Approach to Muscle Disease - Horses PDF

A P P R O A C H TO C O M M O N M U S C L E DISEASES OF THE HORSE Dr Charlotte Maile BVetMed BSc PhD MRCVS Lecturer in Veterinary Clinical Sciences (Equine) LEARNING OBJECTIVES • Describe the common myopathies that affect horses, differentiating between those associated with exercise and those ind...

A P P R O A C H TO C O M M O N M U S C L E DISEASES OF THE HORSE Dr Charlotte Maile BVetMed BSc PhD MRCVS Lecturer in Veterinary Clinical Sciences (Equine) LEARNING OBJECTIVES • Describe the common myopathies that affect horses, differentiating between those associated with exercise and those independent of exercise. • Outline the therapeutic and husbandry interventions that would be appropriate to treat and manage equine myopathies. • Detail the prognosis of different myopathies affecting horses. diseases of the horse EQ U I N E M YO PAT H I E S : O V E R V I E W Subdivide myopathies into categories • Are they exertional/non-exertional • Take a good history • Is rhabdomyolysis a feature? • Exertional • • • Recurrent equine rhabdomyolysis PSSM 1&2 Non-exertional • Atypical myopathy • Permanent gait abnormalities • Fibrotic myopathy • Episodic/progressive weakness • • Equine motor neuron disease Hyperkalaemic periodic paralysis • Muscle wasting/atrophy • • • Peripheral neuropathies EMND Autoimmune-mediated myositis Naylor, 2014 A QUICK REMINDER… Breeds you will hear discussed frequently… E X E R T I O N A L M YO PAT H I E S Naylor, 2014 S P O R A D I C E X E R T I O N A L R H A B D O M YO LY S I S Overexertion • Increase in work intensity without foundation of training • Can affect any horse Common in polo ponies early in the season • Aetiology unknown • History of respiratory infection Exhaustion • Racehorses/endurance horses, hot and humid climate • Weakness, ataxia, tachypnoea, sweating… (collapse) • May be hyperthermic • Myoglobinuria and elevated CK, but muscles may palpate normal R E C U R R E N T E X E R T I O N A L R H A B D O M YO LY S I S (RER) • Also known as Monday morning disease, Azoturia and Setfast • Syndrome rather than a disease as aetiology and pathogenesis still unknown • Female > males • Nervous/anxious horses • High prevalence in racing Thoroughbreds (4.9-6.7% of TBs affected) • Also occurs in Standardbreds and Arabians • Historically affects horses on high grain diets Clinical presentation: • Stiff, painful muscles (large muscle groups- gluteals, triceps) • Myoglobinuria • Usually present on day following a rest day Calcium regulation? RER Diagnosis • History and signalment (Trainer often recognises the signs) • Elevated muscle enzymes • Muscle biopsy of semimembranosus- often to rule out other myopathies as no specific changes associated with RER Gold standard: in vitro contracture studies on intercostal muscle (not commercially available) Pathogenesis unknown • Thought to be linked to calcium homeostasis but no abnormalities detected in affected horses • Likely autosomal dominant inheritance. Chronic non-specific changes associated with muscle regeneration (internalised nuclei)and fibre size variation) RER MANAGEMENT Diet • • Low starch diet Use fat for extra calories (20-25% DE) diet. E.g. RE-LEVE by Saracen Competition animals: meet high calorie requirement Reduce post-prandial glycaemic response • • • • Access to a salt block. Reduce caloric intake when not in work. Feed smaller, more frequent meals. Feed forage alongside grain. More detail in nutrition lectures from 2nd year: ‘Diet in the aetiology of muscular diseases’ •Minimise stress •Feed these horses first •Provide company •Avoid negative interactions RER MANAGEMENT Exercise Don’t exercise beyond scope of training Avoid rest days (turn out on rest days if possible) Dantrolene RYR1 antagonist → inhibits calcium release from sarcoplasmic reticulum 2-4mg/kg orally Short half-life. Given 1-2 hours before exercise. Detection time 48hrs (BHA) P O LY S A C C H A R I D E S TO R A G E M YO PAT H Y ( P S S M ) Clinical presentation: • • • • • • Same presentation as RER! Recurrent episodes Muscle pain, weakness, tremors or fasciculations Shifting lameness Sweating Myoglobinuria Reluctance to move or in extreme cases recumbency