How to Diagnose and Treat Neuromuscular Diseases: “The Weak, Trembling Horse”

Joan L. Norton, VMD; and Amy L. Johnson, DVM, Diplomate ACVIM

1. Introduction botulinum, an anaerobic, spore-forming rod. Botu- Disease states affecting the lower motor neuron lism spores are found in soil throughout the United (LMN), neuromuscular junction, or muscles can result States. There have been eight toxin types identi- 1 in vague clinical signs of weakness and trembling that fied (A, B, C1, C2, D, E, F, and G). More than 85% make these diseases difficult to distinguish from one of cases seen in North America are caused by toxin another as well as from non-neuromuscular problems B.2 Infection can occur in one of three ways: in- such as electrolyte disturbances, colic, or pain. Early gestion of the preformed toxin, ingestion of spores recognition of neuromuscular disease is important with subsequent elaboration of toxin in the gastroin rapid diagnosis and early, appropriate treatment. intestinal tract (Shaker Foal Syndrome), or contam- Clinical signs in acute cases often include trembling, ination of a wound with spores leading to production tachycardia, unwillingness to stand still, an abnor- and absorption of the toxin. Equine cases usually mal stance (elephant on a ball), repeated attempts to occur sporadically, whereas bovine cases can be seen lie down, and prolonged periods of recumbency. as herd outbreaks.3 There are several disease processes that have been The toxin acts at the presynaptic nerve terminal recognized in the horse that result in these signs to block release of acetylcholine into the synaptic either acutely or chronically. This summary de- cleft. The toxin binds irreversibly to receptors on scribes these diseases and presents a stepwise pro- the presynaptic terminal and is internalized in a cess that practitioners can use to differentiate vesicle. Because the biding is irreversible, neuro- the diseases from each other as well as from more muscular function only improves when nerve end- common causes of weakness and trembling. In ad- ings have been regenerated. dition, this summary reviews diagnostic and thera- Clinical signs are the result of muscle weakness peutic options. that may progress to diffuse flaccid paralysis. These signs can occur anywhere from 12 h to 10 days 2. Botulism after intoxication or infection. The most classic Botulism is one of the more common LMN diseases clinical signs associated with botulism in horses are seen in the horse. The signs seen are the result of poor tongue tone and dysphagia. Early signs in- a neurotoxin produced by the bacterium Clostridium clude generalized muscle weakness, gait abnormal-

