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Show .f. Clill. Nf'Ufl,-,'phth,Jillh11. 2: 2(,1-270, IQ~2. Central Nervous System Regeneration Can Scientists In1plelnent Functional Regrowth? RONALD G. CLARK, Ph.D. Abstract Basic concepts in neurobiology .He reviewed with emphasis on axonal transport and the nerve growth faclor. Our current understanding of the regenerative capacity of the mammalian central nervous system, and research designed to minimize neuronal damage following trauma are discussed. Introduction Restor.ltion of axon.ll function is an area of vital concern to the neum-ophthalmologist. To most effectively treat patients with neurologic disorders, it is essential to have an up-to-date knowledge of the intracellular events which occur in response to serious neuronal injUry. Research in the field of neuroscience, however, is advancing so rapidly that it is becoming increasingly more difficult for the chnician to keep pace with the literature. This is particularly true in the area of cellular and molecular neurobiology. The following paper summarizes our current understanding of the regenerative capacity of the nervous system, with a brief review of the most closely as~ociated neurobiological concepts. While emphasis is placed on the mammalian central nervous system, significant peripher.ll nervous system studies are discussed. Fundamental Principles of Neurobiology Axonal Transport No longer can we depict the neuron ,1S .1 static structure, permitting the conductance of .111 electrical signal along its outer membrane to trigger the release of a chemical transmitter which, in turn, stimulates another neuron. Contrarily, the living nerve cell is a highly dyn,lmic entity which, when viewed by cinemicrography,1 appears like .1 metropolitan expressway, filled with ,lrg,lIlell,H tr,lffic flOWing in both directions, with sl,'w-d,'wns, snarls, and head-on collisions. Tie a ligature around ,1 living ,lxon ,1I1d ,1 swelling appears immediately proximal to the knot. Weiss December 1982 ,lnd his colleagues performed this deceptively simple but revolutionary experiment in 1948." They were the first to demonstrate bulk transport of .lxnplasm, showing that subjstances produced in the neuronal cell body leave it and move steadily along the axon. This led to what has become one of the most intensely pursued areas of neurobiological research, namely axonal or axoplasmic transport. It is now well-documented that materials move in both directions within the axon at varying rates of speed."-" The nerve cell body has the prodigious, mindboggling responsibility of producing most of the substances required by the neuron for growth, normal maintenance, and, if necessary, recovery from injUry and disease. It must manufacture all of the components that form the extensive membranous labyrinth of the nerve cell: axolemma, neurofilaments, neurotubules, endoplasmic reticulum, Golgi apparatus, mitochondria, Iysosomes, and synaptic vesicles. (n addition, the neuron must supply substances vital to the investing elements such as the myelin sheath, and Schwann and glial cells. Materials that move from the cell body towa rd the axon terminals pass in an anterograde or orthograde direction; those returning, in .1 retrograde direction. Slow ,1\011.1/ transport includes the subst.lIlees that move .It the r.lte "f 0.5-5 I11m/d.1Y, while t~l~t ,1XOtJ,1/ tr.lI1sport innlfpor,ltes rn,lteri.lls mlwing .It r,ltes of 200-400 mm/d,lY. III Intermedi.lte tr.1I1sport rates, 10-100 mm/(I.ly, ,llso h.lVe been rep,lrted and undoubtedly investig.)tors will e"p.1I1d the nomenclature to include the terms slow. intermedi.lte. and f.1st r.ltes nf .1Xnn.ll tr.1I1sp'lrt. 1 ' It is nllt fe.lsible, however, tn impl'se too rigid ,1 cl.)ssific.lti,)[l since the r.lte "f .lxnn.ll tr.1I1spllrt i~ dependent uplln .1 number nf v.Hi.lble~ including tempcr.lture, nUIllbl'r "f Cl,lI.1ter,11~, ,llld .1',,'n length. Ie. 'I C,'nsequently, .1 specific ~ub~t,lnce nlllving .It ,lne r.lte in ,1 given .lxon m.1Y nH've .It ,1 different speed in ,mother. I,'nie tr,lIl~port ,Kross the .1 Xl)[l.l I Illembrane enCl'Jllp.l~~(,S.mother pertinent .He.l but will not be diseu~sed in this review. Slow Anterograde Transport. Table 1 summarizes the m.lteri.lls included under the category of 261 I ..\111 I !'>Iuw Anl'·rHl\".,J,· A,,,,,,,I T"dn'I"'" (05-5 Illln/JdyJ ~trll(llIn' Comments /\ Nt·lIlplllblll{·... (23 11111 di.lIl1l'lt·r) H 'l'urtlld,lllH'lll'. (Il) 11111 dl.llllt'lc'rl .• II,·t! 1l1l1 ,,,IIIbll"" ill ,.11 "Ihn «,11, whl're Ihey function d~ ,truclurdJ Jnd motile j·[I'IlWllt .... I1l1l1llrl.11l1 III l('11 pn1u·....... fllrmJtion Jnd elnng.ltion; tubufin I':, ite, mdin prClij'Jll Ikl,,"~: I" 11ll' II1!1'l"I1ll"d',J1" I IJ" "r fddml'nh; thl' IJrgl'r the ",Iibe, of dxon, the III I In' Illllllf'rlIU", till' IH'UfllfdJrnl'nh in relJtion III the number uf neurotubules; "",1.,", Ih,' IlIrld 1'"lvl"'rlidl" (mw 200,000; 145,000; t>8,OOO) I'/f· ...I·"1 In '-1I.IlIY IVfll'.... of f I'll ... Lpl.lled In the periphery of dxuplcJsm next tu the .1\111"111111.1, t 1I111.11I1 ,I( 1111 (1111111' 11111111 !Illlldrl.1 lilt lVI' With ... J,I\V tr.ln"'ptlrt ~ll)1V .1Iltcrl'gr.ldc tr,lll~pllrt. l'rim.lrily, th('y repr('~ l'llt the l'ytll~"ckt.ll elemellts 'If the neurlln .Jnd Me ~lIffilielltly I.uge tll be Vi~u.llized with ckctron- I miuoscllpy technIques (Figs, Ja and lb). Many of thv fildmenh dnd tubules appear to be linked t(lgether by extremely thin "arms," and their trans- 1'I~url·I., Illllrlllllllllrllhf.lplldeplltlllg.J",m,lllll1\'l'11I1.lted l'l..ln(~1'\)Jdl] (' tt t ~ I f J .lInl .I\llll', //\) II 1 L " .l n l) a dSliC e 0 unmye In- "\ .111' ' .. p.II,'k, 'v b.1",1 I.,mll',\(' (Ali ,ll1d "'I1'1l'd'VI' tissue where collagen (e) fibrils .il l 'I" I ''-,I'lll L,t 11\\,11111 ll,lI (~<'II..Vtllpl')"'1ll lllll\p,lctciv \\'r.1I1<'; the unIllvclin,tnd 'X1ns P' t t' , I I ' ' . ," u, , 1Il0CV 0 IC ves,c es l I (.111 Ill' '-."