acvim forum part i

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Volume 24, Number 8 333 Meeting Report T he 22nd Annual American College of Veterinary Internal Medicine (ACVIM) Forum was held in Minneapolis, Minn, on June 9-12, 2004. As usual, an excellent group of veterinary clinicians and researchers presented a variety of equine medicine topics. Summaries of a few presentations are provided below. More summaries will be provided in the next issue of JEVS. STACKING NSAIDS Dr Jonathan Foreman discussed the “stacking” of nonsteroidal anti-inflammatories (NSAIDs). He said, “Stacking in reference to the use of multiple non- steroidal anti-inflammatory drugs (NSAIDs) is a term borrowed from human weight lifters and body builders. In those sports, more than one anabolic agent is used ei- ther in sequence or “stacked” (taken multiply) to maxi- mize the benefit from each drug in combination with the others. In equine practice, NSAIDs are also stacked to maximize the benefits from each individual drug. In both situations, the weight lifter or the veterinarian is relying on the use of two or more different drugs that may be synergistic in their effects when used in combination. There is, however, a dearth of objective scientific data on the efficacy of stacking NSAIDs in horses in clinical practice.” He pointed out that the legality of stacking varies under the different groups governing equestrian sports. Concerns over limitations on the use of NSAIDs in com- petition are two-fold. First, it is possible that NSAID use may provide an unfair advantage in that an unsound horse may, with medication, be able to compete on an equal plane with one which is innately sound and which re- quires no external medication. This concern is one of fairness and is often referred to as “masking” or the use of an NSAID to hide a lameness. The second concern is one of toxicity. A considerable body of data shows that NSAIDs in normal or excessive dosages can precipitate a wide array of clinical problems in horses and ponies. 0737-0806/$ - see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2004.07.011 ACVIM Forum Part I Dr Foreman described studies in which he was in- volved that used this model to investigate the efficacy of various NSAIDs administered singly and compared with a saline placebo. “We showed that flunixin meglumine was more ef- fective than ketoprofen in reducing heart rate (HR) and lameness score,” he said. He added that a treadmill step test further documented the greater efficacy of flunixin over ketoprofen during and after exercise. The studies also showed that phenylbutazone was more effective than ketoprofen in reducing HR and lameness score; also, in a treadmill step test, the researchers documented the greater efficacy of phenylbutazone over ketoprofen dur- ing and after exercise. Recently they have shown that “stacking” or use of multiple NSAIDs simultaneously was more efficacious than use of single NSAIDs. In that series of experiments, they studied phenylbutazone and ketoprofen combina- tions and flunixin and ketoprofen combinations. A com- bination of phenylbutazone and flunixin was not much more effective than either drug individually, but the com- bination was clearly more effective than either a negative (saline) control in one experiment and a positive control narcotic (meperidine) in a second experiment. Dr Foreman has concluded that stacking NSAIDs can be shown to be synergistic, depending upon the combina- tion of the two drugs used. Ketoprofen and phenylbuta- zone seemed to be especially complementary, probably owing to the earlier onset of action of ketoprofen and the later duration of action of phenylbutazone. Flunixin and phenylbutazone are more similar in their onset and dura- tion and thus are less likely to be synergistic. The superior efficacy of a phenylbutazone/flunixin combination over a narcotic makes the allowance of that NSAID combination highly questionable during competition. EQUINE IMMUNODEFICIENCIES Dr M. Julia B. F. Flaminio said that immunodefi- ciency is a rare disorder of the immune system that re- sults in failure to build protection against pathogens and, consequently, in predisposition to recurrent infections. Studies have shown that approximately 7% of horses showed a type of immunodeficiency that was not related

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Page 1: ACVIM Forum part I

Volume 24, Number 8 333

Meeting Report

The 22nd Annual American College of VeterinaryInternal Medicine (ACVIM) Forum was held inMinneapolis, Minn, on June 9-12, 2004. Asusual, an excellent group of veterinary clinicians

and researchers presented a variety of equine medicinetopics. Summaries of a few presentations are providedbelow. More summaries will be provided in the next issueof JEVS.

