Lathyrism in Rabbits 717

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1962;44:717-729.J Bone Joint Surg Am.Elizabeth J. Bottcher Lathyrism in Rabbits

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La thy rism in R abb itsB Y EL IZA BETh J. BO TT UIIE R , M .D ., ROCHE STE R , N EW YORK

/l ,o,,l th e 1)epar tmen l o f Pa tho log y , I?oehe stcr G en era l H o sp ita l , I? och .e .sle r

Remnarkab le eliaum ges im i the c ( inm m ec tive tissue , im m clu d im m g bom ie am id ca rtilag eas m ve l 1 as aort ti , h av e b eem m prod u ced exp e ri m ne rm t.a lly b y th e la t.h y rogeu iic age iits .T h is su ggests tha t m im am iy d iseases affee tim ig the iu iterce lltila r g rouu id subs tan cem na l)e re la ted ali( i i)r im igs a Of l if l i ( i1 i physio lo g ic process t.(i such seem im ig ly d ive rseem it it ies 5 m im use le w eakness, ex ostoses, n iyo sitis o ss ificaum s, slip ped ep ip hyses ,os teo poro sis, pa ra ly sis, a .m m d d issecting a.m m etm rysm of the ao rta h O.h 1 ,I2 ,Is ,1 9# {1 49 }Th e re -seuf l l) l t t lmce l )e t .ween la thy ri&nm and M arfaum s syn dronm e (a h ered ita ry m etabo lict lefect . ) ttli(l im ifam it.ile co rtica l Im ype rostos is (C affey s d isea se ) is especia lly im o te-w orthy . E xp er im en ta l an im als h ave b eem i fed o r ium jected w ith th e la thy riticagen ts by th e hum m d reds. A ltho ugh m am iy of the legum inoseae com ita in th ese agen ts ,tim e m im ost. ac tive is La th ru s o dora lus ( t ime c ommo n sw eet p ea) from w hich be ta-aun im m op ropu iom nt.rik , an ac tiv e prim ic ip le , has beem m ol)ta ined . O the r subst.am mcesm i tF i a sinm ila r pm opensit.y fo r d istu rb im m g tim e groum id substan ce o f tissue h av e alsol ieeim enuuuera t .e ( i 3,9,12#{149}

\Vh i le th e m iia jo r ity o f tim e w o rk wa s dom m e om i ra ts , the effec t on am ph ib ians( espec ia lly th e tadp o le ), m ice , u im onkeys , fom v l, gu im iea p igs , ca ttle , h o rses , p ig s,ai i t l canm els w as a lso stu d ied um ,u4 (1om m sid eraiile variatiom i w as fou nd , p a rtly due tothe use o f tlif fe iem m t spec ies o f L a thy rus am id a rt.ly ( lim e to a va ria tion im m reac tionby (1 i f feue i 1 t U I 1 1 n ia ls . T h e m vom d s in u ro lu .th /jris nl an d os l(o la th yrisn i w ere c iii mm cd tod iffeuem m tia t.e tim e two nnm iim fo ruim s of the d isease I ii m im ttm i, om ily m ie tm ro la thy risrnhm ts been dese rii)ed du rim m g t inmes o f fan iim ie m i-h en th e L at.hy ru s pea is used fo rfood , pu-imiiau i ly in Imid ia Ui O st.eo lathy rism n h as beem m seem i on ly iii ex p e r i nmem i t a lam m inm als, bu t it has m um m y of tim e typ ica l ch aracte r is tics seem m im m n iam iy ske le tal( l is e as es ( . )fu n am i uu

T im e l)t tm i)05 e (if t hi s i miv es ti ga t. io ii \Vf ls to study th e e ffec t o f ex pe rim em m ta lla t imyr isun Oh tim e vascu la r syst.em m m am id O theP coumnect .ive tis sues of ra l)b its . T im eske le ta l chaum ges lrod uced w ere so dram a tic tha t a dese rip t.iom m seeu ns ind ica tedin orde r to try to d ifferen tia te tox ic d rug e ffec ts , sp ecie s d iffereum ces, an d 1)asicmeta l )ohc d efects p ro duced in la thy risrn . R ab l)its have b ee um u se d e xpe rim em ita llym uch le ss o ftem m than ra ts . T h e w ho le seed o f v a riou s L atim yrus spec ie s ex cep t fo r(ido rttt.u s m vas fed to ra l)b its b y S to ck nnam i in 1917 , w ith no e ffect., a lthou gh alk alo idde riva tive s p rod uced sign s sug gestive o f m m euro lath y risnn m4 ,O 3 Se lye desc ribedumeurolat imyr isn i prod uced b y 1)et.a , l)e ta -i m im m odip rop riom m itr ile am id osteo la t.hy rismp ro du ee (l l iy a ui um io ac et .o mn ti -i le i im r al )i )i t. su m# {1 49 }

