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Ben with student Jennifer Ree. Ben is a 5-year-old male Golden Retriever with an acute onset of difficulty walking.

Case Study: Difficulty Walking in a Dog

Presenting Complaint

Ben is a 5-year-old male castrated Golden Retriever who was presented for an acute onset of difficulty walking.

History
Two days prior to presentation, Ben stopped walking halfway through his walk .
One day prior to presentation, Ben was examined by his regular veterinarian. On physical examination, he had a stiff, crouching pelvic limb gait. He was unwilling or unable to walk. A CBC and serum biochemical panel were normal. Lateral abdominal, spinal and pelvic radiographs were normal. A NSAID was prescribed.
Since yesterday, the owner has not noted any worsening or improvement, and does not think he is painful.  Ben is not coughing, sneezing, or having any vomiting or diarrhea. He is drinking and eating well.
There is no other significant medical history prior to this event.

Physical Examination
Ben was bright, alert and responsive, T = 101.5, P =120, R= panting, with a mild amount of saliva around his mouth. He had a body condition score of 6/9, and was able to sit up, but was non-ambulatory.  There were no heart murmurs or arrhythmias, and he had strong synchronous pulses; the remainder of a complete physical examination (including a rectal examination) was normal.

Neurological Examination:
Mentation: Bright and alert.
Gait/Posture: Non-ambulatory. When encouraged to walk, Ben ambulates with a short-strided gait in all four limbs. With exercise, the  crouching and hunched posture worsen, his strides become shorter, and he sits down.
Cranial nerves: Normal.
Segmental reflexes: Normal.
Proprioceptive Positioning: Difficult to assess in the pelvic limbs due to Ben’s attempts to sit.
Palpation: No apparent pain, symmetrical musculature and fat.

Ask Yourself

Discussion Questions:

Normal or abnormal neurologically?

Ben’s neurological examination is essentially normal, however we are unable to assess his proprioceptive positioning. Causes of exercise intolerance in dogs may be problems outside or inside of the nervous system. Causes outside the nervous system include cardiac problems (e.g. right to left shunting), vascular problems (e.g. thrombi in external iliac arteries), and metabolic disease (eg hypoglycemia).  Causes inside the nervous system include neuromuscular disease. In the absence of physical examination abnormalities on Ben, causes outside of the nervous system are considered less likely than neurological causes.

Neuroanatomical localization

Ben has evidence of generalized weakness that worsens with exercise, with an essentially normal physical and neurological examinations. These findings are most consistent with a neuromuscular problem.

Possible Causes

Neuromuscular problems may be causes by myopathies, neuropathies, or junctionopathies. Causes of myopathies and neuropathies may be inflammatory or non-inflammatory. The most common cause of a junctionopathy is myasthenia gravis.  Generalized weakness that worsens with exercise with a normal neurological examination is most consistent with a junctionopathy such as myasthenia gravis.

Diagnostic Plan
CBC: Unremarkable.
Chemistry panel: Unremarkable.
UA: USG 1.035.
Thoracic radiographs: No evidence of megaesophagus or pneumonia.
Tensilon Test
AChR antibody test

Diagnosis: Acquired Myasthenia Gravis

Acquired MG is a disorder of neuromuscular transmission, caused by an antibody mediated autoimmune destruction of the nicotinic acetylcholine receptor (AChR) in skeletal muscle, resulting in depletion of this receptor, resulting in muscle weakness.  Dogs may have focal or generalized clinical signs.  Ben had a positive response to edrophonium (Tensilon Test, see video below). 

AChR: 1.99 nmol/L (> 0.6 nmol/L considered positive for MG).

Treatment

Pyridostigmine 45mg TID (1mg/kg)

Increased to Pyridostigmine 60mg PO TID in 2 days
Meatballs, vertical feeding

Outcome

After 3 weeks at home Ben was clinically normal according to the owners

Myasthenia Gravis

Diagnosis
The gold standard for the diagnosis of MG in dogs and cats is the presence of serum autoantibodies against skeletal muscle AChR. The test is done on serum at the Comparative Neuromuscular Laboratory, at the University of San Diego (http://vetneuromuscular.ucsd.edu/). This assay is species-specific, and autoantibodies against the AChR are demonstrated using an immunoprecipitation radioimmunoassay. This test is very specific and sensitive. Approximately 2% of dogs with generalized MG will have a negative test (so called “seronegative MG”); false positives have not been reported. An AChR antibody greater than 0.6 nmol/l is considered positive in the dog and greater than 0.3 nmol/l is positive in the cat. Interestingly, there is no correlation between the clinical severity of the MG and the level of the AChR antibody. There is anecdotal evidence that the antibody level for an individual may reflect the clinical severity when monitored over time.
Immunosuppression for greater than 7-10 days may lower AChR antibody concentrations, and therefore, AChR antibody concentrations should ideally be evaluated initially before the patient is immunosuppressed. 
Electrophysiology can be used to support the diagnosis of MG, particularly in dogs that have negative AChR antibody test results. Reduced amplitude of compound muscle action potential (CMAP), decrementation of the CMAP with repetitive stimulation (and reversal with the IV administration of edrophonium) as well as increased Jitter all support the diagnosis of MG. Since dogs and cats must be placed under general anesthesia for these electrophysiological tests, they are usually not recommended initially. Dogs with megaesophagus are particularly at risk for developing aspiration pneumonia secondary to general anesthesia.

