Myasthenia gravis and masticatory muscle myositis in a dog

Abstract

A 21-month-old, castrated male Vizsla was presented for pelvic limb weakness, difficulty opening his mouth, ptyalism, voice change, and urinary incontinence. Myasthenia gravis and masticatory myositis were diagnosed. The unusual clinical findings, diagnosis, treatment, and case outcome are described, followed by a brief discussion of myasthenia gravis and masticatory myositis.

A 21-month-old, 18.4 kg, castrated male Vizsla was presented to the Veterinary Teaching Hospital, University of Guelph, with the complaint of progressive gait abnormality, dribbling of urine, and voice change, progressing over the previous 3 to 4 d. The gait abnormality was described as hindend weakness with an unwillingness to take more than a few steps, followed by sitting. The onset of the gait abnormality coincided with a fall while the dog was playing with another dog. The day prior to presentation, the referring veterinarian noted that the dog had a hunched back and delayed proprioception of the pelvic limbs. Trismus, drooling, and inefficient drinking and eating behavior were also noted 7 d prior to referral. Similar signs, first appearing 4 mo earlier, were attributed to suspected masticatory myositis; however, further diagnostic testing was not pursued and treatment with amoxicillin (Apo-Amoxi; Apotex, Toronto, Ontario) and meloxicam (Metacam; Boehringer Ingelheim, Burlington, Ontario) appeared to resolve the clinical signs. The dog had been assessed to be healthy at the time of vaccination 8 mo earlier.

Physical examination revealed a thin body condition, severe atrophy of the muscles of mastication, and constant ptyalism. Pain and trismus prevented a thorough oral examination. The dog could prehend and swallow food normally, but he drank with difficulty. A grade II/IV left apical systolic heart murmur was detected on cardiac auscultation. The murmur had not been noted previously, and although not typical for the breed, mitral valve endocardiosis with regurgitation was suspected. Intermittent urine dribbling was observed during the examination; the bladder was large and easily expressed. Neurologic examination revealed that the dog was quieter than normal. The palpebral reflex was absent bilaterally; however, vision and a pupillary light reflex were present. There was a 2- to 3-mm corneal opacity in the left eye, which did not take up fluorescein stain. The dog was ambulatory, but obviously weak and reluctant to bear weight on the hind limbs. Despite having an arched back, the dog did not react painfully to spinal palpation. Proprioception was reduced in the pelvic limbs and normal in the thoracic limbs. Spinal reflexes were present; however, flexor reflexes in all limbs were decreased, with the pelvic limbs being more affected than the thoracic limbs. Deep pain sensation was present in all limbs and perineum. No orthopedic abnormalities were detected. The neurologic examination indicated a diffuse hyporeflexia involving the spinal nerves, cranial nerve VII, and, possibly, the laryngeal innervation. The signs were most consistent with masticatory myositis and a peripheral neuropathy; the differential diagnoses included polyradiculoneuritis (Coonhound paralysis), metabolic disorders (adrenocortical insufficiency, hypothyroidism, hypoglycemia), paraneoplastic syndrome, and idiopathic causes. Atypical myasthenia gravis, a primary myopathy, immune-mediated or infectious polymyositis (toxoplasmosis, neosporosis), and a diffuse or multifocal encephalomyelitis were also considered. A concomitant thoracolumbar spinal cord lesion, possibly due to trauma, could not be ruled out.