MATI I (IAL AN D M ET IIOD Sl le ta-ai imiuiopuopr iouii tr i le w as g ivem i to tw em ity -five s tock labo ra to ry rabb its ,

uno stly fem nm nle , rang im m g f ro um i m veam m liu ig (800 grain s) to ad u lt am iinm als . T h eym vere fe (l a l)a laneed d ie t ( \V ay lm e rab i)it pe lle ts) ad lth itum , am m d one gram o f be ta-anmimmopropr io tm i t r i le pe r 10 0 cub ic eeum t.im ne t.ers is -as added to the ir d rim ik im ig w a te r.rI 1 (onresp( i lmde( l to a da ily (lo se o f rou gh ly (iliC gran i pe r k ilog ram of 1 )o dyw eigh t, a lt.im ough it w as m m oted tlm a t a fte r th ree to fo u r days the an im als usua lly

. * This research proje ct a s s iu l) l)or te( l in l)art i)V a re sea rch g ran t fro nm the heart C om m itteeof tim e H ea lth Associat ion o f R oc he ste r amid Moumr o e County , New York .VOL. 44 -A , N O . 4 . JU NE 19 62 71 7


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F I G . 1

71 8 E. J. BOTTCHER

TH E J O UR NA L O F BO N E AND J O INT SUR G E R Y

drank le ss and thereby decreased the dose . They w ere kept on this drug con-tinuously as long as possible in order to ascertain the end stag es o f the disease.The prog ressio n of the changes w as fo llow ed by serial ro entgenog rams and byrecords o f the ir w eight and g eneral appearance . The amminials w ere killed onlywheim they appeared to be dy ing ; nine w ere found dead. A utopsie s w ere performedand the v iscera, bones , and soft; tissues w ere studied his to lo g ically . Roentgen-o graphic s tudy of g ro ss tissue w -as also done .

C L IN IC A L R E SUL T S

Within a few days the rabbits becam e noticeably thinner, w ith rougher furthan the contro l animals. The experim emmtal animals soomm i)egamm to have diff icultyin hoppimig and w ould s it w ith one or more o f their legs out to the s ide . A fterone to tw o w eeks, a common position w as a spread-eag le po se w ith either bothfront. legs or all four legs out to the side (Fig . 1 ) . When these animals sat imp,they sat further hack than normal so that. they w ere sitting on their tails w ith

Rabbit show s emaciatio um , po sition o f forel imbs produced by sl ipping o f the upper humeralepiphy sis, roughening o f fur, and drooping of ears. This animal had ing ested be ta-am inoproprioni-true fo r tw elve w eeks.

their rear legs s tretched forw ard ; they moved as little as poss ible . A fter a montho r more , tumors became palpable about hip and shoulder jo ints .

The younger the aim imals, the more rapid the progress ion of chaniges. A fteronly one w eek, w eanling animals lay flat w ith the ir legs out to the sides. A lllo st w e ight rapidly am id became markedly emaciated, and by the end o f tw o w eeksre fused to mov e or eat. N one surv ived beyond three w eeks. The half-grow nrabbits deterio rated rapidly in four to six w eeks, and only fiv e stm rv ived morethan tw o months . In these , the deform itie s g radually became more marked,mo tio n more lim ited, and emac iation more prom inent (Figs. 2 -A and 2-B ). A fix edkyphosis dev e loped. The long est that any surv ived w as three and a half months.

W hile they ate le ss than the contro ls , they did eat. In none o f the groupsdid the experimental animals e ither grow or gain w e ight. One rabbit, for instance,


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F I G . 2 - B

L A THY RISM IN RA BB IT S 719

VOL . 4 4 -A , NO . 1 , J 1 N I uII62

Fig. 2-A : H oentgenogram shov ing elevat ion of the Per iostelmm of the fenmora an(1 hmmuneri ands h i p i 1mg of t im( hunmeral eI ) i l )hV ses. This rabbi t h:ul had heta-annoproprioum i tri l e f or three weeks.

F ig . 2 - 11 : 1 ) ( Im t genogranm shiovi rmg enmac iat ion , tumor-l i ke overgrow tlm of time simomul (I ers ammd ps( I i sl (I catioum of t ime hi l l s, hy erOStOSis of the f emora and humer i , exostoses of the elbow s, ribs, ar idhmnh o ur t .r au msv er s( l l r(1(eSSm 5. T im is ani nm al had hoof beta-annoproprioum i tr i l e f or eigim t. w eeks.V1 i i ( I i \v eig i i e(l I 700granms when started oum beta-am immopropriom i i tri l e w eighedonly I 120 grammms af ter f ourteen weeks, w hi le the commtrol ammimal w eighed 2900g r a ms .

