Acute Necrotizing Myopathy in a Dog

Introduction

Rhabdomyolysis literally means “disintegration or dissolution of skeletal muscle, associated with excretion of myoglobin in the urine.”¹ Rhabdomyolysis should be suspected in patients with a markedly elevated serum creatine kinase (CK) concentration and “Coca-Cola” colored urine.^1,2 Rhabdomyolysis may be associated with trauma, infectious diseases, inflammatory myopathies, or necrotizing myopathy.

The following report documents a case of acute necrotizing myopathy in a dog with profound weakness, a markedly elevated serum CK concentration, electrolyte abnormalities, and acute renal failure (ARF).

Case Report

A 9 yr old, 12.8 kg, spayed female cocker spaniel was presented to the Pet Emergency and Specialty Center (PESC) with a 2 day history of progressive weakness, lethargy, and decreased appetite. The dog had no significant travel history, no known toxic exposure, and no known incidences of dietary indiscretion. Abnormalities detected on the physical examination included generalized weakness and otitis externa. There was no pain on manipulation of the long bones or spinal cord, and a complete neurologic examination was unremarkable. Initial in-house diagnostics included a CBC^a, chemistry panel^b, electrolytes^c, and abdominal radiographs. Laboratory abnormalities included an ALT of 581 U/L (reference range, 10–100 U/L), hyponatremia (139.9 mmol/L; reference range, 144–160 mmol/L), hypochloremia (102.6 mmol/L; reference range, 109–122 mmol/L), and hyperglycemia (188.3 mg/dL; reference range, 77.0–125.0 mg/dL). The dog was administered 300 mL subcutaneous (SC) fluids^d and was discharged with instructions to monitor her progress.

The dog represented to the PESC 8 hr later due to progressive weakness. A physical examination revealed a profoundly weak dog that could not support its own weight. A second neurologic examination showed diminished withdrawal reflexes, but the dog was otherwise normal and the examination was most consistent with neuromuscular weakness. Diagnostics included electrolytes, venous blood gas^e, blood urea nitrogen (BUN), and blood glucose. The potassium was 5.5 mmol/L (reference range, 3.2–5.8 mmol/L), the BUN was within normal limits, and the dog was hyperglycemic 207 mg/dL. The venous blood gas revealed a lactic acidosis (3.9 mmol/L; reference range, 0.0–2.0 mmol/L). All other values within the reference range. A urinalysis revealed RBCs in the sediment, the urine specific gravity was 1.033 and the urine was pink in color. The dog was administered IV dexamethasone sodium phosphate^f (1 mg/kg) and a 500 mL IV bolus of 0.9% sodium chloride^g. An ACTH stimulation test, thoracic radiographs, and abdominal ultrasound were performed and considered normal.

Over the next 24 hr, the patient's weakness progressed to lateral recumbency. A Tensilon test was performed (via administration of edrophonium chloride^h 0.1 mg/kg IV) but no obvious increase in muscle strength was noted. At this time, the dog's urine was a “Coca-Cola” color. Myoglobinuria was suspected and was supported by centrifuging a hematocrit tube containing a peripheral blood sample that showed clear serum (consistent with myoglobin versus hemoglobin).³ An outside laboratoryⁱ confirmed the myoglobinuria. A serum chemistry panel and electrolytes were repeated 36 hr after presentation along with serum magnesium and CK concentrations. The following abnormalities were found: hyperkalemia (6.4 mmol/L; reference range, 3.2–5.80 mmol/L), elevated ALT (2,115 U/L) ALP levels (306 U/L; reference range, 23–212 U/L), hypocalcemia (6.81 mg/dL; reference range, 7.9–12.0 mg/dL), hyperphosphatemia (10.05 mg/dL; reference range, 2.5–6.8 mg/dL), and hypermagnesemia (5.19 mg/dL; reference range, 1.40–2.38 mg/dL). The CK concentration was elevated above the analyzer's range. The serum sample was therefore sent to an outside laboratoryⁱ for a more accurate assessment of the CK concentration, which was >130,000 U/L (reference range, 59–895 U/L). Acute rhabdomyolysis was suspected based on the elevated CK and myoglobinuria. The etiology was unknown.