('11 III till' '-,t h\\',11111 ll'lll VtllpLlSlll I.,\t the myelin ltl.'d .1\ lt1 The t' --' '. f . • l.· I~SU(, IS d cross section rom the ,1"I",i1 Illlll·. III .1 ,h""ll'-. I1lPIl"('V (X24,OOOI. . . . . . . F ,/, .. (7 T . , Figure lb. [Ied",n microgr~rh "f <In enl~rged <"C<1 of the myclin~ted <lX'''' in Fig. 1./. deri,ting the m~i,'r component.. ('If ... 1(IW JXllll ..lJ tr.ln"'pllrt. AL = .l'\tllemm.l (.ll~tl rC'fcrrcd tll .IS pIJSm..l!clllm,l l'f rl.bm.1 membrJn('); MT = mihlCh\lndrion; MF = mirrc'lfiI.1Il1ent.s; NF = nl'lIn)fil.1Jnc:nt~; NT = nl't1rlltllblllc~. r"llte the Mml,ke slrudures interconnecting the neurofil~ments.,nd c\tt'nJing fHlm the nellr,'lllbllies (Xtlll,OOO). port has been compared to a cage-like structure, moving as a whole within the axon .1t ,1 slow r,lte of speed.'" Slow transport was responsible for forming the "bulge" in Weiss's ligature experiment. The mechanisms regulating slow trdnsport ,He unknown. Many investigators consider neurotubuIes (microtubules) to playa role, and some hypothesize that, because of the presence of ,lCtin within the microfilaments and myosin within the December 1982 axopl,lsm, ,1 muscle-like nmtr,lctile n1l'ch.mism is involved. ". Fast Anterograde Transport. T,lble 2 SUIl1Il1,lrizes the m.lteri.lls included under the c,ltegory of f.1st ,mterogr,lde tr,mspl'rt .1nd include the m,lcromolecul. 1r building bl'lCks "f membr,lIles, organelles, ,md l1eurotr,1I1smitters. R.ldioactive tracer and two-dimension,11 gel electrophoresis techniques h.1ve en,lbled rese,Hchers to inject labeled amino ,Kids ,1I1d (.ther precursor substances into the vi- 263 1:\1111 2 I a,' Anll'rull"old" Tran'I",,1 (200--100 mm/dayl fv1.h It'llll'['" tll.1I Htlddlll~~ IHIlI k·, til M"lllhr,II11'''' .lIld t\"'lJlllll'.1I1"1l1l11c'," .\ 1'ltlil'1Il-, (, N"1lItl\r.1I1'dllllll'r', .'Jill pn'\ IH<.,llre, II (.I\'tI 1plt 1lc'lll·, II V.".III.··, 1'I"d·. I "0111(" Ilulp, !lPlldn., 11 :\lIl1lln.h Ill.. I ( .dt IIl1n 1 !\:Ih II,tl··oIdt·.... '" R.IlII'II.lllt'lnl prl'l L1r ....t'p.. 1 1 ... t1.l~.11 ... I, Iltlrl.,,'r.llil'·.h lH'r",\,d.,..,,' linitv of the nerve cell body .Jnd to follow their upt,lkl', inn)rpor.ltion intll proteins, .lnd ,>ubsequent tr.lnSpl)rt. I " Anllxi.1 .1I1d oxid.ltive Ilwt.lboIJ( bll)lking .lgents frequelltly h.llt bst tr.lnsport, .1'0 dl) .lgents th.lt disrupt the neurotubule" (e,g., colchicine), but the precise mech.lIlism of f.Jst tr.1I1spl) rt h.1S J1l't been determined. Retrograde Transport. T.lble 3 summJrizes the T11.1teri.lls included under the c.ltegory of retrogrdde tr.1I1spl)rt. Some of these substdnces Jre trdn"ported .It r.ltl'S compJr.lble to f<1st dnterogrdde tr<1nsport; hl)wevl'r, the mdjority l)f mdteridls JrC reported to move (10- 100 mm/day, J rate 50-70% that of fast trJnsport. l ; Mdterials to be degraded Jnd "reprocessed" trJvel from distal regions of the .1xon to the nerve cell body by retrograde transport. ('erh.lps the most significant substances in this type of tr.1I1sport include messengers, both known and reputed, which serve JS feedback vehicles and sign.ll the synthetic machinery within the cell body to produce 5ubst<1nces requi red to meet the specific needs of thl' neuron and its investing structures. One of these messengers is nerve growth factor. Svnaptic Vesicle Turnover Synaptic vesicles (neurotransmitter vehicles) fu~e with the presynaptic membrane, empty their contenh into the synaptic cleft, <1nd then become P.lft of thc membrJne. I' Apparently this procedure is capable of being reversed such that by pinocytosis, small portions of the presynaptic membrane invdginJte, fill with residual neurotransmitter substance in the cleft, dnd then pinch-off to form "new" vesicles. With time, these new vesicles are resecreted or taken up by Iysosomes and transported back to the cl'11 bl)dv for the recycling of mJterials When horseradish peroxidase and other tr.:lcer substJnces are injected into the extracellular sp.:lce. thev Jre taken up bv this means and then trJnsported to the cell bt)dv. I" TABLE ~, Retrograde Axonal Transport (00--100 mm/daYI ~t rUl tu r('/~ub... t~l n((' A I\:"rl)).)1 IntrJ(l'lIul.n C,'mp,'nl'nt, I f'.:l'rv(' ~rll\\"h f~l(h.'r .., Prt.)t('ill~ ~l, l,lvulprlllcin... 4, I'h"'ph,,lipiJ, 5. PlIll1rylutH. \'l· ... ll·I('~ l"l I.Y l) .... ll!l1l· ... 7 In ulin ~ ~llllH' mito(hllndri.l B ~t·un.tr.1I1 ... rnlth·r M.lten.,I ... <. ~JVlllH' .2 (101IlHll.l-.1J1lIIlPbutyn,, .h.ld J (,lul.lI11,lte '-,,"rlllllllill :. A... p.nt.11t' f\ I )llp.ll1l1IW 7 1\4 dvlllHtlilH' IlItl'l IJlIU .....llld 1'1I\1l I\gl'llh I il-IIW" ("'Impl.·" ,Illd IP.... Il'r) 2 I'I d1l11l\\.'t'IIII'" .