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A STUDY OF CANINE HYSTERIAPRODUCED BY FEEDING CERTAIN BAKED DOG FOODS AND

WHEAT GLUTEN FLOUR 1J. R . WAGNER AND C. A. ELVEHJEM

D epartm ent of B iocH tm istry, C ollege of A griculture, U niversity of W isconsin, M adisonTOUR F IGURES

(R eceived for publication A ugust 8, 1944)The ex istin g k nowled ge an d th eo ries co ncern in g can in e hy steria w erecarefully discussed by Hewetson ('36). He was unable at that time

to arrive at any definite conclusions regarding the disease from consideration of the know n facts. A t best it is an ill-defined m alady w hose nom enclature, cause, and treatm ent are in dispute. N umerous other term shave been suggested and used for the syndrom e, nam ely, running fits(A rnold and Elvehjem , '39), fright disease (G race, '30), epizootic hysteria, en zo otic h ysteria, in fectio us h ysteria (C ampbell, '27 ), an d h yp er-kinesia (L intz and L intz, '29).T he symptom s generally associated w ith the disease are paroxysm alattacks of hyperexcitability characterized by running, barking or how ling, faulty vision, deranged balance, dem entia, and often clonic con

vulsions. The secretion of a heavy m ucous saliva is common especiallydur in g th e c onvu lsio ns . Dur in g th e c onvu lsio ns u rin atio n and d efe ca tio nfrequently occur. The affected dogs seem indifferent to injury or to efforts to quiet them . E xcitem ent and physical strain influence the onsetand frequency of attacks. H eredity (Berrym an and Schlotthauer, '41)is also believed to be a factor affecting the anim als ' susceptibility. B etween attacks the anim al may appear norm al but is often nervous andapprehensive. A ttacks are usually precipitated by stimuli such as asudden noise or a flash of light.A num ber of afflictions have been reported to produce sim ilar sym ptoms. Meln ick an d Cowgill ( '3 7) ob serv ed h ysteria amon g ex perimen taldogs receiving rations containing gliadin. A rnold and Elvehjem ('39)found that a baked dog food m ade of w heat flour and m eat scrap causedfits in young dogs and thought that a lysine deficiency was involved.1 Published w ith the approval of the D irector of the W isconsin A gricultural Experim ent Sta

tion. This work was supported in part by a grant from Wilson and Company.431

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432 J. K , W A G N ER A N D C . A. ELV EH JEMThey also suggested that a toxicity m ight be a contributing factor. Pat-ton ('39) attributed sim ilar sym ptom s in dogs fed a baked dog food to athiam ine deficiency. M cG hee ('36) thought that the condition w as due toa low blood m agnesium level. C ham bers ('30) reported a case in w hichthe addition of quantities of tallow to a ration of m eat and baked breadcured hysteria. O thers have believed that distem per (G race, '30), earm ites (Cham bers, '30), intestinal obstruction (Brow ning, '29), vitam inA deficiency (W alston, '33), or ticks (M acfie, '30) w ^re the cause of thedisease.M any of the w orkers w ho believe the disease to be related to thenutrition of the affected anim als have com m ented on its frequent association w ith the feeding of baked dog foods. For this investigationit w as originally intended to select com m ercial baked dog foods onthe basis of their hysteria-producing potency and secure sufficient quantities of the w orst offenders for further experim entation. In the m idstof this program , D r. H . B. Parry,2'3 w ho had been conducting feedingexperim ents w ith gliadin in this laboratory discovered that by feedingcom m ercially produced w heat gluten to young dogs all of the usualsym ptom s of canine hysteria could be produced w ith great rapidity, andintensity. The frequent occurrence of w heat products as an ingredientof baked dog foods, and the sim ilarity of the sym ptom s suggestedthat the disease w as the sam e in both cases. The use of w heat glutenoffered a m ore productive approach to the problem than the feedingof com m ercial dog foods and subsequent efforts w ere directed to theinvestigation of this m aterial.