Although col l apse of the ear carti l ages, as descr ibed by Selye in lathy ri ti c1Ithi) i ts nial l i v T homas im i papaim i -treated rabl )i ts, did not develop in army of thesemmiu i imLIs , IL f loppy ear dev el op ed i n one and the ti ps of the ears drooped imm severalr : th lI i ts as if th( V w ere too w eak to imold them up (Fig. I ).

Jim t l ie three adul t rai i bi ts gi v en l i eta-ani i umopropr ioni tri l e, no observable


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72 0 E . J . BOTTCHERc lin ica l ch an ges occu rred u p to n in e m on ths, a lthou gh a ll lo st a little w e igh t.O ne d ied of an in fec tion a fter f ive m on ths , one d ied w ith a pneum otho rax a fterseven m on ths , and the th ird w as ap pa ren tly w ell a f ter n in e m on ths .

ROENTG ENOGRAPH IC FINDING S

The roen tgenog raph ic ch an ges foun d in the yo ung rabb its a re sum m arizedin Tab le I . T he ch an ges w ere a lm o st a lw ays sym m etrica lly b ila te ra l. S lipp iu igo f the ep iph ysis o f the head of the hum erus, v ary in g from the ba rely p ercep tib leto com ple te sl ipp ing , o ccurr ed in all bu t fou r rabb its . T h is usu a lly w as closely

TABLE IRO EN TGENOGRA PH IC CHANGES FOUND IN TW ENTY -TW O YOUNG RABB IT S

N um be r o fAumiu al s

A bnorm ali ty of shoulderSl ipped e iphysls of h um eru s 18T um or-like ove rg row th 15A ngu la ted p rox im a l hum erus 3

A bn orm ality o f h ipT um or- lik e ov erg row th 151 )isloca tio n of the h ip 2Fra ctu re o f neck of fem ur 3A bnorm a lity o f k nee 12E leva ted pe rio steum (hype ros tosis)Hume r im s 16F em um r 22Phalanx 1E xos tosis o r loca liz ed so ft-tis sue densityAbou t e lbow 101 )is tal tib ia 2R ib s 8O th er 5

O s teopo rosis of p elv is 9

fo llow ed 1)\ in creased density , a s seen by roen tgeno gram s, abo u t the p rox im alend of the h um erus, p ro g re ssin g w ith in a few w eeks to a m arked , pa rtia lly ca lci-fled , m o ttled , dem ise en la rg em en t a ssoc iated w ith e leva tion of the pe rio steumof th e en tire sha f t o f th e hum erus an d d en sitie s ab ou t the scapu la an d tip o f thec lav icle (F ig . 6 ) . T hree an im a ls w ith a slip ped hum era l ep iphy sis had on ly asm oo th ly angu lated d e fo rm ity o f th e p rox im a l end of the hum erus (F ig . 3 -B ).

T he pe rio steum of the fem ur w as e leva ted in ev e ry an im a l. T h is becam e ev i-dem it as ea rly a s one w eek in the y ounge r an im a ls , u su ally sta rtin g in the m id -sh aftor the p rox im al po rtion o f th e sh aft. A t the sam e tim e so ft- tissu e d ensitie s , asseen by ro en tgeno gram s, ap pea red arou nd the h ip jo in t w h ich , in th e la te s tag es ,becam e so la rge as to ob scu re bo th th e h ip and the p e lv is (F igs. 4 -A and 4 -B ).Th is chang e wa s b ila te ra l in all in s tan ces bu t on e. A sim ila r, a lth ou gh les s m arked ,chang e occurred a round th e kn ee jo in ts b u t w ith the d iffe rence tha t h ere it w asum iila tera l in e igh t o f th e tw e lve rabb its a ffec ted .

Exostos is o r loca liz ed so ft- tissue ca lc ific a tion deve lo ped o n lo ng bones a ts ite s co rre spo nd in g to m u sc le and ten don in se rtion s in ov er ha lf o f th e an im a ls .T hese va ried from very sm a ll n on-calc if ied fa in t densitie s to ca lc ified n odu leso f ove r on e cen tim e te r in d iam e te r (F ig . 5 ) . T he transv erse v erteb ral p roces se san d the r ib s, especia lly the low er r ib s, w e re also freq uen t s ite s fo r elo nga tedex osto se s (F igs. 2 -A and 2-B ). Th e fla t b one , such as th e m and ib le and pe lv is ,w e re o ften too poo rly v isua lized to asce r tain w he the r o r n o t ex osto se s w ere p re s-