Initial diagnostic tests, consisting of an acid-base analysis, an electrolyte panel, blood urea nitrogen and glucose estimations, and an electrocardiogram, were normal. Palliative support care consisted of IV fluid therapy (50 mL/kg bodyweight (BW)/24 h + 20 meq/L KCl, Plasmalyte 148; Baxter, Toronto, Ontario,), intermittent bladder expression, and application of ophthalmic lubricating ointment (Duralube; Alcon, Mississauga, Ontario) q6h OU. On day 2, results from a complete blood cell count and serum biochemistry were normal, except for a low urea level (1.9 mmol/L; reference range, 3.5 to 9.0 mmol/L). Serum creatine kinase activity was 130 U/L (reference range, 40 to 255 U/L). Analysis of urine obtained by cystocentesis revealed 1+ bacteria; however, the culture was negative. Blood was submitted for determination of an acetylcholine (ACh) receptor antibody titer, a type 2M myosin antibody titer, and Toxoplasma gondii and Neospora canis antibody titers. Thoracic radiographs were normal. An echocardiogram was not performed, because the electrocardiogram was normal and there was no radiographic evidence of cardiomegaly.

On day 3, the clinical signs and findings on a repeat neurologic examination were unchanged. With the history of dysphagia and pytalism, radiographs of the oral cavity and pharynx were obtained to evaluate for foreign bodies, masses, abnormal anatomic structures, and dental or temporomandibular joint disease. No abnormalities were noted. Results from analysis of cerebrospinal fluid and electromyographic (EMG) examination of the limbs and epaxial muscles were normal. Electromyography detected fibrillation potentials and positive sharp wave activity bilaterally in the muscles of mastication and in the tongue. Biopsies from the right masseter and hypoglossal muscles were formalin-fixed and frozen, and then submitted for histopathologic examination and immunocytochemical analysis at the Comparative Neuromuscular Laboratory, University of California-San Diego School of Medicine.

The following day (day 4), the dog was observed to be walking almost normally on initial exercise after rest in its cage. When walking, the dog rapidly deteriorated into severe paresis of the pelvic limbs and stiffness of the thoracic limbs. He had also developed a soft productive cough. Serial thoracic radiographs now revealed aspiration pneumonia and megaesophagus. Because of the megaesophagus and the dramatic deterioration in gait with exercise, a Tensilon test (edrophonium chloride (Enlon, Baxter) 2 mg IV) was performed, with resultant rapid and dramatic improvement in limb strength, body posture, and palpebral reflexes. These results were suggestive of myasthenia gravis. Treatment for myasthenia gravis was initiated with pyridostigmine bromide (Mestinon; ICN Canada, Montreal, Quebec), 1 mg/kg BW, PO, q8h; the aspiration pneumonia was treated with enrofloxacin (Baytril; Bayer Animal Health, Etobicoke, Ontario), 5 mg/kg BW, PO, q12h, and clindamycin (Antirobe; Pharmacia and Upjohn Animal Health, Orangeville, Ontario), 15 mg/kg BW, PO, q12h. The dog responded well to therapy with improvement in muscle strength and palpebral reflex, decreased ptyalism, and resumption of urinary continence. Nutritional management included small frequent feedings from an elevated position of a canned food diet (Eukanuba Nutritional Recovery Formula; The Iams Company, Dayton, Ohio, USA).

Histopathologic examination of the masseter muscle revealed moderate multifocal areas of mononuclear cell infiltration (lymphocytes, macrophages). Fibrosis was not observed. Positive staining for type 2M fiber antibodies was detected within the muscle biopsy section. Circulating antibodies against type 2M muscle fibers were also detected in the serum. Based on these findings, a diagnosis of masticatory myositis was made. Histopathologic examination of the biopsy of the hypoglossal muscle was unremarkable, ruling out myositis as a cause of the abnormal EMG findings in the tongue. The titer of the ACh receptor antibody was positive (6.89 nmol/L; reference range, less than 0.6 nmol/L) confirming myasthenia gravis. Titers of antibody to Toxoplasma and Neospora were negative.

