Evidence for preserved direct pupillary light

442 Deprtment of Ophthlmology, Kitsto niversity School of Medicine, Sgmihr, Jpn M Wkkur J Yokoe Correspondence to: Msto Wkkur, MD, Deprtment of Ophthlmology, Kitsto niversity School of Medicine, 1-15-1 Kitsto, Sgmihr, Kngw 228, Jpn ccepted for publiction 9 December 1994 British3ournl of Ophthlmology 1995; 79: 442-446 Evidence for preserved direct pupillry light response in Leber's hereditry optic neuropthy Msto Wkkur, Junko Yokoe bstrct ims/bckground-pupillry light response is usully defective in ll types of optic neuropthy However, the uthors hve observed in ptients with Leber's hereditry optic neuropthy (LHON) reltively norml light response, with consequent misdignosis psychogenic visul loss in some cses To confirm this clinicl impression, fferent pupillry defect ws ssessed by mesurement of djusted constriction mplitude (C) nd escpe rte (ER) by infrred videopupillogrphy (riscorder-c 2515) Methods-Thirteen consecutive ptients (26 eyes) with LHON (verge ge 27*2 yers) were exmined; 12 hd the mitochondril DN 11778 muttion nd one the 14484 muttion Seven of these ptients hd positive fmily history For comprison, the bove rtes were determined in 19 ptients (23 eyes) with idiopthic optic neuritis (ON; verge ge 35*1 yers), 18 ptients (19 eyes) with nterior ischemic optic neuropthy (ON; verge ge 58-1 yers), nd 25 volunteers (5 eyes) with helthy eyes (verge ge 39*6 yers) Results-The distribution of visul cuity ws essentilly the sme in ll optic neuropthy groups Reduction in C nd increse in ER were significnt in ptients with ON nd ON, but not in those with LHON Only slight fferent pupillry defect ws evident even 2 yers fter the onset of LHON C in ON nd ER in ON were correlted sttisticlly with visul cuity nd Humphrey men threshold devition, while C nd ER in LHON were not Conclusion-Pupillry light response in ptients with LHON obviously differs from tht in ptients with other types of optic neuropthy LHON ppers to be pthophysiologiclly chrcterised by well preserved fferent fibres for pupillry light response (probbly from W cells) Besides being of pthogenetic interest, the detection of clinicl fetures should fcilitte the dignosis of LHON prticulrly when fmily history provides no indiction (Bry Ophthlmol 1995; 79: 442-446) Leber's hereditry optic neuropthy (LHON) is mternlly inherited disese chrcterised by bilterlly cute or subcute centrl visul loss in young men Despite the extrordinry development of mitochondril (mt) DN nlysis in LHON, the dignosis of this disorder remins difficult, prticulrly soon fter its onset There being mny ptients with n onset intervl for bilterl involvement, norml disc ppernce, bsence of circumppillry telngiectsic microngiopthy, unconfirmed fmily history, nd/or lte onset my be the resons for this Colour vision tests my be helpful in detecting the erly involvement of LHON,2 symptomtic crriers, nd presymptomtic eye3 n visully evoked corticl potentils, Crroll et l 4 found bnorml vlues in some symptomtic fmily members Nevertheless, some LHON ptients hve been misdignosed initilly by the uthors or others5 s psychologicl visul loss owing to the fct tht pupillry light response ws nerly norml LHON would thus pper to be chrcterised by highly preserved pupillry light response n this study, pupillry light response ws ssessed in ptients with LHON nd the results were compred with those for ptients with other types of optic neuropthy nd controls by videopupillogrphy Subjects nd methods review ws mde of the results of videopupillogrphy of 13 consecutive subjects (26 eyes) with LHON (verge ge 27-2 yers), 19 subjects (23 eyes) with idiopthic optic neuritis (ON, verge ge 35'1 yers), nd 18 subjects (19 eyes) with nterior non-rteritic ischemic optic neuropthy (ON, verge ge 58 1 yers) Ech ptient group ws formed by lumping together the results from left