Continuous ECG^j monitoring was initiated. There was a relative sinus bradycardia (80 beats/min) and noninvasive blood pressure monitoring^j was normal. The hypermagnesemia was treated with a bolus of calcium gluconate^k (1 mg/kg IV) delivered over 40 min followed by a constant rate infusion (CRI) at a rate of 10 mL/kg/24 hr. After the initial bolus, the dog's heart rate increased to 90–100 beats/min with no detectable arrhythmias. Diuresis (0.9% NaCl^g) was continued at an increased rate of 100 mL/hr, and one dose of furosemide^l (2 mg/kg IV) was administered to promote urinary excretion of magnesium and potassium. A metoclopramide^m CRI (2 mg/kg/24 hr) and recumbent care were also instituted.

Twenty-four hours after documenting myoglobinuria, the dog's magnesium remained mildly elevated at 2.90 mg/dL and the ALT and ALP concentrations remained elevated but static. All other biochemical abnormalities had normalized. Prednisoneⁿ (1 mg/kg q 12 hr SC) was administered for a possible immune-mediated process. Forty-eight hours after presentation, the magnesium had normalized, the calcium gluconate^k CRI was discontinued, and the dog was placed on maintenance IV fluids with normosol-R^d.

Four days after presentation, unfixed and fixed biopsies were collected under general anesthesia from the vastus lateralis and triceps muscles and delivered to the Comparative Neuromuscular Laboratory, University of California in San Diego, under refrigeration. Serum for antibody titers against Neospora canium and Toxoplasmosis gondii (against both immunoglobulins G and M) were submitted to an outside laboratoryⁱ. Clindamycin^o per os (PO) q 12 hr was started to cover for toxoplasmosis while awaiting serology results.

By the end of the fourth day of admission, the patient was becoming stronger and was able to lift her head. Dark, tarry stools developed, and sucralfate^p (250 mg q 8 hr PO) was initiated for suspected gastric ulcers. The CKⁱ had decreased to 9,410 U/L. The patient's IV fluids were discontinued and the patient was discharged with sucralfate^p (250 mg PO q 8 hr), famotidine^q (5 mg PO q 12 hr), metronidazole^r (125 mg PO q 12 hr), clindamycin^o (150 mg PO q 12 hr), and metoclopramide^s (5 mg PO q 8 hr). Owners were given extensive nursing care instructions including those for rehabilitation and recumbent care.

Eleven days after initial presentation, the dog became polydypsic and lethargic but was physically stronger. The patient returned to the PESC for re-evaluation. The ALT was 280 U/L, BUN was 40 mg/dL (reference range, 7.0–27.0 mg/dL), she was hypercalcemic (14.6 mg/dL), hyperphosphatemic (11 mg/dL), CK was 275 U/L (reference range, 10–200 U/L, measured in-house), sodium was normal (156 mmol/L), and potassium was slightly elevated (6.0 mmol/L). The urine specific gravity was 1.012 with a few granular casts in the sediment. The serum creatinine concentration was normal at 1.0 mg/dL (reference range, 0.5–1.8 mg/dL).