TH E JOURNAL O F BONE AND JO IN T SURGER Y


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F I G . 3 - A

LATHYR ISM IN R ABB I T S 721

VO L . 44 -A , NO . 4 , J UN E 1962

F igs . 3 -A . aum (l 3-1 : Sagi t .tal sect ioums :01(1 rouumt geum (Igramns f rouim t w o auui nmal i showi uu g shi j i1i cdl) rox inmal eI )ihi \ si s of time hiuumus v it im h y ero st osi s aum(I exost(Ises. I ig. 3-A simows a t i uummou-h ik eovergrov tim aumd Fig. 3-B , sni oot I i angiul ation. T imese tv o au mi unal s l ma(l had i )et a-aI mm iu mo pro ui (I um it .rm lef or twel ve \V ((ks.eim t. T ime pel s Of te l i i )e(am mm e so osteopomotie t hat. it w as ext remnely f a immt . Severalof the ammimm ls 1i td f ract ured toes. H vperostosi s am id svel l i ui g of tw o of I li e l ) i ia -l a mi g e s \eme ( i i ise lved i mm o ne a mu i mi ma l .

Jim t l i e t hi ee I t ( l t il t. am i i m im al s, m mo (l il mi (m ll ( li am mg es W ( i iiot ( (I , I iut. 1 li e J)CI1( 1st cm i i iof time enti re shaf t of the f eunur L oud of the pm (I x iulmal por t i oum (if the ti bi a, especial l yovem- time t ib ia l tu i )erosi ties, becamm ie el eval e(i , aum tl ( iste(ip(.i 1( isi s of I l i e l )el v i s ev idemmt. Jim the ral i i i i t w hich (l i ed of au iu m fcc t iom m a ft e r five m on t h s clev a t iom i o f th e


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FI G 4-A

FIG. 4-BFigs. 4 -A aui( l 4 -B : R .oentg enogranoi and sag ittal sec tion sho v ing tumor and dislo cation o f time

right hip and hyperost.osis (if t i m e shaft o f the femur. This rabbit had had be ta-am inopro rio um it.rilefo r term w eeks.

7 2 2 E . J . B O T TC H E R

TH E J O U R N AL O F BO N E A ND J O INT SUR G E R Y

periosteuni in the m id-shaft o f the humerus resulted imma slight. broade im iim g of theshaft bilaterally . Exotoses dev eloped in the low er tw o ribs of the 1a1 .)1 ) it. w -hiehdied w ith a pneumo thorax after sev en months. The rabbit w hich surv iv ed w asstill normal after nine months.

GROSS FIND INGSThe shoulder jo int w as affec ted in mos t o f the animals . S lipped epiphy ses

o f the humeral head accoumited for the charac teris tic spread-eag le pose that hasalready been mentio ned. This v aried from w idening o f the cartilag inous epiphyseal


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( os s s ll(( in i( t1 :Ium (I ro (um t.g cn (Igr :um m sim (i\v ium g (x (Is tu )5 i5 (If t im e ( liS t:L l Ilo ut ioum (If tim e t i h i: u im u a rabbitv hu irim lm a( I li:u I i )(ta-an um o n )pr ioum i t r i be 1(Ir f ) mu rt ee mm e ek s.

L. THYR ISM IX R AB B ITS 72 3

VOL . 44 -A , N O . 4 , JU NE m 962

( ro ss s pe ciu ien a fl( l roen t gen ograun show ing (x(Ist()s(s im \l)er( st ( ) 5 i5 , shi p le d ep i l)im ys is, aum ( I I u n u safo rm m iatio n (if a fo re lin ib o f a rai)b it fe d i)eta -a un ium op ro liu i(Im m itu ile fo r eigh t \v (eks .

p la te w ith ang u la tiom m of tim e head to com im ple te slipp ium g o f the e iphy sis (F ig s. 2 -A ,2 -B , 3-A , 3 -B , and 6) . r I m e i)u rsal cysts aeconm pam m yium g th is som e tinm cs a t ta im m eda hu ge s iz e, s tretch ing ha lf th e leng th of the im um erus (F ig . G ). lu i om m e a um im a la ll the m u sc le a tta chm eum ts to tim e sha ft. o f tim e im unm eru s w ere co n ip le te ly avu lsedb ila te ra lly . T he la te stage f o ummd m m anm ium m als surv iv ium g two m im om ith s o r m ore w asmost. often a tum om -- like ov erg row th o f irm egu la r, rou gh , friab le , po orly ca lc ified


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F io . 7-A

lu .. 7 -fl , . ,I E \lI(u I)S t((S is sm muu((m mu m(h iuu g I hu e I u : uu I v ( u

I i m( lu uunlm au v (u t(h lua( . l ig . ;-. i . I im e hUl l m um (I lu g . 7 -1 is I im ( m mi umvI lied t u L im sv(use l I r( , 5 5( ,5

:Lum( l ( ( (S ih i ( )< 4) . Ilm is t u mi u mma l(Ium i t tile fo r (ig ilt \ ((ks .