nd right eyes for individul subjects The dt were compred with those of 25 helthy volunteers (5 eyes, verge ge 39-6 yers) LHON ws the dignosis for 12 ptients bsed on the mt DN muttion t position 11778 The mt DN muttion ws noted t position 14484 in the other ptient Seven ptients hd positive fmily history of this disorder Exmintion ws performed t vrious stges of optic neuropthy For comprtive study of three types of optic neuropthy, initil exmintion results (7-6 dys fter subjective visul loss) were used Direct pupillry light response ws recorded with n infrred videopupillometer (Binoculr riscorder Model C-2515, Hmmtsu Photonics nc, Hmmtsu, Jpn) originlly developed by shikw et l6 This device consists of n infrred sensitive silicon vidicon cmer, microcomputer system for clculting vrious vribles including chnge in pupillry re, monitor scope, nd printer Light emitting diodes served s the light source (pek wvelength, 65 nm) Photometric Br J Ophthlmol: first published s 11136/bjo795442 on 1 My 1995 Downloded from http://bjobmjcom/ on 4 December 218 by guest Protected by copyright

Evidence for preserved direct pupillry light response in Leber's hereditry optic neuropthy 443 4 35 h 29 H 23 H 17 H (mm2) 8 t -6 C 4 X 2-2 c ON 1 secndd '! instructed not to blink s much s possible nd Light stimulus mintin their gze on trget ppering on viewing screen inside the pupillometer nitil nd mximl pupillry constrictions were mesured from direct pupillry response to light of 1 second durtion Only the direct pupillry response of the ffected eye ws evluted The djusted constriction mplitude (C) ws expressed s percentge nd the difference in initil nd mximl pupillry res ws divided by the initil re Repetitive pulse stimuli of 25 ms durtion, essentilly the sme in the cse of continuous light stimulus, were used for escpe rte (ER) deter- light mintion ER, the degree of l = Pupillry re t the moment of tihe refrctoriness stimulus (mm2) from light stimuli,7 ws mesured nd the 3 = Mximl chnge in pupillry re cused by results re shown in Figure 1 For mesurement of corrected visul cuity, Lndolt rings the stimulus (mm2) CR = Constriction rte (%)(3/l) were used s the trgets, viewing distnce B ws 5 metres, nd the results were notted in 25 deciml cuity Snellen frction cuity is not ~~~~~xj--j "-Seconds used in Jpn The Jpnese visul cuity system follows the recommendtion of the l1th nterntionl Congress on Ophthlmology (199) Visul cuity t the strt of the exmintion ws rnged from 1 to 1l 2 4 6 8 1 Time These were comprble with 6/6 nd 6/6 in frction cuity, respectively npired t tests were conducted for comprison of C, ER, men devition, or fovel sensitivity in ech group Liner regression nlysis ws crried out for comprison of C or ER with (1) visul cuity or (2) men threshold devition of Humphrey utomted perimetry (progrm 3-2) exmined on the sme dy Escpe rte (ER) ER = S33-S2/S 1-S2 Figure 1 ctul recordings ofpupillry light response defining djusted const; rction mplitude () nd escpe rte (B) Results There were no sttisticl differences in visul cuity between the three optic neuropthy quntifiction of the light stirriulus ws groups when ech group ws divided by the 3X JO-3 lm/sterd (lumen/stercdin) (SD cuity t -2; the Mnn-Whitney test ws used 1 /o) Men devition nd fovel sensitivity in The light stimulus (dimeter on the pupil, Humphrey perimetry did not differ sttisticlly 1 2 mm) ws focused to the centre cf the pupil mong the three ptient groups under open loop conditions, the stimulus field being 15 centrl degrees ll meisurements were mde following subject dptntion to the CONSTRCTON MPLTDE (C) drk for t lest 15 minutes in roonn with only Men C in LHON ws 45 (SD 9) n dim red light source The subjects were the controls, this vlue ws -48 ( 13), nd 4NS lc oo LHON ON ON Contr*ols Figure 2 Comprison of constriction mplitude (C) for the three optic