Following discharge, the dog exhibited intermittent episodes of muscle weakness, exercise intolerance, and urine dribbling. The dose of pyridostigmine was increased to 2 mg/kg BW, PO, q8h on day 9, and prednisone (Apo-Prednisone; Apotex, Westin, Ontario) was added to the treatment at 0.5 mg/kg BW, PO, q24h, following resolution of the aspiration pneumonia (day 21). The dose of prednisone was gradually increased to 2 mg/kg BW, PO, q24h over 4 wk. A second episode of aspiration pneumonia occurred 10 wk after discharge; this was treated empirically with enrofloxacin (Baytril, Bayer Animal Health), 5 mg/kg BW, PO, q12h. After 12 wk of therapy, serial titers of antibodies to ACh receptor and type 2M muscle fiber were 1.07 nmol/L and negative, respectively. At that time, the dog appeared to be in clinical remission, except for radiographic evidence of megaesophagus.

This case report emphasizes some unusual clinical aspects of the presentation of acquired myasthenia gravis. Hyporeflexia is an uncommon finding and may represent a more severe form of myasthenia gravis. The urinary incontinence is also a unique feature. Disorders associated with generalized muscle weakness can affect bladder function and, in association with decreased urethral sphincter function, may lead to incontinence; the incontinence would seem unlikely to be due to the involvement of neuromuscular transmission of muscarinic type of ACh receptor in the smooth muscles. In a study by King et al (1), 2 of 5 dogs presenting with acute fulminating myasthenia gravis were noted to have bladder distension requiring assistance to urinate. Other causes of urinary incontinence were not pursued in this case following the rapid clinical resolution of the incontinence following therapy for myasthenia gravis. In humans, voiding dysfunction in conjunction with myasthenia gravis is rare and seems to be associated with a recent diagnosis of myasthenia or an exacerbation of the disease process (2). It has been hypothesized that autonomic dysfunction in patients with myasthenia gravis might indicate a unique subset with a worse prognosis (2).

The clinical presentation of an arched spine with pelvic limb proprioceptive deficits, representing profound muscle weakness, is also an unusual finding in a nonrecumbent animal. Most ambulatory patients with myasthenia gravis present with normal proprioception. The proprioceptive deficits in this patient, however, may have been attributable to an additional disorder, such as a polyneuropathy, in which case, a nerve biopsy might have proven useful. Interestingly, following treatment for myasthenia gravis, the proprioceptive deficits resolved. In addition, this patient initially did not have the typical historical complaint of fatigue associated with exercise seen in many cases of generalized myasthenia gravis. If fatigue had been present, it might have aided in an earlier diagnosis of myasthenia gravis. It was also unusual that with rest while hospitalized, the progressive weakness was unabated.

The masticatory myositis was likely chronic, given the patient's previous history; however, there was no histopathologic evidence of fibrosis, which is often seen with chronicity (3). The excessive ptyalism on initial presentation was attributed to the esophageal disease associated with the myasthenia gravis and not to masticatory myositis.

Previously, Hackett et al (4) reported myasthenia gravis and concurrent masticatory muscle myositis in a 10-year-old dog presenting with regurgitation, cough, and a thymoma. Myasthenia gravis was diagnosed, based on a high antibody titer to ACh receptor. Histologic examination of the masticatory and extraocular muscles revealed extensive lymphoplasmacytic infiltration, and circulating antibodies against temporalis muscle proteins were documented by immunohistochemical staining.

The unusual clinical presentation of this case and the presence of autoantibodies to ACh receptors and type 2M muscle fibers prompted testing for concurrent or underlying autoimmune disease. Human myasthenics have an increased occurrence of several associated disorders, including autoimmune diseases such as hypothyroidism, lupus erythematosus, and rheumatoid arthritis (5). Although not as well characterized in the dog, some of these conditions are believed to be associated with canine myasthenia gravis (3,6). In this case, antinuclear antibody (ANA) testing was negative and total thyroxine, free thyroxine, and thyroid stimulating hormone were normal.

Acquired myasthenia gravis is an immune-mediated disease in which autoantibodies that react with nicotinic acetylcholine receptors of the skeletal muscle neuromuscular junction are produced (5,7). Clinical signs of myasthenia gravis vary depending on the muscle groups involved. Appendicular muscle weakness can manifest as weakness, stiff gait, or collapse. Facial muscle weakness can manifest as reduced or absent palpebral reflex; esophageal muscle weakness as megaesophagus with regurgitation; pharyngeal weakness as dysphagia; and laryngeal muscle weakness as voice change or inspiratory stridor (7,8). Less common clinical signs that have been associated with myasthenia gravis include hyporeflexia, lameness, shortening of stride, collapse, tremors, and distended bladder (1).