NOTES

AAEP PROCEEDINGS ր Vol. 55 ր 2009 167 MEDICINE—NEUROLOGY ities (stiff/shuffling), decreased ability to eat, and Aminoglycosides (gentamicin and amikacin) and increased episodes of recumbency. These horses polymixin B should be avoided.6 Lidocaine will have normal mentation because the central nervous also affect neuromuscular transmission and should system (CNS) is not affected. Cranial nerves re- not be used in these cases.7 Although these horses main intact though there can be a decrease in lid have difficulty standing for prolonged periods, resist tone and pupillary light reflexes. the urge to place them in a sling. This may lead to Diagnosis of botulism is usually presumptive and struggling, exhaustion, and increased mortality. based on clinical signs, as well as vaccination his- Mechanical ventilation may be required in the most tory. A “grain test” can be performed. This in- severe cases and is feasible in foals but is not usually volves feeding 8 oz of grain in a shallow tub. A possible in the adult horse. normal horse should be able to finish the grain in Ͻ2 Outcome and duration of recovery are dependent min.4 Hematology and serum chemistry may re- on the amount of toxin that is initially present in the flect dehydration and horses with prolonged diffi- circulation. Prognosis is difficult to determine at culty standing can have muscle enzyme elevations. the onset of clinical signs, and success can be depen- Cerebrospinal fluid (CSF) is normal. Definitive di- dent on the secondary complications of recumbency agnosis is made by the demonstration of toxin in the such as pneumonia and decubital ulceration. A gastrointestinal (GI) contents, serum, or wounds. highly effective vaccine is available in North Amer- The most sensitive test is a mouse bioassay where ica but only protects against type B toxin. Horses serum of a suspected horse is injected into a mouse, in endemic areas should be vaccinated. which is observed for signs of botulism. Mice that have been pretreated with antiserum are also in- 3. Equine Motor Neuron Disease jected and should be protected if the toxin is present. Unfortunately, horses are sensitive to low levels of Equine motor neuron disease (EMND) is a more toxin that may not produce disease in these mice; recently reported disease of horses. It is associated therefore, many cases of equine botulism are not de- with decreased serum vitamin E levels, and the dis- finitively diagnosed. Enzyme-linked immunosorbent ease can be reproduced by holding horses off fresh assay (ELISA) and polymerase chain reaction (PCR) grass pasture for months to years and feeding low tests have been developed but are not commercially vitamin E diets. Small intestinal malabsorptive available. diseases could also lead to low levels of vitamin E The most important treatment in the manage- and other antioxidants. Because histopathologic ment of a botulism case is the administration of changes are similar to those of amyotrophic lateral antitoxin. The antitoxin binds and neutralizes the sclerosis (ALS), oxidative stress likely is involved in circulating toxin. Timing is important because the the observed neuronal injury and denervation. outcome is favorable in 70% of cases when the anti- These changes are especially seen in type I myofi- toxin is administered while the horse is still stand- bers, which are more oxidatively active than type II ing.5 The prognosis decreases significantly once fibers. the horse becomes recumbent and is highly fatal if Clinical signs are reflective of the skeletal muscle the antitoxin is not administered at all except in denervation and include generalized weakness and very mild cases. A polyvalent antitoxin is available muscle atrophy. The onset can be insidious or from the University of Pennsylvania, New Bolton acute. It is not uncommon for these cases to Center. This form of antitoxin is available in present for chronic weight loss because of the 500-ml units, and one unit is usually sufficient for a chronic nature of the muscle atrophy. As the pos- 500-kg adult horse. A monovalent antitoxin is tural (antigravity) muscles are predominately af- available from Veterinary Diagnostics Inc. in fected, trembling and increased periods of Templeton, CA. It is important to anticipate a pro- recumbency are often seen. These horses also gression in clinical signs for 12–24 h after adminis- stand in a characteristic position of an “elephant on tration of the antitoxin because it can only bind a ball” with all four feet placed close together to freely circulating toxin. The toxin that has al- better distribute weight over all four weak limbs. ready entered nerve terminals will still bind with These animals also frequently shift their weight and receptors.5 are more comfortable walking than stand- The remainder of treatment in these cases is ing. Thus, they are often perceived to be anxious or mainly supportive. The dysphagia commonly seen in pain. Head carriage in these cases is often low, will necessitate nutritional support, either enterally and there can be wasting of the neck and shoulder or parenterally. Ileus is another sequelae that may musculature. Conversely the tail head in these require withholding enteral feeding. Horses that cases appears elevated because of the atrophy of the are dysphagic may aspirate. This tendency, com- coccygeal muscles. Mentation and cranial nerves bined with prolonged recumbency, predisposes these are unaffected, and no proprioceptive ataxia is seen cases to aspiration pneumonia, and antimicrobial in these cases. In some instances, fundic examina- therapy may be necessary. It is important when tion will show deposition of brown-black or yellow- treating these cases to avoid the use of pharmaceu- brown lipofuscin pigment at the tapetal–non-tapetal ticals that potentiate the neuromuscular blockade. junction.5

