yes Steroidt U 7 14 Mle Oulr Yes Yes None O The results of tretment were poor; ortiosteroids were disontinued one week before exmintion tthe results of the tretment were exellent; ortiosteroids were being tken t time of exmintion eye nd vidion The light ws 3 m in front of the subjet's eye Only the diret light response of the right pupil ws mesured The position of the eye ws followed through the monitor sope typil pupillry response nd derivtive urve following one-seond pulse stimulus obtined from norml subjet is shown in Fig i The pupillry response urve represents the tul re of the pupil during vrious phses of its retion to light stimulus ny point on the derivtive urve indites the rte of hnge in the pupil t tht time during its retion to light The slope of ny prt of the derivtive urve reflets the elertion or deelertion of the hnge during tht phse of the retion We mesured the following ten prmeters by the method desribed previously (Morgn nd others, 968): i P: pupillry re t the moment of the light stimulus (mm2) 2 P: hnge in pupillry re used by the light stimulus (mm2) 3 P/P x ioo: rte of onstrition (perentge) 4 T: lteny time (ms) 5 MRC: mximl rte of pupillry onstrition (mm2l/s) Light stimullus ls 5- -E23 g\ ~~~D 17 x68 FG Pupillry response urve nd its derivtive urve obtined from norml subjet for one seond light stimulus Methods of nlyses of the dt re shown 6 MRD: mximl rte of pupillry dilttion (mm2l/s) 7 : elertion of pupillry onstrition (mm2/s2) 8 D: deelertion of pupillry onstrition (mm/2s2) 9 d: elertion of pupillry dilttion (mm2/s2) O Dd: deelertion of pupillry dilttion (mm2/s2) n order to obtin preliminry bseline of the pupillry response, t lest five-seond intervl ws given between pulse stimulus nd three reordings were obtined fter this proedure, 5 mg edrophonium (hlf dose of ordinry use) ws injeted into the ubitl vein within O seonds The pupillry responses in eh subjet were reorded eh minute for five minutes fter injetion of the drug the response to series of t lest three pulse stimuli ws reorded t five-seond intervls Then the bove prmeters were mesured nd verged The results re presented in grphs in whih the verges of the mesurements for seven mysthenis nd three ontrols re plotted ginst the time elpsed sine injetion of the drug Results PUPLLRY RESPONSES TO SNUSODL NPUTS STMUL s the frequeny inresed from o25 to 2-75, the pupil response deresed in mplitude nd its phse inresingly lgged behind the stimulus input Typil exmples of the frequeny response of the pupillry retion in ptient with MG (no ) re shown in Fig 2 Bode plots of verged mplitudes nd verged phses obtined from five ontrols (dotted line) nd five ptients (solid line), exluding ses 5 nd 6, re shown in Fig 2b Vertil brs denote stndrd devitions For both results, Bode plots were similr to those previously reported (Strk, 959, 968) in group of norml subjets n ddition, no mplitude exhustion ws deteted in mystheni ptients PUPLLRY RESPONSES TO PULSE STMUL Typil superimposed reordings of the pupillry retion nd its derivtive urve in response to Br J Ophthlmol: first published s 11136/bjo68575 on 1 ugust 1976 Downloded from http://bjobmjom/ on 15 Otober 218 by guest Proteted by opyright
Liqht intensity -o -5-75 175 W V V m reo 75 2 ~/ \ 2-25 ~~~~~ 25 2 5 5 \N/V/\f\ 2 75 VJVVVVV V H z 1s -4- -8- -12 3-24 _2 u ' -2b- -28- -32 bnorml putpillry responses 577 1 2 5 2 3-1 2 5 Liqht flux () FG 2 () Pupillry responses (pupil re) to sinusoidl light stimuli obtined from mystheni givis (MG no ) with vried frequenies Light intensity is vried from o to -75 mw Pupil re hnged from i8 to 1 mm2 t o5 mplitude of responses grdully redued nd phse lgged with the frequeny inrese (b) Bode plots of verged mplitudes (pupil re redution in deibels (db)) nd verged phse shift in degrees (deg) ginst light flux in Solid line: verges of five ses zvith MG Dotted line: verges of five norml subjets Vertil brs denote stndrd devitions No bnorml pupil response is seen nd no mplitude exhustion is deteted in mystheni ptients one-seond pulse stimulus in mystheni ptient both before (solid line) nd one minute fter 5 mg edrophonium injetion (dotted line) re shown in Fig 3 The wve forms of both the pupillry retion nd its derivtive urve re lerly modified by the edrophonium injetion To quntify the response to edrophonium injetion in mysthenis nd norml subjets, detiled omprisons of the Liqht stimulus -E E 4-35 - 29 23-17- X 17 v ' is -17 E Z_5-34 -51 - FG 3 Superimposed pupillry responses nd their derivtive urves in response to one-seond light (pulse) stimulus in MG (no ) both before (solid line) nd one minute