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MYASTHENIA GRAVIS – CLINICAL SIGNS, DIAGNOSIS AND

THERAPY
Author : Laurent Garosi

Categories : Vets

Date : September 16, 2013

LAURENT GAROSI considers the pathophysiology of muscle weakness in dogs and cats,
available treatments and the long-term prognosis for patients

MYASTHENIA gravis (MG) is literally defined as “serious muscle weakness” and is

associated with failure of neuromuscular (NM) transmission.

There are two types of MG: congenital and acquired. A clear understanding of the anatomy and
physiology of the normal NM junction is important to understand MG’s pathophysiology (Figure 1).

The sequence of events at the neuromuscular junction leading to an action potential in the muscle
fibre plasma membrane, consists of the following.

1. Action potential increases the permeability of the motor neuron terminals to calmodulin-
dependent protein kinases II (Ca2+).

2. Ca2+ enters the terminals and triggers exocytosis of acetylcholine- containing vesicles.

3. Acetylcholine diffuses to the muscle nicotinic acetylcholine receptors (AChRs) .

4. Two molecules of acetylcholine bind to these receptors, increasing the sodium ion (Na+) and
potassium ion (K+) conductance of the membrane.

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5. The resultant influx of Na+ produces a depolarising potential called the end plate potential.

6. The current sink created by this local potential depolarises the adjacent muscle membrane to its
firing level and the voltage-gated Na+ channels open, leading to propagation of the action potential
in the muscle membrane.

7. The acetylcholine is then removed from the synaptic cleft by the enzyme acetylcholinesterase
and hydrolysed into choline and acetate.

8. Choline is actively taken up via a transporter into the cholinergic axon terminal.

9. Acetylcholine is synthetised from choline and acetyl-coenzyme A (acetyl-CoA), catalised by the

enzyme choline acetyltransferase (CAT). Acetyl-CoA is synthesised in the cell mitochondria when
the acyl group in acetate bonds to the carrier molecule coenzyme A (CoA).

The main difference between congenital and acquired MG lies in the pathophysiology.

Congenital MG is the result of a single, or combination of, presynaptic (mutations in the choline
acetyltransferase gene), synaptic (mutation of the acetylcholine- esterase associated collagen
gene) or postsynaptic defect (s) (deficient synthesis of AChR, defect in membrane insertion,
acceleration in AChR degradation).

In acquired MG, the deficiency of AChR is due to a heterogenous group of autoantibodies – mostly
immunoglobulin class G (IgG). A specific region of the alpha sub-unit on the AChR has been found
to be the binding site for most of the antibodies in acquired MG; this region is known as the main
immunogenic region (MIR).

Antibody-receptor complexes may lead to impairment of the NM transmission by encouraging

endocytosis of the AChR; activating complement- mediated destruction of postsynaptic muscle cell
membrane near the AChR; decreasing synthesis and membrane incorporation of new AChR; and
directly interfering with AChR function by bound antibody. Regarding the exact mechanism, the
result is a decreased number of functional AChRs, leading to decreased NM transmission.

Congential MG
Congenital MG is rare and is defined as an inherited disorder in which the safety margin of NM
transmission is compromised by one or more specific mechanisms; it can arise from presynaptic,
synaptic or postsynaptic defects.

A recessive mode of inheritance has been recognised in Jack Russell terriers, springer spaniels
and smooth-haired fox terriers. Suspected cases of congenital MG have also been reported in two
young related mongrel dogs. A few cats have also been reported with congenital MG (Bailey,

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2012).

These dogs are young – between six and 12 weeks old – when they present with clinical signs
consistent with NM weakness. Compared to the acquired form, circulating receptor antibodies are
not present. Definitive diagnosis is obtained by electrophysiological testing and quantification of
nicotinic AChR in an external intercostal muscle biopsy.

Long-term prognosis is usually considered poor despite symptomatic treatment with oral
pyridostigmine bromide.

In contrast with previously reported cases of congenital MG in dogs that are relentlessly
progressive, spontaneous remission of clinical signs has been reported in two dachshunds by six
months of age without medical therapy (Dickinson, 2005).

