BOVINE MALIGNANT CATARRHAL FEVER IN MICHIGAN II. PATHOLOGY I. OCCURRENCE III. DIFFERENTIAL DIAGNOSIS IV. COMPARISON W ITH SIMILAR SYNDROMES IN OTHER COUNTRIES By Robert Nelson Berkman A THESIS Submitted to the School for Advanced Graduate Studies of Michigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Veterinary Pathology 1958 ProQuest Number: 10008584 All rights reserved INFO RM ATION TO ALL USERS The quality o f this reproduction is dependent upon the quality of the copy subm itted. In the unlikely event that the author did not send a com plete m anuscript and there are m issing pages, these will be noted. Also, if m aterial had to be removed, a note will indicate the deletion. uest ProQ uest 10008584 Published by ProQuest LLC (2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code M icroform Edition © ProQ uest LLC. ProQ uest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346 *59 c7 TABLE OF CONTENTS ACIRTOTLEDGMENTS................................................. i IN T R O D U C T I O N ................................................... 1 STATEMENT OF P R O B L E M .......................................... 1 I. O C C U R R E N C E ................................................. 5 A. Materials and Methods. ......... 5 B. Results and Discussion ............................. 5 5 1 • Seasonal Incidence................ 2. Age; * Breed, and S e x ................. 6 3. Role of Sheej> ..... ..6 4. Susceptibility of New Additions................7 5. Mortality.......... 8 5 . Morbidity..................... 8 7 . As a Cause of Abortion. ....... .....9 8 . Economic Aspects. .......... .......9 9 • Symptoms of the Disease. ........... 10 10. Forms. ....... 12 11. Clinical Pathology. .................... 13 ....... 14 C. Summary and Conclusions ii. p a t h o l o g y ; ................................................ is A. B. C. D. E. III. ............. 18 Introduction. Materials and Methods.......................... .....18 Results ...... 19 1. Skin............................ 19 2. Eyes........................ 22 3. Digestive Tract........... .......23 4• Lymphatic System. ...... 28 5. Cardiovascular System..........................29 6 . Respiratory System............................. 30 7 . Urinary System. . ......... 31 8 . Reproductive S ys t e m ..... 34 9 . Endocrine System. .36 10• Nervous System. ..... 37 Discussion. ............. 39 Summary and Conclusions............................ 42 'DIFFERENTIAL DIAGNOSIS .................................. 55 A. Rinderpest. ......... 55 B. Mucosal Disease (Iowa Type)......... 57 C. Virus Di arrhea...................................... .60 D. Infectious Bovine. Rhinotrache it is .................. 62 E. Hyperkeratosis........ 63 F. Foot and Mouth D i s e a s e..................... .64 G. Vesicular Stomatitis................................66 II. Listeriosis............................... 66 I. Sporadic Bovine Encephalomyel it is ................ 68 PAGE J. K. L. M* IV. R a b i e s ........ . • *•....... • . . • •.....................69 Leptospirosis . *........... ..................... *71 Infectious Herato-conjunctivitis........*.......*72 Summary and Gonclus ions .............. ........... 73 COMPARISON W I T H SIMILAR SYNDROMES IN OTHSR COUNTRIES.74 A. Union of South. A f r i c a ................. ..74 79 B. K e n y a ........................... C . Europe •••.............••..••••...•.••••••••.S3 D. Palestine ........... 84 L. Pinland. ........ 84 P. Discussion.......... 87 G. Summary and Conclusions................ .89 NSEEKSNCES 90 AC KtTO\/LEDGrMBNTS The author wishes to express his sincere thanks to his major professor, Dr. R. D. B a m e r , who first recognized the problem of bovine malignant catarrhal fever in Michigan and initiated the studies herein presented. In addition, Dr. Barner has provided a constant supply of ideas, information, and enthusiasm which were invaluable in this undertaking. The author is also indebted to Dr. C. C. Morrill and Dr, R. P. Langham for their help in reviewing the material and suggestions regarding the photography. Mich credit is due the veterinarians of Michigan who supplied the cases upon which these studies were based. The author is indebted to the technicians-Mrs. Laurie Belch, Mrs. Joyce Trier, Mrs. Nancy Malik, Miss Marjorie Leopold, and Miss Barbara Myers -for their preparations of the tissue sections and the blood examinations. The author appreciates the research funds supplied under the regional project, "The Mucosal Diseases of Cattle1', (NC-34). 1 INTRODUCTION \ Bovine malignant catarrhal fever (MCP) has a world­ wide distribution. The disease has been reported from the continents of Europe, Africa-, South America, and North. America (Stenius, 1952)* Bovine malignant catarrhal fever was first reported in the United States by Marshall et a l . (1920) in Pennsylvania. The disease has been reported also from Ohio (Goss et a l .* 1947), North Dakota (North Dakota Livestock Sanitary Board, 1937), Colorado (Parquharson, 1946), Michigan (Earner and Montgomery, 1954), and New York (Udall, 1956), Hutyra et a l * (1949) state that uthe disease has been observed and described from the end of the eighteenth century *,#Anker (1832) described it as a typhus of cattle and re ­ garded it, with Spinola, as originating from benign nasal catarrh...Haubner and Roll, and later Lucet, described it as a diphtheroid infection of the mucosa, but it was first des­ cribed as a specific infectious disease of cattle by Bugnion in 1877•M STATEMENT OP PROBLEM Bovine malignant catarrhal fever has not been extensively investigated in this country and it is generally considered to be of minor importance. However, the possibility that the disease occurs in forms other than the clinically obvious "head-and-eye” type appeared to be probable on the basis of preliminary studies# Several investigators have described different types in other countries. It was felt that many 2 cases were probably misdiagnosed as such things as so called “hemorrhagic septicemia” , infectious kerato-conjunctivitis, atypical pneunomia, or as entities of the mucosal disease complex. The cases which had been observed in Michigan in prelim­ inary studies had indicated that the syndrome was not fully compatible with some features described in other countries. A need for an accurate picture of the disease as it occurs in North America was indicated. The recent appearance of the several syndromes making up the mucosal disease complex pointed up the need for means of differential diagnosis. Clinically, many of our cases re­ sembled diseases of the complex — particularly the condition first described by Ramsey and Chiver3 (1953) in Iowa. This condition has been our major problem in differential diagnosis. We must keep in mind the possibility of exotic diseases which may invade our country through several increasing means as international traffic increases. Foremost among such possible invaders are rinderpest and the vesicular diseases. The accurate diagnosis of these conditions is a necessity if they are to be combatted. Thus, we find that although the number of reported cases of MCF is small, yet the possibility of unrecognized cases, the need for characterization of the disease as it occurs in this country, and the necessity for its differential diagnosis furnish jtistification for the studies herein presented. Many investigators have worked on the transmitsibility of MCI? "but have reported conflicting results. Mettam (1923) reported the successful transmission through bacteria-free blood to cattle. results. Daubney and Hudson (1936) reported similar Gfttze (1930), Binjard (1935)* and Magnusson (1940) reported the successful transmission of the disease to cattle in a similar manner. Piercy (1952) utilized several different inocula to achieve successful transmission to cattle in S. Africa. Other workers (Bobberstein and Hemmert-Halswick, 1928; Stolnikoff, 1933; de Kock and Heitz, 1950) failed to transmit the disease to cattle. The disease has been transmitted to rabbits by Ernst and Hahn (1927), Zwick and Witte (1931), Pattison (1946), and Plowright (1953). Other researchers (Mettam, 1923; Dobberstein and Hemmert-Halswick, 1928; Stolnikoff, 1933; Bisbocci, 1934; Aleska, 1935; Bendixen, 1940) have failed to transmit the dis­ ease to rabbits. G-tttze and Liess (1930 ) failed to infect rabbits mice, rats, and guinea pigs. Meissner and Schoop (1934) did not succeed in infecting rabbits and guinea pigs. Pattison (1946) was unsuccessful in infecting rat3 and guinea pigs. Daubney and Hudson (1936) reported successful transmission to rabbits, mice, and guinea pigs. The disease is not confined strictly to cattle. Stenius (1952) states that buffalo, sheep, goats, gnu, deer, steenbok, carabou, and the giraffe are susceptible. Several causative agents of the disease have been sug­ gested. Bassi (1930) believed that MCE was due to poisoning by Polytrichium trifolii. The lack or surplus of calcium 4 affecting vasomotor responses was suggested "by Linlcies (1926) • Sjollema (1937) reported a deficiency of calcium and vitamin A in diseased animals. Vyssman (1938) "believed that meteor­ ological factors were involved. with an parus. Otte (1925) connected MCI1 invasion of Eristalis larvae and Lictyocaulus vivinumerous investigators have "believed the disease to "be caused "by "bacteria (^e Clainche, 1896; Isepponi, 1902; Stolnikoff, 1926; Guizzardi, 1931; Huynen and Logiudice, 1911; Reisinger, 1926). G&tze (1940) did not find evidence of a rickettsial infection, but did demonstrate a spirochete. Stenius (19 52) could not find spirochetes in 10 cases in w hich tissues were stained wi th Levaditi’s stain. He also reported that serological tests failed to incriminate Toxoplasma as the causative agent. Mettam (1923) described "snotsiekte" of cattle in S. Africa as caused by an ultramicroscopic agent (this disease is believed to be MCF). Ernst and Hahn (1927) were the first of the European workers to suggest a viral agent. Investigators have subsequently utilized bacteria- free blood and tissue emulsions to transmit the disease as previously mentioned. This historical review does not cover all the literature on MCE. Literature pertinent to the stucies are included in the respective sections. 5 I* OCCURRENCE MATERIALS AND METHODS A total of 39 cases of MCE was collected in Michigan “beginning in 1954 and extending to the present writing. Of these 39 cases, 31 animals were examined post-mortem and material was collected for histopathological examination. In 8 cases the animals were not secured for necropsy hut are included “because they were classical pictures of the "headand -eye" form of MCE occurring on farms with a past history of the disease. The majority of cases came from an enzootic area in southeastern Michigan, RESULTS AND DISCUSSION SEASONAL INCIDENCE Previous investigators (North Dakota Livestock Sanitary Board Reports, 1937; Mackey, 1956) have observed the greatest seasonal incidence of the disease in the spring and fall, Marshall et a l ♦ (1920) described an outbreak in one herd in Pennsylvania in which ca es develojoed from December through June, Earquharson (1946) reported that the disease may occur during any season but the greatest incidence was found during the winter and early spring months. In Michigan the greatest incidence of the disease occurred during Eebruary and March gradually declining through June, One practitioner (Earnssf 1956), who has practiced in the heart of the MCE area for 15 years, has noted a correlation of the onset of the condition with the marked fluctuations of temperature during the late winter and early spring. Wyssman (1938) has suggested a 6 similar correlation with temperature variation. Gases have also occurred in the fall hut these numbered only 3 of our 39 cases. A G S , BREED, AND SEX Marshall et a l . (1920) indicated that the most suscept­ ible animals were those between two and five years of age. Our studies indicated that all age groups may be equally susceptible. old. The youngest animal affected was four months If the cases were divided into three age groups — ma­ ture cattle (2-5 years), 1-2 years, and one year or less — it was found that the disease was distributed almost equally among these groups* No particular breed susceptibility was noted. dairy and beef cattle were affected. Both The disease was observed in females, males, and steers. RODE OF SHEEP Many investigators have suspected s h e e p as the inter­ mediate carrier of the virus without showing symptoms of the disease themselves (Grtttze, 1930; Rinjard, 1938; de Kock, 1950; Piercy, 1954). The exact relationship, if existent, has not as yet been satisfactorily demonstrated. Earquharson (1946) has pointed out that there was undeniable clinical evidence that the incidence of the disease in Colorado was much higher on farms and ranches where both sheep and cattle were raised. The greatest incidence of MCE in Michigan occurred in the la.rgest sheep-raising area in southeastern Michigan. Here, commonly, sheep and cattle share the same 7 “barn and often use the same yards and watering troughs. Sheep are raised on 23 percent of the farms in this area as compared to 6 percent for the rest of the state (Hill, 1956). If the greater percentage of farms in this area contain no sheep, why do they not have a corresponding incidence of MCF if other factors are responsible? All of the 39 cases re­ ported occurred on farms where sheep were raised. In one instance, the disease occurred in a Hereford steer on a farm where sheep raising was the main endeavor and no permanent cattle herd was maintained. This