Breed predilection: How you differentiate between RER and PSSM: Pattern recognition • Quarterhorses, Appaloosa, Paint • European draft breeds- Percheron, Belgian Draft • Less common in UK breeds (but not unheard of) Image credit: FEI breed profile P O LY S A C C H A R I D E S TO R A G E M YO PAT H Y ( P S S M ) Diagnosis: • Marked elevation of muscle enzymes (CK and AST) • Myoglobinuria in more severe cases • Muscle biopsy of semimembranosus • reveals abnormal polysaccharide in myofibres • Genotyping for PSSM1 NB: Severity of clinical signs does not correct with severity of histopathological abnormalities P O LY S A C C H A R I D E S TO R A G E M YO PAT H Y T Y P E 1 (PSSM1) • Majority of PSSM cases (~70%) • Associated with a single dominant missense mutation in the equine muscle glycogen synthase gene (GYS1). • Glycogen synthase catalyses the formation of a1-4 glycosidic bonds in the glycogen molecule • The ratio between GS and glycogen branching enzyme should result in normal branched glycogen formation • The mutant enzyme is unable to be switched off thereby altering the GS:GBE and making abnormally polysaccharide • Pathogenesis not fully understood • Working hypothesis: • All glucose channelled into glycogenesis and abnormal polysaccharide unable to produce glucose through glycogenolysis • Resultant energy deficit during exertion P O LY S A C C H A R I D E S TO R A G E M YO PAT H Y T Y P E 2 (PSSM2) Still a disease of abnormal glycogen storage. • Pathogenesis unknown • Likely to be a group of conditions: MFM?, MIM? Abnormal polysaccharide on muscle biopsy , but absence of GYS1 mutation. • Quarter horse, Warmbloods, Connemaras PSSM MANAGEMENT Dietary changes 1. Limit glycogen synthesis (reduce insulin activity) 2. Promote breakdown of glycogen • • • • • • • Low starch, high fat Provide 1.5-2% BWT as roughage < 10% Digestible energy as non-structural carbohydrates >13 % fat Vegetable oil up to 1ml/kg/day Supplemental Vitamin E Commercial diets 15 PSSM MANAGEMENT Exercise is key! • Maintain regular work/turn out routine Avoid days off • Fibre type switching by exercise • Minimise stress • Minimise changes in management • Don’t exercise beyond scope of training • Prognosis fair if managed correctly MFM & MIM MFM: Recently classified as a separate disease to PSSM2. MIM: No peer reviewed publications on this terminology but may see it referred to. R H A B D O M YO LY S I S T R E AT M E N T A I M S – A C U T E PHASE 1. Minimise continued muscle damage • Strict rest • Can use ACP if necessary • Anti-inflammatories/antioxidants 2. Analgesia • NSAIDs • Opioids 3. Correct fluid deficit/induce diuresis • Enteral fluids • Intravenous fluid therapy 1. MINIMISE CONTINUED MUSCLE DAMAGE Rest Deep bed Don’t exercise in acute phase ACP? Anti-inflammatories (NSAIDs) Flunixin Phenylbutazone (Meloxicam) Check fluid status! Acepromazine Vasodilation (Anxiolytic) Antioxidants Vitamin E (α-tocopherol) Selenium 2. ANALGESIA • NSAIDs Check fluid status! Easy to leave for owner to administer • Opioids Buprenorphine/butorphanol licensed for horses Efficacy? Methadone more potent but use on cascade Morphine commonly used, not licensed in any veterinary spp. • Paracetamol Use as an adjunct, not sole analgesic • Lidocaine infusion Logistics require hospitalisation • Ketamine infusion Requires hospitalisation 3. CORRECT FLUID DEFICIT/DIURESIS Correct systemic abnormalities • Correct fluid balance (oral or IV fluid therapy?) And maintain diuresis if required • Electrolyte abnormalities Remember the kidneys! • Myoglobin → pigment nephropathy • NSAIDs → renal papillary necrosis • Hypovolaemia Dehydrated from exercise Not drinking Check fluid status! N O N - E X E R T I O N A L M YO PAT H I E S Naylor, 2014 Image credit: Equine Medicine, Surgery and Reproduction P O S T - A N A E S T H E T I C M YO PAT H Y • Localised rather than generalised myopathy • Hard, hot, swollen muscles • Gluteals, epaxial muscles, triceps • Onset may be delayed • Compartment syndrome i.e. inappropriate positioning ↑ pressure within muscle → ischaemia → muscle swelling →↑ pressure • Careful consideration r.e.: positioning on table • Dorsal recumbency: symmetrical • Lateral recumbency: