Disorders of MM tone & exertional myopathies Flashcards
Spastic paresis is seen in what age calves? And manifests as:
Calves: 2 months-7 months
— decreased ability to flex the hock because of continuous tension on the gastrocnemius & straight angle to hock & stifle
What is a similar condition to spastic paresis in calves seen in horses?
Shivers
Shivers is seen in horses of what breed/size typically
Draft breeds, warmbloods and warmblood crosses older than 1 yr of age
**usually taller than 16.3 hands
Define myotonia
Prolonged contraction of mm contraction
Clinical signs of shivers:
Primarily affects hindlimbs
-periodic, involuntary spaspsm of muscles in the pevlic reigon, pelvic limbs and tail
**exacerbated by backing and up or picking up hind libs
** tailhead usually elevates concurrently/trembles
-hindlimb is suddenly raised, semi-flexed and abducted with hoof held in air for several seconds or minutes
Myotonic muscle disorders share the feature of what?
Delayed relaxation of muscle after mechanical stimulation or voluntary contraction
**abnormal muscle membrane excitability
Appearance of myotonia congenita in horses
Mild to moderate pelvic limb stiffness
**bilateral bulging of thick and rump muscles
Pronounced when exercise begins & diminishes as exercise continues
Is there progression of myotonia congenita in horses?
Not beyond 6 to 12 months of age
In goats what is the inheritance of myotonia congenita?
Autosomal dominant mutation in skeletal muscle chloride channel (CLCN1) that is incoplete penetrance
Myotonia dystrophica is separate from myotonia congenita in horses. What are the differences?
Severe clinical signs of myotnoia that progress to amarke dmm atrophy & involve a variety of organ systems
—> Quarterhorses, Appaloosa, Italian-bred foals
What is the definitive diagnosis of myotonia in horses?
Based on electromyographic examination
Examination of muscle biopsies from foals with myotonia congenita show:
Normal or demonstrate extremely variable muscle fiber dimensions up to twice those of normal age matched controls
+/- Type 1 fiber hypertrophy or hypotrophy
Changes in muscle biopsy seen with myotonic dystrophy
Ringed fibers
Alterations in shape & position of myonuclei, sarcoplasmic masses & inc in ednomysial & perimysial connective tissue
Fiber type grouping & atrophy of both type 1 & type II muscle fibers may be present
What are the treatment recommendations of myotonia?
No treatment
Myotonia prognosis
Variable & dependent on clinical signs
**regression of C/S unknown
** euthanasia often warranted
Is myotonia congenital?
Unknown
**warn owners of possibility of this disease is heritable
Equine hyperkalemic periodic paralysis (HYPP) is caused by:
Inherited defect in the skeletal mm sodium channel
Equine HYPP manifests as
Abnormal skeletal mm membrane excitability leading to episodes of myotonia or sustained mm contraction and paralysis
How is HYPP inherited in horses?
Autosomal dominant trait in Quarterhorses, American Paint Horses, Appaloosas & QH horse crossbreeds
In HYPP, intermittent clinical signs start at what age?
2 to 3 years of age with no apparent abnormalities between episodes
What are examples of diets high in potassium (>1.1%)?
Alfalfa hay
Molasses
Electrolyte ysupplements
Kelp-based supplements
**sudden dietary changes
What can precipitate clinical signs of HYPP?
**unpredictable
Fasting
Anesthesia or heavy sedation
Trailer rides
Stress
Exposure to cold
Fasting
Pregnancy
Concurrent dz
Rest following exercise
Clinical episodes of HYPP start as
— brief period of myotonia
Prolapse of third eyelid
Sweating & muscular fasciculations
**muscular weakness is a common characteristic of HYPP
Clinical signs of severe HYPP attacks
Apparent weakness with swaying
Staggering
Dog sitting
Recumbency w/in a few minutes
INC HR and RR
How long do HYPP episodes last?
15 to 60 minutes
Respiratory distress can result in HYPP episodes due to:
Paralysis of upper respiratory muscles
** may require tracehostomy
What is the concern for horses homozygous for HYPP?
Dysphagia/respiratory distress
However horses with HYPP may be normal between attacks, does electromyography show any abnormalities?
Yes
* abnormal fibirllation potentials
Complex repetitive discharges with occasional myotonic potentials & trains of doublets between episodes
What is the exact mutation that leads to HYPP horses?