fter 5 mg edrophonium (dotted line) dministrtion The wve forms of both the pupillry responses nd derivtive urve re lerly modified by intrvenous edrophonium injetion B Tble Comprison of pupillry light responses before nd one minute fter the dministrtion of 5 mg intrvenous edrophonium in MG (no i) nd in norml ontrol Differene in the prmeters of P/P, MRC,, d, nd T re pprent Prmeter Before edrophonium 2 3 One minute fter edrophonium MG Control MG Control P mm2 32'4 3-1 34' 32- p mm2 7 i86 219 i8-5 P/P x ioo Perentge 52-8 62-o 64-4 58-5 T mse 3-278-o 282-28- MRC mm2/s 35-7 47'5 47'5 49- MRD mm2/s 13-6 5' 6'i 15-8 mm2/s2 88'7 3-246-5 36o D mm2/s2 49'3 98-o 4-8 12-5 d mm2/s2 49'3 42'5 74 411 Dd mm2/s2 13-6 42 15-4 145 time ourse of the effets of edrophonium on pupillry responses to pulse stimuli were mde omprison of MG (no i) with norml ontrol (one minute fter edrophonium) is shown in Tble Differene in the prmeters of P/P, MRC,, d, nd T re pprent ll dt obtined from the seven ses nd three ontrols before nd fter edrophonium re given in Figs 4 nd 5 Pupillry re (P) showed very slight inrese between one nd two minutes fter edrophonium injetion in mysthenis Lteny (T), P/P, nd MRC, ll of whih were modertely bnorml before edro- Br J Ophthlmol: first published s 11136/bjo68575 on 1 ugust 1976 Downloded from http://bjobmjom/ on 15 Otober 218 by guest Proteted by opyright
578 British Journl of Ophthlmology 4 MG Norml E X t + t, nq o 2-1 32- -, 3- E _ 6 28- E, 26- - 24 22 5 5 t,, B x ex x x 4C 8o o x _ 5 t Time from injetion (t) of edrophonium (min) MG C Norml D FG 4, b,, d ll dt obtined from seven ses (different symbols) with MG nd three ontrol (norml) subjets before nd fter edrophonium injetion rrows indite the time t edrophonium dministrtion Men vlues re expressed with open str with solid line ginst time in minutes : pupillry re, B: lteny time, C: mximum hnge in pupillry relstedy stte of pupillry re, nd D: mximum rte of onstrition These re modertely bnorml before edrophonium, pprohing nerly norml vlte one to two minutes fter injetion phonium injetion, pprohed nerly norml vlues by one to two minutes fter edrophonium injetion (Fig 4, b,, d) The most striking effet of edrophonium ws upon the rte of elertion of pupillry onstrition () s shown in Fig 5 Even one of the treted individuls showed positive response Chnges in the rte of deelertion of pupillry onstrition (D) were less thn hnges in (Fig 5b) n ontrst, hnges in the prmeters (MRD, d, nd Dd) of pupillry dilttion were miniml nd only d showed very slight inrese with edrophonium dministrtion n summry, in mystheni ptients edrophonium injetions used mrked improvement in the prmeters of pupillry onstrition (espeilly ) but only miniml hnges in the prmeters of pupillry dilttion No response to edrophonium injetion ws noted in norml subjets Disussion Using eletroni pupillogrphy, bnorml pupillry retions to n open-loop stimulus were observed in group of ptients with mystheni grvis Five ptients without erlier tretment nd one ptient with previous ortiosteroid therpy showed redution in the mplitude of pupillry onstrition s well s redued veloity nd elertion in the pupillry light response The prmeters of P/P, MRC, T,, nd d were bnorml before edrophonium injetion nd pprohed nerly norml vlues fter the dministrtion of edrophonium n ontrst, the sme dose of edrophonium hd no effet upon responses of norml ontrols The more severely ffeted prmeters were P/P, MRC, T, nd whih refleted iris sphinter funtion n ontrst, the prmeters of pupillry dilttion, with the exeption of d, whih my reflet iris sphinter relxtion, were unffeted by edrophonium injetion Therefore, it ppers tht mystheni grvis primrily ffets the sphinter rther thn the diltor musle This my be relted to the differenes in innervtion to the two musles; the sphinter is predominntly innervted by holinergi nerves while the diltor is predominntly innervted by drenergi nerves (Lowenstein nd Loewenfeld, 969) Defetive ommodtion hs lso been reported in ptients with mystheni grvis, beuse the iliry musle, too, is innervted by holinergi nerve fibres (Mnson nd Stern, 965) Clinilly evident pupillry bnormlities inluding nisoori, nd sluggish or ftiguble pupillry responses to light hve osionlly been reported Br J Ophthlmol: first published s 11136/bjo68575 on 1 ugust 1976 Downloded from http://bjobmjom/ on 15 Otober 218 by guest Proteted by opyright