\ I':'.lhl!'''' 1'.'l.lIltl·, hl'I" , (holl·r.t h."n c, In'll It'tllll'" I) I )YI' I LII ('( l.,lIb·.l.II11t· ... Iltlf·.I'r.ld, ....h p,·1t1\ld.l ...I' .2 1"1111111 -' I V,HI·'. Idlll' 1111Itll",I c·,,1 dVI· ... Journal of Clinical Neuro-ophthalmology Embryonic Neuron.1! De.lth IncongrulHls .15 it m,ly sccm, ccll de.lth is ,IS vit,11 to the norm,11 devcll)pmcnt of the llervlHls systl'lIl .IS is cell prl)lifcr.ltil)(1. MlIst, if 11llt .111, ,lrl'.IS of the centr.ll ,1I1d periphcr.11 Ill'rVlIUS systems, illdudillg the rdill.l, prllducc m.lllV 1l11lrC Ill'UnlllS th.1I1 IlCCess, lrv. Deprlldillg Upl)n tlw rcgillll, .1S m.1I1Y .IS 00% ~)f the nerve cells pr'lduccd f.lil tll m.ll-.l' hllll'til) Il.11 Cl)(1t.let .1I1d subsequentlv dil'.~11 The nH'ch.lnisl11s regul.lting this phenl)(11l'lll)(1 .He Pl)llrly undersh) l)d. Neurllns ,liT th'lught hI Cl)(11pdl' for Sl)l11e betl)r l)r ch.lI'.1Cll'ristic which is provided by their t,lI'~l'ts but which is limitcd ill supplV rl'l,ltivl' tl) the e'mbrv,)nic pllpul.ltil)1l size. Nl'Ur~)(1.11 surViV, ll h.1S been shl)wn tl) depclld UpOIl synaptic inter.lctil)(1 with the t,Hgl't; in the C,lS,' "f the spinal nll)tl)neUwns. the fin.ll number l)f Ileuwns depends UPl)(1 the size l)f its muscle t.lrget.~11 Growth Cones Scientists h..lve been p.uticul.lrly interested in the grl)wing ends of developing dendrites and axl) nS where mech..lnisms regul..lting growth and guid.1l1ce ..Ire focused. Unique structures called growth cones have been found to occupy the tips of these active regions. Electron-microscopy studies reveal th..lt growth cones contain numerous microfilaments, occasional neurotubules, and no neurofilaments.~' After several years of concentrated effort, Pfenninger perfected a density gradient centrifugation technique for the isolation of nerve growth cones from developing neurons.~~He has found that new membrane materials are added directly to the growth cone surface. This is accomplished by rapid axonal transport of preformed vesicles which become inserted into the plasma membrane by exocytosis- like fusion. In contrast, in the adult neuron, new membrane structures (e.g., sodium channels) gradually migrate from the cell body along the proximal plasma membrane to reJch distal portions of the plasma membrane by lateral diffusion.~~ This mechanism is regulated by nerve growth factor, calcium, and calmodulin.~" Nerve Growth Factor In 1948, Bueker reported th.lt mouse S.Hcoma tissue grew rapidly when transpl..lnted into the hind limb area of chick embryos."" Hr obsrrved .111 accompanying increase in the size of the dorsal root ganglia innervating the transplant zone. Thr ganglia were significantly larger (by 33%) than those of the control animals, and had undergone both hyperplasia and hypertrophy. He concluded that this increase in neuronal growth resulted from the enlargement of their periphrral field of innervation. December 1982 Clark H"\.lusl' of .1 long-standing interrst in the growth .llld Jiffl'rl'nti.ltion of the embryonic nervous systl'lll, combined with .1 continued search for agents th,lt might influence these processes, Levi-Montalcini .1I1J her colle.lgues pursued Bueker's findings in the chick embryo. They discovered that the nl'uron.11 growth was not restricted to the dorsal root g.lngli.l but included the sympathetic ganglia which grew to .111 even greater extent."' Furthermore, they obsprved that not only the ganglia illlH'rv.lting the sarcom.l, but .llso those remote from it were affpcted. This led to a conclusion different from Bucker's, namely that the tumor reledsed .1 diffusable dgent into the circulation that enhanced the growth potentialities of sensory and symp.lthetic nerve cells.~"· ",; Shortly thereafter, Levi-Montalcini and her colleagues abandoned the chick embryo model because it failed to provide the most favorable conditions for investigating the chemical nature of the growth agent. They established a tissue culture system that proved to be so successful that a modification of it still serves as the primary biological assay for nerve growth factor. Basically it consisted of incubating fragments of mouse sarcoma with explants of sensory or sympathetic ganglia. Within 24 hours, a dense halo of nerve fibers appeared in the experimental cultures; few new fibers appeared in the controls.~7 Cohen, one of Levi-Montalcini's associates, was responsible for two subsequent major breakthroughs, one fortuitous, the other by design. While attempting to determine whether the growth factor was a nucleoprotein, he treated homogenates of sarcoma tissue with snake venom.~x He was surprised to learn that the venom alone had a more pronounced effect on the growth of sympathetic ganglia than the sarcoma tissue. This finding of two nerve growth factors from such disparate biological sources as mouse sarcoma tissue and snake venom, raised the strong possibility that still other sources might exist. Cohen reasl)(1ed that since snake venom is manut.1ctured in a modified saliV. lry gland, .1l1d a growth ,1gent is present in mouse sarcon1<l tissue, it might be worthwhile testing the mouse s.lliv.lry glands as .1 possible source.~'-' His assumption was correct, but inexplic.lbly the nerve growth factor was detected only in the .ldult male mouse subm.lxillary gland~" where it is synthesized in the convoluted tubules under the control of 'Ill testosterone.' More recently, the f.lCtor h.ls been identified in the prostate gl.1I1ds and seminal vesicles of the guinea pig, rabbit, sheep, gO.lt. .1I1d bull.:!'·:!