March 2000

NEUROMUSCULAR DISORDERS

Information in this issue is summarized from the recent Antech Medicine Consultants Conference call with Dr. Diane Shelton of the University of California at San Diego (UCSD) and from their web site: www.medicine.ucsd.edu/vet_neuromuscular. 

The clinical presentation of myasthenia gravis (MG) is highly variable. In dogs, focal MG (e.g. megaesophagus, dysphagia) comprises > 50% of cases. Peracute collapse with generalized weakness resembling polyradiculoneuritis can also occur. The classical episodic weakness with exercise intolerance is uncommon in dogs. Hypothyroidism is present in ~ 20% of canine MG cases. In cats, focal MG is uncommon as most cats present with generalized weakness. Dysphagia, megaesophagus, and decreased palpebral reflex can occur in cats. Thymoma related to MG is present in ~ 3% of canine cases, but occurs in ~ 25% of feline cases, especially in Abyssinian and Somali cats.

Diagnostic confirmation of MG uses 3 approaches. The most commonly used and reliable test is for acetyl choline receptor antibody (ACRA) titer. This test is 98% sensitive for generalized MG and ~ 75% sensitive for focal MG. Immunosuppressive doses of corticosteroids given for > 7-10 days will lower ACRA titers. Hemolysis and lipemia do not appear to affect the test.

The "Tensilon" (edrophonium response) test can also be used, and is specific for MG if the response is dramatic. Weak responses can be seen in patients with MG, polymyositis, or peripheral neuropathy. False negative responses can occur. The dose of edrophonium is 0.1-0.2 mg/kg IV. Pre-treatment with atropine is usually unnecessary.

Repetitive nerve stimulation can also be used to diagnose MG but requires general anesthesia. A decremental muscle action potential in response to repetitive stimulation is seen with MG.

The clinical presentation of masticatory muscle myositis (MMM) in dogs reflects focal inflammatory myopathy of the muscles of mastication, while limb muscles are spared. Signs range from acute swelling of the temporalis and masseter muscles, restricted jaw movement, jaw pain, and exophthalmus, to muscule atrophy. The classical clinical sign of acute MMM is inability to open the jaws even under anesthesia. If the jaw can be opened, then temporomandibular joint disease (TMJ) is more likely. In chronic MMM, masticatory muscles are atrophied and there may be no pain or jaw restriction. CPK concentration is often normal or only slightly elevated because of the small amount of involved muscle mass and the chronic presentation.

Diagnosis of MMM is confirmed by the 2M-antibody test and a muscle biopsy. Antibodies against type 2M masticatory muscle fibers are detected in an immunohistochemical assay. The test is highly sensitive in acute stages of MMM, but can become negative in end-stage disease when little muscle antigen remains to stimulate an immune response. Breeds such as the Samoyed, Doberman Pinscher, and Rottweiler are especially affected with end-stage disease. Lowered antibody titers can result if the dog has received immunosuppressive doses of corticosteroids for > 7-10 days. Hemolysis and lipemia do not appear to affect the test.

Muscle biopsy is also recommended to determine the degree of myofiber destruction or fibrosis, for these affect prognosis. Open biopsy of the temporalis muscle is recommended, as punch biopsy is generally inadequate. Incise through the platysma muscle and thick fascia of the temporalis muscle to ensure biopsy of the correct tissue. Remove a 0.5cm 3 piece of muscle, moisten it by dipping in normal saline, and place in a red top tube and transport on ice directly to the UCSD lab, as it must be received within 24 hours. A formalin-fixed smaller (1/4 size) piece of muscle should also be submitted to UCSD at the same time, and is evaluated at no extra charge.

Early diagnosis and therapy with immunosuppressive doses of corticosteroids before muscle atrophy and fibrosis is advanced usually yields a good prognosis.

Cases of polymyositis (PM) can be difficult to diagnose. Clinical presentation can include generalized weakness, megaesophagus, dysphagia, stilted gait, and muscle pain. Differential diagnosis includes: toxoplasmosis, neosporosis, Ehrlichia canis, Lyme disease, leptospirosis, Rocky mountain spotted fever, paraneoplastic syndrome (e.g. disseminated mastocytosis), drug-induced disorder, MG, hypothyroid myopathy or neuropathy, lipid-storage myopathies, and lactic acidemias (very painful and require pre- and post- exercise lactate concentrations to confirm).