EXPEBIM ENTA LAnimals

M ongrel dogs w ere obtained at w eaning and fed a m ilk diet for several days. D uring this interval they received as a verm ifuge f-grain ofsantonin and f-grain of phenolphthalein following a 12-hour starvation period, after w hich they w ere transferred to a norm al, adequate,dry ration for 1 w eek before being used for experim ental purposes.The anim als w ere kept in a heated, lighted room in individual cages ofheavy w ire m esh, the floors ofw hich w ere of concrete covered w ith w oodshavings. The proxim ity of the anim als to one another w as such as toperm it ready transm ission of the m alady if an infectious agent w ereresponsible.

* U np ub lis he d d a ta .3Present address: Im perial C hem ical Pharm aceuticals, Entebbe U ganda, B ritish East A frica.

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C A N IN E H Y ST ER IA 433A t the end of each experim ent anim als w hich had received hysteria-producing rations w ere transferred to a norm al ration for a recoveryperiod of at least 1 w eek. B y this procedure it w as possible to useeach anim al for several experim ents. A fter anim als had attained theage of 6 to 8 m onths their susceptibility w as so reduced as to m akethem unsatisfactory for assay purposes.

Production of canine hysteria with commercialbaked dog foodsThe baked dog foods used in this portion of the w ork w ere regularcom m ercial products. They w ere coarsely ground and 97 parts of theground m aterial m ixed w ith 1 part cod-liver oil,1 part N aCl,and a partLiver Fraction B 4. Prelim inary experim ents had dem onstrated that

the above supplem ents did not prevent the occurrence of attacks ofcanine hysteria. The above rations and w ater w ere supplied ad libitum .TA BLE 1

Canine hysteria from the feeding of baked dog foods.SAM PLEESULTS1

fed 18 days;nottacks2fed 34 days;nottacks3fed 41 days;nottacks5fed 34 days;no attacksSA M PLE66799R ESU LT Sfirst

attackon 14thaySA M PLE10firstattack 10on 5thayfed83 days;

nottacksfirstattackon 5thayfirst

attackon5th day1111

plus5% caseinR ESU LTSfirst

attackon 24thayfirstattackon llthayfirstattack

on 32ndayfirstattackon 28th day

Results obtained on nine sam ples are listed in table 1. Lim ited quantities ofsam ple 1 prevented a m ore prolonged assay. Tw o sam ples w erefound to cause attacks in less than a w eek. Tw o other sam ples alsocaused hysteria but m ore slow ly. Five sam ples failed to show activity.The affected anim als displayed sym ptom s of nervousness, fright, running, how ling, and in som e cases convulsions. Secretion of a heavym ucoussaliva occurred during attacks. The loss ofsight w hich occurredw as not com plete nor w as it perm anent. The anim als' pupils w ere di-4W ilson Laboratories.

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434 J . R . W AGNER AND C . A. E LVEH J EMlated and the ey es w ere f ix ed and staring. N o interference w ith the lightre fle x was apparent.

T he ef fects of a num ber of com pounds, the lack of w hich hav e beenassociated w ith seizures of hysteria by other w ork ers, w ere studiedw ith those sam ples found to produce attack s. T he responses of a testanim al receiv ing sam ple 6 to supplem entation w ith thiam ine hydro-chloride, casein, dried canned dog food, and ly sine hydrochloride are

727 .0g6.6

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436 J. E. WAGNEB AND C. A. ELVEHJEM

days. D ogs nos. 78, 8 0, 81 and 82 w ere then changed to ration W -2 (w heatgluten). In addition, dogs nos. 81 and 82 received d-lysine dihydro-chloride 5 equivalent to 0.6% of the ration. Dogs nos. 79 and 83 werem aintained on the casein ration as controls. Control dogs nos. 79 and83 continued to grow at a good rate and were normal in behavior. Thefour litterm ates fed rations containing w heat gluten all had attacks ofhysteria 3 days after the change in rations. Six-tenth per cent d-lysinedihydrochloride in the diet did not retard the onset of attacks.