~ While the factor is present in the subm.lxillary gland of the m.lle mouse, it is not found in any other organ of that animal. The guine..l pig, r.lbbit, and bull cont.lin the factor in the prostate gland but lack it in their salivary gl.lnds. The prostate glands of the rat, mouse, hamster, and human contain none of 265 the Llcltl", The re,lson..; ior "uch v,lri,ltions ,lr{' UnklllIWn,"" Nt'rve growth LIdoI' h,IS been isol.lted ,1Ild studied e\lPnsivl'ly u"ing dis"oci,lteJ dors,d root ,1IlJ "Ylllp,lllwtil g,lIlgli,1 grown in li"sue ndture ,IS hitllogiLll ,1SS,lY", It is ,1 peptidl' hOrllllll11', structur, Illy ITI,llPd 10 insulin, whid1 slilllul.ltes lhe growth "nd Ill,lint,lin" the vi.lhilily of "Ylllp,llhdic neuron" h,'th if) l'il'(I ,1Ild if) I'itn',," It' ,11,,0 "tiIllUl.ltl'S the elllbrYtlnic growlh oi cert.lin "ensury neurun".'lC, The ,ldlllinistr.ltiun ui nnve growth f.Jctur-.lIlliserUIll III nelYbllrll ,1Ililll.ll" c,ll,,,e,, Je"trullion of SYIll p,ltiwi ic ,1I1d s{'nsury g'lngl i,I.~" Speci fic r{'cepI" l'S .Ire present flll' the f.Jdor on the nll'mbr,lne surLlt'e tli pnipheral ,ldr{'nergic ,lnJ s{'nsory neuHillS," The growth f.lctor travels by retrogr,lde Ir,msp,'rt tll influence the n{'rve cell b"dy ,lnd it h,1S ,1 direct .lffecl on the growth cones oi dev{'ltlping ,D~ons""',,IIi Most recently, it h.1S been shown tll r{'gulate the slldium, potJsium-pump perform,1I1ce in .111 Llf its t.lrget cells, and pump performance is {'ssenti,ll for the surviv,ll of n{'rve growth f.Jctorsupport{' d neurons."~ Most of our knowledge regMding the nerv{' growth bctllr rel,ltes to its ph.lrm,lcologic effects experiment,llly ,1nd lillie is known of its .lctual physiologic role. Its function in venom, salivaf\', ,1nd prostr,lIe glands is unknown. 1.1 Indirect ev'idence suggests th,lI effector organs innervated by certain sympathetic and sensory neurons produc~ low levels of the nerve growth factor, and th,lt it is this endogenous growth factor that is responsible for affecting differenti,ltion and surviv.ll of tJrget neurons,I" Regardless of many unresolved questions, today, nerve growth factor serves as the prototyp{' model in the se,Hch for, ,lnd investig,ltion of, other neuronotrophic factors and h,lS become a powerful tool in today's neurllbill!llgic,lI rese,Hch. Central Nervous System Regeneration N{'urons in the .ldult m.lnlm,lli,lIl c{'ntr,ll nervous system .Ire irr{'pl,lt'eable, the CllSt "i eVtlluti,'n,lrv speciJliz,ltion. Tr,lnsection oi ,1'wns in btlth th~' centr,ll and pniphl'r.ll lll'rvlIUS systems /c,lds 1" tot,ll destructi,'n lli the dist,ll seg~lent (W,1Ikri.1I1 degeneration), while the proxim,11 StUlllp ,lnd nerve cdl b"dy undergll ch,lnges ,1SStlCi,lted with pr"tein "ynthe"i", regnlwth, ,ml! rep.li ... M,my regener,lting ,lxun" in the peripher'll IWrv,IUS system est,lblish funcliun.ll svn.lpSl'S; nHlsl .IXtlnS' in the LTntr.ll nervuus system dtl Illll. The progllllsis in sl'ri"us br,lin .lnJ spin,ll l'llrJ injuries is irequentlv 1'",,1' bec,lu"l' uf this, A nUl11lll'r uf re,lsunS h.1\'e been suggeslPd tIl expl,lin why u'ntr.lllll'rv,'us systel11 ,lx,lns ,1btlrt in their .llll'l11pl to cUlllplele the ~l'gl'nl'r.l1ivl' proCl'SS. TIll' nw"l prev.llenl of thesl' include: I) ddiciencY in guiding p.lthw.lys, 2) lllech.1I1ic,11 block resulting from glial SCM formation, 3) lack of trophiC factors r{'quired to stimulate the growing sprouts, and 4) inlrinsic genetic structure is programmed to predude extensive regrowth. Repeated efforts to enh, lIKe regeneration by treatment with growth faclors, anli-inflammatory drugs, surgical removal of SCM tissue, and the installation of various "guide" devices, h,lVe met with limited success. 1'a.,t regeneration efforts frequently focused on he.lVily myelinated pathways, particularly the corticospinal ,1Ild posterior column tracts (i.e., fasciculi gr,lcilis and cuneatus) of the spinal cord, Frustrated in most of these attempts, investigators began to ,1"k different questions and examine other systems. Thei I' efforts h,lVe resulted in the discovery that cert,lin ,lxonal pathways within the central nervous sy"tem have the cap.:ICity for axonal regeneration and restoration of synapses. Considerable data is now available regarding the aXllnal response to injury and the relationship of termmal sprOUls to growth cones. Trophic influences are better understood and the principle of call,lter,ll sprouting is well established, One of the most e'>,citing findings is that certJin catecholaminergic pathw.1Vs ,1ppeJr to be cap,lble of functional regeneration Nerve Cell Response to A\on Tr,msection Most of ,1ur knowledge regarding the neuronal response to axonJI transecti,1n hJS been obtained from peripheral nervous system and tissue culture studies. The bJsic principles, however. applv to nerv\' cells of the central nervous system, ex~ept tor their interrel.ltionships with the investing elements. CIi,ll cells surmund neurons in the central nerYLIUS system. whereas SchwJnn cells. basallamin, le, ClIII,lgen, ,1Ild c,'nnective tissue sheaths (epineurium. perineurium, ,md endoneurium) provide the investing milieu in the peripheral nervous SYS-tem. . Retrograde Messengers. Immedi,ltely following tr,lIlSectl'lIl. mLI)ecul.n signJls .He presumed to tr.1\'el retr'1gr,ldeIY t,1 the cell bLldv to set the synthetIC lll,lChinery in nllltion. These messengers are p""rlY underst""d. S"me m,lV ,Hise from the injured il1\'esting tissues ,1Ild/,'r the disl.!1 degener,1tlng .1x,ln. Nerve Cell Body Reaction. Following axotomv, Ihe nerve cell b"dY undergoes ., series of chang~s c1,ISSIC,lIIY rdefred t" ,IS chrom,lIolvsis, a term that lill'r~l."Y me,lI~.s the dissolution or d'isappearance of the Cllklred subst,lnce, the Nissl bodies, Basophilic str.lining fl've,lls th.'