animal was purchased as one of 16 feeder animals in October, 19 56, and came down w ith the disease in February, 1957. A similar case had occurred three years previously in a feeder steer. Inasmuch as no permanent cattle herd had been maintained on the farm for several years, the involvement of sheep as a carrier seems indicated; however, this does not preclude the possibility of prior infection or another source of infection. Stenius (1952) confirmed successful transmission from cattle to sheep and sheep to cattle reported previously by Zanzucchi (1934). Stenius further reported that the test animals showed only slight clinical symptoms not typical of malignant catarrhal fever. SUSCEPTIBILITY OF HUV ADDITIONS The apparent susceptibility of new additions to the herd lias been noted in Finland (Stenius, 1952). vations have been made in this study. Similar obser­ New additions to the herd have become infected up to one year after joining the 8 herd suggesting that previous exposure was not a factor* Farquharson (1946) "believed that we must accept the fact that either most cattle are immune or have had subclinical infec­ tion* It seems probable that the explanation for the occur­ rence in animals born and raised on the farm is a matter of individual resistance and stress factors (such as weather changes)« MORTALITY Marshall et a l * (1920) recorded a morta-lity of 100 per­ cent in an outbreak in Pennsylvania* Farquharson (1946) observed a mortality of at least 90 percent in colorado. Stenius (1952), citing a total of 120 cases, observed that 27 percent died, 38 percent were slaughtered, and 35 per­ cent recovered. The mortality rate in Michigan has been almost 100 percent. A practitioner with 15 years* experience in the enzootic area reports only one recovery during this period (Eames, 19 56). A few cases, in which MGP had been diagnosed clinically, have appeared to be recovering only to suffer relapse and die within a few days# MORBIDITY Bovine malignant catarrhal fever is enzootic in nature; varying intervals of time may elapse between cases. Old- timers in the enzootic area recall cases up to 50 years previous to the time of the present episode. Thus, histor­ ically, the disease is not a new condition in Michigan. Farquharson (1946) a,nd Stenius (19 52) have stated that once the disease occurs on the premises it is likely to recur; 9 these studies lend support to this statement. Usually only one animal is affected in a herd; rarely, as many as three cases have occurred. A similar morbidity rate has been re­ ported in Colorado (Farquharson, 1946). Seemingly, only in rare instances are several animals simultaneously affected; but it must be born in mind that outbreaks ascribed to socalled 11hemorrhagic septicemia" , infectious kerato-conjunctivitis, mucosal disease, or pneumonia may be MCF. AS A CAUSE OF ABORT 1017 The evidence seems to indicate that malignant catarrhal fever is not a cause of abortions. No history of an unusual abortion rate on infected premises has been reported. In one case a calf was dropped one month prematurely; neverthe­ less, the calf showed no signs of the disease. The animal was weak but survived with good cure suggesting that the a/bor. tion was not due to the agent per s e » but to the debilitating effects of the disease on the dam. The calf was born a month after the acute episode; the dam later died in the chronic stage of MCF. One fetus _in utero was examined oost-mortem and showed no gross or microscopic evidence of infection although the dam had died of the acute head-and-eye form of MCF. In Pennsylvania it was noted that several calves dropped during an enzootic outbreak were not affected by the disease (Marshall et a l .. 1920). ECONOMIC ASPECTS The exact economic importance of MCF is difficult to as­ certain. Few reports of this disease are made yearly in 10 Michigan but the cases investigated in this study indicate that the disease may be masquerading undrr other names such as hemorrhagic septicemia, infectious kerato-conjunctivitis9 atypical pneumonia, and mucosal disease* The individual farmer unfortunate enough to hove this disease on his premises suffers intermittent financial loss w i t h varying intervening periods of no losses. investigators Marshall et a l . (1920), North Dakota (1937), and Farquharson (1946) have reported cases of an enzootic type. The chronic case may cause the owner considerable loss; the animal appears to be improving slightly, thus encouraging the farmer to continue treatment and care , only to relapse and die several months later. SYMPTOMS OF DISEASE The onset of the disease is sudden; no indications of impending sickness are seen. to little or nothing. not at all. Milk nroduction droos sharply The animal eats and drinks poorly or A profuse mucopurulent exude,te hangs from the nostrils and, in some cases, an accumulation of this material may be seen on the floor or in the manger (fig. l). A characteristic nasal roar and severe dyspnea develop as the disease progresses; distinct rattling sounds may be heard as exudates collect. The breath has a fetid odor. During the early phase of the disease a serous fluid drains from the medial ca.nthi of the eyes, coursing its way ventrally down the lateral surfaces cf the head leaving swaths of matted hair; after three to four days this fluid becomes mucoid in nature and collects in the corners of the 11 eyes# A peripheral corneal cloudiness usually begins on the first or second day terminating in complete opacity and blind­ ness in four to five days (fig, 2)# This ''frosting" of the cornea is a prominent feature of the syndrome. scleral injection is noted. Marked epi­ The eyelids often ore mildly swollen with somewhat rounded margins. The epithelium of the muzzle is at first slightly reddened; later, a thick crusting of necrotic epithelium and exudate may partially mask this change. If this thickened, cracked layer be dislodged, a raw red surface which may bleed pro­ fusely is presented, in small patches. Gradually the nasal epithelium sloughs The anterior nasal mucous membrane is covered by a gray pseudomembranous layer which overlies the inflammed and necrotic nasal mucous membrane. On examination of the oral cavity one may find changes varying from a diffuse necrosis of the buccal mucosa to a macular appearance formed by small areas of erosion (figs, 3,4), A diphtheritic coating may be found in some cases, but may have been washed away if the animal has been drinking. The skin may exhibit certain features of diagnostic im­ portance, The epidermis is dry, leathery, and folded as one would expect in a severely dehydrated animal: in addition, however, a characteristic tufting of the hair in small catches, particularly over the cervical region, has been observed in several cases. Localized thickenings of the skin underlie these tufts; occasionally small contiguous lymph nodes have been swollen. Raised circumscribed areas, measuring approx­ 12 imately five mm* in diameter, have been observed on the udder. Patchy erythema may occur anywhere on the body but has been noted particularly on the udder and lips of the vulva. The teats may be ruborous early in the disease followed by develop­ ment of a characteristic thickening of the skin crisscrossed by deep fissures exposing the subcutaneous tissue; dark brown scabs may develop on the teats and, less frequently, on the udder and vulva (fig* 5). Temperature elevation to 106 P. is noted on the first two to three days of illness and gradually declines on the fourth or fifth day to a level of 103 F.-104 F. The animals are commonly in a state of abject depression, standing motionless with the head lowered and neck extended. Gases have been reported by some investigators in which ex­ treme excitement and viciousness to the point of attacking the handlers have occurred; but in the cases observed in this study only mild symptoms of such nervous excitement — uneasiness and shifting of the feet — were seen. marked Marked hy­ per the sia was common but this is believed due to the inflamma­ tory processes in the integument rather than a central nervous system disturbance. Urinary disturbances may be present in some cases, but are not a constant feature. Blood-tinged urine may be passed at the end of micturition accompanied by straining and dribb­ ling of the urine. FORMS Gtttze (1930) described four forms of the disease: viz., 13 (l) peracute, nign. (2) head-and-eye, (3) intestinal and (4) b e ­ Several peracute cases have been diagnosed in Michigan; these cases run a course of two to three days* The majority of cases in this study have been of the head-and-eye form* The course in these cases was generally from four to fourteen days; the most common duration was seven days. One case of the intestinal form has been diagnosed on the basis of histopathological features. A fifth or chronic type of MCF has been observed in Michigan. This type runs a course of up to six months or longer, terminating in death. Some of these cases may be mistakenly assumed to be recovering as the symp­ toms abate. The animals begin to eat and drink but do not seem otherwise to improve nor deteriorate until they suddenly relapse and die; often large patches of skin will slough in the later stages. Cases of the benign form have not been recognized here. It must be emphasized that atypical variations of the symptoms previously described were not uncommon. cases the corneal opacity was absent; oral erosions were not found. In a few in others, muzzle and/or In one instance no character­ istic clinical features were present except a temperature elevation of 106 F. which did not respond to antibiotics. The diagnosis was made on the basis of post-mortem lesions which will be discussed In the next section. CLINICAL PATHOLOGY Examination of blood and urine specimens can be of value in diagnosis. Leukopenia with a shift to the left may be 14 present in the early stages of the disease. Damage to the urinary tract may be indicated by albuminuria, glucosuria, or hematuria. The latter has been observd clinically toward the end of micturition and apparently indicates hemorrhage in the bladder. SUMMARY AMD CONCLUSIOHS Bovine malignant catarrhal fever as observed in Michigan is an enzootic disease characterized clinically by fever (106 E.), nasal and ocular discharge, corneal opacity, erosions of the muzzle and oral cavity, marked depression, anorexia, rapid weight loss, erythema of the skin (particularly the udder and vulva) and, occasionally, thickening and cracking of the teats, tufting of the hair, and hematuria. Leukopenia, may be present. A definite seasonal incidence involving late winter and early spring is indicated. Clinical evidence points to sheep as carriers of the causative agent. The disease is usually fatal in from 4-14 days although chronic cases may occur. Atypical cases may be misdiagnosed as atypical pneumonia, infectious kerato-conjunctivitis, hemorrhagic septicemia, as entities of the mucosal disease complex. or Fig* 1-Cow w it h head-'and-eye form of malignant catarrhal fever showing mucopurulent nasal discharge and excoriation of the muzzle* 15 Fig. 2-Eye of cow showing marked corneal opacity due to malig­ nant catarrhal fever. Fig. 3-Mucous menibrane of lower lip and gum of cow showing patchy erosions (arrows) in a case of acute malignant catarrhal fever. 16 rig* 4-Lateral surface of bovine tongue showing irregular erosions (arrows) of the mucous menibrane in an acute case of malig­ nant catarrhal fever. rig. 5-Bovine teat showing hyperkeratinization w it h scaling and cracking due to malignant catarrhal fever. 18 II. PATHOLOGY INTRODUC TION Pew reports on the pathology of bovine malignant catarr­ hal fever have been published in the United States* Smith and Jones (1957) in their book, Veterinary Pathology* state the,t "considerably more study of malignant catarrh is needed, as are better methods for its recognition." The few available reports of the disease in North America are mostly of a clinical nature or have dealt with only the gross lesions (Marshall et a l .. 