W E EK SFig. 2 Supplementation of wheat gluten ration with lysine. Control dogs, no. 79 and no. 83,

fed casein ration W -l throughout experiment. H = hysteria attack.III. (figs. 3a, 3b). A fter a 12-day recovery period on ration W -l dogs

nos. 78, 79, 80, 81, 83 and 85 w ere placed on the follow ing experim ent.N o. 78 w as m aintained on the casein ration as a control. N o. 81 w as fedration W-2; nos. 79, 80, 81 and 85 received W -2 plus the supplemen ts d esig nated o n th e g rap hs. N eith er 1 .2% d -ly sin e d ih yd ro chlo ride,18% case in , 1 8% case in h yd ro ly sa te , n or 18% gela tin p re vente d h yste ria .The onset of the disease seemed to be slightly delayed in the dogs receiving the protein supplem ents and the grow th rate w as increased bythe addition of casein or casein hydrolysate. C alcium pantothenate (fig.3) did not alleviate the sym ptom s.IV . A fter a 9-day prelim inary feeding period on ration W -4 (casein),two black Irish-Setter-Germ an Shepherd Cross litterm ates, nos. 90and 91, were fed ration W -3 (wheat gluten). The ration of no. 91 was' Me rc k.

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C A N IN E H Y STE RIA 43 7supplem ented w ith 4.97% dl-lysine m onohydrochloride. D og no. 90developed hysteria in 2 days ;dog no. 91 had its first attack in 3 days.The grow th of the anim al fed lysine w as slightly better.

WEEKSFig. 3a Effect of supplem enting w heat gluten rations. Supplem ents of 2.5, 2.0 and 10.0

m g. of calcium pantothenate w ere adm inistered orally to dog no. 79 during the seventh, eighth,and tenth days on ration W -2 plus 1.2% d-lysine dihydroehloride. D og no. 81 in a sim ilarm anner w as fed 2.5, 5.0, and 10.0 m g. of calcium pantothenate during the ninth, eleventh,and tw elfth days on ration W -2. H = hysteria attack.

^W -2 -C AS E IN HY DR OLY -S A T E

W EEK SPig. 3b Effect of supplem enting w heat gluten rations. H = hysteria attack.

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438 J. R . W A G NER A N D C . A . ELV EH JEMExper iment V (fig. 4). Effect of va rious levels of whea t gluten inta ke.If the effects of w heat gluten w ere due to a partial deficiency of theprotein, one m ight expect the deficiency to be less acute at higher levelsof intake. O n the other hand the effects of an im balance or of a toxicitym ight be expected to be accentuated by greater consum ption.A fter a recovery period of14 days or m ore, dogs nos. 78,79,82,83, and84 w ere fed rations (1) W -12, (2) W -7, (3) W -8, (4) W -9, (5) W -10,

respectively, containing 0% , 10% , 15% , 20% , and 25% w heat glutenin addition to 20% casein. The results w ere as follow s: (1) The controlanim al w as m aintained on the casein ration in norm al condition for 36days. (2) First hysteria attack w as observed aft r22 days on the 10%

9.4

5 .4

W-IOW-

12

I _L I I I IWEEKSFig. 4 Effect of level of w heat gluten intake. H = hysteria attack.

w heat gluten ration. (3) D eath occurred after 15 days on the 15% w heatgluten ration. (4) First hysteria attack w as observed after 9 days onthe 20% w heat gluten ration. (5) First hysteria attack w as observedafter 7 days on the 25% w heat gluten ration.The hysteria attacks observed in these experim ents w ere sim ilar tothose occurring in dogs fed the baked dog foods. "W heat gluten causedhysteria m ore consistently and, in general, m ore quickly. Convulsionsoccurred frequently, varying in severity from brief attacks of a half-m inute's duration to a series of convulsions lasting for m ore than anhour. Post-m ortem exam ination of a num ber of dogs failed to revealany m orphological changes in the viscera w hich could be attributed tothe feeding ofw heat gluten w ith one exception ;in one anim al w hich died

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440 J. B . W A G N ER A N D C . A . ELV EH JEMThe disease does not seem related to pyridoxine-deficiency fits of ratsand pigs reported by C hick ('40), nor the valine-deficiency staggers of

