Recognising myopathies and neuromuscular disease 

There are two major clinical signs associated with dysfunction of the neuromuscular system: weakness (myasthenia) and stiffness (spasticity/hypertonia). Some disorders display only one of these signs, but others may have characteristics of both. 

Possible causes:

•   Rhabdomyolysis (see below for general and under Rhabdomyolysis for

  specific disorder/detail)

•   Botulism (see later)

•   Equine Motor Neurone Disease (see appendix)

•   Hyperkalaemic periodic paralysis (see appendix)

•   Hypocalcaemia (late stage) (see appendix)

•   (myaesthenia gravis) (see appendix) 

•   Fasciculation/muscle twitching

•   narrow based stance

•   increased periods of recumbency

•   low head carriage at rest and during exercise

•   reluctance to bear weight when a limb is raised

•   sudden rapid recumbency (as opposed to gentle lowering to the ground)

•   dysphagia 

0. Spasticity and hypertonia 

   possible causes 

0. Possible causes

•   Rhabdomyolysis (see below)

•   Tetanus (see below)

•   Hypocalcaemia (early stage) (see appendix)

•   Shivering and stiff horse syndrome (see appendix) 

• fasciculation

•   trismus (spasm of masticatory muscles)

•   stiff and stilted gait (hypometria?)

•   other bizarre gait abnormalities

•   dysphagia 

Caused by the toxin of Clostridium botulinum, a gram positive, anaerobic, spore forming bacteria found ubiquitously in soil. 

• Eight antigenically distinct toxins produced by various subtypes of C. botulinum

•   Toxin is thought to block acetylcholine release at neuromuscular junctions, peripheral cholinergic nerve terminals in autonomic ganglia, and post ganglionic

  parasympathetic nerve endings.

•   Peripheral sensory nerves and the CNS are unaffected. 

• C. botulinum grows best in neutral or alkaline pH and grows and produces toxin in anaerobic environments such as decaying vegetable matter and animal carcasses.

•   Silage provides a suitable medium for growth and toxin production.

•   Animal carcasses may be accidentally baled into bales or chopped into cubes or

  pellets.

•   Three modes of intoxication are possible

  •   ingestion of preformed toxin (forage poisoning)

  •   growth of the agent in the GI system (toxicoinfectious botulism)

  •   contamination of wounds (wound botulism)

    In adult horses in the UK, Botulism is usually secondary to eating big bale silage

     

• May be acute in onset, with dyspnoea, severe diffuse paresis, and rapid progression to recumbency.

•   In some horses, the onset and progression are slower, occurring over several days.

•   Weakness and trembling (which improves during periods of recumbency)

•   Inability to fully retract the tongue.

•   Dysphagia and drooling of saliva.

•   Flaccidity of the tail

•   Gradual onset of clinical signs is associated with a better prognosis c.f. acute onset.

•   In fatal cases, death occurs quietly.

•   In non-fatal cases, recovery takes weeks to months.

  In foals - referred to as “toxicoinfectious botulism” or “shaker-foal syndrome”.

•   Initially appear alert

•   Progression is associated with paresis, stilted gait, and most prominent and

  generalised muscle trembling - “shaker foals”.

•   Ptosis and decreased tail tone is frequently evident.

•   Dysphagia is present despite a normal appetite.

•   May show slow PLR, ileus, constipation and urine retention.

•   Death is caused by respiratory paralysis, or complications such as pneumonia.

•   Mortality in this form - >90%. 

• Definitive diagnosis by identification of toxin in serum, GI contents or food - mouse inoculation.

•   Toxin can be identified in serum up to 6 days after the onset of clinical signs. However this is difficult (c.f. small dose required in horses compared to others and localization at nmj)

•   Culture of the organism from feedstuffs is difficult

•   Recovery from the GI tract - interpret with care - normal inhabitant? 

• Mainly symptomatic

•   In cases of wound contamination or toxicoinfectious botulism, antibiotic therapy is

  indicated (metronidazole/penicillin).

•   Antibiotics associated with neuromuscular weakness should be avoided if

  possible e.g. aminoglycisides, tetracyclines and procaine penicillin.

•   Antitoxin - not widely available for clinical use in the UK. Available in USA.