Point mutation that causes a phenylalanine/leucine substitution in voltage- dependent skeletal muscle sodium channel alpha subunit
The result of the mutation in HYPP causes:
Resting membrane potential is closer to firing than in normal horses
- subpopulation of sodium channels inactivate when serum potassium concentrations are increased
—> excessive inward flux of sodium and outward flux of potassium ensues
—> results in persistent depolarization of muscle cells and temporary weakness
Does serum concentration of potassium increase in HYPP episodes?
6 to 9 mEq/L increase during episode
** serum potassium concentration return to normal following abatement of C/S
What are differentials for hyperkalemia?
Delay before sample centrifugation
Hemolysis
Acidosis
Renal failure
Severe rhabdomyolysis
High-intensity exercise
Treatment options for HYPP episodes
Feeding grain/corn syrup to stimualte insulin-mediated movement of potassium across cell membranes
Epinephrine 0.006 mg/kg/500 kg IM
Acetazolamide: 3 mg/kg PO every 8 to 12 hours
**most recover from episodes of paralysis and appear normal by time a veterinarian arrives
In severe cases of HYPP intravenous treatment with what medications can be used to enhance intracellular movement of potassium?
Calcium gluconate: 0.2-0.4 ml/kg of 23% solution in 1 L of 5% dextrose or combinated with sodium bicarbonate (1 to 2 mEq/kg)
How does calcium gluconate assist in treatment of HYPP?
Increase in extracellular calcium concentration raises muscle membrane threshold potential— decreasing membrane hyperexcitability
For horses with recurrent episodes of muscle fasciculations with HYPP?
Acetazolamide: 2-3 mg/kg PO every 8 to 12 hours
Hydrochlorothiazide: 0.5 to 1 mg/kg PO, every 12 hours
Chronic fibrotic myopathy stride
Short anterior phase with characteristic hoof-slapping gait
Clinical signs of exertional rhabdomyolysis
Develop a stiff, stilted gait, with excessive sweating & high respiratory rate during or after exercise
- seen 15 to 30 minutes after light exercise
- firm, painful muscles (back and hind limb mm)
- myoglobinuria
Sporadic exertional rhabdomyolysis is seen in what population of horses?
Any age, breed or sex involved in a wide variety of athletic disciplines
Diagnosis of sporadic exertional rhabdomyolysis
History
C/S
Elevations of serum muscle enzymes
What are causes of sporadic exertional rhabdomyolysis?
Overexertion
Exhaustion
Dietary imbalances
What are clinical signs of heat exhaustion?
Weakness
Ataxia
Rapid breathing
Muscle fasciculations
Sweating
Severe cases of collapse
Body temp: 105 to 108
INC Ck activity
Myoglobinuria
Sporadic forms of exertional rhabdomyolysis due to
an extrinsic event or recurring extrinsic events that induce muscle damage with exercise
Causes of sporadic exertional rhabdomyolysis include
focal or generalized trauma to muscle
exercise performed beyond any training adaptation or performed to the point of exhaustion
dietary imbalances that affect muscle fasciculation
Resolution of sporadic exertional rhabdomyolysis occurs after:
- period of rest
- provision of balanced diet
- gradual introduction of a training program matched with performance demands
dietary imbalances that can trigger exertional rhabdomyolysis episdoes
high nonstructural carbohydrates (NSC) & low forage content
diets deficient in electrolytes
+/- exacerbation inadequate selenium/vit E
Horses competing in hot, humid weather what electrolytes require higher concentrations?
sodium chloride
- 30 to 50 g/day combined with 15 to 25 g of “lite” salt containing KCL
- ideal Ca:Phos ratio of 2:1
Reason for administration of dantrium sodium in exertional rhabdoymyolysis?
in severely affected horses may decrease muscle contracture sand possible prevent furthe rmuscle necrosis
Overdoing dantrium sodium can lead to?
muscle weakness
What are causes of chronic exertional myopathies in horses?
Polysaccharide storage myopathy T1
Polysaccharide storage myopathy T2
Malignant hyperthermia
Recurrent exertional rhabdomyolysis
Idiopathic exertional rhabdomyolysis
Mutation in what gene has shown to be highly associated with the presence of amylase resistant polysaccharide in skeletal muscle from Quarter Horses with PSSM?