! the nucleus becomes l'ccentnc,llly !l'c,lted ,1Ild the center of the cell bod beCllmes p,lle with ,1 rim of Nissl substance re~ m.lInlllg ,It the periphef\!, Nissl bodies consist ~f aggregates of ribosomaII. ldened, rough endoplasmic reticulum interspersed with still more ribosomes in the form of Journal of Clinical Neuro-ophthalmology free polysl'Ilws. Collectively thC'y co 111 prise the RNA-enriched (('IllpOnent vit,ll tl) the cell's synthetic ,1pp,H,ltUS. Tl)d,lv we kl1lIW th,lt Nissl bodies do (wt ,lctu,llly dis,lppe.ll' in the cell bllLiy re,ldion; instead, hl)wever, they be(()nH' sWllllen ,1I1d 1110re dispersed, ,llld tlwrdl'l'e nlllre diHintit tll st,lin with routine techniques. During dlWI11,ltlllysis, the Nissl Ill,lteri,ll ,lctively p,lrticip,llcs in pwducing the prl)ducts l)f ,lllterl)gr,lde tr,1I1sportth,lt ,liT SUI11moned for rep,lir ,llld regener,ltil'Il. The ('(,II body beCl)IlleS engl)rged with newly synthesized l11in(lfilaIllents, neurlltubull's, neuwfil,ln1l'nts, ,1I1d Iy5t" lSl1111f'S. Axonal Reaction at Injury Site. FolIl)wing severe d,1Il1,lge, there is ,1 reductilln in ,1XlHl,11 di,lIlleter directly prl)pl)rtil'Il,ll tl) ,1 dene,lse in the neuwfil, lments. This shrink'lge is 11l)t restricted to the zone l)f tr,lUIll,l but extends seYer,ll nlld,ll segIllents to\\'. ud the cell bl)dy. '" Neuwfil.llllent loss is maxinul ,lt 2 weeks pl)st-tr,lllm,l. During this time, slow ,mtewgr,lde tr,lllsport p['(wides micwfilaments ,llld micwtubules necessary fl)r the regenerative outgwwth of the proximal stump. Neurofilament production ensues and the axon caliber increases.:IH Shortly ,ltler transection, terminal sprouts arise from the proximal stump. The sprouts are tipped with growth cones containing numerous microfilaments enmeshed within filopodia that actively reach out in all directions, but extend almost selectiYely in the direction of the preexisting fibers which have undergone Wallerian degeneration.~1 Schwann cells proliferate and subsequently participate in generating basal laminae, myelin, and connective tissue sheaths. These elements are thought to provide signals that direct the growing sprouts,~l The growth cones may facilitate in this process by secreting enzymes that assist in "clearing" the way.~l Local presynthesized "pools" of proteins are thought by some to provide the initial membrane building blocks."1 As the growth cone membrane elongates, new membrane material is supplied by rapid anterograde transporl."~ Trophic Influences and Transplantation Studies In the central nervous system, noradrenergic neurons have been the only axons demonstrated to respond to nerve growth factor.'" ThC're is strong evidence, however, that other subst,lllcC's, possibly similar to nerve growth factor, function to stimulate growth in the central nervous system.'" There have been numerous successful rC'generation studies involving the transplantation of V,Hious portions of fetal neural tissuC' from their normal region to other areas of the centr,ll nervous system."~ Recently, trophic intC'ractions h,lVe been examined while small portions of centr,ll nC'rvous system tissues were grown in the ,lllterior chamber of the eye. lO The transplants in most of these December 1982 Clark experil11enh survived ,llld made synaptic connections. Il11pl,lI1t,ltion experiments have demonstrated th,lt foreign tissues exert a trophic affect on regener, lting ,lxons. When ,1 portion of the iris is transpl'lI1lcd into the centr,ll nervous system, lesioned ,ldrenergil ,Ixons grow preferentially to it.'~' Transpl. lllh th,lt cont,lin Schw,llln cells and other peripher, 11 nervous system components result in a 111,lrKl'd elong,ltion of central nervous system axons, some growing longer than their normal length . . II III VIVO. RcgcncrMion of Synapscs and Col/Mcral Sprouting It is now clear that regenerating neurons in the central nervous system are capable of forming synapses. Sprouting axons form multiple synapses on almost any neighboring nerve cell body or axon in the immediate vicinity, proximal to the lesion.'~ They even form abortive synapses upon local blood vessels. It is thought that such aberrant synaptic formation may contribute to the failure of further axonal growth.~" In other words, perhaps each neuron is preprogrammed with respect to the total number of synapses it can make. Thus, following trauma, the regenerating axon would make random synapses on local structures and once reaching its quota, cease the growth process, never having a chance of reaching its distant, functional target. Collateral sprouting is a phenomenon now accepted as a fundamental principle in nervous system regeneration, To explain this, imagine two afferent systems (A + B), projecting to a given nuclear group. If the axons in tract"A" are transected, the intact axons of tract "B" will generate preterminal collateral sprouts that form synapses on the neighboring neuronal cell bodies which have lost their afferent input. In the same ex,lmple, if tract "A" had been partially severed, the rem,lining intact ,lxons of th,lt same system would ,llso generate coll'lteral