STACKING NSAIDS

Dr Jonathan Foreman discussed the “stacking” ofnonsteroidal anti-inflammatories (NSAIDs). He said,“Stacking in reference to the use of multiple non-steroidal anti-inflammatory drugs (NSAIDs) is a termborrowed from human weight lifters and body builders.In those sports, more than one anabolic agent is used ei-ther in sequence or “stacked” (taken multiply) to maxi-mize the benefit from each drug in combination with theothers. In equine practice, NSAIDs are also stacked tomaximize the benefits from each individual drug. In bothsituations, the weight lifter or the veterinarian is relyingon the use of two or more different drugs that may besynergistic in their effects when used in combination.There is, however, a dearth of objective scientific data onthe efficacy of stacking NSAIDs in horses in clinicalpractice.”

He pointed out that the legality of stacking variesunder the different groups governing equestrian sports.Concerns over limitations on the use of NSAIDs in com-petition are two-fold. First, it is possible that NSAID usemay provide an unfair advantage in that an unsound horsemay, with medication, be able to compete on an equalplane with one which is innately sound and which re-quires no external medication. This concern is one offairness and is often referred to as “masking” or the useof an NSAID to hide a lameness. The second concern isone of toxicity. A considerable body of data shows thatNSAIDs in normal or excessive dosages can precipitate awide array of clinical problems in horses and ponies.

0737-0806/$ - see front matter© 2004 Elsevier Inc. All rights reserved.doi:10.1016/j.jevs.2004.07.011

ACVIM Forum Part I

Dr Foreman described studies in which he was in-volved that used this model to investigate the efficacy ofvarious NSAIDs administered singly and compared witha saline placebo.

“We showed that flunixin meglumine was more ef-fective than ketoprofen in reducing heart rate (HR) andlameness score,” he said. He added that a treadmill steptest further documented the greater efficacy of flunixinover ketoprofen during and after exercise. The studiesalso showed that phenylbutazone was more effective thanketoprofen in reducing HR and lameness score; also, in atreadmill step test, the researchers documented thegreater efficacy of phenylbutazone over ketoprofen dur-ing and after exercise.

Recently they have shown that “stacking” or use ofmultiple NSAIDs simultaneously was more efficaciousthan use of single NSAIDs. In that series of experiments,they studied phenylbutazone and ketoprofen combina-tions and flunixin and ketoprofen combinations. A com-bination of phenylbutazone and flunixin was not muchmore effective than either drug individually, but the com-bination was clearly more effective than either a negative(saline) control in one experiment and a positive controlnarcotic (meperidine) in a second experiment.

Dr Foreman has concluded that stacking NSAIDs canbe shown to be synergistic, depending upon the combina-tion of the two drugs used. Ketoprofen and phenylbuta-zone seemed to be especially complementary, probablyowing to the earlier onset of action of ketoprofen and thelater duration of action of phenylbutazone. Flunixin andphenylbutazone are more similar in their onset and dura-tion and thus are less likely to be synergistic. The superiorefficacy of a phenylbutazone/flunixin combination over anarcotic makes the allowance of that NSAID combinationhighly questionable during competition.

EQUINE IMMUNODEFICIENCIES

Dr M. Julia B. F. Flaminio said that immunodefi-ciency is a rare disorder of the immune system that re-sults in failure to build protection against pathogens and,consequently, in predisposition to recurrent infections.

Studies have shown that approximately 7% of horsesshowed a type of immunodeficiency that was not related

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to failure of passive transfer or severe combinedimmunodeficiency. She said that this finding would sup-port that immunodeficiency should be investigated whenevaluating a patient with infectious processes.

Primary immunodeficiencies are congenital pro-cesses associated with a genetic hereditary defect.Secondary immunodeficiencies may occur at any time inlife. These are acquired disruptions in the immune func-tion that, similarly to primary immunodeficiencies, re-duce the ability of the system to fight against opportunis-tic and/or pathogenic organisms. Conditions that maypredispose to secondary immunodeficiencies include im-munosuppressive treatment, infectious diseases, infiltra-tive diseases, metabolic/endocrine diseases, age, andmalnutrition. These diseases are grouped according to thecomponents of the immune system affected: 1) antibodyimmunodeficiency disorders (B cell deficiency); 2) cyto-toxic and helper cell deficiencies (T cell deficiency); 3)combined B and T cell deficiencies; 4) phagocytic defi-ciency; and 5) complement deficiency.