Tensilon Test
The “Tensilon Test” is a clinical test used to presumptively diagnose MG, while awaiting results of the AChR-antibody test from the Laboratory. The tensilon test may result in false positive and false negative results, but it is relatively sensitive, and many dogs and cats with MG will have a positive test. Therefore, we consider it a valuable adjunctive test while awaiting the ACh antibody result, assessing animals with a negative serologic test, and in assessing treatment.
The “Tensilon Test” is where a short-acting acetylcholinesterase inhibitor (such as edrophonium) is given to a patient intravenously; muscle strength is then subjectively evaluated. This test is easiest to assess in patients with the generalized form of MG, who tire with exercise. The dosage of edrophonium used in the dog is 0.1-0.2 mg/kg intravenously, and in the cat, 0.25 to 0.5 mg total dose. Usually, the low end of the dosage is initially given. (If an overdose is given (or this drug is given to a patient without MG) then signs of SLUD (salivation, lacrimation, urination, defecation) may develop. If these signs develop, then atropine (0.02-0.04 mg/kg IV) should be given intravenously. (I like to have the atropine already drawn up, so that I have it ready if I need it).
To do the “Tensilon Test”, an indwelling intravenous catheter is placed. The patient is then gently exercised until fatigued. The edrophonium is administered IV, the catheter is flushed with sterile saline, and then the patient is immediately lightly exercised, or if non-ambulatory, encouraged to rise. In patients with focal MG such as facial muscle weakness, the palpebral reflex may be assessed after IV edrophonium.  Patients are assessed as having a positive or negative “Tensilon Test”.


Treatment

In dogs, anticholinesterase drugs are the cornerstone of therapy. Anticholinesterase drugs enhance muscle transmission by prolonging the length of time that acetylcholine remains at the neuromuscular junction. The dosage is titrated to effect, to minimize adverse effects and maximize muscle strength. The most common drug used is pyridostigmine bromide, at a dosage of 1-3 mg/kg PO q 12 or q 8 hours. For animals that cannot tolerate oral medications, it may be used as a constant rate infusion (dosage 0.01-0.03 mg/kg/hour). (Injectable pyridostigmine is light sensitive).

In addition to anticholinesterase drugs, dogs with MG often require supportive care to treat concurrent problems such as megaesophagus, inadequate nutrition, aspiration pneumonia, thymoma etc. Some dogs with megaesophagus may simply require elevated feedings, while some may require placement of a gastrotomy tube. Dogs are generally fed two to three times daily, usually in an elevated (standing or vertical sitting position) position for 20-30 minutes after each feeling. A “Bailey Chair” may be used to help support the dog in an upright position after feeding, both in the hospital and at home.  Joe and Donna Koch developed this specialized chair (named after their dog “Bailey”), where the dogs are comfortable, can eat, drink, receive medications, and remain in a stable, upright position following a meal. The Bailey Chair is not available for purchase, but a video or DVD is available that demonstrates how to easily build this feeding chair.

Rarely, some dogs with MG do not clinically improve with supportive care and anticholinesterase drugs. In these dogs, corticosteroids are added to the treatment regime. Because some dogs may develop a short-term increase in muscle weakness, the dosage of prednisone recommended is lower that what is used for most other immune mediated diseases (0.5 mg/kg q 48 hours). Some dogs with MG have been treated with high dose steroids such as methylprednisolone initially, followed by oral prednisone with positive outcomes. Other immunomodulatory drugs such as azathioprine and mycophenolate have been used with apparently good outcomes. Contraindications for the use of corticosteroids and other immunomodulatory druges include aspiration pneumonia, gastrointestinal ulceration, and infections.

 

Therapeutic apheresis

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.  
Preliminary data for treatment of refractory MG has been encouraging. Three dogs showed significant improvement after 2 treatments. All dogs received a total of 3 treatments within 5 – 7 days. Treated dogs became ambulatory within 3 days of starting TPE treatment with subsequent resolution of regurgitation and megaesophagus.
Advantages of successful TPE may include:
• More successful treatment of medically refractory cases
• More rapid resolution of clinical signs
• Lower incidence of complications

 

Also, many dogs with MG go into spontaneous remission (27-89% in two studies) an average of 6 months after diagnosis.

Click more information on Myasthenia Gravis

Myasthenia Gravis clinical trial.