Acquired MG
Acquired MG is a relatively common neuromuscular disease affecting dogs and, occasionally, cats.
This acquired form of MG is due to antibodymediated (predominantly IgG) destruction of nicotinic
AChR on the postsynaptic membrane of the neuromuscular junction. The deficiency of functional
receptors results in reduced sensitivity of the postsynaptic membrane to the neurotransmitter
acetylcholine and failure of the NM transmission.

Several conditions have been associated with canine acquired MG, including other autoimmune
disorders and neoplastic disorders.

Autoimmune disorders reported to occur concurrently include hypothyroidism,

hypoadrenocorticism, thrombocytopaenia, systemic lupus erythematosus, haemolytic anaemia,
polymyositis and inflammatory bowel disease. (Bailey, 2012)

Acquired MG has been reported as a paraneoplastic syndrome in association with a variety of

tumours including cholangiocellular carcinoma, osteosarcoma, anal sac adenocarcinoma, lung
carcinoma, cutaneous lymphoma and thymoma (Shelton, 2002). With the latter, thymoma cells
may express antigenic epitopes similar to those of nicotinic AChR. The immune response to these
epitopes results in the lack of functional AChRs in skeletal muscle.

Finally, acquired MG has also been reported in hyperthyroid cats receiving methimazole therapy.
This is known as acquired drug-induced MG.

Acquired MG has been reported in dogs ranging in age from seven weeks to 15 years with all
breeds and both genders being potentially affected (Dewey, 1997; Shelton, 2002; Bailey, 2012).
Breeds with the highest risk of acquired MG are Akitas, several terrier breeds, German shorthaired
pointers, and Chihuahuas. A familial predisposition has been suggested in Newfoundlands.

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A bimodal age of onset with peaks of incidence at approximately three and 10 years of age has
been reported in affected dogs (Bailey, 2012). Rare cases of juvenile-onset autoimmune MG have
also been documented.

In cats, a breed predisposition for acquired MG has been recognised in Abyssinians (and related
Somalis). Similarly to dogs, there is a bimodal distribution for the age of onset of clinical signs in
cats, with peaks occurring at two to three years and nine to 10 years of age (Ducote, 1999).

The characteristic clinical presentation of acquired MG is appendicular muscle weakness that

worsens with exercise and improves with rest.

Concurrent megaoesophagus causing regurgitation and aspiration pneumonia is also common in

dogs because of the large amount of skeletal muscle in the oesophagus in this species.

Approximately 40 per cent of cats with acquired MG have a megaoesophagus, a lower prevalence
than seen in dogs. This is probably because the feline oesophagus has a smaller skeletal muscle
component. Occasionally, facial, laryngeal, or pharyngeal weakness accompanied the
appendicular muscle weakness.

Clinical signs of acquired MG may be focal in nature, associated with regurgitation

(megaoesophagus), dysphagia (pharyngeal dysfunction) and decreased palpebral reflex (facial
muscles), without detectable limb muscle weakness. The reason for selective involvement of
particular muscle groups is not known.

Some cats can, in addition, present with cervical ventroflexion and a dropped jaw. An acute
fulminating form of MG has also been described in dogs and characterised by frequent
regurgitation of large volumes of fluid associated with megaoesophagus and rapid loss of muscle
strength resulting in recumbence. Respiratory failure, presumably caused by aspiration pneumonia
and loss of strength in muscles involved in respiration, is a consistent complication of acute
fulminating MG and a common cause of death.

The diagnosis of acquired MG can be challenging. Other NM disorders may mimic MG, including
botulism, polyradiculoneuritis, tick paralysis or infectious neuropathies/myopathies, and should be
considered when diagnosing MG. A minimum database including a complete blood count,
chemistry profile and urinalysis should be obtained. Although none of these tests are definitive for
acquired MG, other causes of generalised weakness may be ruled-out (such as electrolytes
disturbances or hypoglycaemia).

In addition, the minimum database will provide baseline health screening that will be helpful in
guiding diagnostics requiring general anaesthesia and designing therapeutic protocols.

The definitive diagnosis of acquired MG is based on demonstration of serum antibodies to muscle

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AChRs by immunoprecipitation radioimmunoassay. This test is objective and quantitative, and
proves an autoimmune response to AChRs, which differs from other causes of muscle weakness.