  No pathognomonic signs are found at necropsy. 

• Good husbandry: vermin control, adequate disposal of carcasses, avoiding the use of spoiled foodstuff and poor quality silage.

•   Type B toxoid available in USA for areas where botulism is endemic. 

•   Clostridium tetani - large gram positive spore forming bacillus.

•   Found in soil and is a commensal in the GI tract of man and domestic animals.

•   The spores of C. tetani can persist in the environment for many years.

•   In the body, requires anaerobic conditions to survive.

•   The common sites of contamination include: puncture wounds, surgical wounds,

  mucosal wounds and ulcers, umbilical cord, retained placenta and haematogenous spread to devitalised tissue. 

• Produces a potent exotoxin - tetanospasm causing spastic contractions of striated muscles.

•   Tetanospasm acts primarily on the CNS - transported partly by the vascular system and partly by retrograde axonal migration along the motor nerves to the ventral horns of the spinal cord grey matter.

•   Thought to act mainly by preventing the release of inhibitory neurotransmitters from the interneurons at the motor synapses in the spinal cord.

•   Locally further tissue necrosis and exudation is aided by another toxin, tetanolysin. 

• Horse VERY susceptible to toxin but may take a few days to several weeks to appear.

•   First signs are usually a change in the horse’s gait (stilted action) and demeanour.

•   May also notice a difficulty in eating at this early stage (spasm of muscles of

  prehension, mastication and swallowing).

•   Generalised spastic muscular contractions are provoked by external stimuli (touch

  and sound) - especially evident in the third eyelid when the cheek is tapped or

  when fingers are snapped in front of the eye.

•   The disease may worsen dramatically over the next 24 hours or take several days

  - the horse will stand square on four stiff limbs with its head and neck extended

  and the tail raised.

•   It will have an anxious expression with the nostrils flared, eyelids retracted and

  ears erect.

•   Sweating and tachycardia may result (effects on adrenal medulla).

•   Drooling may be seen due to involvement of the pharyngeal and laryngeal

  muscles - food and water may be regurgitated down the nose and/or pass into the

  lungs.

•   Progression to recumbency (poor prognosis) and death often from convulsions

  leading to respiratory and cardiac arrest. 

• Clinical signs supported by a history of non-vaccination.

•   Wounds are not always detectable.
   CK levels may be used as a measure of response to treatment - but clinical

  judgement is the best guide. 

0. 1. Musculoskeletal injuries 

   2. Rhabdomyolysis
   3. Laminitis
   4. Lactation tetany

   5. Meningitis
   6. Strychnine poisoning 

• In each case - consider the prognosis and the welfare aspects.

•   Recumbent adult animals should be destroyed.

  Cases with the best prognoses show mild clinical signs over several days, and are still able to eat and drink. 

  Management measures: 

   

  - quiet dark stable
  - peat or shavings bedding 

  - elevate food and water
  - soft moist food
  - quiet, gentle handling 

• 
  

  acetylpromazine: 0.05-0.1mg/kg ( diminishes the respnse to external stimuli) 

  sodium benzylpenicillin: 20 mg (35,000 iu)/kg i/v qid

•   procaine penicillin: 20 mg (20,000 iu)/kg bid (but may wish to avoid i/m

  injections)

•   antitoxin: 5,000 - 10,000 iu sid for three days (neutralises circulating toxin:

  any toxin bound to the gangliosides will have to be broken down by the body)

•   hydrogen peroxide: 1% in wound (may inject antitoxin around the wound) 

• Vaccination

•   The vaccination programmes vary according to the product manufacturer -

  generally two injections 4-6 weeks apart followed by a booster one year later -

  subsequent boosters at one to three year intervals.

•   Common practice to vaccinate mares one month prior to foaling to maximise

  passive immunity in the foal - the maternally derived antibodies in these

  circumstances will last approx. 3 - 4 months.

•   Foals from unvaccinated mares should receive a minimum of 3,000 units of

  antitoxin soon after birth. 