1920; North Dakota Livestock Sanitary Board, 1937; Parquhargon, 1946; Hines and Barner, 1955). Schofield (1950) described round cell and mononuclear cell infiltrations in the brain, liver, and kidneys in a case in Canada. Goss et a l ♦ (1947) described a ser©-catarrhal to diphtheritic inflammation involving the mucous membranes; cytoplasmic inclusions were reported in the epithelial cells of the mucous membranes. It is hoped that the studies reported herein, based on material collected from 31 field cases of bovine malignant catarrhal fever, will contribute to the knowledge regarding the nature and diagnosis of this disease, particularly the recognition of relatively atypical cases which, in our experience, were quite common. MATERIALS AND METHODS Tissues were fixed in 10 percent formalin with sodium acetate as described in the Armed Porces Institute of Path­ ology Manual (1957). The tissues were next dehydrated in a series of graded alcohols, passed through xylene, and embedded 19 in paraffin* Sections were cut at 6-7 microns and stained w i t h hematoxylin and eosin according to the method described by Malewitz and Smith (1955)* Sudan IV was used as a fat stain as described by Mallory (1938). Other special stains used were L e n d r u m ’s, Poliak’s trichrome, Masson’s trichrome, V e r h o e f f ’s elastica stain, Mall ory ’s aniline blue collagen stain, and the phloxine methylene blue stain* These stains were used according to methods and formulas in the Armed forces Institute of Pathology Manual (1957). The phloxine methylene blue stain was modified in that the slides were stained in phloxine for three hours at 56°C. or overnight followed by decolorization in one percent acid alcohol for ten fjeconds. RESULTS SKI3ST The animals presented for post-mortem examination were usually markedly underweight. The hair coat was dull and roughened; occasionally, tufting of the hair was found (in chronic cases hairless areas were present), particularly in the cervical area. In many cases, thickened crusts, 1-2 mm. in diameter, were observed in the skin, most often in the cervical region, but, occasionally, scattered over the entire body. The vulva was frequently markedly reddened. In many instances, marked lesions of the udder were found: cracking and crusting of the skin of the teats, areas of erythema, and raised papules, 1-2 mm. in diameter. Lesions of the muzzle varied from thickening and scaling to complete 20 erosion of the muzzle epithelium exposing a raw, reddened sur­ face* Generally, there was a profuse mucopurulent nasal discharge• The microscopic lesions of the skin as well as other stratified squamous epithelia have been grouped for convenience of description. Representative sections from the muzzle, vulva, udder, eyelids, affected skin areas, and squamous portions of the digestive tract were examined. Specimens from macro- scopically normal as well as visibly affected areas were studied. It was discovered that many of the apparently normal tissues contained excellent examples of microscopic lesions. By comparing tissues from these areas with tissues from more severely affected sites, the pathogenesis of the lesions could be reconstructed. Lesions from all cases were remark­ ably similar although their distribution varied from animal to animal; in other words, the variations were quantitative rather than qualitative. The process ap eared to begin as multiplication of cells of the basal layer of the epithelium together w i t h an increase of connective tissue cells and lymphocytes in the dermal papillae (fig. 11). Increased cellular activity was apparent about blood vessels which were markedly congested. The epithelial cells formed loose networks which were interconnected by fine cytoplasmic strands. Occasional ballooning cells with condensed acid­ ophilic cytoplasm were found in the central areas of the rete pegs. shaped. Many of the rete pegs were elongated and club- The basal cell layer was not distinct due to the 21 loss of polarity of the nuclei and proliferation of the cells (mitotic figures were frequently observed in the basal area). Occasional necrotic epithelial cells, identified by their bright pink cytoplasm and fragmented nuclei, were scattered through the cellular masses in the dermal papillae. Thickened ker­ atin layers often maintained the external continuity of the tissue; in other instances, portions of the keratin layer were elevated by the underlying disease processes. In more severe lesions, large clumps of ballooning cells underwent reticulating colliquation with resultant vesicle formation in the upper epithelium (fig. 13). The vesicles contained cellular debris, protein-containing fluid and, occasionally, abundant polymorphonuclear leucocytes. Russell's bodies were sometimes observed in the epithelial cells. The hy- percellular masses in the dermis were often markedly pleo­ morphic. Many spindle-shaped connective tissue cells with large pale oval nuclei (fibroblasts) were present. Often numerous lymphocytes, many of which were large immature forms, were seen. E osinophiles, macrophages, plasma cells, and mast cells were usually present in smaller numbers. These changes were not restricted to the upper dermis but were very evident around blood vessels in the deeper portions of the dermis. Hyperplasia in and about blood vessels and capill­ aries was usually pronounced and, in some cases, obstruction of the vessels occurred due to masses of endothelial cells which projected into the lumen (fig. 14). Hyperplasia of the epithelial cells of the skin adnexa,© wag often prominent (fig* 15). Occasional lymphocytes and proliferating capill­ ary endothelial cells were observed in these areas* in the underlying muscle were sometimes involved* Vessels Generally* it may be said that in early lesions hyperplasia was paramount in the more advanced processes infiltration of lymphocytes and sometimes eosinophiles was prominent. Special stains were used to identify the proliferating tissue in the dermis and about the blood vessels* M all ory 1s collagen stain and Masson1 and P oli ak ’s trichrome stain indicated that this was collag­ enous connective tissue. EYES Bilateral corneal opacity was usually marked; however, cases with only slight or no cloudiness were encountered. The conjunctival vessels were generally injected. were thickened and rounded. The eyelids Abundant mucopurulent exudate was often present in the medial canthi. \ The corneal opacity observed macroscopically and the nature of its development (initial peripheral cloudiness which gradually spread to the center of the cornea) may be explained by the lesions found on microscopic examination. The most severe changes were found in the rea of the corneo­ scleral junction, but extended into the cornea, becoming less marked as they approached the center of the cornea. Essentially, the pathological process was one of a prolifer­ ative and infiltrative nature. The conjunctival epithelium usually showed ballooning degeneration and irregular hyper­ plastic projections into the lamina propria. In these areas 23 mitotic activity wag evident# was absent. In some areas the epithelium The underlying lamina propria and sclera, nar- ticularly in the anterior portions, contained pleomorphic and abundant cellular aggregations composed of mononuclear cells, lymphocytes, and some eosinophiles and plasma cells# connective tissue cells were increased in Large number (fig. 22). Many mitotic figures were observed dn large cells of varying shapes which were difficult to classify. Swelling, rounding and hyperplasia of capillary endothelial cells were observed# Blood vessels were affected by proliferative and infiltrative lesions as in the skin. The corneal epithelium showed balloon­ ing degeneration and occasional areas of erosion# Kupture of the substantia propria of the cornea sometimes occurred. The connective tissue in the substantia propria of the cornea was often granular and somewhat disrupted. Polymorphonuclear leucocytes were occasionally abundant in the cornea; the humors of the eye sometimes contained polymorphonuclear leucocytes as well as monocytes, lymphocytes, and cellular debris# Cell accumulations, similar to those described in the conjunctival lamina propria and sclera, were found in the iris, ciliary body, and retina# Occasional vascular les­ ions occurred in the connective tissue of the o^tic nerve and periorbital fat .and orbital muscles# Congestion of seem­ ingly all parts of the eye was marked# DIGESTIVE TRACT Mouth, pharynx, and esophagus. The mucous membranes of the mouth usually showed a severe necrotizing process 24 which varied from distinct ulcer-tions of irregular shape and size to diffuse necrosis of the epithelium of almost the entire cavity, in which the epithelium was easily scraped a,way with a knife* Commonly, a thick grayish-white diphtheritic membrane was found in the pharynx; sophagus and trachea also# it often involved the e- This diphtheritic membrane covered a necrotic mucous membrane. When distinct ulcerations were present, they might be found in any area of the oral cavity; usually, the remaining intact membrane was dull and gray in appearance# In some cases, petechial hemorrhages were present on the ventral surface of the tip of the tongue# The diph­ theritic inflammation in the pharynx usually extended into the proximal distance. squamous portion of the esophagus for a short Occasionally small ulcers or diffuse necrosis were found throughout the length of the esophagus# Flattening of the longitudinal folds and dullness of the esophageal epithelium v/ere observed in some cases. Microscopically, the stratified squamous portion of the digestive tract contained lesions as previously described# Blood vessels were markedly congested and showed lesions as described for the skin. The salivary glands were often the site of proliferative and infiltrative processes# The epithe­ lial cells of the salivary ductB were often hyperplastic and disarranged; proliferation and infiltration of cells were observed in the lamina propria of the ducts# The secretory units adjacent to the affected areas were compressed. Forest omachg. Gross lesions were variable in the fore- 25 stomachs• Occasionally, diffuse areas of hemorrhage and/or erosions were found. In a few cases, the papillae of the rumen showed particularly striking hemorrhages (fig. 6). Microscopically, the lesions involved the squamous epithelia as previously described under "skin” (fig. 12). Ah omasum. The abomasum was commonly the site of extreme congestion, hemorrhage, diameter (fig. 7). and often ulcers up to 3 cm. in Microscopically, scattered areas of epi­ thelial desquamation were observed in many cases. The pri­ mary change appeared to involve the blood vessels, particular­ ly those in the submucosa* These vessels were surrounded by cuffs of lymphocytes, monocytes, and occasional eosinophiles snd plasma cells. Adventitial and endothelial cells were- often increased in number; the media often contained areas of fibrinoid degeneration, pyknotie nuclei, or foci of prolifer­ ating cells which appeared to extend from the adventitia or endothelium. Vascular congestion was generalized. Occasionally, hemorrhages were noted in the mucosa. Small intestine. ly involved. The small intestine was rarely severe­ Abundant mucus was usually present* harely, petechiae, congestion, and/or small erosions were found. Microscopically, the lesions resembled those of the abomasum except that they were less frequently found. Large intestine. In a few instances, the ileocecal valve was markedly hemorrhagic, thickened, and edematous (fig. 9). In several cases the cecum and colon were congested and petebhiated; they sometimes contained small erosions. 26 The rectum displayed similar charges; petechial hemorrhages were usually arranged linearly on the crests of the rectal folds * Microscopically, severe lesions were found in the large intestine in several cases* Hemorrhage into the mucosa of the ileocecal valve was common; smaller hemorrhages were ob­ served in the mucosae of the colon and rectum, Minor desqua­ mation of the epithelium was seen in scattered areas through­ out the large intestine. In several cases blood vessels, particularly in the submucosa, were surrounded by cuffs of lymphocytes, monocytes, eosinophiles and pla,sma cells* Ad­ ventitial and endothelial cell proliferation was usually evident in such cases and often extended into the medio.* Submucosal edema, was generally pronounced in the pathologic portions of the large intestine. Liver* liver* Prominent gross lesions were not found in the Usually swelling and indications of fatty degeneration were present. Microscopically, conspicuous lesions were consistently found in the periportal areas. These areas were greatly distended by cell accumulations which compressed but did not extend between the hepatic cords (fig. 16). Many of the liver cells which were so compressed by the cell accumulations'showed pyknosis or lcaryorrhexis. The periportal cell collections were composed ui several types of cells, but monocytes and lymphocytes were the more prominent (many of which were markedly pleomorphic). More variably found were eosinophiles, plasma cells, and, occasionally, poly­ 27 morphonuclear leucocytes. was pronounced. Mitotic activity in these areas The “blood vessel walls were often greatly masked by the collections of cells, being recognized only by a central collection of erythrocytes surrounded by an occasion­ al area of recognizable mural structure# The bile duct epi­ thelium was often hyperplastic as evidenced by on irregular piling up of pleomorphic duct cells. Capillaries in the por­ tal areas were markedly congested and the endothelial cells were enlarged and hyperplastic. Sections from 4 of 31 cases were stained for fat and revealed mild to severe diffusely distributed fatty degeneration of the hepatic cells* Gallbladder. In a few cases macroscopic evidence of congestion and thickening of the wall of the gallbladder were noted. Microscopically, the changes followed the pattern found in other organs. The epithelium was intact except for an occasional small area. There was an increase of primarily monocytes, fibroblasts, and lymphocytes in the lamina propria. Plasma cells and eosinophiles were observed in small numbers. Proliferative re?ction was noted around the blood vessels, particularly the capillaries. vessels were markedly congested. hyperplastic All blood Occasional glands appeared in the areas of proliferative activity in the lamina propria. The muscle layers were disrupted by cellular infiltrates which appeared to emanate from blood vessels affected by the proliferative and infiltrative processes. Pancreas. not observed. Macroscopic lesions of the pancreas were Microscopic lesions were not prominent. 