rats observed by K ose ('39).The nature of the toxic factor is still in question. It appears to bedistinct from selenium w hich has been found to be the toxic substancein certain grains (M oxon, '37). Recent analyses m ade by D r. M oxonof the South D akota Experim ent Station show the selenium contentsof tw o sam ples of our w heat gluten flour to be 1.2 and 2.4 parts per m illion. Even w hen these m aterials w ere fed as 30% of the rations theintake of selenium w as w ell below the m inim um levels reported to betoxic. Balls and H ale ('40) have reported a m aterial extracted fromw heat flour by petroleum ether and found to be toxic (Coulson et al., '42)for m ice and certain m icroorganism s. W e have not found w heat glutenflour toxic for m ice w hen fed as 30% of the ration.7A s a further point of interest it should be m entioned that in prelim inary studies w e have been unable to detect any of the usual sym ptom sof canine hysteria in the chick, rat, guinea pig and m onkey w hen fedrations containing large am ounts ofw heat gluten, for periods of 3 w eeksor m ore.7 M elnick and Cow gill ('37) have also reported the rat to beim m une to the toxic factor in gliadin.The chem ical properties of the toxic m aterial in w heat gluten are nowunder investigation. A lthough details of the w ork cannot be presentedhere, it is significant that the w heat gluten can be rendered w ater-soluble by digestion w ith pancreatin.7 It does not seem probable thatit can be causing any physical interference w ith gastro-intestinal function in spite ofits extrem ely gum m y character previous to digestion.

SU M M A EYCanine hysteria of the nutritional type has been produced in dogs byfeeding baked dog foods containing w heat gluten flour and experim entalrations containing w heat gluten flour. The disease appears to be causedby som e toxic factor present in the w heat products. A lthough the proteins of these products are deficient in lysine, protein and lysine supplem ents do not prevent the disease. H ysteria can be caused in dogsreceiving nutritionally adequate rations by the addition of w heat glutenflour to the rations. LITER A TU R E C ITED

A RN O LD, ., A N D C.A . ELVEH JEM 1939 Is running fits a lysine deficiency! J. A m . V et. M ed.A ssn., vol. 95, p. 303.BA LLS,A. K., AN D W . S. HA LE 1940 A sulfur-bearing constituent of the petroleum etherextract of w heat flour (prelim inary report). C ereal C hem ., vol. 17, p. 243.

1U npublished data.

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C A N IN E H Y STER IA 441BERRY M AN ,G., AN D C. F. SCHLOTTH AU ER1941 Is fright disease an avitam inosis? NorthA m . V eterinarian, vol. 22, p. 34.BR O W N IN G , .W . 1928 Convulsions in dogs. V et. M ed., vol. 23,p. 318.CA M PBELL,.M . 1927 V eterinary m edicine in 1927. V et. M ed., vol. 22,p.485.CH A M BERS,. 1930 H ysteria o the dog. V et. M ed., vol. 35, p. 274.CH ICK ,H ., M .M .EL SAD RAN DA . N . W O RD EN 1940 O ccurrence of fits of an epileptic naturein rats m aintained for long periods on a diet deprived of viatm in Bs. Biochem .J., vol. 34,p. 595.CO ULSON ,. J., T. H. H AR RISA N D B. AX ELROD 1942 Effect on sm all laboratory anim als ofthe injection of a sulfur protein from w heat flour. C ereal C hem ., vol. 19, p. 301.G RA CE,W . E. 1930 Fright disease a com plication of distem per. V et. M ed., vol. 25, p. 102.H BW ETSON ,H . B. 1936 H ysteria in dogs. V et. Becord, vol. 48, p. 1202.LIN TZ,W ., A N D G .LIN TZ 1929 H yperkinesia Eunning fits. V et. M ed., vol. 24, p. 326.M cG H EE, J. 1936 Biochem ical aspects of canine hysteria treatm ent. V et. Eecord, vol. 48,p. 416.M AcriE, B. A. 8. 1930 Canine hysteria in Lunds: Third report. Vet. J. (London), vol.86, p. 265.M ELN ICK ,D ., A N DG .R. CO W G ILL 1937 The toxieity of high-gliadin diets. Studies on the dog

and on the rat. J. N utrition, vol. 14,p. 401.M O X O N ,A . L. 1937 A lkali disease or selenium poisoning. South D akota A grie. Exp. Sta.B ul. 311.PATTO N ,J. W . 1939 Fright disease an avitam inosis. V et. M ed., vol. 34, p. 372.EO SE,W . C., A N D S. EPSTEIN 1939 The dietary indispensability of valine. J. Biol. Chem .,vol. 127, p. 677.W ALSTON ,H. D. 1933 Hysteria in dogs. N ature, vol. 132, p. 243.