168 2009 ր Vol. 55 ր AAEP PROCEEDINGS MEDICINE—NEUROLOGY Diagnosis is based on clinical signs and history of is known to be HYPP homo- or heterozygous or if poor access to green forage. The most consistent HYPP status is unknown. biochemical abnormality in these cases is hypovita- minosis E. Increases in muscle enzyme activity may 6. Other Myopathies be present in acute cases but may also be normal in Two additional myopathies, polysaccharide storage more chronic states. There are no typical changes myopathy (PSSM) and recurrent exertional rhabdo- seen in CSF. Muscle or nerve biopsies will show myolysis (RER), warrant mention because these denervation. These changes along with appropri- cases can present with similar clinical signs. Like ate clinical signs are needed for a definitive diagno- HYPP, these myopathies are often associated with sis of EMND. The muscle biopsy is the most recent exercise. RER is more often described in common invasive diagnostic. The sacrocaudalis Thoroughbreds, whereas PSSM is associated with dorsalis medialis, the tailhead muscle, is predomi- Quarter Horses and Draft breeds. The exact mech- nantly type I fibers and highly sensitive to denerva- anism that causes RER has not been identified, but tion. This sample can be easily obtained with it is thought to be a defect in calcium regulation. sedation and local anesthesia. PSSM is a result of accumulation of abnormal poly- Vitamin E supplementation is the recommended saccharide. Significant accumulation occurs over treatment for EMND. This can be given as a fresh time, and signs may not been seen in the first few source of grass or alfalfa or oral vitamin E supple- years of life.10 ments. Natural vitamin E supplements have been Clinical signs for both diseases include signs of shown to have a higher bioavailability than the syn- cramping, stiff gait, muscle fasciculations, anxiety thetic versions. Unfortunately, there has been no (sweating, tachycardia), refusal to move, and some- clinical trial showing that vitamin E supplementa- times recumbency. Signs are mainly limited to the tion is effective in halting or improving the disease muscles of the hindquarters (gluteal and quadri- process. Although some cases show improvement ceps), but the front limbs may also be affected. or stabilization of clinical signs initially, long-term Muscles are firm and painful on palpation. prognosis is poor, and many cases are ultimately Biochemical abnormalities are also similar for euthanized.8 both RER and PSSM. The hallmarks of these diseases are severe elevations in serum creatine kinase 4. Electrolyte Abnormalities (CK) and aspartate aminotransferase (AST) enzyme Mild to moderate electrolyte aberrations can lead to activities caused by their release from damaged diffuse weakness similar to LMN disease, but these muscle fibers. CK rises rapidly and peaks within signs are reversed with correction of the abnormal- 4–6 h of exercise and can exceed 100,000 U/l. Typi- ities. Hypokalemia can lead to lethargy and weak- cally, AST levels take 12–24 h to reach maximum ness and myopathies. This can often be seen with levels. If there is no longer any ongoing muscle concurrent hypomagnesemia. Low serum levels of damage, the CK levels should rapidly decrease over magnesium can lead to muscle fasciculations, rest- 24–48 h, whereas AST levels will take 4–7 days to lessness, and weakness. Hypocalcemia is another return to normal.11 This severe muscle damage electrolyte abnormality that can lead to muscle also leads to the release of myoglobin and subse- weakness and recumbency. Most of these derange- quent myoglobinemia. The high level of myoglobin ments are seen secondary to an inciting disease pro- is filtered by the kidney, which will cause myoglo- cess and can be easily identified on a serum binuria and pigment nephropathy. It is therefore biochemistry profile. Correction of these abnormal- important to perform a urinalysis in these cases. ities should be complete before evaluating the horse The urine will be dark colored and will not clear with for neuromuscular disease.9 centrifugation. Myoglobinuria can easily be distin- guished from hemoglobinuria by showing that the 5. Hyperkalemic Periodic Paralysis serum is clear when spun down. Hyperkalemic periodic paralysis (HYPP) is caused Clinical signs, history of recurrent episodes of my- by a mutation passed on by the Quarter Horse stal- opathy, and biochemical abnormalities only provide lion “Impressive” and subsequent descendants. a presumptive diagnosis. Pre- and post-exercise It is not a disease of lower motor neurons nor is it CK and AST levels may help confirm suspicions and characterized by true weakness. This disease does aid in the diagnosis of subclinical exercise-induced share clinical signs with LMN disease and may be myopathies. To definitively diagnose these dis- confused with LMN diseases. HYPP episodes can eases a muscle biopsy (Ϯgenetic testing) is required. lead to diffuse muscle fasciculations and recum- The most commonly sampled muscle is the semi- bency. These signs are usually secondary to an membranosus muscle. The sample can be evalu- exercise event and are temporary, and these cases ated for the presence of abnormal polysaccharides or also have known predisposition (if pedigree or geno- evidence of recurrent myopathy. type is documented). If a Quarter Horse is seen Immediate treatment of these episodes should in- with muscle fasciculations or in recumbency, appro- volve correcting dehydration and providing analge- priate treatment for hyperkalemia (dextrose, cal- sia. Care should be taken in administering cium, Ϯ bicarbonate) should be initiated if the horse nephrotoxic drugs such as non-steroidal anti-inflam-