The preferred diagnostic test for canine acquired myasthenia gravis is the detection of circulating autoantibodies to ACh receptors (6). This immunoprecipitation radioimmunoassay carries a high sensitivity and specificity, detecting approximately 98% of dogs with generalized acquired myasthenia gravis (6). False positive results are rare. A positive response to the short-acting anticholinesterase drug edrophonium chloride is suggestive of myasthenia gravis; however, false positive and false negative results are possible (3,8). Therapy for myasthenia gravis involves the use of anticholinesterase medication. In many dogs, muscle weakness is not adequately controlled with anticholinesterase therapy alone, in which case immunosuppressive therapy is recommended either in conjunction with anticholinesterase treatment or as the sole therapy (5,6,9). Prednisone is the most commonly used immunosuppressive agent; however, azathioprine, cyclophosphamide, and cyclosporine therapy have been reported to be efficacious (6,7,9). Dogs with megaesophagus are managed with small, frequent feedings in the upright position, of a solid or semiliquid diet, depending on individual response, and are monitored closely for signs of aspiration pneumonia. The prognosis for dogs with myasthenia gravis is variable; however, severe aspiration pneumonia, persistent megaesophagus, acute fulminating myasthenia gravis, and the presence of a thymoma carry a poor prognosis (3,10).

Masticatory muscle myositis (MMM) is an inflammatory disorder selectively involving the muscles of mastication (3). It is presumed to be immune-mediated, based on the detection of autoantibodies reacting with type 2M muscle fibers, the presence of a mononuclear inflammatory cell infiltrate, and the clinical response to immunosuppressive doses of corticosteroids (3). Masticatory muscles are composed primarily of unique type 2M myofibers that are not present in limb muscles (11). Masticatory muscle myositis is usually bilaterally symmetrical, and affects dogs of any age, sex, or breed; however, large breed dogs are most commonly affected (3). Acute and chronic forms of MMM have been described. In the acute form, swelling of the muscles of mastication is observed with myalgia. The animal is reluctant to open its mouth, has difficulty eating, and may exhibit ptyalism. Exophthalmos, linked to enlargement of the temporal muscles, can lead to exposure keratitis and conjunctivitis (10,12). In most cases, such as in this case, MMM is a chronic condition with severe progressive muscle atrophy and reduced ability to open the mouth (10,11). Clinicopathologic evaluation in affected dogs is typically nonspecific; however, the serum creatine kinase (CK) activity may be increased and a leukocytosis attributable to a neutrophilia or, less commonly, an eosinophilia may be present (3). Diagnosis is based on biopsy of the affected muscles and documenting the presence of antibodies to type 2M muscle fibers, which can be demonstrated in more than 85% of affected dogs (11,12). Histopathologic findings commonly include sites of necrosis and phagocytosis of the 2M fibers with perivascular infiltration of mononuclear cells. Abnormalities in the EMG may include increased insertional activity, fibrillation potentials, positive sharp waves, and bizarre high-frequency discharges (3). The treatment for MMM is prednisone, initially at 1–2 mg/kg BW, PO, q12h; however, the dosage can be tapered gradually in accordance with improvement in clinical signs. Azathioprine (2 mg/kg BW, PO, q24h) may be required, if clinical signs are not well controlled (3). Treatment for MMM was delayed in this patient due to the presence of complicating aspiration pneumonia. It has also been documented in human and canine myasthenics that initial immunosuppressive dosages of prednisone can exacerbate muscle weakness; therefore, the dose was gradually increased (5,7,9). The prognosis for MMM, if treated appropriately, is good; however, relapse may occur (3,10,12). CVJ