extend lower forelimb forwards • Monitor and maintain blood pressure under anaesthesia • Drop in blood pressure and oxygenation fall within the muscle, muscle swells, constricted by muscle fascia • Symptomatic and supportive treatment AT Y P I C A L M YO PAT H Y ( S YC A M O R E M YO PAT H Y ) Acute, severe rhabdomyolysis, affects horses at pasture Risk factors Mast years: bumper crop of seeds from trees • Autumn and spring so higher risk of AM • Wet and windy weather • Presence of Sycamore trees (UK) • Access to pasture (Gonzalez et al. >6hrs a day, median duration 35d prior to onset) May be mistaken for cases of colic, severe laminitis, botulism (neurological exam normal in AM) Why do some horses get AM and others don’t? S. Gonzalez-Medina et al. AT Y P I C A L M YO PAT H Y Clinical signs • Weakness: Horses struggle to walk and stand. May be found recumbent. • Muscle tremors and painful, firm muscles may be appreciated on palpation • Myoglobinuria • Tachycardia, tachypnoea, congested mucous membranes • Signs of severe colic but normal appetite • Distended bladder on rectal palpation Pasture mates can be sub-clinically affected. Diagnosis • Elevated muscle enzymes (CK>10,000iu/L) • Myoglobinuria and acidic urine • Submit plasma for acylcarnitine profile/serum for hypoglycin A and conjugated MCPA Confirmation takes 48-72h via RVC Neuromuscular Lab Image credit: Atypical Myopathy: An update. Votion, D. 2016 Post mortem: necrosis and lipid accumulation in deep postural muscles, necrosis of respiratory and cardiac muscle (Type 1 fibres) AT Y P I C A L M YO PAT H Y Hypoglycin A toxicity: Seeds and seedlings of some Acer trees UK: Sycamore (Acer pseudoplatanas) USA: Box elder maple (Acer negundo) • Ingested toxin from Sycamore tree seeds/seedlings. Hypoglycin • [HGA] varies between different trees A MCPA Blocks energy metabolism • Toxic metabolite • Binds to FAD to inhibit acyl-CoA dehydrogenase • β-oxidation of long chain fatty acids blocked • Type 1 muscle fibres worst affected AT Y P I C A L M YO PAT H Y Treatment Must start treatment and not await definitive dx (takes 48-72h) • Rest Some guidelines say don’t transport…HOWEVER should strongly consider moving to nearby hospital before deterioration as require intensive supportive care and nursing • Fluid therapy (monitor renal function) • • • Add glucose (5% glucose to provide alternative energy source) or give high CBH meals Analgesia Multivitamins: • • • • Vitamin B2 (riboflavin) : 10g/day approx. Vitamin E Antioxidants selenium ?carnitine Stimulates glucose metabolism and supports mitochondria **Remove co-grazing horses from pasture and check serum muscle enzymes.** AT Y P I C A L M YO PAT H Y Prognosis • Guarded (up to 84% mortality reported) • If horse survives the first few days of treatment, they usually go on to recover fully although this may take months. • ↓ prognosis: hypoxia, dyspnoea, tachypnoea, sweating, hypothermia, bladder distension, tachycardia, CK >100 000 IU/litre and recumbency • Elevated levels of circulating MCPA/HGA carry a worse prognosis and are usually associated with worse clinical signs. • ↑ vitamin administration (advised for all cases) Boemer F, Detilleux J, Cello C, et al. Acylcarnitines profile best predicts survival in horses with atypical myopathy. PLoS One. 2017;12(8):e0182761. AT Y P I C A L M YO PAT H Y Prevention • Avoid sycamore trees • Provide supplementary forage in the autumn. • Clear fallen sycamore leaves and seeds from grazing area (especially in stormy weather). • Fence off areas where sycamore leaves/seeds have fallen. • Bring horses in at night. • Check neighbouring areas for high-risk plants/seeds. • Test for the prevalence of HGA in your own horse’s pastures. M E TA B O L I C M YO PAT H I E S Horses present with signs of AM but do not have HGA or MCPA detected on blood tests. H Y P E R K A L A E M I C P E R I O D I C PA R A LY S I S ( H Y P P ) QH, Paint, Appaloosa - descendants of a single stallion (Impressive) Gene mutation alters voltage-dependent skeletal muscle sodium channel Membrane potential close to firing Some sodium channels fail to inactivate = ↑ sodium in, ↓ potassium out = persistent depolarisation of muscle cells Clinical