0. Approach to the investigation of the suspect muscular or neuromuscular case : History and clinical exam 

0. History and clinical examination
   Key aspects to consider would include the following:

   •   Age bred and sex: Young TB fillies are prone to exertional rhabdomyolysis. Quarter Horses are prone to some chronic forms of chronic muscle disease and HYPP. Older horses get EMND.

   •   Vaccination history (lack of tetanus toxoid vaccination for tetanus)

   •   Previous history of similar signs (chronic types of rhabdomyolysis)

   •   History of silage feeding (botulism)

   •   History of exercise induced signs (mainly rhabdomyolysis; occ.

     hypocalcaemia in endurance horses)

   •   Lactation (predisposes to hypocalcaemia)

   •   Lack of access to outdoors/good quality grazing (most cases of EMND) 

0. Approach to the investigation of the suspect muscular or neuromuscular case: Clinical signs  

0. see above and under specific conditions. Most cases present with either weakness and/or hypertonia. Some clinical signs will be characteristic of certain disorders, e.g.

    Thumps/synchronous diaphragmatic flutter: diaphragm twitching in time with the heart beat in cases of hypocalcaemia

    Trismus: spasm of the facial muscles is very characteristic of tetanus  Third eyelid flickering on menaces response: common with tetanus 

0. 0. Approach to the investigation of the suspect muscular or neuromuscular case 

   Further diagnostic tests:
   

0. Some disorders may be diagnosable on history or clinical signs alone. However others may require confirmation with further tests:
   First line evaluation: Blood biochemistry:

o Muscle enzyme levels (esp. myopathies: see rhabdomyolysis notes) o Electrolyte levels
o Vitamin E and Selenium 

• Muscle biopsy (very useful: see below)

•   Genetic testing for Type 1 PSSM. This tests for the specific point

  mutation that has recently been detected in the glycogen synthase 1

  (GYS1) gene in some cases of PSSM

•   Electromyography (EMG)

•   Fractional excretion of electrolytes

  0. Rarely required/done:

     Genetic analysis (HYPP)
     Enzyme activities (GBE [for GBED] and GAD [stiff horse syndrome]) 

   

0. General approach to the acute ‘tied-up’ horse: acute rhabdomyolysis 

• Common in working horses and ponies

•   Vast majority sporadic and associated with exercise (therefore sporadic

  exertional rhabdomyolysis)

•   A variety of commonly used terms describe the clinical signs: ‘tying up’,

  ‘azoturia’, ‘set fast’, ‘Monday Morning Disease’, ‘paralytic myoglobinuria’.

•   New techniques are identifying specific chronic disorders, leading to concept of several different pathophysiological processes leading to common clinical

  sign of myopathy (see appendices under rhabdomyolysis). 

• Large variety in the severity of clinical signs seen from a slight change in gait to a reluctance or inability to move, to in a few cases recumbency and death. Severity of clinical signs does not reflect degree of muscle damage.

•   Signs occur during or sometimes immediately following exercise. In a minority of cases signs may even occur on leaving the stall/box, or following minimal exercise. These cases are often the chronic types.

•   Occasionally, signs are not associated with exercise: non-exercise related myopathies.

•   With acute tying-up both hind limbs are usually affected - especially gluteal, femoral and lumbar muscles. Affected horses develop a stiff gait and may refuse to move. Palpation reveals affected muscle groups to be painful, hard and swollen. The animal is frequently distressed, sweating, with increased temperature, HR and RR. If forced to move, and in severe cases, the animal may become recumbent.

•   Other more subtle signs which the owner may describe and may indicate muscle disease in the chronic forms are poor performance, difficulty lifting limbs, ‘shivering’ gait, muscle atrophy.

•   In severe cases the urine may be red/brown in colour due to the presence of myoglobin. The excess myoglobin may lead to renal failure (due to the accumulation within the renal tubules). If the horse is oliguric - poor prognostic sign - important to monitor the serum creatinine levels. 

0. 1. Elevation in the serum levels of the enzymes creatinine kinase (CK), aspartate aminotransferase (AST) and lacate dehydrogenase (LDH).The degree of increase reflects the degree of muscle damage (but NOT the degree of clinical signs). A more accurate diagnosis and prognosis may be possible if all three enzymes are measured and allows the determination of acute or chronic muscle damage.

