ACQUIRED MYASTHENIA GRAVIS: BEYOND BAILEY CHAIRS Laura Harvey, DVM, DACVIM (Neurology) Veterinary Neurology of the Chesapeake

Outline

¨  Case Presentation ¨  The Neuromuscular Junction ¨  Acquired Myasthenia Gravis

¤ Pathophysiology ¤ Clinical Presentation ¤ Diagnosis ¤ Treatment ¤ Prognosis ¤ Future Directions

Case Presentation

Sage

¨  7 YO SF DLH ¨  Acquired as a kitten ¨  Indoors only ¨  Up to date on vaccines ¨  Previously healthy ¨  No medications ¨  **Owned by a

veterinarian**

Sage: Differentials

¨  Oral cavity disease ¤  Resorptive lesions ¤  Fractured teeth ¤  Mass – abscess vs neoplasia ¤  Foreign body

¨  Pharyngeal Disease ¤  Mass – polyp vs abscess vs neoplasia ¤  Cricopharyngeal achalasia ¤  Foreign body

¨  Esophageal Disease ¤  Megaesophagus ¤  Foreign body ¤  Mass

¨  Neuromuscular diseases

Sage: Examination

¨  Physical Examination: ¤ Normal sedated oral examination ¤ Matted fur, but otherwise normal examination

¨  Neurological Examination: ¤ Ambulatory without signs of paresis or ataxia ¤ Normal cranial nerves – no gag performed

Sage: Diagnostics

¨  CBC, Chemistry, T4, Urinalysis: Normal

¨  Thoracic radiographs: ¤ Gas dilation of the esophagus

¨  Abdominal ultrasound: ¤ Mild mesenteric lymphadenopathy

n Histopathology: reactive lymph nodes

Sage: Diagnostics

¨  Acetylcholine receptor antibody test: ¤ 10.9 nmol/L (reference <0.3 nmol/L)

¨  Diagnosis: Acquired, focal myasthenia gravis

The Neuromuscular Junction (NMJ)

NMJ: Anatomy

¨  Skeletal muscle fibers are innervated by large, myelinated nerve fibers ¤ Each nerve fiber branches and stimulates from three to

several hundred skeletal muscle fibers

¨  Each nerve ending makes a junction ¤ Neuromuscular junction

Diagram Credit: http://www.vetmed.ucdavis.edu/vsr/Neurology/Disorders/Myasthenia%20Gravis.html

NMJ: Anatomy

Diagram Credit: http://bioserv.fiu.edu/~walterm/Fund_Sp2004/review_fall05_bone_musc.htm

NMJ: Acetylcholine Production

¨  Acetylcholine (ACh) is synthesized in the cytoplasm of the nerve terminal ¤ Absorbed into synaptic

vesicles à quanta ¤ Quanta: 1000-5000

molecules of Ach

Diagram Credit: Physiology of Domestic Animals, Figure 3.8

NMJ: Acetylcholine Secretion

¨  Neuronal action potential triggers calcium influx ¤ Calcium influx triggers

exocytosis of vesicles into the synaptic cleft

Diagram Credit: http://pharmacology-online.blogspot.com/2011/04/cholinergic-transmission.html

NMJ: Acetylcholine Receptors (AChR)

¨  Ligand-gated ion channels ¤  Located in subneural clefts ¤ Nicotinic AChR

¨  Activation triggers Na+ influx à Miniature Endplate Potential (MEPP) à à Muscular Contraction

Diagram Credit: http://www.nature.com/nrn/journal/v11/n6/fig_tab/nrn2849_F1.html

α α

β δ

ε

NMJ: Acetylcholinesterases

¨  Acetylcholinesterase (AChE) is concentrated within the synaptic cleft ¤ ACh à acetate +

choline

¨  Diffusion of ACh out of the synaptic cleft

Diagram Credit: Neuroscience, 4th Edition

NMJ: “Safety Factor”