Clinical conditions that may indicate immunodefi-ciency are: 1) two or more episodes of pneumonia withinone year; 2) two or more episodes of sinus infectionwithin one year; 3) multiple sites of infection (pneumo-nia and sinusitis); 4) recurrent pyodermatitis, deep skinor organ abscesses; 5) single episode of meningitis or os-teomyelitis; 6) two or more months on antibiotics withlittle or no affect; 7) failure to gain weight or grow nor-mally; or 8) history of primary immune deficiency in thefamily.

The most common clinical indication of immunode-ficiency is recurrent infections with frequent treatmentfailures. In many cases, the patient does well while on an-tibiotic therapy. However, when antibiotic therapy is dis-continued or bacterial resistance to antibiotic develops,the clinical signs of infection re-appear. In addition, auto-immunity and neoplasia may be associated with an im-munodeficient state.

Laboratorial assays and in vivo diagnostic experi-ments are useful in confirming and characterizing im-munodeficiency conditions. For all tests, the use of age-matched controls is advised. She advised starting withCBC (neutropenia, neutrophilia, lymphopenia, lympho-cytosis, anemia, thrombocytopenia) and blood cytology(neutrophil granules, lymphoblasts) before specific testsfor: humoral function (serum immunoglobulin levels),antibody response test (tetanus toxoid), circulating Bcells, cellular function, and complement component andfunction. In addition, bone marrow aspirate cytology andflow cytometry may indicate hypoplastic cell deficien-cies or immune-mediated conditions. Genetic tests are

available for certain hereditary diseases to identify thecarrier state or affected animals.

GLUCOCORTICOIDS AND RAO

Dr Virginia Buechner-Maxwell explained that glu-cocortocoids (GCs) are hormones that are produced bythe adrenal cortex and released into blood in a circadianpattern. Release of endogenous glucocorticoids is in-creased in response to stress, resulting in alterations inglucose metabolism, immune response, and endocrinefunction.

Glucocorticoids enter the cytosol of the cell by pas-sive diffusion. Their influence on gene expression re-quires binding to the glucocorticoid receptor (GR) andentry into the nucleus. After the GC enters the cell cyto-plasm, GC-GR binding occurs in conjunction with disso-ciation of the chaperone proteins, phosphorylation of thereceptor, and translocation into the cell nucleus. Beforeinteraction with the nuclear DNA, GC-GR form homo-dimers with an orientation that allows zinc fingers accessto the major grove of DNA. Once in the nucleus, thiscomplex can influence gene transcription through severalmechanisms. The GC-GR receptor complex regulatesgene transcription by binding, as a homodimer, to spe-cific DNA sequence known as a GC response element(GRE). Glucocorticoid receptors may also influence genetranscription through chromatin remodeling. Chromatinis comprised of DNA that is tightly wrapped around pro-teins known as histones.

Recurrent airway obstruction (RAO) is a disease thatresults from bronchoconstriction and inflammation of theairways in horses. Clinical RAO develops in response toexposure to inhaled irritants or debris and is incurable.Glucocorticoids are frequently prescribed to treat the in-flammatory component of this disease. Recent studies byRush and her coworkers demonstrated the positive effectsof glucocorticoid therapy in the treatment of equineRAO.

Horses with clinical RAO demonstrated improvedpulmonary function with 3 to 7 days after initiation oftherapy with systemic dexamethasone or inhaled bec-lomethasone dipropionate, and inflammatory cells inbronchoalveolar (BAL) fluid concurrently decreased.Pulmonary function, after therapy was discontinued, re-turned to pretreatment values within 1 (beclomethasone)or 3 days (dexamethasone). While receiving either treat-ment, endogenous cortisol concentrations were sup-pressed, although response to ACTH was not affected.

Robinson and his coworkers recently evaluated theresponse of RAO horses to three glucocorticoids; dailyintravenous dexamethasone solution; intramuscular dexa-

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methasone-21-isonicotinate, given every third day; andoral prednisone, given daily. Pulmonary function andBAL cytology was most improved in horses given intra-venous dexamethasone, and all but one horse demon-strated a significant improvement in pulmonary function(but not BAL cytology) while receiving intramusculardexamethasone-21-isoniconate. Horses receiving oralprednisolone exhibited a much-delayed response, andonly 50% had significant improvement in pulmonaryfunction by the end of the therapeutic trail (10 days).These findings suggest that oral prednisolone has a re-duced and/or delayed effect in horses. It has been specu-lated that absorption of prednisone from the horse’s gut isa limiting factor, although it is possible that the ability toconvert prednisone to an active form is reduced, and/orabsent, in some horses.