FIG. 8

72 4 E . J . B OT TCHER

THE JOU RNA L O F BON E AND J(iIN T SU RGER Y

b(im ie tissue ai ) ou t tim e pro x im m m al p ortiom i o f th e hum erus aceom pauu ied l)y a hy pe r-os tosis o f th e s (apula am id clav ic le (F igs. 3 -A am id 6). H ow eve r, ifl th ree (If th eamm inma l s there was oum ly w idem iim m g o f tim e cortex of the hum erm (F ig . 3 -B ).

A sim iiila r tun iom --like perios tea l o vergro v th w as foum id abou t. t ime ui1) jof lmtin fifteem i o f the am iim im als (F igs . 4 -A am id 4-B ). T h is s im ila rity o f tim e les ions a t. theS im O U l(.1 (m afl(l h ip jo in ts nm ay b e rela ted to the fac t th at bo tim jo im m ts are po im m t sof n iax ium m uni m usc le tem ision am id stress im i the rah iiit.. 1m m the la te s tages , tim e over-

\Iic rosco liir section of a slm o iulder jo in t sh ow ing disorg am m izatioum a im d cyst foru natioum ium tim eepip hy sea l P late w ith ea rly slipp in g o f th e epip hy sis ; a lso hyperostosis o f the scapu la (hematoxylinan d eo sin , X 4). Th is rabb it had h ad beta-am inoprop rion itr ile fo r th ree w eek s.


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Fuo . 9-A

P _ .v

. ,/l . ., i

.,$ g m

,.

4 , I.

LA TH YR ISM IN R A BB ITS 72 5

\( iL. 44 -A , N h. 4 , JU NE 1962

Plmotonmirrogradm slm (Iw ilm g 1 is( m m (I(Isa rconat mm s l i r o l i f er at . n I If f ih)r(I illast S i t ii fo rnm at ion ofOSteOi (I ( im (hIIatO xV hitm :Lu UI ((1 5111 , N 70) .

. . p (W

. .., . . ...t . i: - r

r : : 1, . . - -s:.. . -- . #{149}1_, ,,

. :#{149} .. ,, , -Fu u . 9 - B

I huot Im mii(r(I Iil) im sho v ing p seudo sa rcom atx iim s P ro life ra tion of c artila ge w ith fo rm a tio n o f osteoi(1( io rm mato x hium :111(1 (!O 51fl, X 70) .

gnow tlm w as so m im arked tha t no re latio n o f the m ass to any one m usc le co u ld be( le te rnmi mie(l .

The Peri(ist.ea l e leva tion or hyp erostos is so com m only seen in the hum erusI)(l feum im m r (om m sisted o f a th im i she ll o f b oum e su rrouu id ing the in tac t sha ft (F igs.4-A , 4-B , a lm (l 6 ) . 1m m th e fem u r, th is she ll u sua lly sp ira led d ow n from the le sse rtrocham iter. T he hyperos tos is fo und on the fla t bon es w ere usua lly ro ugh an d so ft..


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N1 .

, _____I. 4 ..

14 .I

726 E . J . BO T T C H E R

T H E J O UR NA L O F BO N E AN D J O INT SU R G E R Y

T he rii)s, the transverse processes amid spines of the vertebrae, the distal end oftime clavicle, and the scapula were commommly involved. The transverse processesamid rii)s were oft.emi so covered that they were several times their- original size;this soft miemv bomme could sometimes simply i)e lifted off the umiderlyimmg i)Ohle (Figs.7-A a.mmd 7-B ). T he rib) tumors most often occurred oui the posterior timird of thelower ribs.

Gross examimiatiomi generally revealed a few more exostoses amid soft-tissueswellimigs at the site of muscle amid tendon insertions than were denmommstratediiy roentgenograms, because some were too poorly calcified to cast a siiadomv.rfhi was especially true of the pelvis amid mandible (Fig. 10), althouglm oh thelong 1)O fles they were usually prominent both roemitgenographieally ai md grossl y(Figs. 5 and 6). 1mm a few animals, a small miodule was foumid omi the lateral rib)(age just beneath the inferior angle of the scapula and closely associated withthe latissimums dorsi. The pelvis was occasionally so soft. it could he cut. w ith akmiife.

M IC R O S(O P I (. F IN D ING S

T ue histological chamiges were of two general types, degemmerative amid pro-liferative. I )egeneration of cartilage was best. seemi iii the ( i 1iysea.l plates of thehead of the huniermms and tibia. The cartilage (if the plates lost its or(I elly l immear

Fuu. 101 xost.oses of the nman( lii)le vit.h a umoruual man(1ih)le (_V ) for (a)nml)aris( Ium. ilmis rabilit hm:u1 h :u I beta-

aummi nopro rioI mitrile for (. igimt. w eeks.

arrangeunent, i)ecanT me wider w ith more imitercellumlar suhistaumee, amid became vas-cularized. T he new ly fo r m ed t r a i)ecu la e of the metaphysis also were disorgammized.\V ithimm this disorderly plate a space often developed (Fig. 8) ; w ith slipping of theepiphysis, heunorrhage became evi( lemmt within this space amid beneath the adjacentperiosteumn, muscle amid tendomi imisertions. T he fibrocartilage of the ligamentumteres al so oceasi oum al lv had a similar disorderly arraumgeunemmt and mi-as toni in thetwo aumimals with dislocated hips.