¨  The ratio between the number of ACh quanta released and the number of ACh quanta required for depolarization of a muscle fiber ¤ How much interference can be tolerated before there is

failure of neuromuscular transmission

¨  Typically, ACh quanta released >>> ACh quanta required

“Severe muscular weakness”

Myasthenia Gravis (MG)

MG: Pathophysiology

¨  Disorder of neuromuscular transmission ¤ Deficiency or functional disorder of nicotinic AChR

within the NMJ à loss of the “safety factor” ¤ Congenital and acquired forms

¨  MG is the most well studied and well characterized neuromuscular disease

Acquired MG: Pathophysiology

•  Antibody mediated autoimmune disease1 1.  Antibodies are present at the NMJ 2.  Anti-AChR antibodies cause clinical signs of MG when

injected into rodents 3.  Immunization of animals with AChR reproduces MG 4.  Therapies that remove antibodies decrease the

severity of MG clinical signs

1: Conti-Fine et al., 2006.; Journal of Clinical Investigation

Conti-Fine et al., 2006.; Journal of Clinical Investigation

Acquired MG: Dogs

¨  Bimodal age distribution ¤ Modes of distribution at 3 years and 10 years of

age1,2

¨  Higher relative risk: Akitas, terrier group, Scottish terriers, and German shorthaired pointers1

¨  Inherited predisposition: great Danes3 and Newfoundlands4

¨  No sex predilection 

1: Shelton et al., 1997; JAVMA. 2:Ducote et al., 1999; Compend Cont Educ Practi Vet 3: Kent et al., 2008; JSAP. 4: Lipsitz et al., 1999; JAVMA.

Acquired MG: Cats and beyond

¨  Abyssinian cats may have a higher relative risk than other purebred cats1

¨  Acquired MG has been reported in: ¤ 10 year old captive male Siberian tiger2

¤ 7 month old neutered male ferret3

¤ 7 month old Hereford heifer4

n  “Myasthenia gravis-like syndrome”

1: Shelton et al., 2000; JAVMA. 2: Allan et al., 2013; J. Comp. Path. 3: Couturier et al. 2009; JAVMA. 4: Wise et al., 2008; JVIM. Photo Credit: http://www.streamcattle.com/for_sale.html

Acquired MG: Examination ¨  Focal MG:

¤ 36-43% of canine patients1 n Weakness present in one or more muscle groups n May see facial weakness or megaesophagus n Typically no clinical evidence of thoracic or pelvic limb

weakness

¤ 14.3% of feline patients2 n Focal MG associated with megaesophagus and dysphagia

1: Khorzad et al., 2011; JVECC. 2:Shelton et al., 2000; JAVMA

Acquired MG: Examination ¨  Generalized MG:

¤ 57-64% of canine patients1 n Mild to severe weakness, often episodic n Pelvic limbs affected more than thoracic limbs n Megaesophagus and regurgitation may be present

¤ 74% of feline patients2 n Generalized weakness n Megaesophagus and/or dysphagia: 20% n Generalized weakness associated with hyperthyroidism and

methimazole: 4.8%

1: Khorzad et al., 2011; JVECC. 2: Shelton et al., 2000; JAVMA

Acquired MG: Examination

¨  Fulminant MG: ¤ < 5% of canine patients1

n Acute onset and rapid development of clinical signs n Non-ambulatory tetraparesis to tetraplegia n Respiratory distress +/- aspiration pneumonia

1: Khorzad et al., 2011; JVECC.

Acquired MG: Differentials

¨  Myasthenia gravis ¨  Polymyositis ¨  Idiopathic polyradiculoneuritis ¨  Botulism toxicity ¨  Tick paralysis ¨  Metabolic: hypoglycemia, hypocalcemia, hypokalemia,

hyperkalemia ¨  Endocrine: hypoadrenocorticism, hypothyroidism ¨  Toxicity: organophosphates, carbamates ¨  Orthopedic disease

Acquired MG: Diagnostics

¨  CBC, Chemistry, Urinalysis, T4, +/- ACTH stimulation ¤  R/O metabolic and endocrine causes of weakness

¨  Chest radiographs +/- CT ¤ Megaesophagus ¤ Aspiration pneumonia ¤  Thymoma

n  5% of dogs with MG have a thymoma n  25% of cats with MG have a thymoma

¤ Metastatic disease n  MG may occur with cholangiocellular carcinoma, CNS lymphoma,

and anal sac adenocarcinoma1

1: Inzana K. D., 2004; Vet Clin Small Anim.