LIPOXINS

Dr Samuel L. Jones said that inflammation is indis-pensable for host defense against invading pathogens andtissue repair. Host cells (both somatic cells such as ep-ithelial or endothelial cell, as well as leukocytes) expressreceptors that recognize pathogen-associated molecules(such as, for example, lipopolysaccharide) that, when ac-tivated, stimulate the expression of mediators, enzymes,and cell surface receptors that regulate the physiology ofinflammation. During the course of an inflammatory re-sponse, a dynamic balance is struck between proinflam-matory and anti-inflammatory signals resulting in the ini-tiation, propagation, and, ultimately, the resolution ofinflammation.

When this balance goes awry, dysregulated inflam-mation results in tissue damage. Neutrophils are impor-tant host defense cells that are recruited to sites of in-flammation where they are activated to produce a varietyof products that are non-specifically lethal to invadingpathogens. However, the products of activated neu-trophils are also quite toxic to host cells and proteins.Indeed, neutrophils and their products have an importantrole in the pathophysiology of many inflammatory dis-eases, including infectious and non-infectious gastroin-testinal and pulmonary disorders, endotoxemia, andarthritis. Thus, neutrophil activation must be tightly reg-ulated during inflammation to prevent inappropriate acti-vation once the inciting stimulus is eliminated, whichlimits tissue damage.

A critical feature of neutrophil regulation is the re-quirement for adhesion to tissue matrix proteins for opti-mal activation of the full complement of inflammatoryeffector functions. This adhesion is mediated by integrinadhesion receptors. Integrins are heterodimeric receptors

that require activation to bind ligands expressed on othercells and in the extracellular matrix.

Proinflammatory mediators are important activatorsof leukocyte integrins. Once activated and bound to li-gands, integrins initiate intracellular signals that enhanceneutrophil cellular activation. The absence of leukocyteintegrins (as in calves, people, and dogs with leukocyteadhesion deficiency) renders neutrophils poorly respon-sive to stimulation by pro-inflammatory mediators. Therole of leukocyte integrins can be thought of as a mecha-nism to sense when neutrophils have entered an inflamedenvironment where optimal activation is required.

Much is known about how integrins are activated tomediate adhesion, but little is known about how integrinfunction is down-regulated during inflammation todampen or stop neutrophil activation during the resolu-tion phase. Lipoxins (LXs) are endogenous arachidonicacid-derived lipids with potent anti-inflammatory proper-ties. Lipoxins are a structurally and functionally distinctclass of eicosanoids that are important regulators of theresolution phase of inflammation. Their synthesis is tem-porally dissociated from that of other classes ofeicosanoids, peaking later in the course of inflammation.

Dr Jones described his studies that provide proof ofthe principle that lipoxins are anti-inflammatory inhorses (at least with respect to neutrophil function). Hesaid that it remains to be seen whether stable syntheticlipoxin analogs are therapeutically beneficial and cost ef-fective in horses.

CONTROLLING DISEASE IN HOSPITALS

Dr Josie L. Traub-Dargatz said that, although pre-vention of all infections acquired by hospitalized patientsis an ideal to be aspired to, many factors make this anunattainable goal. Factors that place animal patients atheightened risk of acquiring infections in the hospital in-clude their original underlying disease, treatment withdrugs that may alter their immune response or normalgastrointestinal flora, stress associated with change indiet, as well as transport to the hospital. In all likelihood,in a busy veterinary clinic, it will be impossible toachieve the goal of zero prevalence of nosocomial infec-tions. Thus, it is important for each veterinary hospital todevelop a strategy for monitoring for infectious diseasesamong their patients and establish a baseline level of in-fection among hospitalized patients so that occurrencesout of the norm can be quickly identified and resolved.For example, there may be a zero tolerance for certaintypes of infection such as vesicular stomatitis, while arate of salmonella fecal shedding of 5% among hospital-ized equine patients may be expected and acceptable.

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Infection control in hospitalized patients is now aspecialty within human medicine. The term “hospital epi-demiologist” was first used to identify an individualwhose role it was to track certain problems among hospi-talized patients. The hospital epidemiologist is generallya physician, and the infection control practitioner is gen-erally a nurse. A professional society of physician epi-demiologists, the Society of Hospital Epidemiologists ofAmerica (SHEA), was formed in 1980. National confer-ences regarding infection control, including the secondinternational conference on nosocomial infections in1980, have disseminated new information on occurrenceand control of nosocomial infections and provided aforum for infection control personnel to exchange expe-riences. Over time, more efficient methods of detectinginfections through surveillance have been developed.