neurropthy groups LHON=Leber's hereditry optic neuropthy, ON=idiopthic optic neuritis, ON=nterior non-rteritic ischemic optic neuropthy, NS=not significnit - l - essentilly the sme s the former (p> 1) n the ON nd ON groups, men C ws sig- * <5 nificntly less compred with the controls **P < (p<-5) Sttisticl significnce ws only mrginl between C in LHON nd ON (p=l) The results for C re shown in Figure 2 Follow up C results for more thn 2 yers fter initil exmintion were obtined for eight eyes of four ptients but no definite decrese ws noted (Fig 3) Liner regression ' nlysis of C versus visul cuity showed LHON to hve the lowest slope ( 23), while ON, the highest slope ( 38) The scttergrm in Figure 4 indictes C not to be correlted with visul cuity in LHON (r=5, p=77) The liner reltion ws reltively high in ON (r=-72, p<-1), but poor in ON (r=-27, p= 9) The correltion coeffi- cients of C versus visul cuity differed sttis- ticlly for ON nd LHON (p< 1), but no Br J Ophthlmol: first published s 11136/bjo795442 on 1 My 1995 Downloded from http://bjobmjcom/ on 4 December 218 by guest Protected by copyright

444 Wkkur, Yokoe 7 6 4 O- E 3 +) 2 2 2 c 4 (2, c u 2 V ~lllllllll 21 5 1 15 Dys fter initil exmintion Figure 3 Repetitive exmintion of constriction mplitude (C) for more thn 2 yers fter the initil exmintion in eight eyes with LHON No definite proogressive chnge in C could be detected during this period * -1-1 Visul cuity Figure 4 Scttergrm showing correltion between visul cuity nd d mplitude (C) in LHON nd the other types of optic neuropthy (O Regression line (LHON): Y= 232x+ 441 (ON+ON): Y= Correltion coefficient (LHON) = 5 (p= 77), (ON+ON) = F bbrevitions see Figure 2 ESCPE RTE (ER) Men ER in LHON ws 418 (SD -18) n the controls, it ws 415 ( 12) Men ER in LHON ws somewht higher thn in the controls, but not sttisticlly so (p> 1) ER in ON nd ON ws high compred with the controls (p<-1) nd LHON (p<-1) The ER results for the four groups re shown in Figure 6 ER in eight eyes followed up for more thn 2 yers showed no significnt increse (Fig 7) Liner regression nlysis of ER versus visul cuity filed to indicte good correltion in LHON (r=-25, p=-12) nd ON (X42, p= 9), but moderte correltion ws shown in ON (r=64, p=-1) ER in LHON ws reltively independent of visul cuity, s shown by the scttergrm (Fig 8) The liner reltion between ER nd the Humphrey men devition ws moderte in ON (r=-52, p= 9), but poor in ON (r=-27, p=16) nd LHON (r=-29, p= 12) The slope in LHON ws lowest mong the three optic neuropthy groups (Fig 9) The correltion coefficients of these groups did not differ sttisticlly in plots of ER versus visul cuity nd men devition Discussion Videopupillogrphic nlysis clerly indicted direct pupillry light response in LHON to be other significnt difference could be found essentilly the sme s tht in norml controls The liner reltion between C nd even though the ptients exhibited consider- moderte in ble visul loss, in support of our initil clinicl Humphrey men devition ws ON (r=57, p=1), buit poor in ON impression Thompson et 18 showed tht (r=-2, p=l1) nd L ON (r= 5, pupillry deficit ws not lwys relted to p= 82) s shown in Figure 5 The correltion visul cuity, wheres pupillry defect ws sigdevition in the nificntly relted to visul field loss The sttic coefficients of C versus men three groups did not differ stt:isticlly utomted perimetry demonstrted reltively good correltion between men threshold devition in the centrl 3 of vision nd loss of pupillry function hs been reported in vrious types of optic neuropthy9 nd glucom' n these studies, however, n ttempt ws mde to detect reltive fferent pupillry defect n severl ptients with n onset intervl, slight or moderte reltive fferent pupillry defect ws * u noted t the erly stge of the disese n this study, no ttention ws directed to differences *z in pupillry response in