Elevation of CPK are neither sensitive nor specific for PM. Levels are persistently elevated in ~ 75% of cases, and the degree of elevation depends upon the amount of muscle involved and the degree of muscle necrosis. In some cases, the inflammation is perivascular and not within the muscle tissue itself; these cases may have little to no CPK elevations. Persistent CPK elevations of 40,000-50,000 U/L are more consistent with muscular dystrophies than PM. Newfoundlands are a breed affected with both MG and PM. In the latter case, they typically have megaesophagus and dysphagia with elevated CPK, although ~ 25% have normal CPK concentrations.

Anorexic dogs rarely have elevated CPK concentrations, whereas these are often very high in anorexic cats. In seizuring animals, CPK increases within hours and then decreases again within 48 hours.

Diagnostic confirmation requires an open muscle biopsy as punch biopsy is inadequate. Biopsies from 2 sites are preferred because the disease can have patchy distribution. For patients with generalized weakness, the biopsy sites should be from proximal limb muscles: triceps (forelimb) and vastus lateralis (hind limb). Even with focal signs of PM such as megaesophagus, some histologic changes will be seen in limb muscles. Requirements are a 0.5 cm x 0.5 cm x 1 cm piece of muscle tissue, with the 1 cm taken along the longitudinal length of muscle fibers. Treat fresh biopsy tissue as described above for MMM. If there is muscle atrophy having a distal distribution, this is suggestive of peripheral neuropathy (e.g. as seen in male Leonbergers), and so distal limb muscles such as cranial tibial and extensor carpi radialis should be biopsied.

References: Shelton, J Sm An Pract 39: 368-372, 1998; Lipsitz, Berry, Shelton, JAVMA 215: 956-958, 1999.

Magnesium is an abundant intracellularcation, and is an activator of a wide variety of enzyme systems. About 1/3 of blood magnesium is bound to albumin, and the remainder circulates as free magnesium ion. Homeostasis is maintained primarily by renal excretion/ reabsorption. Serum magnesium concentrations may not correlate well with total body magnesium.

High serum magnesium concentrations are seen periodically and usually have little clinical significance. They may occur in end-stage renal failure, with hypocalcemia and adrenal insufficiency.

Low serum magnesium concentrations are seen in critical care patients, which may result in cardiac dysfunction; neuromuscular weak-ness; seizures; hypokalemia, hypophosphatemia, hyponatremia and hypocalcemia. In hypomagnesemic tetany (grass tetany) of cattle, the majority of cases also have hypo-calcemia. The diagnosis of grass tetany can be differentiated from parturient paresis by finding very low levels of urine magnesium in affected cattle (normal urine Mg ++ is ~ 50 mg/dL). Hypomagnesemia can also occur with chronic nutritional deficiency of magnesium; prolonged anorexia; increased losses from vomiting, diarrhea, renal failure, use of diuretics; and altered distribution from sepsis, infusion of blood products, cathecholamine release; hypoaldosteronism; hyperthyroidism; and imbalances of parathyroid metabolism. Disturbances of magnesium metabolism in cattle (calves & adults) and sheep produce similar clinical syndromes of hypomagnesemic tetany that can occur seasonably and on certain pasture types. Goats also can have hypomagnesemia from grazing on fertilized grass pastures. 

References: Rosol and Capen, Clinical Biochemistry of Domestic Animals, 5th edition, Academic Press, San Diego, 1997, pp. 678-687; Norris et al, Am J Vet Res 60: 1159-1163, 1999.

IMPORTANT REMINDER

The Department of Transportation and OSHA are increasing regulatory scrutiny of the shipment of biopsy specimens. We need your help to comply with these necessary requirements.

Please make sure that biopsy samples are shipped only in appropriate containers with Biohazard labels, which we provide for you in various sizes. Large masses must be submitted following procedures in the December 1999 Antech News.