The standard of care of hospitalized animals is everevolving with advances in diagnosis and treatment of theindividual animal. So too have there been advances informalizing infection control strategies for hospitalizedanimals. Several veterinary teaching hospitals have de-veloped biosecurity programs or infection control plansin order to minimize nosocomial infection among theirpatients. The extent of these programs and the areas ofemphasis vary; some programs have been developed witha single focus such as a single disease within a segmentof the hospitalized patients. An example of a single focuswould be salmonellosis in equine patients. Other pro-grams are extensive and involve a plan for monitoring fornosocomial infections with many pathogens, and the en-tire hospital patient population is included in the pro-gram. Even with extensive infection control strategies inplace, outbreaks of infectious diseases can occur in hos-pitalized animals.

Historically, the principles of outbreak investigationwithin veterinary medicine have been applied predomi-nantly to problems experienced in the food animal live-stock areas. However, since many animals are managedin groups or have exposure to other animals while in aveterinary hospital, it is important for the veterinary prac-titioner to be prepared to take a leadership role in the pre-vention and investigation of outbreaks of infectious dis-ease among hospitalized animals in their care. In someinstances, advancement in available diagnostic tests hastranslated to the availability of very rapid results. In ad-dition, techniques for handling and analyzing data havebecome more accessible to those without extensive spe-cialized training in such endeavors. Some outbreaks ofinfectious disease may require the expertise provided bya team of people with specialized training or on the jobexperience in various areas such as diagnostic testing,

epidemiology, hygiene, and pathology. However, in situ-ations where there is not a hospital epidemiologist or in-fection control coordinator appointed, the clinician withsome basic knowledge of outbreak investigation princi-ples can go a long way toward solving an outbreak, or atleast play a role in leading the investigation team.

An outbreak is the occurrence of disease at a rate thatis clearly higher than expected or the norm for the popu-lation of animals in question. The expected frequency ofdisease occurrence may vary with the characteristics ofthe population of animals (eg, age, use, breed, or hospi-talized patients versus the general population), season,the disease-causing agent, and the geographic location.Generally, the goal of the outbreak investigation is con-trol of infectious disease transmission. In order to ac-complish this goal, there needs to be a recognition thatthe infection is occurring at a rate higher than the norm,determination of the cause, and determination of thesource and mode of transmission of the infectious agent.Control is contingent on interrupting the transfer of in-fectious agent to susceptible hosts.

In summary, she said that investigation of outbreaksof infectious diseases in hospitalized patients requiressome key components to be successful. These includeclear goals for the investigation, skilled people doing theinvestigation, a concise and clear plan for the investiga-tion, adequate commitment on the part of the customer tomeet the goals of the investigation, and recognition ofwhen to include the services of a veterinary diagnosticlaboratory and of specialists in various areas in some in-vestigations.

GRASS SICKNESS

Dr Bruce C. McGorum described equine grass sick-ness (EGS) as a multi-systems neuropathy of equidaecharacterized by damage to neurons of the autonomic,enteric, and somatic nervous systems. The disease has anextremely high mortality rate and carries serious welfare,emotional, and financial implications. Although north-east Scotland has the highest incidence of grass sickness,the disease has been recognized throughout the UnitedKingdom and most other Northern European countries.In the Americas, the disease is well recognized in Chile,Argentina, Colombia, and the Falklands, but inexplicablyonly a handful of cases have been identified in NorthAmerica.

Since the first report of EGS as a specific disease en-tity in central Scotland around 1907, it has been the sub-ject of extensive research. While there is increasing evi-dence that EGS is a toxico-infection with Clostridiumbotulinum types C or D, definitive proof of this is cur-

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rently lacking. Interestingly, an identical disorder occursin wild and farmed rabbits, hares, dogs, and cats.