"E E 4 35 t itc) L t 4 s C= 3-25- 2 MG E Norml +--+~+-~+ + +O3 tn x+ x x : 5 Time from injetion (4) of edrophonium (min) _ 141 E -12- u C] 8 4 MG t B 5XX o 5 t bnorml pupillry responses 579 Norml tz\ - _^ S FG 5 () Rte of elertion Most striking effet of edrophonium, exept one se (no 5), is seen upon rte of elertion of pupillry onstrition (b) Rte of deelertion Chnges in rte of deelertion of pupillry onstrition re less thn hnges in in Fig 5 No response to edrophonium injetion is noted in norml subjets in previous reports (Bptist nd Souz, 96 ; Herishnu nd Lvy, 197) However, in our ptients, only one (no 5) showed n bnormlitytht is, sluggish pupillry light responses tht ould be observed without pupillogrphy Similrly, in none of our ptients were the pupillry responses ftigued by repetitive stimultion Whether this is relted to differene between neuromusulr trnsmission in somti musle nd the iris or simply to nother degree of mystheni involvement in our ptients is not known Reent experiments suggest tht the number of vilble etylholine reeptors t neuromusulr juntions is redued in ptients with mystheni grvis (Fmbrough, Drhmn, nd Stymurti, 1973; Stymurti, Drhmn, nd Slone, 1975) t is of interest tht topil dministrtion of tropimide, whih ts by binding the holinergi smooth musle reeptor sites bloking the tion of etylholine, redues P, MRC,, nd d without ler mydrisis in norml subjets (Morgn nd others, 968) Sine the pupillogrphi responses in our ptients were nerly identil to those in norml subjets treted with tropimide, it seems likely tht the number of vilble etylholine reeptors t the pupillry sphinter musle in ptients with mystheni grvis is redued The x positive response to edrophonium supports this ide One of two ptients treted with orl prednisolone showed inresed elertion of the pupillry response Further work is needed to explin this phenomenon, lthough it hs been reported tht there is supernorml eletroretinogrm with inresed '' s well s 'b' wves in humn eyes fter the orl dministrtion of prednisolone (Zimmermn, Dwson, nd Fitzgerld, 973) Finlly, our results indite tht reording of pupillry responses in ptients with mystheni grvis provides nother mens to dignose mystheni grvis objetively s well to quntify effets of tretment Summry Using n open-loop stimulus (Mxwellin view), the diret pupillry response to light nd its derivtive urves (veloity nd elertion of pupillry retions) were reorded by infrred video pupillogrphy in seven ptients with mystheni grvis nd in three norml subjets Responses before nd fter intrvenous injetion of 5 mg edrophonium hydrohloride were determined Five of the ptients hd never tken ntiholinesterse drugs exept for dignosti injetions of edrophonium 5 Br J Ophthlmol: first published s 11136/bjo68575 on 1 ugust 1976 Downloded from http://bjobmjom/ on 15 Otober 218 by guest Proteted by opyright
58 British J7ournl of Ophthlmology Referenes while the other two ptients hd been treted with orl preprtions of ortiosteroids nlyses of the pupillry responses showed redued mplitude, mximl veloity, nd mximl elertion of pupillry onstrition in the mystheni ptients On the other hnd, hnges in prmeters of pupillry dilttion were miniml bnorml vlues returned towrds norml within five minutes fter edrophonium injetion in ll ptients exept in one individul who ws being treted with ortiosteroids t the time of exmintion These results suggest tht involvement of the iris sphinter my be ommon in ptients with mystheni grvis nd this n be demonstrted by nlysing the pupillry retion nd its derivtive urves in response to n open-loop stimulus This work ws supported in prt by Grnt from the Jpnese Deprtment of Helth, No MG 1974-76 The uthors wish to express their thnks to Dr )vid Zee, Deprtment of Neurology, Johns lopkins University, for his help BPTST, G, nd SOUZ, H S (96) Neutrology (Minnep),, 2 FMBROUGH, D M, DRCHMN, D B, nd STYMURT, S (973) Siene, i82, 293 HERSHNU, Y, nd LVY, S (1971) Ophthlmologi (Bsel), 163, 32 SHKW, S, NTO, M, nd NB, K (197) bid, 6o, 248 LOWENSTEN, O, nd LOEWENFELD, 1 E (969) n 'The Eye', ed H Dvson, vol 3, P 267 demi Press, New York nd London MNSON, N, nd STERN, G (965) Lnet,, 935 MEYER, M E, OGLE, K N, HOLLENHORST, R W, nd MOYER, N J (969) Exp Eye Res, 8, 355 MORGN, S S, HOLLENHORST, R w, nd OGLE, K N (968) ner Y Ophthl, 66, 835 OSSERMN, K E (958) n 'Mystheni Grvis', pp 74 nd 4 Grune & Strtton, New York STYMURT, S, DRCHMN, D B, nd SLONE, F (1975) Siene, 87, 955 STRK, L (959) n 'Medil Physis', vol 3, P 7, ed Glsser Yer Book Publisher n, Chigo (968) ni 'Neurologil Control Systems Studies in Bioengineering', p go Plenum Press, New York ZMMERMN, T J, DWSON, W W, nd FTZGERLD, C R (1973) nzvest Ophthl, 12, 777 Br J Ophthlmol: first published s 11136/bjo68575 on 1 ugust 1976 Downloded from http://bjobmjom/ on 15 Otober 218 by guest Proteted by opyright