I roliferalion of connective tissue of the periosteum, muscle, and fascia occurred


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L AT H YR I SM IN R ABB IT S 72 7adjacent to hone w ith the formation of pseudosarcomatous fibrous and chondro -osse ims tissue amid new bomme (Fig s. 9 -A arid 9-B ).

The 1iy erOst.OsiS , seen omi the scapula, verte l)ral pro cesses , and shafts o flommg bones, hiad a ce llular thick periosteum overly ing a lay er of spommgy mmew 1 )0mwmnatle imp chief ly (if calc ified osteo id spicules, o riemmted at rig ht ang le s to the origimialim itact. cortex (F ig . 8 ). IsltU ids of cartilage w ere occas iom iaily presemmt. The hyper-o stos is o f the shafts ( if long bones v aried from this pattern in that there w asaui ex ternal rim of demise cortical homie (Fig . 4 -B ). The marrow o f this new spongybone w as lo ose ly fibrous except in one o lder rai)bit w here it w as red. Subperiostealhemorrhage w as seen only adjacent to jo ints .

The ex ost.o se s w ere compo sed o f f ibroblasts , o s teo id, am id new bomie , but therew as more cartilage , calc ify ing cartilage , am id fibroblastic pro liferatiom i (Figs . 9 -Aand 9-B ). 1mm general, the adjacent musc le bummidle s and tendon fibers w ere w ide lyseparated by this ce llular pseudo sarcomatous someti mes myxomatous connec tivet issue. The numse le cells thenise lves w ere oft.em i compressed am id multim iuc leated.In the acut.e phase seemm mi very young am iimals, there w as so metim es an as so ci ate dmoderate im iflanimatory reac tion. N ear the periosteum , this ce llular fibrous tissueo ften cont.aim ied bands of hyaline eosinophilic material and this f ibrous tissuegradually fused w it.h osteo id, irregular islands of cartilage , and spongy bone (Fig s.9 -A and 9-B ). The o lder the le sio n, the g reater w as the amount o f bone present.

The tum or-like ov ergrow ths about the shoulder, hip, and knee jo ints show edall these changes to ge ther w ith los s o f the no rmal architec ture . The o rig inalcortical out.limie of the diaphy sis w as lost arid the marrow , w hich no rmally w as red,w as fibrous , very lo ose , and myxomatous . That this ground substance containedac id mucopolysaceharide w as demonstrated by the alcian blue stain. The synov ialniembranes o f the dislocated jo im its w ere stre tched i)ut still show ed papillary andV ill(iU S proee sse w ith occasional hy alim ie c lo ts . Sym io v ial pro liferation w as appar-em it over the jo int cartilag e . B ursae , vary ing from m icroscopic sym io v ial out-pouchings to hug e cy sts , w ere especially prominent about the shoulder jo int.

O s t e o p o r o s i s as ev idenced 1 )y very thin or absent bone trabeculae and thinnedcortex w as o fteum obscured by tissue o verg row th in the femur and humerus, butv ery ev idem it. in the pe lv is am id in v ertebral processe s. S om etim es osteopo ro sis\\. iIs aceompammied by enlargememmt o f the bom ie.

N o dissec tim ig aneury sms of the aorta w ere found, although one animal hada rather ex temnilve aneurysmal dilatiomi of the descending aorta w here the mediaw as stre tched thimm amid contained a caleif ic deposit. The remainder o f the aortaof this animal, as w e ll as o f the o ther animals, w as histo log ically normal. This typeo f calc if ication w as seen, although to a lesser degree , in one contro l animal.

N o specific abnormalities o f the nerv ous sys tem w ere found histo log ically .Occasiom ially , how ev er, nerv es w ere comple te ly ensheathed by the pro liferatedf ibroblasts adjacemit to bones and musc le insertions .

Tim e ear cartilages w ere examined histo lo g ically , but no apparent dev iationfrom the no rmal w as found. Thyro id and parathyro id g lands w ere also his to log i-cally no rmal.

C OMM E N TThe ehamiges foumid in the rabbits w ere prim arily ske le tal, fuimdamentaliy

sim im ilar to those (iesc rii)ed im i time other aum imals .20 1)ut differing in deg ree am idsite (if activ ity . The s im ilarity betw eem i o steo lathy rism iii the rabbit am id certaim iske le tal diseases o f maui w as ev en more ev idem it in the rabbit than im i the rat,partly due , poss ibly , to the larger size o f the animal am id partly due to a spec iesdifference . The overproductio n o f f ibroblasts , o steo id, cartilag e, and new bone w asVO L. 44 -A , NO . 4 . J UN E :1 962 .