sprouts. De,lfferentiatil)n studies such ,1S these h,lVe reve,lled that many ,He,lS of the nervous system arc c'lpable of undergoing synaptic restitution by the form,ltion of (()II,lte 1',1 I sprouts.:n , Areas in 'which coll,lteral sprouting h,lS been induced include the hippoc,lmpus, !.lter,ll geniculate body, olbctory tubercle, red nucleus. sept, ll nuclei, spin,ll cord, superil)r Cl)lliculus, ,llld ventr,ll posteril)f th,ll.ll11ic nucll',H Cl)Illp!ex. When ,1 nucle,lr gwup in the nC'rvous system parti,llly loses its input, loc,ll he'llthy ,,,ons ~prout coll,lter,lls ,1I1d inv,lde the denerv,lted region. The mechanisms evoking ,llld regu!.lting this growth arc unknown. The ability of int,Kt axons to expand their termin,ll fields in response to the death of others, underscores the central nervous system's potenti,ll for remodeling. 267 True A \olla! !xegc/7cr,ltio/7 Rl'n'nt studies indic,ltl' th,lt cert,lin sm,llicaliber ,lxon,ll systems ,lfe C,lp,lble of undergoing true rl'gl'nl'r,ltion in the sense of growing b,lck ,md svn,lpsing up\ln their origin,ll t,lfgl'ls ,lftl'r chl'mic,ll ,1xotomv.:I!1 In the r,ll, tur l'X,llllpll', both the serot\ lninl'rgic ,lIld nor,ldrenergic projections from the br,lin skill t\1 the spin,ll cord will regenl'r,lte, with gO\ld restitution in the cervic,ll region ,1Ild p,lrti,ll rl'innl'rV,ltion in the th\lf,leic ,md lumb,lf ,In'as. The strudur,ll ,Ind fundion,ll signific,mn' of the regenl'r, ltl'd tl'rmin,lls, however, is uncledf. The authors cite Indired evidence and suggest th,lt such axonal rl'gener,ltion results in functi\lIlal recovery. \'. Post-Trauma Therapy Severe tr,wm,l to the central nervous system frelluently induces hypoxic edem,l and hemorrh, lgic necrosis leading to irreversible damage. Minimizing these changes has been the focus of extensive experimentation. Recently the study of endorphins has ,lttracted considerable attention. Endorphins are endogen\ lus morphine-like substances that can be activ, lted by various intrinsic neuronal pathways or by the systemic administration of morphine. ' \ They mimic the pharmacologic actions of opiates and, thus, relieve pain. Following trauma, endorphins are released and thought to cause a decrease in local blood flow. II Attempts have been made to reduce this effect by the experimental administration of naloxone, an opiate antagonist, during the first few hours following spinal cord trauma in the cat. II The addition of naloxone significantly improved the neurologic outcome in these experiments. Unfortunately naloxone blocks the an,llgesic effects of endorphins and its administr,ltion could increase post-traumatic pain." To l)bviate this undesirable side effect, another series of experiments was carried out with thyrotropin-releasing hormone, a partial opiate ,1I1togonist th,lt sp,Hes the analgesic system. It was found th,lt thvrotwpinreleasing hormone was even more effective than naloxone in improving the neurologic \lutcome. II Signific,lIltly, corticosteroid treatment W,lS l)f n\l benefit in these studies. Some investigat\lrs suggest th,lt hypoxia ,llone is insufficient to ,le\'ount tot,llly f\lr post-tr,wm,ltic necrosis ,1Ild propose th,lt free r,ldic,ll form,ltion ,wgments the severity \If the conditi\lI1. I :' Frce r,ldic, lls ,He molecules or ,ltoms with ,m unp,lired electron ,1Ild C,lIl re,ld in ,m ,ldverse f.lshil1l1 with nH'mbr,lne lipids. I" Tr,wm,l m,lY induce ,1 prim,lrv defed in the neuron,ll pl,lsm,l nll'mbr,lIlc m,lking it vulrH'r,lble to free r,ldic,ll ,1tt,lCk. ,:, Subst,lnces rl'le,lsl'd from the blo\ld h11l\lwing tr,lUIll,l, such as iron, 1ll,1V \ontribuk to the form,ltion of free r,ldi\ ,lis. ", It' h,ls been delllonstr,lted experinwnt,llly th,lt [('C 'I~ \ ,111 LlllSl' signific,mt necrosis in the spinal cord and that free radical scavengers (alp~a-h .. 4., It tocopheral and selenium) reduce suc lIlJUry. . is also thought that the protective effects of barbiturates on the development of hypoxia edema are related to their protective action against free radical formation. I; Following severe trauma to the central nervous system, such as a stroke, there is often remarkable recovery of function. Obviously much of the early recoverY can be attributed to the reduction of edema and the phagocytosis of extravasated erythrocytes and other cellular debris, which collectively remove the compromising influences on neurons. However these factors can hardly explain the later recovery that so often occurs (see Brodal's'x review of thIS topic). Many investigators feel that neuronal remodeling must occur in order to fully explain this phenomenon. I" Collateral sprouting might account for some of the neuronal restructuring that occurs after trauma, but factors other than morphological alterations are also thought to playa role. For instance, it is thought that previouslv suppressed pathways become "unmasked" as a consequence of trauma and beglll to function. ", Some drugs may aid in producing "unmasking."'" Finallv, the importance of physical therapy, training: and psychological conditioning after severe trauma can not be overemphasized. Though poorly understood, it is thought that any experience involving learning necessitates at least some restructuring of neuronal circuitry." As Brodal points out, "the improvement that occurs after lesions of the nervous system is in essence a learning process, albeit in a d~fective