AAEP PROCEEDINGS ր Vol. 55 ր 2009 169 MEDICINE—NEUROLOGY matories (NSAIDs) to a dehydrated horse with a have ileus and the potential for a surgical gastroin- potential nephropathy. Horses should be stall- testinal lesion. Care must be taken in the diagno- rested until their muscle enzyme activity levels re- sis of these cases. turn to normal before returning to exercise. Kidney function should be monitored closely during 8. Methods for Diagnosis this time, especially when NSAIDs are being When presented with a case that shows signs com- administered. patible with diffuse muscular weakness, it is impor- Specific treatments can include dietary and exer- tant to obtain a thorough history (Fig. 1). Always cise changes. Thoroughbreds with RER may bene- obtain a complete vaccination history and feeding fit from a lower stress environment and training regimen, including access to pasture. Pertinent schedule and a diet that does not provide excessive questions should show the duration of the condition. calories for the work being done. Horses diagnosed If it is an acute episode, inquire about the animal’s with PSSM do well when they are maintained at a activities before the onset such as exercise and any good level of fitness. Exercise intensity should be abrupt changes in feed or activity level. In the case increased slowly, and affected animals may benefit of Quarter Horses, a full pedigree and/or HYPP ge- from living in a field where they can move freely. notype results, if available, should be obtained. Both RER and PSSM cases should be fed a high-fat, A full physical examination should begin with ob- low-carbohydrate diet. servation of the animal at a distance. As men- There are other, less common myopathies that can tioned previously, a colic examination should be occur. The diagnosis and initial treatment plan is done to rule out abdominal discomfort as a cause of largely the same as with RER and PSSM. the perceived muscle weakness. In addition, a full neurologic examination should be done to rule out 7. Colic CNS disease, and a fundic examination should also The signs of acute LMN disease can easily be con- be performed. fused with acute abdominal pain. Restlessness, Simple hematology and serum biochemistry can muscle fasciculations, and recumbency can be a sign be helpful in ruling out electrolyte abnormalities or of colic as well as muscle weakness. A thorough primary myopathies. A packed cell volume (PCV) colic examination should be performed. This in- and total protein will indicate dehydration and se- cludes a rectal exam (if safety allows) and nasogas- rum muscle enzyme activities can indicate the du- tric intubation. In these cases, sedation with ␣-2 ration of the episode and may implicate a myopathy agonists and analgesia may be diagnostic and pal- as opposed to a neuromuscular disease. Serum vi- liative. Cases of neuromuscular disease will not tamin E levels should be measured. A urinalysis readily improve with sedation and analgesia. Also, should be performed to discover pigmentuia, assess keep in mind that colic and neuromuscular disease renal function, and look for casts as a sign of can be concurrent, because many botulism cases nephropathy.

