New Treatments

Myasthenia Clinical Trial

Schematic diagram of the motor unit (peripheral nerve, neuromuscular junction and muscle). Effects of MG are predominantly seen at the neuromuscular junction.

 

Contents

History and Clinical Signs

Treatment

Advances in treatment

Myasthenia Gravis

Myasthenia Gravis is a condition resulting from a deficiency of acetyl choline (ACh) receptors on the postsynaptic membrane resulting in a syndrome of muscle weakness. Both congenital and acquired forms of this condition occur in dogs, cats, and humans. To date, studies suggest the pathophysiology of these conditions are similar among these species.

Acquired Myasthenia Gravis

Acquired (immune-mediated) MG is due to antibody mediated destruction of ACh-receptors. While the immune-mediated destruction of ACh-receptors is well documented, the specific pathogenesis is unknown.

History and Clinical Signs

Acquired MG affects numerous breeds of dog older than 1 year of age. There appears to be a bimodal, age-related incidence, with peaks at 2-4 years and 9-13 years. Signs of muscular weakness may be focal with selective involvement of the esophageal, pharyngeal, and facial muscles, or diffuse, with signs of generalized muscle weakness. In one study it was estimated that one fourth of the canine patients presenting with idiopathic megaesophagus, had focal MG. Signs of generalized muscle weakness may vary considerably, ranging from some intolerance to exercise, which improves with rest, to acute tetraplegia. Patients with focal or generalized signs, and megaesophagus, often present with pneumonia secondary to aspiration. Evaluation of the thorax may reveal the presence of thymoma, which may be implicated in the etiology of this immune disorder.

A: Sensory nerve fiber
B: Dorsal root ganglion
C: Dorsal nerve root

1: Motor neuron
2: Ventral nerve root
3. Spinal nerve
4. Plexus
5. Motor nerve fiber
6. Neuromuscular junctions
7. Muscle fiber

Congenital Myasthenia Gravis

Congenital MG is an hereditary disorder resulting in deficiency of Ach receptors on the postsynaptic membrane. It is reported in Jack Russell terriers, Springer spaniels, Smooth Fox terriers and Dachshunds. Onset of clinical signs is usually apparent at 6-8 weeks of age, with signs of generalized muscular weakness associated with exercise. Megaesophagus is not common. Weakness usually becomes progressively severe, leading to tetraplegia and death. Congenital MG has also been reported in cats. Congenital MG in Dachshunds may resolve spontaneously and has a potentially favorable prognosis.

Diagnosis

The Neurology/Neurosurgery offers comprehensive diagnostic facilities and procedures through the Neuromuscular Disease Laboratory and the electrophysiology laboratory at the VMTH.

Service publications on neuromuscular disease and myasthenia gravis.

Pharmacological Testing
The IV administration of 1-10mg of edrophonium chloride (“Tensilon response test”) may result in transient improvement in the clinical weakness due to inhibition of anticholinesterase activity. A positive test is not definitive, however it is highly is suggestive of MG.

A myasthenic dog exhibiting weakness following excercise.

Injection of Tensilon results in almost imediate improvement in ability to walk.

Electrodiagnostic Testing
Recording of evoked muscle action potentials during repetitive nerve stimulation at 2-10 Hz may provide evidence of dysfunction of the neuromuscular junction. A decline in the amplitude of successive potentials (decremental response), provides a presumptive positive test for MG. A more sensitive repetitive stimulation test looking at single myofiber potentials can also be done. Variation in the single fiber potential (“jitter”) is much greater in affected animals with MG.

emg

Normal response to repetitive stimulation(left). Decremental response torepetitive stimulation.