Acquired MG: Diagnostics

Photo Credit: http://www.vetmed.ucdavis.edu/vsr/Neurology/Disorders/Myasthenia%20Gravis.html

Acquired MG: Diagnostics

¨  Radioimmunoassay for AChR-antibody titers ¤ Gold standard for diagnosis of acquired MG1

n  Sensitive (98%) and specific (100%) ¤  False negative results (~ 2%)2

n  Loss of critical determinants on the AChR during sample preparation

n  Low titers of high affinity antibodies n  Antigenic differences in AChRs n  Antibodies directed against endplate determinants other than

AChRs n  Prior glucocorticoid administration

¤ Cons: Time!

1: Shelton G.D., 1998; ACVIM Forum. 2: Shelton et al., 1990; JVIM.

Acquired MG: Diagnostics

¨  Tensilon Test ¤ Edrophonium chloride

n Short-acting anticholinesterase

¤ Side effects: n Salivation, retching, vomiting, diarrhea n Pre-treatment with atropine

n  Be prepared to intubate

¤ Cons: False positives and false negatives

Acquired MG: Diagnostics

¨  Electrodiagnostics ¤  Repetitive Nerve Stimulation

n  Recording of compound-muscle action potentials after electrial stimulus is applied to the ulnar or tibial nerve

n  Looking at the summation of action potentials from several nerve fibers and from a number of motor units

¤  Single-fiber electromyography

n  Selective recording of action potentials from 2-3 muscle fibers innervated by a single motor unit

n  Evaluation of the NMJ “safety margin” n  The most sensitive test for the diagnosis of MG in humans

(92-100%) ¤ Cons: Require general anesthesia

Photo Credit: http://www.vetmed.ucdavis.edu/vsr/Neurology/Disorders/Myasthenia%20Gravis.html

Normal MG

Acquired MG: Treatment

¨  Anticholinesterase Therapy ¤ Pyridostigmine bromide (Mestinon) or neostigmine

bromide (Prostigmin) n Prolong the action of ACh at NMJ via competitive inhibition

of AChE

¤ Adverse effects: diarrhea, abdominal pain, hypersalivation, weakness, lacrimation, bradycardia, cholinergic crisis1

1: Foy et al., 2011; JVECC.

Acquired MG: Treatment

¨  Immunomodulatory therapy ¤ Corticosteroids ¤ Azathioprine ¤ Cyclosporine A ¤ Mycophenolate mofetil

¨  Immunosuppression has been the only mode of treatment shown to significantly decrease patient mortality1 ¤ Even in the presence of aspiration pneumonia

1: Dewey et al., 1997; JVIM.

Acquired MG: Treatment

¨  Nutritional Management ¤ Elevated Feedings

n Bailey Chairs n Platforms n  Inclines/stairs

¤ Gastrostomy tubes n Require anesthesia n Reduced risk of

aspiration

Acquired MG: Treatment

¨  Mechanical Ventilation ¤ Severe aspiration pneumonia, respiratory failure

¨  Avoid: ¤ Phenothiazines, aminoglycosides, ampicillin, anti-

arrhythmics, and fluoroquinolones1

¨  Supportive Care ¤ Down dog care: urinary catheterization, flipping hips,

prevention of pressure sores and urine scald

1: Foy et al., 2011; JVECC. .