The prevalence of seronegative canine myasthenics is considered to be very low and false positive
results have not been documented. Seronegative, acquired MG may occur due to very low titre, but
highaffinity AChR antibodies with all antibodies complexed to AChRs in muscles or antibodies
directed against other end-plate proteins or in dog treated with prednisone or other
immunosuppressive agents.

Other diagnostic tests that are relatively specific for acquired MG include the edrophonium chloride
(Tensilon) challenge test, immuno-cytochemical staining of muscle endplates, repetitive nerve
stimulation, and single fibre electromyography (SF-EMG). The response to the ultrashort- acting
anticholinesterase drug edrophonium chloride (0.1mg/kg to 0.2mg/kg IV) may help to establish a
clinical diagnosis of MG while the results of antibody testing are pending, especially if a dramatic
response is observed. The dog should be exercised to the point of detectable weakness prior to
testing.

This testing method has been shown to be neither sensitive nor specific as a negative response to
Tensilon does not rule out diagnosis of MG (especially in cases of acute fulminating MG) and some
dogs with other myopathic and neuropathic disorders can also show mild improvement in their
neuromuscular weakness.

Occasionally, this test can cause a cholinergic crisis by overstimulation of AChR producing a
depolarising blockade. Dyspnoea, bradycardia, profuse salivation, miosis, cyanosis and limb tremor
may result and can be reversed with atropine (0.05mg/kg IV). When edrophonium is not available,
neostigmine methyl sulphate can be used (40µg/kg IM or 20µg/kg IV; (Bailey, 2012).

Thoracic radiographs should also be included in the diagnostic plan to evaluate for the presence of
a cranial mediastinal mass, megaoesophagus and aspiration pneumonia. Because other
autoimmune disorders such as hypothyroidism and hypoadrenocorticism have been associated
with acquired MG, adrenal and thyroid testing are recommended in suspected myasthenics.

Treatment
Therapy for acquired MG should be tailored to the individual needs of the patient. The three main
aspects of therapy are anticholinesterase therapy, immunomodulatory therapy and supportive care.

The natural course of autoimmune canine MG was determined in a large number of dogs treated
with anticholinesterase therapy, without immunosuppression. Spontaneous clinical and
immunologic remission occurred in more than 85 per cent of dogs with an average of 6.4 months.
Neoplasia was identified in the 15 per cent of dogs that did not spontaneously remit (Bailey, 2012).

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Anticholinesterase therapy comprises the cornerstone of treatment of acquired MG in dogs.
Anticholinesterase agents prolong the action of ACh at the neuromuscular junction by reversibly
inhibiting acetylcholinesterase. Pyridostigmine is the most commonly used anticholinesterase drug,
and is administered by mouth or a stomach tube at a dosage of 0.5 mg/kg to 3mg/kg q8-12h in
dogs and 0.25mg/kg q8-12h. Common side effects include nausea, cramps, diarrhoea, salivation
and lacrimation. Overdosing leads to weakness as a result of depolarisation and desensitisation of
the postsynaptic membrane.

To avoid a cholinergic crisis, it is recommended to start at the low end of the dose and increase as
needed. If oral treatment is not possible due to severe regurgitation, neostigmine can be given
(0.04mg/kg IM q6 hours).

For critical animals, a constant rate IV infusion of pyridostigmine (0.01mg/kg/h to 0.3mg/kg/h) may
be given until oral feedings are resumed or a feeding tube is placed. Adjunctive
immunosuppressive treatment is indicated if limb muscle strength has not returned to normal
following symptomatic treatment with anticholinesterase therapy and if there is no evidence of
aspiration pneumonia.

Other indications include dogs with persistently elevated AChR antibody titres, seropositive dogs
with a negative edrophonium test, dogs with less than optimal response to anticholinesterase
agents and/ or unacceptable side effects. Corticosteroids and other immunomodulatory drugs
should not be administered until the patient is stable and aspiration pneumonia, if present, has
resolved. If prednisolone is to be given to a myasthenic dog or cat, antiinflammatory doses (for
example, 0.5mg/kg q12-24h) should be given initially, gradually building to immunosuppressive
levels (2mg/kg to 4mg/kg q12- 24h) over seven to 10 days to avoid initial exacerbation of muscle
weakness.