GYS1 gene
**glycogen synthetase gene
Do all horses with PSSM have gene mutations in GYS1 gene?
No–
PSSM type 1- GYS1 gene mutation
PSSM type 2– unknown origin
what is the gene mutation at GYS1?
single base pair mutation in GYS1 gene resulting in arginine to histidine substitution at codon 309
GYS1 gene mutation in PSSM type 1 horses leads to what functional abnormality?
Gain in function in glycogen synthase enzyme= higher than normal activity at basal states & when active by insulin & glucose 6-phosphate
–>a deficit in energy metabolism
The highest prevalence of PSSM1 appears in what breeds?
draft horses derived from Continental European drafts
–>north american belgians, percherons, trekpaards
what are the prevalence estimates for PSSM1 in quarter horses?
6 to 10% Quarterhorses
what is the prevalence of PSSM1 in light horse breeds (arabians, Standardbreds, thoroughbreds)?
very low to nonexistent
What are risk factors for the development of clinical signs with PSSM1?
exercise (<20 minutes especially)
Diets high in NSCs
+/- seasonal incidence
systemic illness
What is a supportive diagnostic for subclinical exertional rhabdomyolysis is present?
lunge for max of 15 minutes– a minimum of 3-fold increase in CK activity 4 hours after exercise
What are distinctive features of PSSM1 on muscle biopsy?
- numerous subsarcolemmal vacuoles
- dense crystalline periodic acid-SCHIFF (PAS) positive, amylase resistant inclusions
When can false-positives for PSSM1 occur on muscle biopsy?
small muscle biopsies
horses <1 yr of age
What is the gold standard diagnosis for PSSM1?
genetic testing for GSY1 mutation– whole blood or hair root samples
What age range do clinical signs of PSSM1 appear?
at 5 years of age (range 1-14 yrs)
In an acute episode of exertional rhabdomyolysis associated with PSSm1, elevations of CK are greater than?
35,00 U/L CK
**myoglobinuria present
What other gene mutation can cause severe clinical signs of exertional rhabdomyolysis with GSY1 mutation?
RYR1 mutation for malignant hyperthermia
**small number of Quarterhorses and paints
Are draft horses with PSSM clinical?
No– asymptompatic
what is the average age that drafts are diagnosed with PSSM?
8 years old
What are the median serum CK and AST activities in draft horses from which biopsies were sent to the Equine Neuromuscular DIagnostic laboratory:
Ck: 459 U/L
AST: 537 U/L
In theory, why does feeding high nonstructural carbohydrate diets to PSSM horses lead to the development of muscle pain?
Nutrient switches do not fully activate enzymes such as pyruvate dehydrogenase during exercise, limiting adequate acetyl-CoA for oxidative metabolism, thus
**do not generate enough Acetyl-CoA to from either carbohydrate or or fat metabolism to fuel muscle contraction during submaximal exercise
What is the prevalence of PSSM2?
approximately 28% of cases of PSSM diagnosed by muscle biopsy in Quarterhorses (that do not have GYS1 mutation)
What is the prevalence of cases of PSSM that are warm bloods that have PSSM2?
Approximately 80%
What abnormality is seen in PSSM2 on muscle biopsy?
increase in normal beta glycogen particles
Acute cases of PSSM2 resemble
exertional rhabdomyolysis in QH, Thghbd, Stdbreds & Arabians
intermittent exertional rhabdomyolysis in warmbloods
Chronic signs of PSSM2
**related to poor performance: undiagnosed gait abnormality, sore mm & drop in energy level & willingness to perform after 5 to 10 minutes of exercise
Do chronic cases of PSSM2 have marked elevated CK/AST values?
No–average warmblood: CK: 323 U/L, AST: 331 U/L)
What is diagnostic for PSSM2 on muscle biopsy?
abnormal amount of amylase-sensitive glycogen= subjective
specificity= low
false-positive results likely occur
What percentage of horses diagnosed with PSSM1/PSSM2 show notable clinical improvement and return to acceptable levels of performance?
70%
**when adhere to diet and exercise regimen**
How much stall confinement should horses with PSSM have?
less than 48 hours after an episode of rhabdomyolysis, then increase turnout in pastures increasing in size gradually
The beneficial response to low-starch, fat supplemented diets only occur when in conjunction with??
a regular incremental exercise program
What are important principles to follow when starting exercise programs in PSSM horses?