the eyes but rther to / i direct pupillry response, since LHON is / generlly symmetriclly involved nd reltive fferent pupillry defect ws hrdly detected t would thus pper possible, bsed on C nd ER results, to detect optic nerve dysfunction in n eye7 Sttisticl nlysis of C in ON nd,,,,, ii ER in ON clerly indicted these vribles to be closely correlted with visul function Vrious clinicl chrcteristics in LHON hve been reported in some cses,1 11 12 including vsculr tortuosity, telngiectsic microngiopthy,13 nd distension of the optic nerve sheth14 Clinicl testings looking t visul function nd specific for dignosis of LHON were reviewed by Beminger et l3 Nikoskelinen et l 2 found the Frnsworth-Munsell constriction 1 hue test to be the most sensitive indictor N+ON) of the erly involvement of LHON Colour 158x+38 48 (p= 2) For vision defects hve been observed in some presumed crriers, but not in ll3 There is Br J Ophthlmol: first published s 11136/bjo795442 on 1 My 1995 Downloded from http://bjobmjcom/ on 4 December 218 by guest Protected by copyright

BE~~~ Evidence for preserved direct pupillry light response in Leber's hereditry optic neuropthy ME m + 3-2- * * \ ~~~~LONN* ~~~~~~ -4 _ J Co~~~~~~~~~~~ 2 ON ON o 1 234 1 ~ 1 2 ~~~~~~~3 4 Men devition (-db) Figure S Scttergrm showing correltion between Humphrey men threshold devition of centrl 3 degree of vision nd the constriction mplitude (C) in LHON, ON, nd JON Regression line (LHON): Y= - -Sx+-44, (ON): Y= - -21x+ -45, (JON): Y= - -94x+-S1 Correltion coefficient (LHON) =5 (p= 82), (ON)= 2 (p=41), (ON,)= 57 (p=-9) 4) Co (L wl 1 8 6 4 2 vv * i --~ NJq ** ~~~p 71 * T LHON ON ON Controls Figure 6 Comprison ofescpe rte (ER) in the three optic neuropthy groups For bbrevitions see Figure 2 6 5 / "'' -4,3 O3, * < O1 25 5 75 1 125 Dys fter initil exmintion Figure 7 Repetitive exmintion ofescpe rte (ER) for more thn 2 yers fter the initil exmintion in eight eyes with LHON No definite progressive chnge in ER could be detected during this period, exceptfor one eye 1) 4- Q co C) Cn 1 1-1 1 Visul cuity Figure 8 Scttergrm showing correltion between visul cuity nd escpe rte (ER) in LHON nd the other types of optic neuropthy Regression line (LHON): Y=-'174x+'23 (ON): Y=- 341x+ 728, (ON): Y=- 392x+ 698, Correltion coefficient (LHON) =-25 (p=-118), (ON) =-639 (p= -1) (ON) = -421 (p= -87) For bbrevitions see Figure 2 no greement s to whether visully evoked corticl potentil ctully fcilittes the detection of presumed crriers or presymptomtic eyes3 Thus, the only clinicl feture specific nd sensitive for LHON my not confirm the dignosis There is not much in the literture on the preservtion of pupillry light response Nikoskelinen found norml light response in 82% of 16 ptients with LHON, even t the finl stge (personl communiction) Cecocentrl visul field defect reflecting selective involvement of the ppillomculr bundle is n importnt clinicl feture in LHON Nevertheless, results of the present sttisticl nlysis indicte C nd ER in LHON not to be relted to the severity of visul disturbnce s ws lso noted in follow up study for more thn 2 yers W cells re the smllest subclss of retinl gnglion cells Stone nd Fukud5 first suggested in cts tht subgroup of W cells Co C) Co Q O ' - o o 445 - M* LHON_ 2 - * * L 1 2 3 4 Men devition (-db) Figure 9 Scttergrm showing correltion between Humphrey men threshold devition nd escpe rte (ER) in LHON, ON, nd ON Regression line (LHON): Y= 44x+ 139, (ON): Y= 127x+ 34, (ON): Y= 79x+ 433 Correltion coefficient (LHON) = -289 (p= 122), (ON) = 516 (p= 9), (ON) =-273 (p= 157) For bbrevitions see Figure 2 Br J Ophthlmol: first published s 11136/bjo795442 on 1 My 1995 Downloded from http://bjobmjcom/ on 4 December 218 by guest Protected by copyright

