Canine myasthenia gravis

Decreased acetylcholine receptor content of the neuromuscular junction underlies the muscular weakness seen in both acquired and congenital myasthenia gravis. Immune mediated mechanisms account for the acquired defect while decreased membrane insertion of receptor leads to the congenital disorder. The congenital form typically presents in the first few weeks of life with generalised episodic weakness as the predominant sign. Although treatment with cholinesterase inhibitors may help temporarily, the prognosis is poor. Acquired myasthenia gravis can occur between eight months and 13 years of age and may present as megaoesophagus alone or as exercise-related weakness in conjunction with megaoesophagus. Although treatment of the immune mediated form is often successful and spontaneous remissions also occur, aspiration pneumonia secondary to megaoesophagus remains a major cause of mortality in affected dogs. Resolution of megaoesophagus must therefore be a major goal for future treatment regimes. The remarkable similarity between canine and human acquired myasthenia gravis suggests that the canine thymus gland warrants greater attention pathologically and perhaps therapeutically considering the value of thymectomy in human patients.     

Mega-oesophagus secondary to acquired myasthenia gravis

Fifteen dogs with confirmed adult onset idiopathic megaoesophagus, in which no generalised muscle weakness was observed, were tested for the presence of acetylcholine receptor antibodies. Of these, six were found to have values greater than 0–6 nmol/litre, previously determined to be diagnostic of acquired myasthenia gravis. The mean serum titre value for these dogs was 5–59 nmol/litre (range 0–78 to 8–72 nmol/litre). It appears that a significant proportion of dogs presenting with megaoesophagus have myasthenia gravis and, if a prompt diagnosis and appropriate treatment can be instituted, clinical signs may improve.     

Megaoesophagus and glucocorticoid-deficient hypoadrenocorticism in a dog

A seven-year-old German shepherd dog was referred for acute onset regurgitation. Muscle weakness and severe dermatological disease were present. Thoracic radiographs revealed generalised megaoesophagus. Diagnostic testing revealed glucocorticoid deficiency, and rapid resolution of the megaoesophagus followed appropriate supplementation. The dog made a full recovery. Unique features of this case include a transiently positive antinuclear antibody titre and clinical features of myasthenia gravis.     

Treatment of acquired myasthenia gravis associated with thymoma in two dogs

Two cases of myasthenia gravis associated with thymoma are reported. Both were female German shepherd dogs and the thymoma was surgically resected. Aspiration pneumonia secondary to persistent megaoesophagus was a complication in both cases. The myasthenia gravis did not resolve, but there was a more satisfactory control of clinical signs with anticholinesterase treatment. Corticosteroid therapy was used in one case, but the resulting polydipsia increased the incidence of regurgitation, resulting in recurrent episodes of aspiration pneumonia.     

Surgical correction of gastro‐oesophageal intussusception with bilateral incisional gastropexy in three dogs

Three dogs presented for evaluation of acute onset tachypnoea and dyspnoea following episodes of vomiting and/or regurgitation. Thoracic radiographs were suggestive of a gastro‐oesophageal intussusception in all three dogs; one dog also showed evidence of aspiration pneumonia. All three dogs underwent surgical correction with a bilateral incisional gastropexy. All dogs recovered from anaesthesia uneventfully and were discharged from the hospital 3 days after presentation. Persistent megaoesophagus was evident in all three dogs, and they are being chronically managed with a strict feeding regime and pro‐motility agents.     