ARF was diagnosed based on the laboratory results and the high risk for ARF with rhabdomyolysis. Other considerations such as prerenal azotemia and gastrointestinal hemorrhage were considered but therapy was instituted for ARF given the high risk associated with rhabdomyolysis and myoglobinuria. The dog was again hospitalized and fluid therapy was initiated with 0.9% NaCl^g at two times maintenance along with a metoclopramide^m CRI (2 mg/kg/24hr). Sucralfate^p, famotidine^q, and metronidazole^r were continued as described above. Since antibody titers to T. gondii and N. caninum were both negative, clindamycin^o was discontinued. Histopathology of the muscle biopsies confirmed a necrotizing myopathy (Figure 1) with no evidence of inflammation, storage disease, or infectious agents. The dog was maintained in the hospital for 48 hr on IV diuresis and supportive care. The dog was subjectively polyuric throughout her hospitalization. Forty-eight hours after presentation for ARF, all hematologic and serum biochemistry analytes were within normal limits and the dog was discharged with instructions to administer 300 mL normosol-R^d SC q 24 hr. The dog was continued on sucralfate^p (250 mg PO q 8 hr) and additionally prescribed omeprazole^t (10 mg q 24 hr PO for 14 days). Metronidazole^r, metoclopramide^s, and famotidine^q were discontinued.

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Three weeks after initial presentation, the BUN was 31 mg/dL, albumin was 1.66 g/dL (reference range, 2.20–3.90 g/dL), and a urine specific gravity was 1.016 with granular casts and rods present. The owners reported that the dog remained polydypsic but was now fully ambulatory and had near-normal activity levels at home. The stools had normalized and her urine color was light yellow. A urine culture was sent to an outside laboratoryⁱ and enrofloxacin^u (5 mg/kg [68 mg] PO q 24 hr for 14 days) was initiated. Gastroprotectants and the daily SC fluids were continued as described above. Escherichia coli and Enterococcus species, both susceptible to enrofloxacin^u, were cultured from the urine.

Four weeks after initial presentation, the dog was clinically normal with resolution of the polydypsia. All laboratory values, including the BUN, were within normal limits. The owners reported the dog was now completely normal at home.

Discussion

With the exception of horses, rhabdomyolysis and myoglobinuria are not well-documented or well-studied in animals.¹ In the case presented here, the histopathology showed myonecrosis with no evidence of inflammation, infectious agents, or underlying storage disease. Myonecrosis is an uncommon cause of rhabdomyolysis and myoglobinuria in dogs. Exertional rhabdomyolysis in horses is the most commonly recognized cause of myoglobinuria and muscle weakness in companion animals and has been the best documented in the literature.⁴ In humans, rhabdomyolysis and myoglobinuria have both acquired and inherited causes.^1,2,5,6 Acquired causes of rhabdomyolysis include exertion, crush/ischemic events, metabolic disorders, hyperthermia, drugs and toxins, and infectious agents.^2,5 Inherited causes of rhabdomyolysis in humans include metabolic myopathies such as glycogen storage diseases, fatty acid oxidation disorders, mitochondrial myopathies, and muscular dystrophies.^1,2,7

Distinguishing between necrotizing and inflammatory myopathies is important, as the clinical course, prognosis, and treatment protocols differ significantly. Differentiation is based on histopathology. Necrotizing myopathies are characterized by infiltrates predominantly comprised of macrophages with prominent myonecrosis. In some acute cases of necrotizing myopathy, histopathology may be either normal or nonspecific. In contrast, cellular infiltrates in inflammatory myopathies consist primarily of lymphocytes and occasionally eosinophils with fewer numbers of macrophages and polymorphonuclear cells. Occasional necrotic fibers may be identified; however, myonecrosis is not a dominant feature of inflammatory myopathies. Histopathology may identify storage products such as glycogen, polysaccharides, or neutral triglycerides suggesting a metabolic myopathy. Specific enzyme defects can be determined with appropriate biochemical and genetic testing.^1,2 In addition, cytoarchitectural changes may reveal an underlying inherited myopathy such as a muscular dystrophy or mitochondrial myopathy.¹

In humans, a variety of infectious diseases including multiple viral, bacterial and fungal organisms have been documented to cause rhabdomyolysis.^2,6 In the veterinary literature, Babesia spp. and Neospora spp. have been documented in a few cases of necrotizing myopathy.^1,8 Toxoplasmosis has been implicated in inflammatory myopathies but has not been confirmed in necrotizing myopathies.