Consideration of the epidemiology improves boththe accuracy of diagnosis and can aid prevention of thedisease. Horse-associated risk factors for EGS includegrazing, especially on “high-risk premises,” young age(peak incidence in 2- to 7-year-olds), good body condi-tion, recent movement to new pasture, recent dietarychange, recent stress, recent deworming with ivermectin,low serum antibodies to C botulinum, and absence ofsupplementary hay feeding. Premises-associated risk fac-tors include geographical area, soil type (sand and loam),seasonality (spring and summer months), weather pat-terns (cool, dry weather in the 10-14 days preceding out-breaks), the presence of recent cases of EGS on premises,many horses on premises, mechanical droppings re-moval, frequent chain harrowing, soil disturbance, andthe rearing of domestic birds on pastures. Protective fac-tors include recent exposure to a horse with EGS, chalksoil, grass cutting, co-grazing with ruminants, and man-ual droppings collection. Many of these epidemiologicalfeatures are consistent with EGS being a toxico-infectionwith C botulinum.

EGS is described as acute, sub-acute, or chronic, ac-cording to the severity and duration of clinical signs.These categories probably reflect the degree of auto-nomic dysfunction, particularly enteric neuronal dys-function. Clinical signs include gastrointestinal stasis,dysphagia, colic, salivation, gastric and small intestinaldistension, secondary impaction of the large bowel, re-duced faecal output, tachycardia, sweating, bilateral pto-sis, rhinitis sicca, muscular tremors, base narrow stance,and cachexia.

While many cases of grass sickness are readily diag-nosed with confidence, solely using clinical examinationand historical information may make it difficult to provediagnosis. Definitive diagnosis is generally considered torequire demonstration of characteristic histological le-sions, although in Dr McGorum’s opinion the clinicalrecognition of rhinitis sicca, which is present in manycases, is pathognomonic for the disease. Antemortemhistopathological confirmation requires collection of in-testinal biopsies via flank or midline laparotomy.Unfortunately, this procedure is invasive, often necessi-tates referral, and likely has detrimental effects on futurerecovery of mild, chronic cases. In acute and subacutecases, however, laparotomy may be indicated to excludeother abdominal conditions, especially those that areamenable to surgery. The major difficulties in the clinicaldiagnosis of EGS include the diversity of clinical signsexhibited, the variability in signs depending on the sever-

ity/form of the disease, and the fact that many of the clin-ical signs of EGS also occur in other diseases.

There is an increasing body of evidence, both his-toric and recent, to suggest that EGS is a toxico-infec-tious form of botulism, caused by production of bo-tulinum toxin(s) within the gastrointestinal tract. Thebotulinum hypothesis was first reported in 1923 when alarge spore-forming bacterium, with morphological andtoxigenic properties similar to those of C botulinum, wascultured from affected horses. Subsequent in vivo chal-lenges in experimental animals including horses pro-duced clinical signs and gross pathological lesions thatwere considered by the investigators to be consistent withEGS. However, Dr McGorum questions the validity ofthis conclusion, given that the reported clinical signs andgross pathological lesions were more consistent with bot-ulism than with EGS. Unfortunately, in the absence ofhistopathological examination for the characteristic neu-ronal pathology, which was not performed in the 1920s,it is unclear whether the experimental animals had bot-ulism or EGS. However, convincing evidence in supportof the botulinum hypothesis came from subsequent vac-cination trials. A botulinum toxin/antitoxin preparationproduced highly significant protection against EGS,when administered in a controlled study involving in ex-cess of 2000 horses. Furthermore the magnitude of pro-tection increased with repeated administration of the vac-cine. Unfortunately, for apparently political reasons, thebotulinum hypothesis was ignored until rekindled by re-searchers in Edinburgh in the 1990s. Recent work hasidentified an association between EGS and the presenceof C botulinum type C and botulinum neutotoxin C(BoNT/C) within the intestinal tract of affected horses.Increased levels of serum antibodies to the surface anti-gens and toxin of C botulinum type C have been detectedin horses which have had recent exposure to affectedhorses, and those increased levels of antibodies havebeen shown to be associated with increased protectionagainst EGS.

However, before accepting the botulinum hypothe-sis, the authors consider that two issues must be resolved.Firstly, while EGS and botulism have some clinical sim-ilarities (including dysphagia, salivation, bilateral ptosis,abdominal discomfort, muscular tremors, and weightloss), there are important clinical differences (only bot-ulinum causes mydriasis and profound myasthenia, whileonly EGS causes rhinitis sicca, marked tachycardia, andlarge bowel impactions) that mean that the two disordersare readily differentiated by experienced veterinarianssimply on clinical grounds. Secondly, horses with bo-tulinum do not have the neuropathology that character-

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izes EGS. Current research is directed at confirming therole of this organism and clarifying which of the bot-ulinum subtypes and toxins are involved, with the aim ofdeveloping a vaccine to control the disease. Additionalwork is directed at identifying the trigger factors forEGS, which could explain its restricted seasonal and geo-graphical distribution. One potential trigger factor underinvestigation is cyanide from ingested white clover(Trifolium repens). Cyanide could predispose to over-growth of C botulinum due to its microbiocidal and gas-trointestinal ileus-inducing properties.