28 Mild proliferative activity among fibroblasts wap, ore sent about occasional ducts; some of the duct cells were somewhat disoriented, suggesting the possibility of an early hyper­ plastic change* The capillaries were moderately c rrg( rJ cc and scmetim.es showed milt; hyperplasia. of the endct2:.e lial cells• L ih a l lA T IG lymph. no d e s * SYSTEM The lymph nodes of the head v/ere usually enlarged, edematous, and congested. In many instances, the lymph nodes throughout the body were similarly affected and contained microscopic lesions. The changes v/ere very consis­ tent and are considered to be of diagnostic value. Blood vessels in the capsule, pulp, and perinodal fat were often markedly affected by proliferation of adventitial and endo­ thelial cells as well as accumulations of lymphocytes, mono­ cytes, plasma cells, and eosinophiles. The cell accumulations extended into the capsule and trabeculae from the vessels masking the normal structure (fig. 19). In some cases the follicular architecture vns absent or represented by a few lymphocytes; in other cases, the follicles were hyperplastic. The majority of cases exhibited marked reticulo-endothelial proliferation, particularly along the trabeculae. mitotic figures were observed. Numerous Marked congestion and edema were frequently found; rarely, hemorrhage was present. The parenchyma often bulged against the capsule, in which case clusters of pyknotic lymphocytes were observed along the capsule. Eosinophiles, plasma cells, and polymorphonuclear 29 leucocytes were variably found in the pulp. Sp lee n. The spleen showed no remarkable gross lesions. Microscopic lesions similar to those in the lymph nodes were seen in some cases. Trabecular disruption and degeneration were evident adjacent to involved vessels. plasia was often evident. Follicular hyper­ Large amounts of hemosiderin were present in some cases. CARDIOVASCULAR SYSTEM He a r t . cardium. Hemorrhages were frequently observed on the epi- The microscopic lesions followed the pattern noted in other organs. Rerivascular cuffs of adventitial cells, lymphocytes, occasional monocytes, and sometimes minor ininf iltrations of eosinophiles, plasma, cells, and polymorpho­ nuclear leucocytes v/ere present. Both fibrinoid degeneration and accumulations of proliferating cells were observed in the media. Proliferation of endothelial cells was seen in some vessels. The lesions occasionally impinged on adjacent muscle fibers but usually extended along the connective tissue tracts from the blood vessels. Mild to severe fatty degeneration was observed in the cardiac muscle fibers in four cases in which special stains were dene. Vascular lesions were not present in the hearts from all of the cases and not all vessels in an affected section showed lesions* Aorta. In one case pa.pular elevations, 1-2 mm. in diam­ eter, were noted on the intimal surfo.ee of the aorta. These proved, microscopically, to be focal areas of endothelial proliferation. Whether this should be considered, an incidental 30 finding or a part of the IiCF syndrome cannot he decided on the "basis of one specimen, although the nature of the lesion suggests that it was a part of the disease process* Accumu­ lations of cells in and ahout the vasa vasorum of the aorta, similar to those described in the heart, were occasionally observed. RESPIRATORY SYSTEM Nasal passages and trachea* Commonly, a thick, greenish, fetid, fibrino-necrotic membrane covered the congested nasal mucous membranes (fig. 9). Usually the proximal portion and occasionally the entire length of the trachea contained a similar diphtheritic layer. Scattered petechial hemorrhages were observed in both the nasal passages and trachea. The epithelial surface of the trachea was generally dull and yellowish in appearance. Microscopically, the epithelium of the nasal passages and trachea contained many ballooned cells* exudate was piled up on the surface. Fibrino-necrotic In several cases little or no recognizable epithelium remained. Aggregations of lymphocytes and monocytes were scattered throughout the lamina propria. Connective tissue proliferation in the lamina propria was evident. Capillaries were markedly congested and the endothelial cells were swollen and hyperplastic# Lungs. The lungs exhibited pleural hemorrhages and areas of firm red hepatization in some cases* In several cases the lung exhibited marked microscopic lesions which were consistent with the pathological picture found in other organs. The larger bronchioles we re the site of marked proliferative and infiltrative changes, although not all of these bronchioles were affected. The lamina propria contained cellular aggregations of monocytes, lymphocytes, fibroblasts, and occasional eosinophiles, plasma, cells, and polymorphonuclear leucocytes which extended into the muscuiaris \fig* 18). The broncliiolar epithelium was pushed into the lumen by the underlying cell collections; loss of polarity and hyperplasia of the bronchioiar epithelium were usually present in affected bronchioles. Many of the respiratory epithelial cells were ballooned. Often there was poor de­ marcation between the epithelium and lamina propria. The lumina of the bronchioles contained mucus, cellular debris, and polymorphonuclear leucocytes. Capillary endothelial cells were generally swollen and hyperplastic* The alveolar walls were thickened by an increased number of septal cells. alveoli v/ere filled with erythrocytes in many areas. The Large and small blood vessels exhibited marked adventitial and en­ dothelial proliferation; fibrinoid degeneration was common in the media, although in areas increased numbers of cells were noted which appeared to extend from the proliferative endothelial or adventitial areas. Accumulations of monocytes, lymphocytes, a,nd occasional eosinophiles, plasma cells, and polymorphonuclear leucocytes were present in the adventitial cuffs. All of the blood vessels were extremely congested. URINARY SYSTEM Kidneys. The kidneys were usually congested and often 32 contained petechial hemorrhages. In one case, white focal areas were present on the cortical surface. The microscopic changes in the kidney affected the blood vessels and Bowgiian^ capsule. These changes were consistent wit h lesions in other organs and were essentially prolifera­ tive and infiltrative in nature. Blood vessels, surrounded by loose cuffs, which, v/ere composed of adventitial cells, lymphocytes, monocytes, and some eosinophiles and plasma cells, were scattered throughout the kidney, although not all vessels were affected# In many cases the glomerular capsule was masked by infiltrations of lymphocytes and mono­ cytes. It was noted that these areas were most frequently seen surrounding the afferent and efferent arterioles,, and, in view of the lesions of the vessels in the kidhey as well as in other organs, it was felt that the accumulations origin­ ated from the arterioles. The lesions were usually semilunar in distribution, but did extend completely around the glomer­ ulus on occasion. capillary tuft. The process occasionally extended into the Compression of the tubules in the areas ad­ jacent to the cell accumulations was evident. generation was usually present in the tubules. Albuminous de­ Marked congestion of the intertubular capillaries and, occasionall 3r, hemorrhage were found in both the cortex and medulla. The pathological findings in the kidney were not constant, but were of frequent occurrence. Mild to severe tubular and glomerular fat accumu­ lations were revealed by special stain of sections from 4 of the 31 cases. 33 Ure ter s. congested* Grossly, the ureters appeared swollen and Microscopically, the transitional epithelium exhibited ballooning degeneration; little or no recognizable epithelium remained in some areas* Occasional sections of epithelium appeared somewhat hyperplastic and blended with the h,ighly cellular lamina propria* numerous monocytes, lymphocytes, The latter contained and large pale connective tissue cells together with a smaller number of eosinophiles, plasma cells, and occasional mast cells. Blood vessels in the lamina propria and muscularis showed fibrinoid degenera­ tion of the media and accumulations of cells, as previously described under "skin", in the adventitia* Marked congestion in most vessels was evident. Urinary bladder. Macroscopically, the bladder was severely affected in several cases. thiclcened. The wall was greatly The mucosa was thrown into large folds; mucosal hemorrhage was often severe (fig. 10) — accounting for th* hematuria observed clinically in several cases. Microscopically, hemorrhage was often pronounced in the subraucosa. The epithelium was absent in many cases; in other instances, transitional cells undergoing ballooning degenera­ tion were noted* The lamina propria was markedly hypercellular containing large mononuclear cells, lymphocytes, fibroblasts, and some eosinophiles and plasma cells (fig. 20)* In a few areas, the cellular masses in the lamina propria blended w i t h the transitional epithelium. Blood vessels were severely involved, undergoing alterations similar to those previously 34 described* Capillary endothelial cells were enlarged and hyperplastic# Congestion was marked# The smooth muscle often contained evident vascular lesions which produced disruption of the muscle layers# KEHUXDUCTIVE SYSTEM Uterus#, ovaries# and oviducts# The uterus, ovaries, and oviducts did not present any macroscopic lesions other than congestion# Sections indicated that severe involvement of the system may occur. Portions of uteri examined revealed lesions in accord with those observed in other organs# Blood vessels throughout the uterus were affected by proliferative, filtrative, and sometimes degenerative phenomena# in­ Endo­ thelial activity was observed in both capillaries and larger vessels# Cuffs of cells surrounded many vessels; these were composed of adventitial cells and infiltrating cells as previously described# The media was either involved with cellular accumulations or undergoing fibrinoid degeneration or both# Fluid accumulations and cell collections were scat­ tered throughout the uterus. Patchy areas of glandular^ hyperplasia appeared to contribute to the proliferative picture. Vascular lesions were also found in the ovaries. - Many areas of hemorrhage v/ere found in and about the affected vessels# One specimen of placenta and fetus were examined# Vascular lesions were present in the placenta bu none could be found in the fetus# The oviducts contained cell accumula­ tions in the lamina propria as well as vascular lesions# 35 Mammary glands ♦ Specimens of 'both lactating and non- lactating mammary tissue exhibited proliferative and in­ filtrative processes. Endothelial cells of small capillaries in the interstitial tissue were enlarged, rounded, and hy­ perplastic# sent. Marked congestion of the blood vessels was pre­ The alveolar cells in many of the secretory units ex­ hibited loss of nuclear polarity and piling up of pleomorphic alveolar cells in a manner which caused them to blend with the activated endothelial cells in the inters tit ittra. In some instances, the lumens of the glands v/ere obliterated by masses of proliferative cells. ducts and teat cisterns. Similar changes were present in the The epithelial cells appeared marked*- ly ballooned and the lamina propria was markedly hypercellular (fig. 21). Monocytes, lymphocytes, and some plasma cells, eosinophiles, and mast cells were present. In some areas the epithelium and lamina propria were poorly demarcated. Vascular changes were the same as observed in other organs. The severe lesions in the mammary gland may account in part, at least, for the sharp decline in milk production in lactating animals which is a prominent clinical feature. Testes♦ Macroscopically, the testes from one bull ex­ amined v/ere congested. Sections from this case revealed that arteries and veins in both parenchyma and capsule were sur­ rounded by cuffs of proliferating adventitial cells, lympho­ cytes, and occasional wandering monocytes. The media of m?ny of the vessels exhibited a fibrinoid appearance; cell accumu­ lations sometimes were present in the media. The endothelial 36 cells in some vessels were enlarged and hyperplastic*. Capillaries in the interstitial area contained hyperplastic endothelial cells. was evident. Compression of the seminiferous tubules All of the blood vessels were engorged with blood. E1TDROCR IKE SYSTEM Thyroid. thyroid. Macroscopic lesions were not observed in the Sections exhibited marked hyperplasia of follicular cells which often obliterated the lumen (fig. 23). The pro­ cess extended into the interstitial tissue blending with proliferating endothelial cells. present in the interstitial areas. Occasional lymphocytes v/ere Fyknotic follicular cells were frequently observed in the lumens of some of the affected alveoli. Adrenal glands. Macroscopic changes in the adrenal glands were not observed. Microscopic lesions of the blood vessels, consistent with those found in other organs, were commonly found in the adrenal glands in both the capsular and parenchymal areas (fig. 24). Compression and disruption of the adrenal architecture were apparent in the areas adjacent to the vascular lesions. Fibrinoid degeneration, of the media and endothelial and adventitial proliferation were observed. Lymphocytes, monocytes, and some eosinophiles, plasma cells, and mast cells were present in the perivascular tissue extending into the capsule. Occasional areas of hem­ orrhage were found; blood vessels were markedly congested. Occasional .affected vessels were present in the fat surrounding 37 the adrenal glands* ~ituitary. were observed. No macroscopic lesions of the pituitary gland Microscopic changes v/ere limited to the blood ves sel s, particularly those in the connective tissue; they were similar to the vascular lesions in other organs* NERVOUS SYSTEM Central nervous system* Gross lesions of the brain were limited to marked congestion and