Worsening clinical signs is a direct effect of glucocorticoids on excitation-coupling of the contractile

elements within myofibres and altered function of the ion channel of the AChR.

Unlike dogs, exacerbation of muscle weakness may not occur as frequently in cats treated with
high doses of corticosteroids. Once muscle strength has returned, dosage of prednisolone can be
reduced very slowly while monitoring carefully for relapse.

If there is no response to immunosuppressive dosage of prednisolone, other immunosuppressive

drugs such as azathioprine (1.0mg/kg to 2mg/kg orally every 24 hours; Dewey 1999), cyclosporine
(4mg/kg q12h; [Bexfield, 2006]) or mycophenolate mofetil (20mg/ kg orally q12h; [Dewey, 2000;
Dewey, 2008]) can be used.

The potential benefits of thymectomy for canine MG patients are unknown; however, a complete
removal of thymomas has been associated with normalisation of the AChR antibody titre and
resolution of clinical signs.

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Decisions regarding duration and treatment regimen should be based on clinical ground (resolution
of clinical signs of weakness) and periodic testing of AChR antibody titres (at least in dogs or cats
that are not on immunosuppressive treatment).

Prognosis
Overall, the prognosis for acquired MG is guarded. Approximately 84 per cent of patients have
megaoesophagus. Aspiration pneumonia is the main cause of death in canine patients and the one-
year mortality rate has been reported to be as high as 60 per cent.

Because fewer cats develop megaoesophagus and aspiration pneumonia, the oneyear mortality
rate for cats is only 15 per cent. There is an inverse relationship between the concentration of
AChR antibodies in cats and the prognosis. Higher concentrations are associated with more acute
and severe clinical signs, therefore this titre may be used to determine the prognosis in cats.

A similarly strong correlation has not been established in dogs; however, monitoring serial AChR
antibody titres in an individual is a good indicator of disease status. There is an excellent
correlation between resolution of clinical signs and return of AChR antibody titre below normal level
of 0.6 nmol/l in dogs. Therapy should therefore be continued as long as a patient has an elevated
titre despite any resolution of clinical signs.

Care must be taken when evaluating serial AChR antibody titres in patients receiving
immunomodulatory therapy, as false-negative results can occur.

References
Bailey K S (2012). Myasthenia gravis. In Platt S R and Garosi L S (eds). Small Animal
Neurological Emergencies, Manson Publishing.
Bexfield N H, Watson P J, Herrtage M E (2006). Management of myasthenia gravis using
cyclosporine in 2 dogs, Journal of Veterinary Internal Medicine 20: 1,482-1,490.
Dewey C W (1997). Acquired myasthenia gravis in dogs – part I, Compendium 19(12):
1,340-1,353.
Dewey C W (1998). Acquired myasthenia gravis in dogs – part II, Compendium 20(1):
47-57.
Dewey C W, Coates J R, Ducoté J M, Meeks J C and Fradkin J M (1999). Azathioprine
therapy for acquired myasthenia gravis in five dogs, Journal of the American Animal
Hospital Association 35: 396-402
Dewey C W, Boothe D M, Rinn K L, Coates J R, Burkholder W J 2000 Treatment of a
myasthenic dog with mycophenolate mofetil, Journal of Veterinary Emergency and Critical
Care 10(3): 177-187
Dewey C W, Harb-Hauser M F, Cerda-Gonzalez et al (2008). Mycophenolate mofetil
therapy for acquired myasthenia gravis in dogs: a comparative retrospective study

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(1999-2007) [abstract], Journal of Veterinary Internal Medicine 22: 721.
Dickinson P J, Sturges B K, Shelton G D and LeCouteur R A (2005). Congenital
myasthenia gravis in smooth-haired miniature dachshund dogs, Journal of Veterinary
Internal Medicine 19: 920-923.
Ducoté J M, Dewey C W and Coates J R (1999). Clinical forms of acquired myasthenia
gravis in cats, Compendium 21(5): 440-448.
Shelton G D (2002). Myasthenia gravis and disorders of neuromuscular transmission,
Veterinary Clinics of North America: Small Animal Practice 32(1): 189-206.

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 Figure 1. Neuromuscular transmission. From Simon Platt and Laurent Garosi (eds), Small
Animal Neurological Emergencies (2012), CRC Press.

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