Diagnostic Plan

Time To Onset

Acute Chronic History <48hrs Multiple Episodes

Vaccination Status Change in Diet Recent Exercise Breed Access to Pasture TB/QH/Draft

Tongue/Tail Tone Colic Exam Muscle Palpation Muscle Wasting Physical Exam Grain Test NGT/Rectal Painful QH Abnormal Stance

Pigmenturia TB Draft Initial Diagnostics PCV/TP CK/AST Urinalysis Vitamin E Genetic Testing

severe low normal-mild elevations HYPP Differentials elevations Myopathy Botulism RER/PSSM EMND

semimembranosus m. sacrocaudalis dorsalis m. Additional Mouse Bioassay Muscle Biopsy Diagnostics Fig. 1. Step-wise plan for the diagnosis of neuromuscular disease.

170 2009 ր Vol. 55 ր AAEP PROCEEDINGS MEDICINE—NEUROLOGY Once abdominal discomfort and electrolyte abnor- mind when evaluating a case with diffuse muscle malities have been ruled out, more extensive or in- weakness. By following Fig. 1, simple steps can be vasive diagnostics can be considered. Muscle taken to properly differentiate and diagnose neuro- biopsies can be helpful in the diagnosis of neuromus- muscular disease. cular diseases and myopathies. If there is question as to whether a myopathy or neuromuscular disease is the cause of the clinical signs, biopsies of both the References semimembranosus muscles and the sacrocaudalis 1. Smith BP. Large animal internal medicine. Philadelphia: dorsalis medialis muscles should be submitted. Mosby, 1996. In chronic cases that involve weight loss, a more 2. Whitlock RH, Buckley C, Messick J. Investigations of herd outbreaks of botulism in cattle and horses. Proc Am Assoc extensive work up should be done to rule out gastro- Vet Lab Diagn 1989;40:38. intestinal disorders that could lead to poor absorp- 3. Whitlock RH, Williams JM. Botulism toxicosis of cattle. tion of nutrients including vitamin E. Glucose Bovine Proc 1999;32:45–53. absorption testing or abdominal ultrasound may 4. Whitlock RH. Botulism type C: experimental and ﬁeld provide further information regarding the absorp- cases in horses. Equine Pract 1996;18:11–17. tive ability of the small intestine. 5. McKay R. Neurodegenerative disorders. In: Furr M, Reed S, eds. Equine neurology. Ames, IA: Blackwell Pub- 9. Treatment lishing, 2008;235–255. 6. Durant NN, Lambert JJ. The action of polymixin B at the Treatment should be appropriate for the diagnosed frog neuromuscular junction. Br J Pharmacol 1981;72: disease process as previously mentioned. If botu- 41–47. lism is suspected and ﬁnancial resources allow, bot- 7. Matsuo S, Rao DB, Chaudry I, et al. Interaction of muscle ulism antitoxin should be administered as soon as relaxants and local anesthetics at the neuromuscular junc- possible. Vitamin E supplementation can be imple- tion. Anesth Analg 1978;57:580–587. 8. Divers TJ, Mohammed HO, Hintz HF, et al. Equine motor mented even while testing is still being processed. neuron disease: a review of clinical and experimental stud- Supportive care should include correction of dehy- ies. Clin Tech Equine Pract 2006;5:24–29. dration and any electrolyte or acid–base abnormal- 9. Hurcombe S. Electrolytes and neurological dysfunction in ities. Nutritional support can be provided through horses. In: Furr M, Reed S, eds. Equine neurology. a nasogastric tube or parenterally if needed. Ani- Ames, IA: Blackwell Publishing, 2008;269–282. mals that are persistently recumbent must be man- 10. MacLeay JM. Diseases of the musculoskeletal system. aged for pressure sores and potential pneumonia. In: Reed SM, Bayly WM, Sellon DC, eds. Equine internal medicine, 2nd ed. St. Louis: Saunders, 2004;476–488. 10. Conclusion 11. MacLeay JM, Valberg SJ, Pagan JD, et al. Effect of ration and exercise on plasma creatine kinase activity and lactate Neuromuscular diseases caused by LMN dysfunc- concentration in Thoroughbred horses with exertional rhab- tion are an uncommon event but should be kept in domyolysis. Am J Vet Res 2000;61:1390.

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