While acute and sub-acute EGS, by definition, areinvariably fatal, some horses with mild chronic EGS maysurvive. Intensive nursing is the mainstay of the treat-ment, but therapeutic intervention in the form of anal-gesics or intestinal prokinetics are occasionally indicated.Unfortunately, the antioxidant acetylcysteine, the ap-petite stimulant brotizolam, or the laxative/antioxidantaloe vera extract do not result in a detectable improve-ment in case outcome. The clinical outcome of horseswith EGS is more dependent on the disease severity thanon the use of such ancillary treatments. Complicationsthat commonly occur during the recovery phase includepersistent weight loss, debility and muscular weakness,aspiration pneumonia, and esophageal choke/spasm.

Interestingly, while many recovered horses may leadan apparently normal life, post mortem studies of recov-ered horses that were subsequently euthanized for unre-lated causes indicate that they have a persistent and sig-nificant reduction in the density of enteric neurons. Thisfinding has important implications for our understandingof the neuronal control of gastrointestinal motility.

EPM

Dr Stephen M. Reed talked about equine protozoalencephalomyelitis (EPM), caused by Sarcocystis neu-rona. In Ohio, Kentucky, Oregon, and one county inPennsylvania, seroprevalence studies have been con-ducted on normal horses and horses with neurologic dis-ease. Seropositive rates of horses with CNS disease areabout twice as high as the general horse population. In astudy of 364 histologically confirmed cases, the highestinfection rate was found in young Thoroughbred,Standardbred, and Quarter horses.

The clinical signs of EPM may vary from acute to in-sidious onset of focal or multifocal signs of neurologicdisease involving the brain, brainstem, spinal cord, or anycombination of the areas of the central nervous system. Insevere cases, the horse may have difficulty with standing,walking, or swallowing, and the disease may progressvery rapidly. Because the organism may affect spinal

cord gray matter, focal muscle atrophy may be observed.In most cases, the disease tends to have a progressivecourse. The neurological examination often reveals anasymmetric weakness, ataxia, and spasticity involving allfour limbs. The most frequent brain or cranial nervedeficits observed in horses presented to our hospital ap-pear to be head tilt, depression, facial nerve paralysis, anddifficulty swallowing, although signs are not limited tothese areas.

Definitive ante-mortem testing remains difficult. Theimmunoblot test measures Sneurona antibodies (IgGclass) in the serum and cerebrospinal fluid (CSF). In nor-mal horses, the concentration of protein in CSF is lessthan 100 milligrams/dL and the normal cell count isfewer than 5 cells per microliter. A positive Western bloton CSF increases the likelihood of the diagnosis of EPM.A negative test may not eliminate the disease since theorganism, and clinical signs, may be present before theonset of antibody production. The immunoblot test can-not differentiate antibodies that have leaked into the CSFfrom peripheral blood from those which are locally pro-duced. In order to differentiate the source or origin of theantibodies in the CSF, the albumin quotient should becombined with a measure of the IgG index. If the albu-min quotient is increased (> 2) and the IgG index is alsoincreased, it is an indication of increased blood brain bar-rier permeability or increased production of intrathecalantibody. If the albumin quotient is increased and the IgGindex is normal, then the horse has increased blood brainbarrier permeability. Finally, if the albumin quotient isnormal but the IgG index is increased, the horse has in-creased intrathecal production of antibodies.

The life cycle S neurona was completed for the firsttime in the laboratory utilizing the domestic cat as the in-termediate host. It was unknown what role the cat playedin the natural life cycle of S neurona, although furtherwork demonstrated that the cat likely plays a role in thenatural infectious life cycle of S neurona. A variety ofmammals appear to be intermediate hosts for Sarcocystisneurona, including the nine-banded armadillo, domesticcat, striped skunk, raccoon, and sea otter.