nervous system."'x Discussion Peripher,ll nerves not only regenerate but also establish functional connections. Similar success h,lS nl)t been ,lchieved in the mammalian central nervous system. Optic nerve axons in fish and ,lmphibians regener,lte following crush injury and gww b,lck precisely to their original target c~lIs in the optic tectum Optic neurons do not regenerate in m,lmm,lls. Scientists ,lre often perplexed by such bioiL1gic,11 disp,Hities among vertebrates. We are still w,liting fl)r the major breakthrough th,lt will en,lble the paraplegic to walk or the p,ltient with l)ptiC nerve ,ltrophy to see, but the picture is nl)t cl)mpletely dismal. The evidence indic,ltes th,lt centr,ll axo~s c,m readily form new syn,lpses. Moreover, when peripheral' nerve segments are transplanted as conduits, central axons C,1I1 regener,lte for considerable distances. Signific, lIltly, when ,1 nuclear group loses some of its afferents, a signal is generated that tells neighboring, int,lct ,lXons to sprout collaterals to innervate the deafferented neurons. Finally, certain unmyelinated and lightly myelinated axonal systems in Journal of Clinical Neuro-ophthalmology the mamm,llian central nervous system c,m regenerate, apparently over consider,lble dist,mces, ,1nd establish syn,lptic restitution with origin,ll t,uget cells. Enormous efforts h,lVe been expended in ,1ttempting to ,1scert,lin the 111,1 X il11,l I potential h,r function,ll regener,ltion in the 111,11ll1ll,1Ii,1I1 cel1tr,ll nervous systelll. Much h,lS beel1 1e.Hl1ed, p.Hticul. uly in the p,lSt few ye.HS, reg.Hdil1g the b,lsil" neuwbiologic,ll principles invl)lved. Very little ,1S of mnv, 1ll1weyer, C,ll1 be ,1pplied tll the hum,1I1 conditiol1 tl) enh,lIKe the regener,ltion of severed .lxons. In the n1l',1I1time, signific.1I1t progress is being ,Khieyed in rese.Hch effl)rts desigl1ed to effect pl)st-tr,1l11ll,ltie, ther,lpeutic regimes that Illinimize ,1Xl)n,11 de,lth, while scientists gr,lpple with the mysteries l)f the l1ervous system. References 1. Fllrm,111 , OS, radjen, A.L and Siggins, G.R.: Axon. 11 transport of org,1I1elles visualized by light microSCOPy: Cinemicrogr,lphic and computer analysis. Br.lin Res. 136: 10 7-213, 1077. "I \·Veiss, P., and Hiscoe, H.B.: Experiments on the mechanism of nerve growth. I Exp. Zool. 107: 3153° 5,1 048. 3 Grafstein, B.: Transport of protein by goldfish optic nerve fibers. Science 157: 106-198, 1967. 4 Oroz, B., and Leblond, c.P.: Migration of proteins along the axons of the sciatic nerve. Science 137: 1047-1048, 1%2. 5. LaVail, J.H., and La Vail, M.M.: Retrograde axonal transport in the central nervous system. Science 176: 1416-1417, 1072. 6. Ochs, S.: Characteristics and a model for fast axoplasmic transport in nerve. I Neurobiol. 2: 331-345, 19n 7. Grafstein, B., and Forman, OS: Intracellular transport in neurons. Physiol. Rev. 60: 1167-1283, 1980. 8. Schwartz, j.H.: The transport of substances in nerve cells. Sci. Am. 242: 152- 171, 1980 9. Lasek, R.J., and Hoffman, P.N.: The neuronal cytoskeleton axonal transport and axonal growth. In Cell Motility, Vol. 3, R. Goldman, T. Pollard, and I. Rosenbaum, Eds. Cold Spring Harbor Conference Cell Proliferation, 1976, pp. 1021-1049. 10. Wilson, O.L, and Stone, G.c.: Axoplasmic transport of proteins. Ann. Rev. Biophys. Bioeng 8: 27-45, 1979. II. Willard, M : The identification of two intra-,lXon,llly transported polypeptides resembling myosin in some respects in the rabbit visu,ll system. I Cell BioI. 75: I-II, 1977. 12. Gross, G. W., and Beidler, LM.: A 4uantitative ,111,11ysis of isotope concentration profiles and r,lpid transport velocities in the C-fibers of the garfish olfactory nerve. I Neurobio/. 6: 213-232, 1075. 13. Murray, M.: Axonal transport in the asymmetic optic axons of flatfish. Exp. Ncurol. 42: (036-646, 1°74. 14. Hoffman, r.N., and Lasek, R.I.: The slow component of axonal transport. Identification of major structural December 1982 Clark polypeptides of the axon and their generality among m,lmm,lli,m neurons. I Cell Bioi. 66: 351-366, 1975. 15. [{oisell, r., Inczedy-Marcek, M., Hsu, L, and Yorke, W.: Myosin: Immunofluorescent localization in neufllll, ll ,11ld gli,ll cultures. Science 199: 1445- J448, 107/\ I(). L'lsek, [{,t.: Bidin'ctional transport of radioactively 1,1belleJ ,1xopl,lsmil u)mponents. Ndture London 21b: 1212-1214, 1967. 17. BI'llk, M.M., ,mJ Lasek, R.J.: Slow components of ,lXl"1.11 tr,msport: Two cytoskeletal networks. I Cell Hiol. 86: 6/6-623, 1080. 18. Heuser, 1.[., ,1I1J Reese, T5.: Evidel1le for recycling of Syll,lptil vesicle membrane during transmitter release ,1t the ffllg neufllmuscular Junction. I Cell BioI. 57: 3/5-344, 1973. 10. L1Vail, JH, and LaVail, M.M.: Retrograde axonal tr,1I1sport in the central nervous system. Science 176: /416-14/7,1972. 20. Oppenheim, R.W .. Regulation of the naturally occurring death of spinal cord motoneurons in the chick embryo. Presented at the Sixth Conference Regeneration Central Nervous System, Miami, Florida, May 1982. (Sponsored by the National Spinal Cord Injury Association) 21. Carbonetto, S.T., and Muller, K.J.: Nerve fiber growth and the cellular response to axotomy. Cur. Tops. Devel. Bioi. (In press.) 22. Pfenninger, K.H.: Plasmalemmal components of the growing axon: Insertion and growth-related control mechanism. Presented at the Sixth Conference Regeneration Central Nervous System, Miami, Florida, May 1982. (Sponsored by the National Spinal Cord Injury Association.) 