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72 8 E . J . BOTTCHERrem in iscen t o f tha t fou nd in m yositis o ssific ans 1. T he p erio stea l eleva tio n and su b-pe rio stea l hem o rrhage w ere sim ila r to th a t seen in scu rvy .

K yphosco lio sis w as foun d on ly to a s ligh t deg ree in on e am m im a l iii th is se rie s .H ow ev er , seve re sco lio sis sim ilar to tha t de sc r ibed in rats w as fo uu id iii o mie a mm im alo f a la te r ex pe rim en tal se rie s now bein g co ndu cted fo r an o the r p u rpose. The ve rte-b ra l co lum n w as often fix ed and kypho tic , p rob ab ly du e to the abm io rm a l pos tu reo f the an im a ls .

T he huge size o f th e b ursae and th e m arked s tre tch iim g of the jo in t cap su le ssug gest the p ossib ility th at th ere w as a lo ss o f ton e o f co nnec tive tissue . H ow ev er ,no h e rn iae w ere fo und . O n ly o ne an im a l had d ila tion o f the b ow el, s im ila r to tha tde sc rib ed in the ra t and asc r ibed to lo ss o f e la stic tissue 18 ; no h isto lo g ical abno r-m a lity co u ld be dem on strated in the bow e l o f th is rabb it. O ne o f the an im a lsco n trac ted co cc id io sis and h ad sev ere b ron ch iecta sis w h ich was sugg estive of aloss o f elasticity o f the b ro nch ia l w a ll. T h is co u ld no t b e co nfirm ed h isto lo g ically .T he lo ca t.iom m of the ex ostoses, so ft- tissue sw e lling s, an d h ype rosto ses ind ica te tha tthe re la tiom i o f stress and tensio n to the ir d ev e lopm en t is p robab ly th e sam e as inthe ra t, w h ere H am re and Y eage r show ed tha t dene rv atin g a m uscle p rev en ted thedevelopm em it of ex os toses at its in ser tio n

R ecen t stud ie s w ith e lec tron m icroscop y sugg es t th at the re is a basic d istu rb -am ice in co llagen fo rm atio n in la thy rism and tha t th is m ay b e a de ficiency m mfibrilfo rmat ion 4. T ha t such a s im p le com pound as be ta -am in oprop rio n it.riie sho u ldcau se su ch pro fo und chang es as a re fo und in the se an im a ls ind ica tes th at indeedbasic s tru ctu ra l m etabo lism is inv o lved . Th e re la tion to g row th , th e e ffect o fin ju ry , and the im po rtance o f stre ss in the p ro duc tion o f the p ro life ra tion a reunansw ered ques tion s.

S UMMARY1 . T he la te e ffec ts o f la thy rism indu ced in rab b its b y feed ing be ta -am im m op ro -

p rio nm itr ile cons isted o f im pa irm en t o f g row th , em acia tion , s lipp im ig of ep iphy ses,so ft- tissu e sw e llings, hyp erosto se s, ex ostoses, and osteopo ro sis .

2 . In the sho u ld er and h ip jo in ts , th e com bina tion o f facto rs o f tem m resu ltediii m assiv e tis sue ove rg row th , w h ile in a few an im a ls the re w as on ly a seve rebowing . T he ch an ges w ere com m on ly , a lthou gh no t inv ariab ly , sym m etrica llyb ilate ral. F la t bo nes a s w ell a s long bon es w ere a ffected .

3 . T he h is to log ica l chan ges w ere bo th degene rativ e ( invo lv ing , cha rac te r-is tica lly , th e ep iphy seal ca r tilag e) and pro lifera tive ( inv o lv in g fib rob la sts o fp er io steum , ad j acen t fa sc ia , and m usc le sheath s).

4 . T he rela tion o f the se changes to m usc le pu ll, tens ion , traum a , an d hem -orrhag e, as w ell a s to a fu ndam en ta l d is tu rbance o f co llagen fib r il fo rm a tio n , isd iscussed .

REFERENCES1 . ACKE RMAN , L .V . : Extr a-Osseous Localiz ed N on -N eop las tic B one and C arti lag e Fo rm atio n1(So-Cal led M yositis O ssif icans) . C lin ical and Pa tho log ica l Confu sio n w ith M aligum ant N eo-

p lasms . J. Bon e and Jo in t Su rg ., 4 0-A : 279-2 98 , A p r. 1958 .2. BENSLEY , B .A . : P rac tic a l A na tom y o f th e R abb it. P h ilade lph ia . P . B lak iston s Son am id Co.,1 9 1 0 .