The initial electrolyte abnormalities (including hyperkalemia, hyponatremia, and hypochloremia) that were noted in the dog presented in this case are commonly seen with hypoadrenocorticism, renal failure, gastrointestinal diseases, and ascites.⁹ These electrolyte shifts have also been documented in severe muscle necrosis in both humans and foals.¹⁰ An ACTH stimulation test was performed and was normal, ruling out hypoadrenocorticism.¹¹ Metabolic derangements associated with rhabdomyolysis are varied and may be severe. Hyperkalemia, hypocalcemia or, in later stages, hypercalcemia and hyperphosphatemia are common.^2,5,6 Hypovolemia, hypoalbuminemia, and anemia can occur due to massive intramuscular capillary destruction and leakage of intravascular contents. In this case, all of these electrolyte shifts were identified. Hyperphosphatemia occurred because of release of organic and inorganic phosphates from muscle breakdown.^2,6 Hypermagnesemia and hyperkalemia both occurred and were presumed to be secondary to cellular leakage. The pathogenesis of hypocalcemia in rhabdomyolysis is likely multifactorial and involves binding of calcium by damaged muscle cells, loss of mass action due to hyperphosphatemia, and by decreased renal 1,25-dihydroxycholecalciferol (1,25(OH)2D) formation.^1,2,5,12

The most common complication that occurs with rhabdomyolysis and myoglobinuria is ARF.^1,2,12–15 The pathogenesis is believed to be multifaceted and includes direct toxic effects of myoglobin in the proximal tubules; renal ischemia from hypotension; the release of cytokines, prostaglandins and other inflammatory mediators that cause renal vasoconstriction (possibly); and lipid peroxidation by free radicals.^2,5,6 In the case described herein, the patient developed ARF approximately 11 days after the initial presentation. The finding of granular casts in the urine supports tubular insult.

Delayed hypercalcemia can occur after rhabdomyolysis-induced ARF. The mechanisms for the hypercalcemia are controversial. Several mechanisms have been proposed including: mobilization of calcium from muscle deposits; secondary hyperparathyroidism; and elevated levels of 1,25, dihydroxyvitamin D.¹⁶ Recent evidence supports redistribution of calcium from soft tissue.¹⁶ In this case, hypercalcemia was delayed and diagnosed concurrently with ARF and resolved with resolution of the ARF.

Myocyte injury leads to the release of intracellular contents including, myoglobin, creatinine, urea, potassium, CK, aminotransferases, aldolase, lactate dehydrogenase, and hydroxybutyrate dehydrogenase.² Increased levels of serum myoglobin precedes CK yet CK is the most sensitive enzyme indicator of muscle injury and a hallmark of severe rhabdomyolysis. In this case, the CK was markedly elevated. The elevation of ALT can also be attributed to the muscle breakdown. Myoglobinuria is seen when serum myoglobin exceeds a concentration of 9–12 mmol/L (15–20 mg/dL).¹⁷ The presence of myoglobinuria indicates significant muscle breakdown.

Conclusion

Although relatively uncommon, rhabdomyolysis should be considered in small animals that present with an acute onset of weakness and signs of neuromuscular disease. A serum CK should be included in the minimum database for any animal with this clinical presentation as it can provide a clue to the underlying disease process. Rhabdomyolysis should be suspected by the presence of markedly elevated CK concentrations and myoglobinuria and confirmed by the histologic presence of myonecrosis in a muscle biopsy specimen. Histopathology will also distinguish between inflammatory and necrotizing myopathies and can help identify an underlying metabolic defect. Once a necrotizing myopathy is confirmed, it is prudent to monitor the animal for profound electrolytes disturbances and fluid shifts. Unless a specific infectious agent can be identified, therapy is mainly supportive and involves monitoring and treating for electrolyte and fluid shifts. It is also important to monitor and protect against renal failure as this is a very common complication of rhabdomyolysis. Idiopathic necrotizing myopathy, as in this case, may have a severe clinical presentation but can carry a good prognosis with appropriate supportive care; therefore, a definite diagnosis is important for both the patient and the client.