Acute lesions are most likely to include hemorrhageand perivascular cuffing of lymphocytes, while chroniclesions often show marked tissue disruption with loss ofneurons, astrocytosis, and gliosis. In any horses, therecan be infiltration of the affected region with mononu-clear cells. Some authors suggest that the central nervoussystem pathology seen in horses may be in part due to theimmunologic reaction of the host to the parasite.Treatment appears to result in successful recovery in ap-proximately 70% of the affected horses, although, with-

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out post-mortem confirmation, it is somewhat difficult toknow the true meaning of this comment.

Dr Reed said that at this time there are two approvedtreatments for EPM in the horse. These include Ponazuril(Marquis, Bayer, Overland Park, KS), which is currentlyavailable as an oral paste and recommended at a dose of5 mg/kg daily for 28 days. Ponazuril is an anticoccidialcompound with cidal activity against Sarcocystis neu-rona. The second approved therapy is Nitazoxanide(NTZ; NavigatorTM IDEXX Laboratories, Greensboro,NC), a benzamide compound with activity against proto-zoa, nematodes, bacteria, and trematodes.

Many horses diagnosed with EPM undergo a pro-longed course (up to 12 to 15 weeks or longer) onpyrimethamine combined with a potentiated sulfon-amide. Treatment often involves the use of sulfadiazine ata dose of 20 mg/kg/os once or twice a day. In addition,affected horses should be placed on pyrimethamine(Daraprim, Burroughs Wellcome). The dosage is 1.0mg/kg given once a day for 90 to 120 days or longer.

ANTI-ENDOTOXIN ANTIBODIES FORSEPTICEMIC FOALS

Dr Benjamin J. Darien said that neonatal septicemiais the most common cause of death in foals during thefirst week of life. Approximately 25% of all septicemicfoals will die even with intensive treatment, but mortalityrates outside of referral hospitals can be much higher. Ifsepticemia develops secondary to gram-negative bac-teremia, the mortality rate may approach 50% despite re-cent advancements in diagnostics and critical caremedicine. Central to the pathogenesis of gram-negativebacteremia is the release of endotoxin (lipopolysaccha-ride, LPS) from the cell wall during rapid bacterialgrowth as well as following bacterial death subsequent toantimicrobial treatment. Endotoxin induces a systemicinflammatory response syndrome (SIRS), which at bestcompromises the function of several organs (multipleorgan dysfunction syndrome, MODS) and at worst con-tributes to the patient’s demise. Highly important compo-nents of SIRS are the interaction between endotoxin andthe cardiovascular and coagulation/hemostatic systems.

While the use of equine plasma of varying types inthe treatment and prevention of septicemia in foals isconsidered obligatory, there are no prospective studiesusing the logical end point of survival to compare the ef-ficacy of the different plasma types in categorically sub-stantiated septicemia.

Consequently, Dr Darien and co-workers designed ablinded study comparing numerous clinical, hemato-logic, hemostatic, and biochemical indices in septicemicneonatal foals treated with either commercial hyperim-mune equine plasma or equine plasma specifically rich inanti-endotoxin antibodies. Foals entered into the studywere client-owned animals admitted to the VeterinaryMedical Teaching Hospital at the University ofWisconsin-Madison over a two-year period.

Client-owned equine neonates presented for evalua-tion and treatment generated the data for this study. Foalswere enrolled based upon a sepsis score 11 at initialevaluation. Foals with a sepsis score < 11 on admissionthat subsequently had sepsis confirmed by positive bloodculture or that developed three or more sites of systemicinfection were also included. Foals underwent a standard-ized work-up and treatment protocol that included the ad-ministration of either conventional, commercially avail-able hyperimmune equine plasma or plasma that was richin anti-endotoxin antibodies. Antimicrobial treatment wassomewhat standardized but varied according to clinicianpreference and case progress. Clinicopathologic data ac-quisition on each case included standardized routinehematologic and biochemical analyses, as well as specifichemostatic parameters and biochemical markers of car-diac dysfunction. Approximately 20-25 foals were en-rolled into each of the two treatment groups and compar-isons were made between survivors and non-survivorswith respect to plasma type administered. Furthermore,each factor used in the assessment of the sepsis score, aswell as the total sepsis score, hemostatic/coagulation, res-piratory/blood gas, cardiac, hematologic, and biochemicalparameters at admission, were compared between surviv-ing and nonsurviving foals. Results are pending.

This report continues next month with Part II.