3. 1 )A s LER , \V ., an d STONER , R .E . : P rod uc tion o f Sp ina l Cu rva ture s in R ats by Chem ica llyi)issim ilar S ub stan ce s. E xpe rientia , 15: 1 12-1 13 , 1 959 .

4 . FO LL IS , R .H ., JR. , an d T0U sIM Is, A .J .: E xper im enta l La thy rism in the Rat . Na ture of 1 .)e fec tin E p iphy se al C a rtilage . Proc. Soc . E xp er. B io l. a nd M ed ., 98 : 843 -84 8 , 1 958 .5. GARDN E R , A .F . ; DASLER , W . ; a nd WE!NMA ,NN , J .P . : M as tica tory Appa ratus o f A lb in o R ats inExperim en tal La thy rism . J . D en t. R es., 37: 4 92 -51 5 , 1 95 8 .

6 . H AMRE , C .J ., and YEAGER , V .L . : In fluence of M uscle Sec tio n on E xo sto ses of La thy ritic R a ts.A .M .A . A rch. Pathol ., 64: 426-433, 1957.7. HAMRE , C .J., an d YEAGER , V .L . : In f luence o f D en erva ted M usc le s on Exo stose s o f R a ts F eda Sw ee t-P ea D ie t. A .M .A . A rch . P a tho l., 65: 21 5-2 27 , 19 58 .

TH E JO UR NAL O F BON E A ND JO INT SU RGERY


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L AT H YR I SM IN R AB B IT S 72 98. LEVENE, 1)1 ., and GROSS , JEROME: A lterations in State o f M ole cular A ggregation of Collagen

lumduce (1 ill Chick Embryos 1w B -Am inoproprionitri le (Lat.hyrus Facthr). J. Exper. M ed.,1 1 0 : 7 7 l - 7 ) 0 , 1 9 5 9 .

9 . Mu LLISER, R .V . , aui(1 1)A smER , W . : O st eo la t .im yr ism . H ist o p a t .h ob ogic a l L e sio n s P r od iu c ed i)ySenmicarbaz ide amid A ce tone Semicarbazone . A .M .A . A rch. Pathol ., 67 : 42 7-4 31 , 195 9 .

10 . P ON SE TI , IV. , and B AIRD , WA . : Sco lios is am id i)issec ting Aneurysm of the A orta in Rats} e(I itim Lathyrus Odo ratus Seeds . Am . J. Pathol., 28 : 10 59 -10 77 , 195 2 .

1 1 . PONSETI, IV . , and SHEPARD , R .S . : Lesions of the S keleton and o f O ther Mesodermal Tissueill Rats Fed Sw ee t-Pea (La thyrus O dora tus) Seeds . J. B one and Joint Sumrg ., 36 -A : 1 031 -10 58 ,( )ct.. 19 54 .

12 . SE u Y E , H AN S: Lat.hvrism . Rev . Canadienne (Ic Biol . , 16 : 1-8 2 , 1 95 7 .13 . S YE , H.uN s: Iuidumction by Aminoacetonitrile o f a Predispos itio n to G iammt Callum s Formation.

Br i t i s i m j . Pathol. , 38 : 18 6-1 89 , 19 57 .14. STO CK MA N, R A I PH : Lathyrism. Edinbumrgh M ed. J., 19 : 277 -29 6 , 1 917 .15. STOCKMAN , ItA LuH: Lathyrisni in Man. Fdinbmurgh Med. J., 19 : 2 97-30 7 , 19 17 .16 . STO(KMAN , RALPH: The Poisonous Princil)le of Lath.yrus amid S ome Other Leg imminouus Seeds .

j. hygiene, 31 : 550 -5 62 , 193 1 .1 7 . Tmioii , IA . : Reversible Collapse of Rabbit Ears afte r Iim travenous Papain, and Prevemmt.iorm

o f Recovery i)T Cortisone . J. Exper. M ed., 10 4: 2 45-25 2 , 1 95 6 .18. \ \ALKER, l) .G . : Elastic Fiber A lte rations iii Rats Treated w ith Latimyrim s ()do ratums. A .M .A .

A rcim . Pathol ., 64 : 43 4-4 45 , 19 57 .19 . \V ALK ER, I ).G ., a u m d WERTSCHAFTER, Z.T. : IIisto atho genesis of A ort.ic Aneurysm s iii time

Lathyrums-Fed Rat. A .M .A . A rch. Pathol., 61 : 12 5-1 35 , 1 956 .20 . YEAGER , V.I , i . , a u m d H AM R E , C.J. : Histo logy o f Lathy rus -Immdtmced Exos toses o f Rats. The

Iumitial Change s at Tendon-B one Jumnction. A .M .A . A rch. Pathol., 6 4: 171 -1 85 , 1 95 7 .

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