CK is the most specific for skeletal muscle damage.
CK rises first and disappears first, followed by LDH, then AST.

N.B. Mild increases in these enzymes may occur after work in unfit, or strenuous exercise in fit normal horse.

2. The presence of myoglobin in the urine. Note that, using a dipstick, this cannot be distinguished from blood (dipsticks detect general haem pigments) 

Assessing chronic cases of tying-up/muscle disease 

When to consider a more complex/alternative diagnosis than sporadic ER:

•   Typical signallment of some disorders

•   Repeated episodes

•   Non exercise related

•   Atypical signs 

0. 1. Exercise tests and plasma muscle enzymes

•   Allow you to detect whether the response of muscles to exercise is ‘normal’

•   Carry out approx. 3 days after return to exercise or following increase in

  workload

•   Take blood samples before and at 2-6 hours post exercise (and at 24hrs?)

  Interpretation:

•   Pre exercise should have CK< 100IU/l (normal 0-50), AST <300 IU/l (150- 230)

•   No more than doubling of CK at 2-6 hours

•   Return to baseline of CK at 24 hours

•   No more than 50% increase in AST at any point

•   No clinical signs of stiffness.

  2. Muscle biopsy

  •   Easy to perform and provides very useful information in recurrent cases.

  •   Specifically useful in cases of polysaccharide storage but also useful in other

    chronic muscle and neuromuscular diseases

  •   Needle (Bergstrom) or excision technique; biopsy muscles with high % of type

    II fibres for rhabdomyolysis.

  •   For techniques see Ledwith and McGowan (2004) EVE 16 (2) pp 62-67 or

    Keen, J.A. (2011) Diagnosis and Management of Equine Rhabdomyolysis. In Practice 33, 68-77.

    3. Fractional Electrolyte Excretion Test

  •   Measurement of FEE is a means of evaluating a horse’s electrolyte balance.

  •   Rarely used nowadays due to high variability.

  •   Excretion of particular electrolyte is compared to that of creatinine (reflects

    GFR)

  •   Collect free catch sample pre-exercise and pre-feeding. Collect blood sample

    soon after.

  •   Interpretation difficult. Very dependant on diet. 

   

0.  Treatments for chronic case of tying up: 

• Diagnosis is important: refer to Appendix for specific disorders which may be diagnosed by typical signallment or may be diagnosable by muscle biopsy.

•   Dietary: Reduced carbohydrate (<10% starch) rations appear to be beneficial

  in both types of chronic disease. If horse on low plane of exercise, only forage required. If require extra energy, then oils may be substituted for carbohydrate. Proprietary feeds are available from companies such as Dodson and Horrell and Waltham. Do not feed in anticipation of an increase in workload. Increased intake should follow increased workload.

•   Exercise. All cases benefit from continual exercise, with adequate warm-ups and without breaks in routine. Turnout is very beneficial also.

•   Stress avoidance: Especially important in the recurrent ER cases (RER: see appendix). Turnout will also be beneficial in this respect. Provide company, or a stimulating environment. Serve first at feed times.

•   Drugs.

o Acepromazine (ACP: 5-8mg per 450kg): has been used to reduce stress

of training in RER cases. No use in polysaccharide storage cases.
o Dantrolene. Anecdotally found to be useful for a number of years. More recently a double blind placebo controlled study has shown this drug to be useful in reducing post exercise levels of CK and AST and preventing myopathy (2mg/kg 1 hour prior to exercise). Phenytoin has also been used but reports of efficacy are only anecdotal. Nb this type of drug has

no place in the treatment of polysaccharide storage diseases.

 Other
o Salt - Horses which are undergoing intense exercise may sweat profusely

resulting in loss of sodium and chloride. Salt can be added to diet (12-56

g per day depending of time of year, work rate and sweating rate).
o Vitamin E and selenium - believed to be useful due to their suspected involvement in oxidative-reduction reactions within the cells. Though VitaminE/selenium deficiency is unlikely to be involved in the disease pathogenesis, supplementation may be beneficial in severe cases to soak up free radicals. More importantly, animals on high fat diets should have additional Vitamin E (100IU Vit E/100ml of oil added to diet.

(specific feeds should have accounted for this)