signs variable May have daily fasciculations and weakness, may be asymptomatic May begin with third eyelid prolapse → sweating/fasciculations Overt cramping Severe attacks may cause swaying, dog sitting, recumbency Even paralysis of upper respiratory muscles → respiratory tract obstruction Episodes 15-60min long Fasting, anaesthesia and stress may precipitate signs. Diagnosis • Genetic testing • Hyperkalaemia and suggestive clinical signs, no/little change in CK If anaesthetising QH breeds worth screening beforehand? MALIGNANT HYPERTHERMIA (MH) Quarter Horses/Paints (and pigs!) Rare RYR1 (ryanodine receptor) gene mutation ↓ activation and ↑ threshold of receptor → dramatic increase in intracellular calcium → contraction → muscle heat and necrosis Clinical signs: • • • Muscle rigidity Abnormally high body temperature Tachycardia, tachypnoea Exercise or anaesthesia induced: • Worth screening before anaesthetising these breeds? • Pre-treat with dantrolene Hyperthermia, renal failure and acidosis N U T R I T I O N A L M YO D EG E N E R AT I O N ( W H I T E MUSCLE DISEASE) Acute degenerative disease affecting cardiac and skeletal muscle Selenium +/- vitamin E deficiency in dam → affected foals/youngstock • Selenium Major component of glutathione peroxidase (GSH-Px) Normal muscle metabolism generates hydrogen peroxide and lipoperoxides – broken down by GSH-Px • Vitamin E Antioxidant within the cell membrane Scavenges free radicals that react with fatty acids to form lipid hydroperoxides Clinical signs • Two forms: Cardiac and skeletal muscle Dyspnoea, weakness, stiffness, trembling, recumbency, sudden death, irregular tachydysrhythmia Aspiration pneumonia common 2ry to tongue necrosis Tongue, gastrocnemius, semimembranosus/tendinosus, biceps femoris, lumbar, gluteals, neck affected N U T R I T I O N A L M YO D EG E N E R AT I O N Diagnosis: Clinicopathologic abnormalities • • • CK/AST elevation Myoglobinuria Electrolyte derangements Low selenium (whole blood), low GSH-Px, low α-tocopherol (vit E) (plasma) Clinical signs Gross pathology • • Pale, oedematous muscle, calcification Hypercontracted muscle fibres on histology Treatment: • Selenium injections IM (irritant, can dilute before injection) • Oral α-tocopherol supplementation • Supportive nursing Prognosis: • Cardiorespiratory disease → poor prognosis • Skeletal muscle disease → better prognosis (usually see improvement quickly) Pale streaks and oedema Aleman, 2008 Clinical signs • Weakness, toe dragging, narrow-base stance • Muscle atrophy • Trembling and muscle fasciculations • Weight shifting Disease in its own right? Precursor to EMND? Diagnosis • SCDM biopsy: Presence of myopathic not neuropathic change in sacrocaudalis dorsalis medialis (SCDM) biopsy • May have normal serum α-tocopherol Treatment Oral α-tocopherol supplementation • Not powders, needs to be bioavailable • Is diet deficient, or can horse not absorb it? Re-test. Bedford HE, Valberg SJ, Firshman AM, Lucio M, Boyce MK, Trumble TN. Histopathologic findings in the sacrocaudalis dorsalis medialis muscle of horses with vitamin E-responsive muscle atrophy and weakness. J Am Vet Med Assoc. 2013;242(8):1127-1137. V I TA M I N E - D E F I C I E N T M YO PAT H Y REFERENCES AND FURTHER READING Further reading: Naylor, R. (2017). Atypical myopathy. UK-Vet Equine, 1(1), pp.12-15. Reed, S., Bayly, W. and Sellon, D. (2018). Equine internal medicine. 4th ed. St. Louis, Missouri: Elsevier, pp.542-579. https://beva.org.uk/News/Latest-News/Details/BEVA-warns-against-the-use-of-unvalidated-genetic-tests-for--PSSM2-MFM-and-MIM References: González-Medina, S., Ireland, J., Piercy, R., Newton, J. and Votion, D. (2017). Equine atypical myopathy in the UK: Epidemiological characteristics of cases reported from 2011 to 2015 and factors associated with survival. Equine Veterinary Journal, 49(6), pp.746-752. Aleman, M. (2008). A review of equine muscle disorders. Neuromuscular Disorders, 18(4), pp.277-287. Isgren CM, Upjohn MM, Fernandez-Fuente M, Massey C, Pollott G, et al. (2010) Epidemiology of Exertional Rhabdomyolysis Susceptibility in Standardbred Horses Reveals Associated Risk Factors and Underlying Enhanced Performance. PLoS ONE 5(7):