edema of the meninges* The most prominent and consistent microscopic alterations involved the blood vessels, both arteries and veins. The vessels were surrounded by cuffs of predominantly monocytes and lymphocytes (fig* 17)* Occasionally, eosinophiles were abundant. The majority of the mononuclear cells v/ere seemingly interconnected by f ine pale cytoplasmic strands. The lymphocytes were pleo­ morphic; large young forms v/ere abundant. was frequently observed in the cuffs* Mitotic activity In some vessels the endothelial cells v/ere enlarged and rounded; occasionally, they were piled up suggesting mild hyperplasia. Free red blood cells were often present in the cuffs and perivascular spaces; they appeared to have leaked through the loose, disarranged structure of the vessel walls* Often the Virchow-Robin spaces were obliterated by the thickened walls and congestion in the vessels; encroachment upon the surrounding brain substance was apparent in many areas* The capillary endothelial cells were generally enlarged and hyperplastic. Sections of the central nervous system examined included meninges, medulla, cerebellum, cerebrum, thalamic area, hippocampus, and spinal 38 cord, all of which contained lesions . In several cases, the cnoroid plexus showed both infiltration of numerous mononuclear cells and proliferation of the capillary endothelial cells. hon-specific changes also were usually present in the "brain. idarked congestion and edema were often pronounced. The neurons appeared normal in many cases and degenerative changes, when present, were not marked, but there were varying degrees of neuronal degeneration, as evidenced by eccentricity of the nucleus, chromatolysis, and ghost cells. Gatellitosis and neuronophagy v/ere present in some cases but v/ere usually not marked. It is believed that the neuronal changes were due to the impaired circulation and pressure produced byaffected vessels rather than to specific infection of the neurons. Both generalized and foGal increases in glial cells were observed. Inclusion bodies as described in Finland (Gtenius, 19 52) were found in the cytoplasm of the neurons of the vagoglosso­ pharyngeal nucleus in 73 percent of the cases examined. These bodies v/ere observed in two patterns of distribution: viz; 3 ingle or multiple inclusions v/ere seen scattered throughout the cytoplasm or conglomerates composed of numerous spher­ ical bodies were located adjacent to the nuclear membrane. Distinct halos were often visible about the bodies; the inclusions varied in size from 300-500 millimicrons in diameter. Both degenerated and otherwise apparently normal neurons were affected. The bodies v/ere difficult or impossible to see w i t h the routine hematoxylin-eosin stain. Among the 39 stains U3ed, Mallory's phloxine-methylene blue stain gave the best res ult s. ITot only was excellent differentiation of the bodies obtained (oright red. to wine), but the Nissl substance was well stained by tiii3 method. Other stains used to demon­ strate these bodies were Sho rr’g III, M a s s o n ’s trichrome, P o li a k ’s trichrome, and Lendrum's. In an attempt to demonstrate the diagnostic importance of these striking bodies, sections of medulla from cattle coming routinely to the post-mortem room were examined. Similar bodies v/ere observed in 13 of 47 cases examined. There was no evidence to suggest the presence of malignant catarrhal fever at the time of necropsy in these cases. Therefore, we do not believe that these bodies are of specific diagnostic importance. Gasserian ganglia. The Gasserian ganglion was removed in several cases for examination for inclusion bodies by special stain. No inclusion bodies were found, though the the observations included several cases wherein such bodies were demonstrated in the medulla. However, microscopic lesions v/ere found consisting of the previously described proliferative and infiltrative changes of the vessel walls which extended into the connective tissue surrounding the cell bodies of the neurons. There did appear to be a mild increase in the capsular cells. Many of the nerve fibers in the affected areas were fragmented. DISCUSSION Grossly and microscopically it is evident that the 40 causative agent of MG 3? may produce lesions in all systems of the "body and therefore it is pantropic in nature; thus it ig no more appropriate to classify this disease as primaril;/- an encephalitis than to so classify hog cholera or canine distem­ per# The lesions in the hrain primarily affect the blood vessels; that neurons are not severely involved is indicated by microscopic examination and by the lack of extreme nervous manifestations clinically in most cases. The pattern of the lesions is consistent in all systems* Ussentially, two different processes are involved: (l) pro­ liferation of connective tissue, endothelial, and epithelial cells is widely distributed in epithelial elements and blood vessels and (2) infiltration is generalized, affecting the lamina propria of many etructures as well as the periportal area of the liver and blood vessels. We can logically attribute the necrosis which may occur, particularly in the squamous epithelia, to any one or, more likely, a combination of several causes# Tirst, the surface integrity of structures such as the skin and mucous membranes is disrupted by the ballooning degeneration, vesiculution, and loss of epithelium wliich exposes the tissue to secondary invaders. Secondly, the involvement of the vasculature by proliferative and in­ filtrative processes which may obstruct the lumen or disrupt the architecture of the wall, thus affecting the circulation to the area, is certainly important. This mechanism is well illustrated in the abomasum a n d intestine* Here one finds only primarily a desquamation of epithelium with an involve- ment of vessels, particularly in the submucosa, which appears to he the logical cause, Uven if not obstructed, these vessel cannot contract or dila.te normally in response to the tissue demands for blood. Thirdly, the great increase in perivascu­ lar cellular elements would seem to produce a pressure which may not only affect the cells directly but probably also shuts off lymphatic and vascular channels. In addition, the functional activity of an organ may be expected to be affected by the lesions in that organ as well 0.3 by influences from other involved organs. We should like to..-present those features of the disease which, in our experience, have proven.,to be of the greatest diagnostic value. One must remember that the distribution of many of the lesions is highly variable. Cases of the typical ’’head-and-eye11 form are obvious; however, cases have been encountered wherein only intestinal lesions have been observed. A. case is described in Canada in which only inflamma tion of the trachea and large bronchi and ecchymoses in the heart were found (Schofield, 1950). Historically, contact with sheep and indication of a previous sporadic occurrence (which one may discover only by further questioning of the owner) are helpful features. Clinically, the temperature of approximately 10 3 7*. early in the disease which does not respond to antibiotics, any indication of skin involve­ ment (erythema, papulation, or scabbing), corneal cloudiness, rapid weight loss and death are suggestive of TiCIV Suggestive post-mortem findings are; diphtheritic inflammation in txie 42 nasal passages^ oral cav i t y , and trachea; enlarged, edematous and/or hemorrhagic lymph nodes; hemorrhage and/or erosions in the digestive tract and bladder. Microscopically, the most helpful lesions are the constant cellular accumulations (primarily monocytes and lymphocytes) around the blood vessels in the brain and in the periportal areas of the liver. microscopic lesions in the skin, lymph nodes, kidneys, adrenal glands may also be of value* The and We believe that correla­ tion of the history, clinical findings, and post-mortem ex­ amination should enable a definite diagnosis to be made even in atypical cases. SUMMARY AKD CONCLUSIONS Grossly, the lesions of bovine MCI1 generally found were marked weight loss, nasal and ocular discharge, corneal opacity, erosions of the muzzle, erythema of the udder and vulva and, in a few cases, encrusting of the skin, tufting of the hair, and thickening and cracking of the epithelium of the teats. Severe oral erosions v/ere found in most cases. Diphtheritic membranes v/ere frequently observed in the nasal passages, pharynx and trachea. Scattered areas of congestion, hemorr­ hage, and/or erosion were variably found in the digestive tr act-usually most pronounced in the abomasum and large intestine when present. Lymph nodes, particularly those of the head, but often of more general distribution were enlarged, edematous, and/or hemorrhagic. Hemorrhage and erosion in the bladder v/ere observed in some cases. Micx’oscopically, MCF was characterized by proliferative 43 and infiltrative changes« In tine esse of squamous o'Ditlne— lial surfaces these were followed by necrosis* The prolifera­ tive lesions were widely distributed, affecting vascular and epithelial structures* Marked elongation of the rete pegs was regularly observed in the squamous epithelium; adnexal akin structures often displayed marked hyperplasia* The der­ mal papillae contained abundant and pleomorphic cellular aggregations composed of monocytes, fibroblasts, lymphocytes, eosinophiles, plasma cells, and mast cells. Similar prolifera­ tive and infiltrative processes were also noted in the lamina propria of the eye, bronchioles, urinary bladder, gallbladder, ureters, and teat cistern; the epithelium of some of these structures appeared to be hyperplastic. Vascular proliferative and infiltrative lesions were present and marked in the liver and brain in each case; they were less constantly found in most other organs. Proliferation in blood vessels was most commonly seen in the adventitia, but the media and endothelium were not infrequently involved. Mild to marked infiltrations of lymphocytes, monocytes, eosinophiles, plasma cells, and mast cells were usually observed in and around the affected blood vessels. Vesicles were frequently found in the squamous epithelium, soiaetimes containing heterophiles; they appeared to originate from coalescence of necrotic and ballooning cells in the stratum Malpighii. The lesions described are believed to be consistent and characteristic enough to be of diagnostic value. Intracyto- 44 plasmic inclusions in the neurons, previously reported in Finland, were observed in the majority of cases; however, their specificity is questioned. Fig. 6-Hemorrhage in the papillae of the rumen in an acute case of MCF Fig. 7-Circumscribed (A) and linear (B) erosions in the abo­ masum in an acute case of MCF. Fig. 8-Diffuse hemorrhage and edema in the ileocecal valve (arrow) and adjacent area in an acute case of MCF. Fig. 9-Diphtheritic membrane (a ) and hemorrhage nasal sinus in an acute case of MCF. (B) in the Fig. 10-Hemorrhage and thickening of the wall of the urinary bladder in an acute case of MCF. Fig. 11-Early lesion in the tongue demonstrating clubbing of the rete pegs due to hyperplasia (A) and cell accumu­ lations in the papillae (B). X135* 47 Fig. 12-Epithelial hyperplasia (A) and hemorrhage a papilla of the rumen. X135. (B) in Fig. 13-Vesiculation (a ) and scaling of hyperkeratinized layer (B) in epithelium of the teat. X135. 48 't^rt v w * m Fig. 14-Artery in dermis of teat showing endothelial (A) medial (B) and adventitial (C) proliferation. Area of pro­ liferation about a capiliary (l>). X250. Fig* 15-Hyperplasia of epithelial cells in meibomian glands of eyelid. Remnant of gland (A) and area of hyperplasia (B). X250* 49 Fig* 16-Cell accumulation limited to portal area of the liver. Lumen of vessel with wall masked "by cell collections (A). X250. Fig. 17-Perivascular cuffing of vessel in medulla oblongata. X250 • Fig. 18-Cell accumulations in the lamina propria of a bronchiole (A). X250. Fig. 19-Lymph node showing reticulum cell hyperplasia (a ) degeneration of connective tissue in a trabecula (B) and infiltration of a trabecula (C). X135. Ar -V m\ f+ : v> x e > ^ 0 S T m <*+ 7?mZ:X? sKdttSiBF '.V *« - l :Vsf •;• -v? *> Fig* 20-Loss of transitional epithelium and cell accumulations in the lamina propria of the urinary bladder. E p i ­ thelial remnant (A). X I 35. Fig. 21-Cell accumulations in lamina propria of the teat cis­ tern (A) ballooning degeneration of epithelial cells lining the cistern (B) and reaction about a duct (C). X135. ** ’ 1 ^ -x. < V ' ;-*.V. r F A ’i p V ? 7 Itti* 3 , • -*rVfft-.PS f.rfv . . P.. 3Tig. 22-Cell accuinu.1 ations in (A) and sclera (B) in junction of the eye. tival epithelium (C). the conjunctival lamina propria the area of the corneoscleral ITote hyperplasia of the conjunc­ X135. Big. 23-Hyperplasia of follicular cells in the thyroid (a ) and ’ pyknotic cells in the lumens of the follicles (B). X250* m 'l'*mr *i.