Immunological Testing
The current “gold standard” for diagnosis of MG involves the use of an immunoprecipitation radioimmunoassay for the determination of ACh receptor antibody titers in serum (“AchRAb titers”). This blood test is available through the Comparative Neuromuscular Laboratory San Diego. (http://vetneuromuscular.ucsd.edu/)

Antibodies to the Ach Receptor can also be demonstrated by incubating a patient’s serum on sections of normal dog muscle. Subsequent incubation with SPA-HRP (Staphylococcal protein A conjugated to horseradish peroxidase) detects circulating antibody (IgG) that has bound to the neuromuscular junction.

muscle pict

Esterase staining to localize end-plates of the neuromuscular junction. IgG staining at end-plates shows deposition of antibodies in MG

Anti AchR antibodies are not present in congential MG. Diagnosis is confirmed by biopsy of selected muscles (intercostal) and a demonstration of a decreased number of Ach receptors.

Treatment

Optimal therapeutic approaches for dogs or cats with acquired MG have not been established. One confounding factor in the assessment of treatments for acquired MG is the frequent occurrence of spontaneous remissions. Up to 87.7% of affected dogs will go into spontaneous remission at an average of 4 months after diagnosis (range: 1 to 18 months). Early and accurate diagnosis is an essential aspect for obtaining a good clinical outcome in most cases of acquired MG. Experienced clinical judgement and cooperative, dedicated owners also are essential considerations. Recognition of esophageal dilation and/or pharyngeal weakness prior to institution of therapy is mandatory.

Supportive Care

Aspiration pneumonia
Prevention and treatment of aspiration pneumonia is an essential consideration in animals with acquired MG. Frequent turning of recumbent animals, antibiotic therapy, nebulization and coupage are examples of treatment considerations for aspiration pneumonia.

Fluid therapy
Maintenance of adequate hydration is essential in animals with acquired MG. Intravenous fluid therapy may be necessary in animals that regurgitate liquids.

Nutritional support
Special feeding procedures (e.g., feeding food and water from elevated feed bowls or holding an animal in a vertical position for AT LEAST 20 minutes after feeding), placement of a gastrotomy tube, and in some cases parenteral nutrition, must be considered. Construction of special chairs (“Bailey chair”) to aid in upright feeding can be invaluable. http://www.caninemegaesophagus.org/support.htm

Respiratory support
Intensive care and ventilatory support may be required in animals with severe aspiration pneumonia or severe generalized weakness.

Modification of gastrointestinal tract function
Management of dysphagia and megaesophagus, with associated complications of aspiration pneumonia, regurgitation and esophagitis, is an essential consideration. Drugs that may improve esophageal motility (e.g., metoclopramide), increase lower esophageal sphincter tone (e.g., cisapride), or increase the pH of gastrointestinal contents (e.g., cimetidine or ranitidine) should be considered.

Specific Therapy
Specific therapy for acquired MG is based on the severity of the disease in a specific animal. To facilitate treatment decisions, a classification system that addresses the heterogeneous and variable clinical signs of acquired MG has been introduced for use in dogs and cats:

Group 1: Mild or focal MG
Group 2: Moderate generalized MG
Group 3: Severe generalized or acute fulminating MG.

1) Anticholinesterase agents
Anticholinesterase agents, that act to enhance neuromuscular transmission by prolonging the action of acetylcholine at the neuromuscular junction, are used in all the above patient groups. Dosage must be adjusted for each dog or cat depending on individual tolerance of adverse effects and response to treatment. Drugs available include pyridostigmine bromide (Mestinon®, 1-3 mg/kg, orally BID or TID) and neostigmine bromide (Prostigmin®, 2 mg/kg/d, orally in divided doses to effect). Pyridostigmine bromide is available in four dosage forms syrup, conventional tablets, slow release tablets and injectable forms.

2) Immunosuppressive therapy
Should an optimal response to therapy not be achieved with supportive care and anticholinesterase drugs, immunosuppressive drugs may be used. Use of immunosuppressive drugs is controversial, particularly as a “first line” treatment, due to the high incidence of aspiration pneumonia (particularly in dogs) and the potential for glucocorticoids to exacerbate muscle weakness. Glucocorticoids. Low dose prednisone therapy (0.5 mg/kg every other day) has been recommended in mildly (Group 1) and moderately (Group 2) affected animals.