Acquired MG: Prognosis

¨  Spontaneous remission ¤  In 47/53 (88%) dogs treated with only anticholinesterase

therapy, immune remission was seen within 6.4 months (range: 1-12 months)1

¨  Overall, prognosis is guarded ¤ Generalized megaesophagus

n  Median survival time: 90 days2 n  19/71 (26.7%) died prior to discharge

¤ Aspiration pneumonia ¤  Respiratory distress ¤  1 year survival rate for 25 dogs was 40.4%3

1: Shelton et al., 2001; Neurology 2: McBrearty et al., 2011; JAVMA. 3: Dewey et al., 1997; JVIM.

Acquired MG: Future Directions

¨  Evaluation of new treatment options ¤ Human intravenous immunoglobulin (hIVIG) ¤ Plasmapheresis ¤ MG vaccines

¨  Controlled prospective studies evaluating immunosuppressive agents

Back to Sage…

¨  Treatment: ¤ Prednisone ¤ Gastrostomy tube ¤ Cyclosporine

¨  AChR titers: ¤ 4/2013: 7.7 nmol/L ¤ 10/2013: 3.3 nmol/L

n Relapse 11/2013

Questions?

References ¨  Abelson A.L., Shelton G.D., Whelan M.F., Cornejo L., Shaw S., O’Toole T.E. Use of mycophenolate mofetil as a resuce agent in the

treatment of severe generalized myasthenia gravis in three dogs. JVECC 2009;19:369-374.

¨  Anor S. Lipsitz D. Williams D. C., Tripp L., Willits N., Maselli R., LaCouterus R. A. Evaluation of jitter by stimulated single-fiber electromyography in normal dogs. JVIM 2003:17:545-550.

¨  Allan K., Masters N., Rivers S., Berry K., Routh A., Lamm C., T-lymphocyte risk thymoma and myasthenia gravis in a Siberian tiger (Pantehra tigris altaica). J. Comp. Path. 2013: 1-5.

¨  Bexfield N.H., Watson P.J., Herrtage M.E., Managementof myasthenia gravis using cyclosporine. JVIM 2006;20:14787-1490.

¨  Couturier J.. Huynh M., Boussaire D., Cauzinille L., Shelton G.D. Autoimmune myasthenia gravis in a ferret. Journal of the American Veterinary Medical Association 2009; 253: 1462-1466.

¨  Conti-Fine b.M., Milani M., Kaminski H.J. Myasthenia gravis: past, present, and future. Journal of Clinical Investigation 2006;

¨  Dewey C.W., Cerda-Gonzalez S., Fletcher D.J., Harb-Hauser M.F., Levine J. M., Badgley B. L., Olby N. J., Shelton G. D. Mycophenolate mofetil treatment in dogs with serologically diagnosed acquired myasthenia gravis: 27 cases (1999-208). JAVMA 2010;236:664-668.

¨  Dewey CW, Booth D.M., Rinn L.L. et al. Treatment of a myasthenic dog with mycophenolate mofetil. JVECC 2000;10:17-187.

¨  Ducote J.M., Dewey C.W., Coates J.R. Clinical forms of acquired myasthenia gravis in cats. Compend Contin Edu Practi Vet 1999;21:440-448.

¨  Dewey C.W., Bailey C.S., Shelton G.D., Kass P.H., Cardinet G.H. Clinical forms of acquired myasthenia gravis in dogs: 25 cases (1988-1995). Journal of Veterinary Internal Medicine 1997; 11:50-57.

¨  Dewey C.W., Coates J.R., Ducote J.M., Meeks J.C., Fradkin J.M. Azathioprine therapy for acquired myasthenia gravis in 5 dogs. JAAHA 1999;35:396-402.

¨  Dickinson P.J., Sturges B.K., Shelton G.D., Lecouteur R.A. Congenital myasthenia gravis is smooth-haired dachshund dogs. J Vet Intern Med 2005; 19:920-923.

¨  Foy D.S., Trepanier L.A., Shelton G.D. Cholinergic crisis after neostigmine administration in a dog with acquired foal myasthenia gravis. JVECC; 2011:547-551.

¨  Guyton and Hall 12th Edition

¨  Inzana K. D. Paraneoplastic neuromuscular disorders. Vet Clin Small Anim 2004;34:1453-1467.

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