-*jj^ >»*^ a? ’ Jlasia and ballooning degeneration (which may lead to vesiculation) in the epithelium in MCP. The wide distribution of lesions in KCF should rule 63 erosion in the forestornachs and large intestine, and, occasion­ ally 9 hemorrhage and erosion in the bladder* Since one or more of these features may he absent in any given case, histopathological examination may be of value* Lesions of affected mucosae in IBR are characterised by a surface accumulation of exudate w ith or without erosion of the epithelium. The submucosa is edematous and infiltratedwith polymorphonuclear leucocytes, lymphocytes, and monoclear phagocytes* -Hyperemia and hemorrhage are common* in MCI? are somewhat similar* Lesions of the nasal passages In contrast to IBR, lesions of the stiatified squamous epithelia in MCI1 consist of pro­ liferation of epithelial cells, dense subepithelial cell accumulations (not containing polymorphonuclear leucocytes) in the dermal papillae and perivascular areas, and ballooning degeneration and vesicle formation of the epithelium followed by erosion. Elsewhere, the constant portal lesions in the liver, perivascular cell accumulations in the brain, and irregularly distributed vascular He sions found in MCE should make a definite differentiation possible. HYEKEKERATOSIS Olafson et a l . (1947) has described hyperkeratosis or X-disease as a chronic disease characterized by depression, emaciation, anorexia, and a thick, dry, wrinkled skin* Pathologic changes observed were papillary proliferation and fibrosis of small bile ducts, thickening of the intestinal mucosa, and cystic dilatation of the renal tubules. skin lesions are due to hyperkeratosis* The Gibbons (1949) 64 descrioed an acute form characterized "by ulccratiYe stom­ atitis* Salivation, lacrimation or mucopurulent ocular discharge were present* Morrill and Link (19 50) reported that animals may die without showing skin lesions and yet be affected internally* It was further reported that ulcerative lesions may occur in the mouth, esophagus, and true stomach* Uephritis may be a feature of hyperkeratosis* The skin lesions observed in MCE consist of scabbing and erythema in many external areas* Diffuse thickening of the Integument was not observed in MCI’. Cases of the "head-and-eye" form should not present a diagnostic problem* elevation (106 F. } is The temperature characteristic of MCE; temperature elevation is not a feature of hyperkeratosis* Hemorrhage, congestion, and ulcerations in the forestomachs and large intestine are suggestive of MCE* Erosions and hemorrhage in the bladder and enlarged hemorrhagic- lymph nodes, which may be found in MCE, have not been observed in hyperkeratosis* Microscopically, there are no similarities between the W o diseases* Epithelial hyperplasia in the renal tubules and columnar epithelial structures in the digestive tract and squamous metaplasia in the genital organs have been described as features of hyperkeratosis (Olafson et al * , 1947; Gibbons, 1949; Morrill and Link, 1950; Smith and Tones, 1957), but have not been observed in MCE* FOOT AMD MOUTH DISEASE Foot and mouth disease in this country. (FMD) is an ever present threr.t Since there are certain points of similarity “between EMD fmd MCE which may cause confusion, it is well to consider the differential features. Clinically, fill is an- epizootic disease; MCE is enzootic* In cattle, the vesicular lesions of EMD have a charo.cter 1stic distribution over the lips, dorsum of the tongue, palate, coronary hand, vulva, teat, conjunctiva, and forestomachs (Smith and Jones, 1957), Although microscopic vesicles have "been observed frequently In MCE, macroscopic vesicles have not been observed- in any of our cases. It is interesting to note that in both diseases the vesicles originate from ballooning cells In the epithelium. The oral cavity usually shows a widespread necrosis rather than a characteristic distribution as in PHD. Hist©patholo­ gically, the accumulation of cells about the blood vessels and in the dermal papillae in MCE would seem to be a differen­ tial feature. Evidence of proliferation of squamous epithelium and 'epithelial cells of adnexal structures may be noted in 1-iCE. The intestinal tract may be involved, in both diseases; however, in EMD the lesions consist of punctate- hemorrhages and edema in the abomasum and small intestine, whereas in lid erosionsi ma y also be found. The hyaline degeneration and necrosis of cardiac muscle along with infiltrations of lymphocytes and, occasionally, neutrophil©s described in EMD are not found in MCE; rather, vascular proliferative and infiltrative lesions are observed, Hecrosis is also found in the skeletal muscles in EMD; again, in MCE occasional vascular lesions are found but necrosis of muscle fibers is not observed. Additional differential aids 66 in MCE are the regularly observed vascular lesions in the brain and periportal cell accumulations in the liver; the lamina propria and vasculature of :7iany other organs are more variably affected by proliferative and infiltrative processes# VESICULAR. STOMATITIS Vesicular stomatitis (VS), another of the epitheliotropic diseases, may resemble MCE. The epizootic nature and low mortality of vesicular stomatitis are contrasted to the enzootic occurrence and high mortality of MCE. The nasal and ocular discharge and corneal opacity, common in MCE, are not seen in VS. As with foot-and-mouth disease, vesicles are observed in VS of cattle but are of short duration; they quickly rupture leaving denuded areas (Chow et a l .,195l). In contrast to MCE, the vesicles arise primarily by a process of spongi­ osis rather than ballooning degeneration. Differentiation of these two disease should not be a problem due to the systemic distribution of lesions in MCE. Skin lesions in themselves may be of differential diagnostic value since in MCE there may be proliferation of epithelial cells in the skin and adnexae as well as prominent cellular accumulations In the dermal papillae ~nd around the blood vessels. LISTEDIOS IS The differential diagnosis of those diseases in which encephalitis is feature will be considered next. Of the common symptoms of listeriosis (Gray, 1954), pushing against objects, circling, incoordination, torticollis and uncontrolled running motions have not been observed in MCE. Cn the other 6? hand, the Following lesions commonly observed in 1TCP are not features of listeriosis; bilateral corne'l opacity, skin lesions, reddening and erosion of muzzle, reddening of the udder and vulva, and papules, particularly of the neck and udder. Pew gross lesions are observed in listeriosis on post-mortem examination* Occasionally, there may be slight clouding of the meninges or pin-point grayish white foci in the brain; rarely, fatty liver, duodenitis, and pulmonary edema are seen. In contrast to this, one often finds marked lesions involving several systems. Commonly, the digestive, reproductive, respiratory, urinary, and lymphatic systems are involved ma.croscopics.lly, Microscopically, the brain lesions of listeriosis are characterized by perivascular cuffing with lymphocytes and monocytes and areas of focal necrosis containing also a few heterophiles; in some instances these foci border on or actually show early suppuration. The brain lesions in listeriosis tend to be confined to the brain stem; in MCP they"are generalized. One cannot always differentiate the vascular lesions in the brain in MCP from listeriosis with certainty; neither focal necrosis nor focal suppuration, however, have been observed in MCP. The pantropic distri­ bution of lesions in MCP coupled with perivascular brain lesions appears to be a solid ba.sis for diagnosis* Parti­ cularly valuable are the constant periportal cell accumu­ lation and the less constantly found lesions in the lymph nodes, adrenal glands, kidneys, and stratified epithelia.. 68 SPORADIC BOV HIE EITCEPIIALOHYELIT IS Sporadic "bovine encepiial it is (SHE) bears many similar­ ities to MCP# McHutt and Waller (1940), Kenges et a l # (1953), and Marshfield (1957) have described SEE. In both diseases temperature elevation, marked depression, discharge from the nose and eyes, and course (1-3 weeks) may cause confusion# Of course, a typical case of MOP with corneal opacity and muzzle, oral and skin .lesions should not present a problem. Even in the less obvious cases of MCP, scattered erosions, congestion and hemorrhage in the digestive tract, end erosions and hemorrhage in the bladder are of diagnostic assistance# Pibrinous pleuritis, peritonitis, pericarditis, and epicarditis are commonly observed in SEE and not in MCP. The mortality rate in SEE varies from 40 to 70 percent whereas it approaches 100 percent in MCP. Enlarged edematous lymph nodes are described for SHE bv MciTutt and Waller (1940) and liarshfield (1957); similar lesions are observed in MCP. Microscooically, the serosal inflammation in SEE consists of infiltration of mononuclear cells, occasional neutrophiles, and eosinophiles; fibroblastic and endothelial proliferation are also observed. McETutt and Waller (1940) reported that the liver and kidney sometimes-contain monocytic foci; Marshfield (1957) described liver and kidney lesions in which lymphocytes., predominated# In- MCP, cell accumulations were commonly around the glomeruli and vessels of the kidney (mainly lymphocytes and monocytes); liver lesions were confined to the portal trinity rather ti&an being-located in the parenchyma as in SEE. In either case, tiie vascular involvement in the liver end. kid.neys would seem to he of diagnostic value in ItCE. Ibllutt and Valler (1940) described the microscopic brain lesions in SHE as primarily perivascular monocytic cuffing, focal areas of monocytic infiltration, and some areas of liquifaction necrosis. Menges et a l , (1953) and Harshfield (1957) re­ ported additionally that the cuffing cells were occasionally polymorphonuclear leucocytes and that the endothelium showed proliferative charges# In TICE the cuffing cells were pre- dominatly lymphocytes and monocytes. infiltration focal areas of monocytic nd necrosis were not features of MCE. Important histopathological differential features of MCE are the pro­ liferative and infiltrative lesions involving blood vessels , which are distrIbutec variably throughout the b b d y , and alato the proliferative and infiltrative lesions of squamous epi­ thelium; in some c-\ses b a l l o o n i n g .degeneration and vesicle formation may be noted (grossly normal epithelium may 3how these microscopic features). Demonstration of the elementary bodies in the brain and serosal exudates in SUE is, of course, of v a lue • RABIES A situation might arise wherein the differentiation of MCE and rabies is necessary (e.g. where the head alone is submitted for examination or an atypical case of MCE is pre­ sented). diseases. Certainly, nervous symptoms may be evident in both Smith and Jones (1957) state that the lesions of "y rabies are microscopic and limited to the central nervous •7C system. Lesions of* MCJ? usually involve several systems# In tne event that only the Lead were.; available microscopic lesions in the oral cavity and muzzle may "be found even though gross lesions are not recognized* The microscopic lesions of rabies in the central nervous system are described as varying from early necrosis of neurons to a diffuse en­ cephalitis consisting of perivascular cuffing, neuronophagic nodules, and other indications of destruction of neurons. Acidophilic intracytoplasmic inclusion bodies in the neurons are considered pathognomonic of rabies# The changes are most prominent in the brain stem , hippocampus and Gasseri&n ganglia. In MCE, marked and diffusely distributed peri- Tasfiular lesions with little evidence of neuron destruction are the prominent findings. The formation of 11"Babes-nodules” in the Gasserian ganglion — a replacement- of the- nerve cell e by nodules of proliferating cells — al# (1954). was described by La pi et The most prominent changes were a marked pro­ liferation of capsular cells and, in some cases, mild infiltration of lymphocytes and plasma cells in rabies. Ex­ amination of sections of Gasserian ganglia in cases of MCE indicated that, in some cases, proliferation and infiltration involving the blood vessels occurs; however, the profuse proliferation of capsular cells forming cellular nodules as in rabies was not a feature. history, In most instances, the clinical findings, and systemic distribution of the lesions in MCE should constitute an adequate basis for diagnosis# 71 HTPTCSPIHOS IS Inasmuch p,s the presence of L e o s p i r a catarrhalis lias "been reported in the digestive tract of animals affected with MCI (o-tttze, 1940) .and In view of the fact that certain lesions of leptospirosis resemble lesions found in MCI1, it is well to consider the diagnostic features of these two diseases« greatly* The clinical picture of leptospirosis may Tary The principal symptoms of "bovine leptospirosis are listed as fever, anorexia, depression, diarrhea, anemia, icterus, hemoglohinemia, hemoglobinuria, 'Oligogalactia or agalactia, emaciation, and abortion (Reinhard, 1951; Heinhard and Hadlow, 1954), Of there, diarrhea, anemia, icterus, hemoglohinemia, hemoglobinuria, a n d fatal abortions are not features of MCP although hematuria, in the bladder, probably due to hemorrhage is not uncommonly observed* The pathology of acute hemolytic leptospirosis includes; icterus, subepithelial, submucosal, and subserosal hemorrhages, and enlarged spleen (Heinhard, 19 51; Heinhard and Hadlow, 19 54)* Generally, the liver is discolored and the kidneys present a mottled or white spotted appearance-apparently very similar to lesions observed in Africa in cases of IICP* Histopathological features of leptospirosis have been described by several authors (JTungnerr, 1944; Mathews, 1946; Ungar and Bernkopf, 1947; Baker and Little, 1948; Reinhard, 1951; Cordy and Jasper, 1952; Reinhard and Hadlow, 1954, Hadlow and Stoenner, 1955), necrosis and hemorrhage, Changes in the liver include infiltration vrith neutrophiles 72 and mononuclear cells, hepatic cord disorganization, cholangi­ tis, and distention of Kupffer cells with blood pigment. Lesions described for the kidney included tubular necrosis, lymphoid and mononuclear cell infiltration, foci of tubular hypertrophy, albuminous degeneration, pigmentation of the renal tubular epithelium, syncytial aggregates of eosino­ philic cells, proliferating tubular cells, and raultinucleated giant cells. Mucosal hemorrhage, necrosis, and ulcer forma­ tion were found in the abomasum. sometimes a prominent feature. Gplenic hemosiderosis was As differential features found in MCF, one may therefore cite the constant vascular lesions in the brain which were more variably distributed in other organs, collections of lymphocytes and monocytes and bile duct proliferation limited to the portal area of the liver, epithelial proliferation, ballooning degeneration and vesicle formation in the squamous epithelium, and the cellular accumulations in the lamina propria of many organs. It is evident that macroscopic differentiation would not be a problem in the typical "head-and-eye" form. Skin lesions found in 3 ome cases of MCF are of diagnostic value. Although culture and demonstration of the leptospiras may be utilized, differentiation may well be made on clinical, historical, and pathological features. utiect ious kmeat o-cotstjwct ivit is (pujic-eym ) Inasmuch as the eye lesions observed in MCF are very similar to those in infectious kerato-conjunctivitis, it is well to consider a few features of diagnostic importance. 