Contraindications for glucocorticoid therapy include ongoing infections or aspiration pneumonia, diabetes mellitus, severe obesity, uncontrolled hypertension, and gastrointestinal ulcerations.

Other immunosuppressive agents (e.g., azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil) may be recommended for animals in Groups 1 and 2 where use of glucocorticoids is contraindicated, or should adverse effects of glucocorticoids become difficult to manage.

Concurrent neoplasia
Should a concurrent thymic mass or other neoplasia be present, then surgical removal, with or without radiation therapy, should be considered. As a majority of dogs with thymoma and acquired MG also have megaesophagus and aspiration pneumonia, and because mortality rate after thymectomy in these dogs is high, it is recommended to delay thymectomy until clinical signs of MG are controlled by means of medical management.

Treatment of Acute Fulminating Myasthenia Gravis
Management of severe generalized acquired MG (Group 3) is difficult. Affected animals should be managed in an intensive care unit. Anticholinesterase therapy and ventilatory support provide the basis for therapy. Ventilatory support usually is required due to weakness of intercostal muscles and diaphragm, or due to concurrent pulmonary infection (often resulting from aspiration pneumonia). Plasmapheresis and intravenous immunoglobulin have been used to treat people with acute fulminating MG.

Monitoring the Response to Treatment
In the absence of immunosuppression, determination of serial AchR antibody titers may aid in determination of both disease status and duration of treatment.

Advances in treatment of Canine myasthenia Gravis

Therapeutic apheresis is an extracorporeal procedure that separates blood into its components for removal or specific alteration prior to return to the patient. Therapeutic plasma exchange (TPE) is an apheresis treatment in which plasma (containing pathologic antibodies) is removed and exchanged with donor plasma. TPE is used routinely to treat MG in human patients with severe disease or disease unresponsive to conventional therapy.

We have had success with the use of TPE to treat several dogs with confirmed MG that was severe and not adequately responsive to traditional therapies. Dogs chosen for treatment were non-ambulatory, recumbent, and demonstrated megaesophagus and aspiration pneumonia. All dogs showed significant improvement after 2 treatments and became ambulatory within 3 days with subsequent resolution of megesophagus and regurgitation.

Research is on-going to further validate the efficacy of TPE for the treatment of MG in dogs, but initial anecdotal experience is promising. While treatment with TPE is not inexpensive, its use may result in more rapid recovery, and decrease secondary complications, such as recurrent aspiration and/or respiratory compromise, thereby significantly decreasing hospital stays and associated costs.

If you would like to know more about this newly available treatment for myasethenia, please contact the Neurology/Neurosurgery Service. We will be happy to discuss the treatment options with you and your veterinarian.

Appointments s can be made through:
Neurology/Neurosurgery service coordinator. Toni Beelard 530 754 0606
VMTH UC Davis Reception 530 752 1393

 

 

 

Publications

Peter J. Dickinson, Beverly K. Sturges, G. Diane Shelton, Richard A. LeCouteur. (2005) Congenital myasthenia gravis in Smooth Haired Miniature Dachshund dogs. Journal of Veterinary Internal Medicine 19:920-923
http://www.ncbi.nlm.nih.gov/pubmed/16355692?dopt=Citation

P.J.Dickinson, R.A. LeCouteur. (2004) Feline neuromuscular disorders. Veterinary Clinics of North America. Small Animal Practice.34:1307-1359.
http://www.ncbi.nlm.nih.gov/pubmed/15474678?dopt=Citation

Añor S, Lipsitz D, Williams DC, Tripp L, Willits N, Maselli R, LeCouteur RA. (2003) Evaluation of jitter by stimulated single-fiber electromyography in normal dogs. J Vet Intern Med. Jul-Aug;17(4):545-50.
http://www.ncbi.nlm.nih.gov/pubmed/12892306?dopt=Citation

2002 P.J. Dickinson, R.A. LeCouteur. (2002) Muscle and nerve biopsy. Veterinary Clinics of North America. Small Animal Practice 32:63-102.
http://www.ncbi.nlm.nih.gov/pubmed/11785735?dopt=Citation