23. Bueker, ED.: Implantation of tumors in the hind limb of the embryonic chick and developmental response of the lumbosacral nervous system. Andt. Rec. 102: 369-390, 1948. 24. Levi-Montalcini, R., and Hamburger, V: Selective growth-stimulation effects of mouse sarcoma on the sensory and sympathetic nervous sYstem of the chick embryo. I Exp. Zool. 116: 321-362, 1051. 25. Leyi-Montalcini, R., and Hamburger, V.: A diffusible agent of mouse sarcoma producing hyperplasia of sympathetic gangli,l and hyperneurotization of viscera in the chick embryo. I. Exp. Zool. 123: 233-278. 1053 2(0. Levi-Mont,llcini, R., Mever, H., ,md H.1mburger, V.: III vitro experiments llll the effects of mouse S.HCOm, lS 180 and 37 on the spin.11 ,1I1d symp.1thetic g,mglia of the chick embryo ClIlcer Re". 14: 40-57, 1054. 27. Levi-Mont,llcini, R., and Angeletti, r.lI.: Essential role of the nerve growth bctor on the surviv,ll and mainten.1nce of dissoci,lted sensorv .11ld symp.1thetic embryonic nerve cells in I'itn). [leI' Bit)! 7: l)53-l,50 , 10()3. 2/\. Cohen, S.: I'urific.ltion ,1I1d ml't,lbolic effects of .1 nerve growth-pfllmoting protein fwm sn.1\..e venom. /. Bio! Chem. 234: I 12Q- I 137, 1°50. 20. Cohen, S.: Purific.1tion of ,1 nerve-growth proml1ting protl'in from the n1lluse s,lliv,lry gl.1I1d and its neurocytotoxic ,mtiserum. I'roc. N.ltl. Ac.ld. Sci. USA 46:302-3/1, lObO, 30. Chretien, M.: Action of testosterone on the differentiation ,md secretory ,1ctivity of d target-organ: 269 (Nc, Rl'g"Ill'r,ltioll rill' sllbm,l,i1I.11"Y gl'lIld of till' mOll"'. Inl. Rcl'. (\'II'! 50: 333-3Ll", ILl77 3', H.lrpl'r, ( .. I'" B,Hdl', YA" BlIrnsto, k, (L, ( .1I"st.lIrs, 1,le 1)l'lllli""1, M.L, C,lId,l, K" ,lIld VI'r1H1Il, (.A (.lIIIH',l pig pl'l"t,ltl' " ,1 ri,h ",un I' of IH'rv,' g ....wth t.ll tor N,IIIIIl' t"/ll/"n 279: 1,,0- ',,2, ILl7ll 32, I Llrpl'r, ( •.1'., .1I1d Tho"IlI'Il, H,: TIll' distributioll of Ill'rvl' gl'll\vth t.ll tor ill thl' m.d,' "" org,1I1s of m,lmIll. lk /. 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I'resented o1t the Si,th Cunference RegenerJtion Cl'ntr.d Nervous System, M',lm" Flurid'l, M,ly 1982, (Spunsured bY' the N,ltion.ll Spin,ll Curd "lJury Assuci,ltion) . 38. Huffm,lIl, r.N .. A,,)[1,1 I tr.IIlSpllrt of cytoskeleto1l pruteins In growth ,lIld regener'ltion, Presented dt the Si,th Conference Regener,ltion Centro1l Nervous System, MiJmi, Flurido1, MolY, 1982, (Sp,)nsured by the No1tion,ll Spin,ll C"rd Injurv Associo1tion I ' 3q BJorklund, A" o1nd Stenevi, 'U,: RegenerJtion of munoJmlnergic o1nd cholinergic neumns In the mdmmo1lidn centr,ll nervous system, Phl'sll,t Rei' 59: ,,2-100, 1979. . . 40 Hoffer, B,I.: Studies on brJin Jnd spino1l cord gr,lfts in silu ,lIld in (lcule,. Presented ,1t the Si,th Cl>nference Regenero1tion CentrJI Nervous System, Mio1mi, Florido1, MolY, 1982. (Spons,)red by the N,ltil>ndl Spin,ll Cord Injurv ASSOCI,ltil)Jl) , 41, AgUo1yO, A,: A potenti'll for ,"on,ll regener,ltion in the o1dult mo1mmo1h,1Il CNS, Presented ,1t thl' Si,th Conference Regener,ltil\ll Centro1l Nervous System, Mi,lmi, FI"rid,l, M,l\', 1<.)82. (Sp,)nsored by the :'oJ,1- tiun,ll Spin,ll C"rd Inlury ASSUCI,1tion.) . 42, Bernstein, j.J" dnd Bernstein, ME: Axono1l regenero1tiun dnd formdtion of syndpses proximo1l to the site of Il'sion fullowing hemisection of the rdt spindl lllrd, Exp. Neuro/. 30: 336-351, 1971 43 Simon, E,J" dnd Hiller, j.M,: The upiJte receptors, Ann Re\', Pholrmolco/' Toxicc'/. 18: 371-394, 1978, 44, F,lden, A,I.: TRH dnd ndloxone tredtment in experin1<' nt,ll spino1l cord injury, Presented dt the Sixth ( "nference Regenerdtion Centrdl Nervous System, Mio1mi, Flundd MolY, MolY, 1982, (Sponsored by the No1ti"n,ll Spindl Cord InJUry Associdtion,) 45 Meo1ns, [D, Jnd Anderson, D.K.. Free rddical scaYengers In Mute splndl curd injury, Presented at the Sixth C"nference Regeneratiun Central Nervous System, M',lml, FlundJ MolY, 1982, (Sponsored by the :\,ltlllno1l SplnJI Cord Injury Association.) 4t> MI' h,1('lson, M, McCord, JM" and Fridovich, L, (I.ds) 5upenl\lde oInd 5upero\ide Dismutdses, Aco1demlc Press :\elV York, 19 77. 47 Fldmm, L5, Demupoulos, HB" Seligman, M,L, Poser, RC, Jnd Rdnsohoff, j.: Free radicals in cerebrJllschemlJ 5lro/..e 9: 445-447, 1978, 48 Brodo1!. A.: ,\'euroloKic,11 An,llomv In Reloltion 10 Clin/lal MediCine O,furd Cniversity Press, New Y"rk, 1081 40 Wo1l!. PD. Mecho1nlsms l,t pldstlClty l)f cunnection fldl"lVlng do1mJge In Jdult mJmmJliJn nervous system. In: Re'''I'en' "f FUIlclllln. Theorelicoll Considerallll/ l'o f'lf BUill In/un' Reh,lbllil,ltlon, P. Bach-y- Rlto1, Ed Huber, Bern, \080, rr 91-105, ' Acknowledgments ThE' o1uth,)r is Indebted tl) JUo1nd AlvarE'z for her E'Xcellent tE'ChnlCo1l o1sSlsto1nCE'. ,md tl' Dr. Marion Gaide for E"rE'nding cl)nslderolblE' time o1nd effort III rE'viewing the m,1I1uscnpt. ThiS wl)rk W,lS surpl'rted In rolrt bv thE' :'o.JJtional Institutes l)t He,llth Cr,mL GM 20227 . :\~~l)(I.1tl' rrtltc-..... \.\r, l'ep.lrtn1cnt ("If :\n.lh.lmv Jnd Cell Bioll)~\', L'nl\'cr";lt\" ",t ~11,lml S(h()l'[ t,f ~1edl(lne. ~1l.lmi. Florida. I \'nle Il'r rcpnnls Il), RC)J1Jld G. CIM"- Ph,D" DepartmE'nt l)t An,1tl>nW ,1I1d CE'II Blolc'gv, LnivE'rsitv of Miami Schl)l)1 l)t ~ lE'd,cll1e, (R-1241, PLio Bo' 01()9~O, Miami, Fll'nd,l 33101 Journal of Clinical Neuro-ophthalmology |