73 Clinically, MCP has a high mortality and a low morbidity in contrast to "pink-eye"* The eye lesions in "pink-eye" may be unilateral wnich is not true of* MCP. epider tial involvement, Signs such as oral erosions, and temperature elevation to about 106 P. should aid in eliminating tiie former. On post-mortem examination indications of systemic involvement will rule out infectious kerato-conjunctivitis• SUMMARY AIPD C OiTCLUS ICPS The epizootiologic, clinical, and pathologic features of MCP, as observed in this study, are singular enough to make possible a differential diagnosis from rinderpest, diseases of the mucosal disease complex, the vesicular diseases, lis­ teriosis, sporadic bovine encephalomyelitis, rabies, lepto­ spirosis, and infectious kerato-conjunctivitis. cal features are particularly characteristic, in nature and distribution. The pathologi­ if not unique, An important diagnostic combination of microscopic lesions which are constantly found are the cellular accumulations around the portal trinity of the liver and the perivascular cuffing v/ith lymphocyte.s and monocytes in the brain; other diagnostically important lesions are the epithelial hyperplasia of the epidermis .and adnexac, ballooning degeneration and vesiculation of the squamous epithelia, proliferative and infiltrative lesions in the lamina propria of several organs, and the vascular lesions variably distributed throughout the body. 74 IV* C GMT AH ISUN V I T H 3 IMILAH 3YlTUnoi-TRS HT CHUT' 0 CUimi XZ3 There has been much, controversy a- to the identity of "snotsiekte", as described in the Union of South Africa, and liCi* >.vS re or ted "by other investigators* Ve should like to examine the work dealing with snotsiokte as well as the reports of researchers in other countries who have inveotigated krCU in order to establish, if oossible, the relationship of these syndromes with MCI? as observed in our studies* UlTIOU CU SOUTH AURIGA Mettan (1923) described a disease of cattle in 3. Africa which he called " snots iekte", as 11an acute specific Infectious disease of cattle caused by an ultramicroscopic but nonfilterable organism and characterized by a general hyperplasia of lymphoid tissue throughout the body, less frequently by inflammation, erosion, and necrosis of the various mucosa." He believed that snotsiekte and MCU were separate entities and made the following distinctions; (l) MCF occurs sporadically, (2) there is an absence of marked lymphatic changes in MCP, (3) the horns often fall off in TK2P, (4) there is a vesicular or papular exanthema in MCU and, (5) snotsiekte can be re­ produced after a 2-5 week incubation period. That MCF occurs only sporadically and often enzootically is born out by our experience* Mettam described the marked lymphatic changes as a generalized enlargement of the lymph nodes up to the size of a clenched fist; the nodes were creamy-pink to a diffuse port wine color; cortical elevations up to 1*6 cm. 75 in diameter were present* "be pathognomonic. Mettam "believed these changes to Histologically, the germinal centers v/erc overcrowded with lymphocytes. We observed changes somewhat similar to tnose described by Mettam except that they were not as marked. The nodes exhibited mild to moderate swelling; no cortical elevations were noted. Microscopically, hyper­ active follicles v/ere observed in some cases; the nodes were deficient in lymphocytes. in other instances, Marked reticulum cell hyperplasia was often evident in our cases. Grossly, skin lesions v/ere commonly observed in our cases whereas Mettam did not observe such lesions. Microscopically, Mettam described colonies of small lymphocytes in the dermis and around blood vessels in the epithelium. The cellular accumulations were of a more varied composition in our cases and proliferation of epithelial cells was very prominent in early lesions; in addition, vesicles v/ere observed in the squamous epithelia. 'However, since Mettam may have observed only the more advanced cases, proliferation and vesiculation may not have been present due to necrosis and sloughing of the epithelium. Lesions in the oral cavity and digestive tract in snot­ siekte were grossly similar to those observed in MC3T• Micro­ scopically, activation of lymphoid elements was stressed by Mettam. In our cases, the lesions were related to vascular structures and consisted of cell accumulations which were primarily lymphocytes and monocytes; and adventitial proliferation were in addition, endothelial often present. 76 Grossly, the lungs in the cases of snotsiekte displayed numerous grayish dots which, microscopically, proved to "be lymphocytic foci around the vessels and near the bronchial cartilages. Gross lesions v/ere not prominent in our cases# but, microscopically, proliferative and infiltrative lesions were found in the lamina propria of the bronchial mucosa and involving the blood vessels. Mettam described pinkish-white granules in a few cases in the heart which, microscopically, proved to be colonies of small lymphocytes most noticeable near the capillaries. No gross lesions were found in our cases, but, in some cases, lymphocytic and monocytic cell accumulations involving the blood vessels v/ere noted microscopically. In the S. African cases the pancreas "resented a pink granular appearance; microscopically, the interstitial con­ nective tissue contained lymphocytic foci. No gross lesions were observed in our cases; however, mild hyperplasia of the duct epithelium and underlying tissue and activation of capillary endothelial cells were occasionally observed. The liver was severely affected in every case according to Mettam. This organ was described, grossly, as greatly en­ larged, deeply bronzed or yellow, and containing soft puttycolored areas. A pink granular or mottled appearance v/as listed as a pronounced feature. Microscopic examination re­ vealed numerous colonies of lymphocytes in the connective tissue of the aortal system which, in some instances, covered the whole microscopic field and pushed between the hepatic 77 ce lls • The description differs somewhat from changes found in our cases inasmuch as, microscopically, the liver showed only parenchymatous changes. Microscopically, sections in our cases contained cell accumulations limited to the peri­ portal spaces. This hypercellular mass was composed of main­ ly monocytes and lymphocytes although eosinophiles were sometimes prominent. Hyperplasia of biliary epithelium was not infrequently observed. In the spleen, Mettam observed 11split pea size" Mal­ pighian bodies which, again, proved to be dense a.ecumulations of lymphocytes. Small colonies of lymphocytes were found near the blood vessels of the trabeculae and capsule. Large numbers of Unna's plasma cells and polymorphonuclear leucocytes were present. In our cases, this marked lymphocytic activity was not observed; occasionally, the capsule and trabeculae were infiltrated with lymphocytes and monocytes. Mettam described lesions in the kidney which were at variance with our findings. He stated that the capsule stripped with difficulty; the surface was mottled with soft yellow areas and numerous white foci up to 3 mm. in diameter. Histo­ logically, compressed strips of kidney tissue were found b e ­ tween lymphocytic foci which, sometimes covered the whole 'microscopic field. Lymphoid cells and many plasma cells were found in the capsule. not observed. In our cases, such gross lesions were Microscopically, cellular accumulations of lymphocytes and monocytes were found infiltrating and surroun­ ding the blood vessels and glomerular capsules. 78 The lesions were not n.g widespread or severe as those des­ cribed by Mettam. Mettam noted that the urinary bladder w^s often swollen and deep red; in ..some cases small erosions v/ere found* ureters were normal. The Microscopic lesions v/ere not reported. Marked thickening and diffuse hemorrhagic inflammation of the bladder were frequently observed in our cases. The entire walls of the bladder and of the ureters were often edemctous and contained cell accumulations composed of lymphocytes, plasma cells, macrophages, and eosinophiles; fibroblasts were increased in number. Mettam described the sexual organs as deep red in c'lor with small pinkish areas which, microscorjically, were foci of lymphocytes. he also reported erosions of the mucosa of the sheath of the mule and the floor of the vulva of the female. Puddening and occasional erosions v/ere observed in the external female genitalia in our cases. Microscopically, we observed infiltrating cell accumulations primarily of monocytes and lymphocytes and proliferation of adventitial and endothelial cells in blood vessels in the sexual organs of both sexes. Mettam described perivascular cuffing with lymphocytes in the brain. Cell accumulations affecting the blood vessels in the brain were composed primariljr of lymphocytes and mono­ cytes in our cases. Bilateral corneal opacity was reported oy Mettam. Mi­ croscopically, he found an increase of small lymphocytes in 79 t-lne substantia, propria,. common. In our cases corneal opacity was Again, we found a more varied collection of Culls, which, were primarily lymphocytes and monocytes, although sig­ nificant numbers of eosinophiles and plasma cells were present. Connective tissue cells were increased in number. Lesions m our cases involved the eyelids* conjunctiva, cornea, lamina propria, sclera, iris, ciliary bodies, and optic nerve. Lesions were often prominent about blood vessels. In summary, we may say that, the distribution of lesions is similar in the disease as described in both countries. There do appear to be some macroscopic variations such as the mottling of the liver and kidneys and the marked lymphatic activity which are features of snotsiekte* Microscopically, more varied. the cell accumulations found in MCH are Mettam stated that "the ifoci are mostly formed of cells w h ic h are analogous to the small lymphocytes of the blood. Rarely are found neutrophile leucocytes, monoe.vtes, large lymphocytes and plasma cells." The marked cell pleo- morphism encountered in our cases was not mentioned in Meotam's work. KEImY A Laubney and Hudson (1936), workers in Kenya, described a disease which they called bovine malignant catarrh. Their description closely parallels Mettam1s description of snotsiek­ te. In man^y of the cases reported* there was no possibility of contact between the effected cattle and wildebeest — which I had occurred in Mettam* s cases. m transmission studies, they 80 found that the transmissibility varied greatly between isolates which helps to reconcile The conflicting results which have been obtained in the transmission studies of other workers* G rossly, the intestinal tract did not show any great variation from the lesions found in our cases* findings in the intestine were not reported* Microscopic An almost con­ stant finding was a mottling of the liver which, microscopically, proved to be collections primarily of lymphocytes distributed perivascularly m the portal canal* The kidneys always v/ere mottled with large white or yellow infarcts. of lymphocytes were observed* Large collections The gross lesions m the liver observed by these workers v/ere not seen in our cases. White focal areas were observed in the kidney in one nf our cases* Microscopically, we observed collections of lymphocytes and monocytes constantly in the periportal' areas of the liver and more variably around the blood vessels ?nd glomerular capsules in the k i dne ys• The urinary bladder in the E. African cases was described as intensely hemorrhagic, the hemorrhages varying from pe- techiae to extensive extravasations* resembled those observed in our cases* were reported* These lesions closely N© microscopic findings Grossly, the macroscopic changes in the res­ piratory system described in Kenya were very similar to those observed in our cases* Laubney and Hudson did not report on the microscopic findings* Laubney and Hudson reemphasized the marked enlargement of the lymph nodes observed by Mettam. In addition to congestion 81 and hemorrhage, protuberant lymphatic follicles were described, ihis marked lymphocytic activity was not a feature of cur c a s e s ; in some cases moderate activity was present end in others, lymphocytic exhaustion