- provide adequate time for adaptation to a new diet before commencing exercise
- recognize that the duration of exercise, not its intensity is of primary importance
- ensure the program is gradually introduced and consistently performed
- minimize any days without some form of exercise
When instituting an exercise program, is it beneficial to recheck serum CK levels in PSSM horses?
No, not unless overt episode of rhabdomyolysis
** common to have subclinical elevations in CK activity when exercise is reintroduced and return to normal levels requiring 4 to 6 weeks of gradual exercise
What is the basis for diet change of lowering daily starch and sugar intake & increasing dietary fiber content in diets of PSSM horses?
- Will decrease glucose load
- Increase availability of non-esterified fatty acid for muscle metabolism
- lower serum insulin concentration
Selecting hay with what percent of NSC for PSSM horses and why?
12% or less (+/- room for fat in diet)
–> because insulin stimulates the already overactive enzyme glycogen synthase in muscle of PSSM1 horses
What form of fat in diet is best for PSSM horses?
long chain fat diets
What are examples of acceptable fat supplementation in horses with PSSM?
rice bran
animal based fat (tallow, lard, fish oil)
Vegetable oils
NSC goal for low starch, high fat concentrate feeds for horses with PSSM?
calories supplied byNSC no more than 10-15% of daily DE
calories supplied by fat comprise 12-15% daily DE
Myofibrillar myopathy clinical signs
exercise intolerance or intermittent exertional rhabdomyolysis
-lack of stamina, unwillingnes to go forward, inability to collect, abnomral canter transitions, inability to sustain a normal canter, unresolved lamness, stiffness, mm pain
Myofibrillar myopathy breed predilection?
warm blood horses (6-8 years age)
Myofibrillar myopathy on muscle biopsy?
cytoplasmic aggregates of cytoskeletal protein desmin scattered muscle fibers
(**desmin aligns sarcomeres at Z-dsic & tether them to cell membrane**)
Myofibrillar myopathy horses management recommendations
**similar to PSSM2
** no information to suggesting limiting NSC or addition of fat is necessarily beneficial
Define recurrent exertional rhabdomyolysis (RER)
subset of exertional rhabdomyolysis is believed to be due to an abnormality in regulation of muscle contraction and relaxation
Recurrent exertional rhabdomyolysis usually occurs in what phases of exercise?
When the horse is held back to a paced speed (ie: racetrack, ER commonly occurs when RER horses are held back to paced gallop)
What is believed to be the pathogenesis of recurrent exertional rhabdomyolysis?
intrinsic abnormality in intramuscular calcium regulation
Risk factors for RER
temperament (nervous temperament)
diet (thghbd fed >2.5 kg grain/day more likely C/S RER)
rest before exercise
Is there a genetic basis for recurrent exertional rhabdomyolysis?
There is not one identified
What management factors need to be managed in horses with RER?
environment
exercise regimen
diet
Is muscle biopsy diagnostic in RER?
No
– best to rule out other causes of exertional rhabdomyolysis
Environmental management for RER is aimed towards:
reducing stressful environments
(**ie: providing daily turnout with other horses**)
Is rest recommended for horses with RER?
No
What forage should horses with RER recieve?
may or may not be as important to select hay with low NSC like in PSSM horses
What is the concentrate recommendation for RER horses?
low-starch, high-fat concentrates
Are supplements containing sodium bicarbonate, B vitamins, branched-chain amino acids and dimethylglycine, have any benefit for horses with RER?
no b/c lactic acidosis is no longer implicated as a cause of rhabdomyolysis
Dantrium sodium MOA
decreases release of calcium from ryanodine receptor in skeletal mm
**tx malignant hyperthermia
Besides malignant hyperthermia dantrium sodium can be used to treat:
RER
** controlled & field studies have shown a decrease in rhabdomyolysis in RER horses
**MUST BE WITHDRAWN BEFORE COMPETITION**
Phenytoin MOA
monoaminoxidase activator
acts on number of ion channels /win mm and nerves (sodium& calcium)
What is an undesirable effect of phenytoin?
drowsiness and ataxia at high doses
**if seen, reduce dose by half
Genetic mutation resulting in malignant hyperthermia in Quarter horses and paints
autosomal dominant mutation that exists in exon 46 of skeletal mm RYR1 gene on ECA 10
What is the prevalence of malignant hyperthermia in Quarter horses and paints?
less than 1 % (rare)
What are risk factors for malignant hyperthermia episodes?
exercise
anesthesia
** episodes can be intermittent in nature**
Horses with GYS1 mutation and RYR1 mutation show what clinical signs?
more severe episodes of exertional rhabdomyolysis
higher serum CK activity after exercise
moderated response to diet/exercise regimens for PSSM1
Is muscle biopsy beneficial for diagnosing malignant hyperthermia?