446 Wkkur, Yokoe (tonic on-centre W cells) functions s luminnce detector nd provides input to pupillry light response This ws strongly supported by precise electrophysiologicl study16 The pthwy of pupillry light response is known to trverse the midbrin W cells project into the midbrin not only in cts'7 but lso in primtes18 nfortuntely, though direct physiologicl or clinicl evidence for this hypothesis still remins unvilble, LHON my be good exmple of the possible selective impirment of retinl gnglion cells W cells would thus pper to remin reltively intct during the course of this disese, in contrst with impired X nd Y cells which re essentil to visul function f mitochondril dysfunction directly cuses visul disturbnce in LHON, differences in mitochondril metbolism in these gnglion cells should thus be studied crefully Krdon et l 19 noted diseses of the fferent visul system to not necessrily ffect the visul threshold nd pupillry light reflex in the sme wy Rther, mt DN nlysis should be recommended even for cses of optic neuropthy with well preserved pupillry light response This work ws in prt supported by grnt-in-id for scientific reserch (c), the Jpnese Ministry of Eduction, Science, nd Culture (No 467182) nd grnt from Kngw Nnbyo Foundtion, Kwski, Jpn The uthors thnk Dr Y Mshim nd Dr Y Hiid for their DN nlysis 1 Newmn NJ, Wllce DC The clinicl chrcteristics of pedigrees of Leber's hereditry optic neuropthy with the 11778 muttion m Ophthlmol 1991; 111: 75-62 2 Nikoskelinen E, Sogg RL, Rosenthl R, Friberg TR, Dorfmn The erly phse in Leber hereditry optic neuropthy rch Ophthlmol 1977; 95: 969-78 3 Berninger T, Bird C, rden GB Leber's hereditry optic trophy Ophthlmic Peditr Genet 1989; 1: 211-27 4 Crroll WM, Mstgli FL Leber's optic neuropthy: clinicl nd visul evoked potentil study of ffected nd symptomtic members of six genertion fmily Brin 1979; 12: 559-8 5 Nknishi M, Mshim Y, Hiid Y, Suzuki S, Oguchi Y Two cses of Leber's hereditry optic neuropthy dignosed s psychogenic visul loss Gnk (Ophthlmology) (Tokyo) 1994; 36: 811-4 6 shikw S, Nito M, nb K new videopupillogrphy Ophthlmologic 197; 16: 248-59 7 shikw S new binoculr infrred videopupillogrphy Shinkeignk (Neuro-ophthlmolJpn) (Sgmihr 1986; 3: 235-4 8 Thompson HS, Cox PMT, Corbett JJ The reltionship between visul cuity, pupillry defect, nd visul field loss m Jf Ophthlmol 1982; 93: 681-8 9 Johnson LN, Hill R, Brtholomew MJ Correltion of fferent pupillry defect with visul field loss on utomted perimetry Ophthlmology 1988; 95: 1649-55 1 Brown RH, Zilis JD, Lynch MG, Snborn GE The fferent pupillry defect in symmetric glucom rch Ophthlmol 1987; 15: 154-3 11 Johns DR, Hehler K, Miller NR, Smith KH Leber's hereditry optic neuropthy: clinicl mnifesttions of the 14484 muttion rch Ophthlmol 1993; 111: 495-8 12 Wkkur M Retin nd optic nerve disorders Curr Opin Ophthlmol 1993; 4: 16-21 13 Nikoskelinen E, Hoyt WF, Nummelin K, Schtz H Fundus findings in Leber's hereditry optic neuroretinopthy rch Ophthlmol 1984; 12: 281-9 14 de Gottru P, Buichi ER, Dicker B Distended optic nerve sheths in Leber's hereditry optic neuropthy J Clin Neuro-ophthlmol 1992; 12: 89-93 15 Stone J, Fukud Y Properties of ct retinl gnglion cells: comprison of W-cells with X- nd Y-cells Jf Neurophysiol 1974; 37: 722-48 16 Hult born H, Mori K, Tsukhr N Theneuronl pthwy subserving the pupillry light reflex Brin Res 1978; 159: 255-67 17 Fukud Y, Stone J Retinl distribution nd centrl projections of Y-, X-, nd W-cells of the ct's retin JNeurophysiol 1974; 37: 749-72 18 Perry VH, Cowey Retinl gnglion cells tht project to the superior colliculus nd pretectum in the mcque monkey Neuroscience 1984; 12: 1125-37 19 Krdon RH, Hupert CL, Thompson HS The reltionship between sttic perimetry nd the reltive fferent pupillry defect m _J Ophthlmol 1993; 115: 351-6 Br J Ophthlmol: first published s 11136/bjo795442 on 1 My 1995 Downloded from http://bjobmjcom/ on 4 December 218 by guest Protected by copyright