occurred. endothelial activity observed m described by Daubney and hudson. ihe marked reticulo­ most of our cases was not Observations of follicular enlargement in the spleen were also reported, which, again, were not observed in our cases. These workers summarized the histological findings as a perivascular infiltration of all organs with lymphocytes and marked production of small lymphocytes in the lymph nodes, ho proliferative lesions of vascular or epithelial structures as found in our cases were mentioned. Plowright Kenya also. {1903) described the pathology of MCP in He reported a rapid depletion of small lymphocytes from the spleen, lymphatic glands, and, possibly, the intes­ tinal lymphatic tissue. Also present was an xiiterise stimulation to proliferative activity ©f lymphocytogenous elements; re­ ticulum cells of the hemapoietic system and primitive cells throughout the body formed lymphocytes and intermediate cells which were difficult to classify. The predominantly perivas­ cular distribution of lesions outside the lymphatic tissue was attributed to the occurrence of undifferentiated cells in these areas. Plowright further described dense mononuclear cell infiltrations of blood vessels; this stands in contrast to the observations of Mettam who stated that "rarely are found neutrophile leucocytes, monocytes, large lymphocytes, 82 and plp.sma cells*" Skin lesions^ which were frequently en­ countered in our cases, were never encountered cases* in the Kenya The parenchymatous organs contained lymphocytic and mac±©phage accumulations* in the liver* Gross lesions were not described Vesicular foci with hemorrhagic borders were observed in the kidneys* In our cases, prominent liver lesions were not observed macroscopically, V/hite focal areas were found in the kidneys in one of our cases# Plowright observed degeneration, diffuse necrosis, and macrophage infiltrations in the adrenal glands# We found predominantly vascular lesions most evident in the capsule but also observed in the periadrenal and parenchymal tissue* The adjacent tissues were often disrupted by accumulations of predominantly lymphocytes and monocytes. that destruction Plowright reported of connective tissue and smooth muscle was observed not only m the blood vessels, but also in the capsule and trabeculae of the spleen and lymph nodes, in loose subepithelial connective tissues, in the meninges, and in the smooth muscle of the wall of hollow viscera. process followed a heavy infiltration of lymphocytes* This very similar disruption and destruction of connective tissue and smooth muscle occurred occurred in our cases. Plowright reported subepithelial and perivascular lymphoid cell accumulations in the surface epithelia* In our cases, more varied cell accumulations were obsei’ved although lympho­ cytes were often plentiful* Meningoencephalitis was common in the cases observed 83 by Plowright; the microscopic lesions were primarily vascular and perivascular. He observed mononuclear cell infiltraoion of the choroid plexus in rabbits; we observed similar lesions in field eases in cattle* Meningoencephalitis was present in all of our cases. EuHCJE Many European worker have described the pathology of MCF. Ackerman (1922) reported proliferation* necrosis, and vesiculation in the cornea. Frank (1924) confirmed these findings although, he was not able to demonstrate epithelial defects. In our cases, the lesions closely paralleled the findings of Frank and Aekerman; we did not note vesicle for­ mation in the eye but vesicles were found in other squamous epithelia. Dobberstein and Hemmert-Halswick (1928) described the lesions found in the oral cavity. < An inflammatory cell infiltration was regularly observed in the tunica propria, in the vicinity ©f small blood vessels, and in the interstitium of the mucous glands* the cell collection were composed main­ ly ©f lymphocytes, plasma cells, and histiocytes. Eosinophiles, heterophiles, and mast cells were present in smaller numbers. Endothelial cells displayed a distinct stimulation. Epithelial cells were undergoing ballooning and reticulating degeneration leading to formation of vesicles which often contained hetero­ philes. Hussell *s bodies were seen. It is evident that this description closely parallels our findings with the addition that some epithelial hyperplasia was observed, particularly in early lesions* 84 PAXKSxIME*; Paiitxson 'believed the his uopa Jiological features •l_ MUP as iu occurred i« Palestine sufficiently different to warrant a description of his findings and a comparison to the reports of other investigators* The features which, he described closely parallel those observed in our cases* Infiltrations observed in the liver were composed of lymphocytes, mononuclear cells, plasma cells, occasional eosinophiles, and rare heterophiles confined within areas. the portal Pattisen noted that Mettam (1923) and Daubney and Hudson (1936) had stressed the lymphocytic infiltrations of this organ* Pattison reported infiltrations ©f lymphocytes, monoclear cells, and, occasionally, plasma cells related to the blood vessels and glomeruli in the kidneys. His findings closely resemble ours. He did not observe the marked lymphocytic activity reported by Mettam and Daubney and Hudson. Pattison commented ©n this observation as compared to the marked increase in lymphocytes observed by the African investigators* He failed to find any marked lymphocytic activity in the spleen* A widespread non-purulent encephalitis was present in all 8 cases investigated, primarily evidenced by vascular infiltrations which were composed of lymphocytes, lajrger monoclears, and plasma cells. Only slight degeneration of occasional nerve cells was noted. PUJIiAHP Stenius (1952) presented an extensive study of HCP in 85 Finland. The description closely parallels our findings. The disease observed in Finland was of sporadic occurrence. Skin lesions similar t© those seen in our cases were found. Slight to moderate swelling of the ljonph glands was observed; marked enlargement and follicular protuberanees9 as described by Mettam (1923) and Laubney and Hudson (I936)?were not described. Stenius observed small grayish foci in the liver in the majority of cases and, occasionally, in the kidneys. In our cases, the foci in the liver were not observed. In one cases we found grayish foci in the kidneys. Stenius reported the lesions of the oral mucosal membranes as an exudative and proliferative process in the propria mucosae. The infiltrating cells were listed as leucocytes (eosinophilic and neutrophilic), lymphoid cells, isolated plasma cells, and histoid elements. These cells were found in the perivascular lymphatic spaces, connective tissue papillae, and interstitium of the mucous glands. Blood vessels were the eife of endothelial swelling and cell divi­ sion phenomena. In some areas, a newly-reproduced granulation tissue consisting of eosinophilic and neutrophilic leucocytes,^ histoid cells, and fibroblasts was observed. Very similar charges were found in our cases. Stenius found edema, infiltration with leucocytic cell elements, and proliferating histogenous cells in the propria mucosae of the nasal mucous membranes. Lymphoid cells surrounded arterioles and smaller veins ^nd regressive alteration in the endothelial cells were noted. Similar 86 changes were observed in our oases. Hyperemia, edema, and infiltration of leucocytic cells adjoining the corneal limbus were described, in the eye* Ballooning and reticulating degeneration and, occasionally, small vesicles in the stratum spinosum were found. Mxudative and proliferative lesions were described in the portal areas of the liver* predominant in some cases* Posinophilic leucocytes were The marked lymphoid cell infil­ trations described in Africa were not observed. Perivascular infiltrates consisting of lympoid cells, leucocytes, and a -few plasma cells as well as proliferation of adventitial cells in the kidneys were described. Again, the marked lymphocytic foci observed in Africa were not reported. The lesions in the liver -and kidneys are very similar to those found in our cases; in addition, we found capsular accumulations of cells* Marked lymphocytic activity as described in the lymph nodes by Mettam a.nd Daubney and Hudson were not reported by Stenius. He did note reticuloendothelial proliferation in. the lymph nodes. proliferation; We also observed marked reticuloendothelial in addition, marked vascular involvement with capsular and trabecular extensions was noted in our cases* Stenius found infiltrates of lymphoid cells, leucocytes, and proliferation of adventitial cells in the heart. Lesions in our cases were similar* Stenius observed a disseminated non-purulent meningo­ encephalitis in every coses. Perivascular cuffs of lymphocytes, plasma cells, isolated leucocytes, and adventitial cells were found* Focal glial proliferation was observed in some areas* He also described marked degenerative changes in the nerve cells* Central nervous system lesions were essentially the same as in our cases with the exception that we did not see pronounced neuronal degeneration, DISCUSSION M e t t a m 1s view that MCF and snotsiekte were different diseases was disputed by du Toit and Alexander (1938), S. African investigators* They stated that Daubney and Hudson (1936) reported the occurrence of a disease in young cattle ii indistinguishable from Gotze’s (1930) mild form of MCF. Extensive skin lesions and marked swelling of the lymph glands were found by Daubney and Hudson. This disease was transmitted to a variable percentage of cattle with difficulty. Du Toit and Alexander also referred to Vyssman (1938) and others who have stated that pronounced lymphatic changes do occur in KCF which, histologically, were not distinguishable from the changes found in the S. African " snotsiekte"• Du Tbit and Alexander cited the success ©f Gdtze (19 30) and Rinjard (1935) in transmitting with some difficulty. the disease., although Thus, they believed that Mettam*a major criteria for separation ©f African "snotsiekte" and MCF (ekin lesions, enlargement of lymphatic glands, and ability t© transmit the disease) were negated. The sporadic nature ©f MCF as pointed out by Kettam was not discussed* In con- clusien* these authors stated that "none of the characteristic 88 on w h i c h the separation was based in reality constitute a well defined "barrier, X-rob&bly the correct conception is t© regard the two conditions as being produced by different strains or types of the same excitant modified by adaptation to different environment in the two countries. The S# African strain has established a reservoir in the wildebeest, it seems to be more easily transmissible than the European form, and it also seems to present some special clinical features," Vyssman (1938) also felt that in spite of a few discrepancies the European and African diseases were identical or closely related. the There are features of the African form which differ from disease as observed in IT. America. Beginning with Mettam* s findings, we should like to roint out the following apparent distinctions; Mettam emphasized exclusively lymphocytic in­ filtrations and pronounced activity of lymphoid tissues with great enlargement of the lymph nodes. We have not found, the prominent liver and kidney lesion© which Mettam noted. Scho­ field (1941), reporting on the disease in Canada, did not observe the prominent mottling of the liver and kidney due to cell infiltrations described in Africa. The epizootic form described in Africa is uncommon in this country. are rare in Skin lesions the African form (found only in a few cases by Daubney and Hudson). Transmission of the African to be much more easily accomplished. form appears Transmission to ca-Lves has as yet not been successful in our cases. Despite these differences, however, we feel that basically the diseases are 89 the same or closely related, llany features of history, clinical course, and the distribution and character of the lesions indicate this relationship. Plowright (1953), in describing the intermediate cells and monocytes as well as lymphocytes in the lesions, established another link in the chain of evidence indicating the identity of the diseases. The repdhtfe from Palestine and Europe are essentially identical to MCE as we have observed it in this study. SUMMARY AMD C CMCLUSIOMS A comparison of disease syndromes occurring in Africa, Palestine, Europe,and XT. America has been made. Certain differential features have been pointed out in the disease as described in Africa; however, generally, the features of the disease are very similar t© those observed in our studies. There appears to be little if any variations in the syndromes reported from Europe, Palestine, arid M. America. 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MO HI GA H s i w m w m I* OCCtJRl^HCE txal dxagkosxb XV* COMPARISON WITH ©XMXRAIl SYNTBOSCS i$r or h s r c o u n t r i e s Eefeort HeXsmn Berksmn as abstract Submitted to the 8e&e#X far M i m a e e d Graduate Studies of Mlehigan ©tat® Uhivereiiy of Agriculture and Applied Bolonoo In partial fulflllaaent of the requirement® for the degree of DOCTOR OF PHILOSOPHY Departnrat of Veterinary Pathology Tear Approved^ W58 Th&a study wm* based sm m eel loot lea of 39 emt»ee of berime malignant catarrhal fever (ICP) occurring ia flehig&n* Of the*® 39 e&**s# 31 wore e&mmtoed peetmortea for do ata&tiom of the gres* and nleroseepi* lesion** Cl to 1sally* woe etorae tori eed by fewer (106 F«)9 sasal sad s e m j u m e t t w l disstorgs* e o m e e l op&clty* erosion* ef the aussle sad ermi eaviiy* m«k