No
How do you diagnose malignant hyperthermia?
genetic testing
what is the treatment for malignant hyperthermia?
malignant hyperthermia episodes are so intermittent that hard to justify premed with dantrolene prior to exercise
Define muscle contracture
Fixation of myofilaments in a persistently shortened position w/o neural input — usu. assoc with rhabdomyolysis
Profound muscle weakness can occur in what disorders?
-neuropathies affecting motor neurons: equine motor neuron disease, hypoocalcemia -decreased neural input at motor end plates: botulism -marked muscle atrophy: EMND Rhabdomyolysis of postural muscles -severe electorlyte imbalances (hypokalemia)
Definition of muscle atrophy
Reduction in muscle size **specifically reduction in mm fiber diameter or cross-sectional area **occurs in response to variety of stimuli
Denervation to muscle causes:
Removes normal low-level tonic neural stimulus that is necessary to maintain muscle fiber mass
Complete denervation of muscle results in more than what percent loss of muscle w/in a 2 to 3 week period
50% loss of muscle mass
Reasons for muscle atrophy:
-denervation -disuse -malnutrition -cachexia -corticosteroid excess -immune-mediated myositis
Rapid muscle atrophy is characteristic of what type of myopathy?
Immune-mediated myopathies
Muscle necrosis is represented by
Injury to organelles w/in a muscle fiber or within a segment of that fiber
Pathogenesis of rhabdomyolysis and muscle necrosis
Generalized rhabdoyolysis — interrupt normal muscle metabolism — cell death results form inability to maintain homeostasis w/in the myofiber
Besides rhabdomyolysis, what other muscle disorders may lead to muscle necrosis
Lipid storage disorders Antioxidant deficiences
Infectious causes of nonexertional myopathies in horses
Viral Sarcocystis fayeri Anaplasma phagocytophilum Streptococcus equi Clostridium spp Abscesses
Immune mediated causes of nonexertional myopathies in horses
Infarctive purpura hemorrhagica Immune-mediated myositis
Nutritional myopathies of nonexertional myopathies in horses
Nutritional myodengeration Selenium deficiency, Vit E deficiency Vit E- deficient myopathy
Toxic myopathies of nonexertional myopathies in horses
Feed contaminants Ionophores Plant toxins Rematones Hypoglycin A
Examples of traumatic or anesthetic causes of nonexertional myopathies in horses:
Focal muscle strain Fibrotic myopathy Postanesthetic myopathy
Examples of muscle cramping of nonexertional myopathies in horses
Electrolyte disturbances Hypocalcemia Synchronous diaphragmatic flutter Ear ticks Shivers
Examples of myotonia, nonexertional myopathies in horses
Myotonia congenita Myotonia dystrophica Hyperkaelmic periodic paralysis
Examples of Genetic, nonexertional myopathies in horses
Glycogenic branching enzyme deficiency Polysaccharide storage myopathy type 1 Polysaccharide storage myopathy type 2 Malignant hyperthermia
Classification of Exertional Myopathies in horses
- Focal muscle strain 2. Sproadic exertional rhabdomyolysis dietary imbalances Vit E, selenium, electrolytes exercise in excess of training exhaustion 3. Chronic exertional rhabdomyolysis PSSM type.1 & type 2 Malignant hyperthermia recurrent exertional rhabdomyolysis idiopathic exertional rhabdomyolysis
Classification of myopathies in food animals
- Infectious clostridium sarcocystis 2. Nutritional selenium, vit E hypokalemia 3. Toxic feed additives, ionophores plants Gossypol, cassia, white snakeroot chemical 4. Traumatic muscle crush syndrome 5. Genetic caprine myotonia Bovine pseudomyotonia porcine malignant hyperthermia bovine and ovine myophophorylase deficiency porcine (RN (-)) glycogen storage disease