Clinical Forms of Acquired Myasthenia Gravis in Dogs: 25 Cases (1988–1995)

The purpose of this project was to investigate the clinical forms of acquired myasthenia gravis in dogs. The medical records from 25 dogs with seropositive acquired myasthenia gravis were reviewed, and the following data were recorded for each patient: signalment, history, clinical findings; results of IV edrophonium chloride administration, repetitive nerve stimulation, and presence or absence of muscle membrane staining by immunocytochemical methods; serum acetyl-choline receptor antibody concentration; treatment; and outcome. Several clinical forms of acquired myasthenia gravis were identified. Nine of the 25 patients (36%) had no historical or clinical evidence of appendicular muscle weakness, and were designated as focal myasthenics. These dogs exhibited focal weakness in one or more of the following muscle groups: facial {3 of 9), pharyngeal (3 of 9), and laryn-geal (3 of 9). The remaining 16 dogs (64%) exhibited appendicular muscle weakness. Four of these 16 dogs had acute onset and rapid development of clinical signs, and were designated as acute fulminating myasthenics. The remaining 12 dogs were classified as generalized myasthenics. All 4 dogs with acute fulminating myasthenia gravis had megaesophagus, 2 had facial muscle weakness, and 1 had pharyngeal muscle weakness. Ten of the 12 dogs with generalized myasthenia gravis had megaesophagus, 4 had facial muscle weakness, 4 had pharyngeal muscle weakness, and 3 had laryngeal muscle weakness. Historical or clinical evidence of exercise-associated appendicular weakness was found in only 6 of the 12 (50%) dogs with generalized myasthenia gravis, and in none of the dogs with acute fulminating myasthenia gravis. Seven of the 12 dogs with generalized myasthenia gravis had weakness primarily (n = 1) or exclusively (n = 6) of the pelvic limbs. Two of the 4 dogs with acute fulminating myasthenia gravis had primarily pelvic limb weakness. Twelve of the 25 dogs (48%) died or were euthanized shortly after admission to the hospital due to aspiration pneumonia. The dogs with acute fulminating myasthenia gravis had a markedly higher 1-year mortality rate in comparison with the other 2 groups. The use of immunosuppressive therapy had a significant positive effect on patient survival, regardless of the type of myasthenia gravis. This investigation demonstrates that acquired myasthenia gravis in dogs is a disorder with a wide spectrum of clinical forms, similar to the analagous disorder in people.     

Oesophageal compliance in naturally occurring canine megaoesophagus

SUMMARY The passive blomechanical property of oesophageal compliance (OC) was measured in 8 naturally occurring cases of canine megaoesophagus, 8 matched control and 7 vagotomised control dogs. Of the 8 dogs with megaoesophagus, 6 had congenital Idiopathic megaoesophagus and 2 had secondary megaoesophagus attributable to generalised skeletal muscle disease. Stepwise distension of the whole oesophagus was employed for measurement of OC at the 4.0 and 8.0 mL/kg Injected volume steps within the control volume range (0 to 12.0 mL/kg). At both Injected volume steps OC was higher In megaoesophagus dogs than in either matched control or vagotomised control dogs (P / 0.01 In both cases), and no significant difference was observed In OC between matched control and vagotomised control dogs. No correlation was demonstrated between OC and the estimated duration of clinical signs of dogs with megaoesophagus. These findings suggest that In most cases of canine megaoesophagus the viscoelastic properties of the oesophageal wall are significantly altered, that In such cases the disorder is unlikely to be purely dynamic and that processes other than the duration of oesophageal dilatation are responsible for the alteration in oesophageal wall blomechanical properties. The relevance of these findings to current concepts on pathophysiological mechanisms underlying the evolution and resolution of various forms of canine megaoesophagus Is discussed.     

The neuropathic oesophagus. A radiographic and manometric study on the evolution of megaoesophagus in dogs with developing axonal neuropathy

Dogs given the neurotoxin acrylamide develop peripheral neuropathy and megaoesophagus. Sequential radiographic and manometric studies on the oesophagus demonstrated that the initial abnormalities consisted of a progressive decrease in the proportion of swallows that initiated peristalsis and a gradual increase in oesophageal calibre. Regurgitation, peristaltic failure and oesophageal dilatation all appeared within three days. The eating behaviour and gait abnormalities quickly resolved on stopping the neurotoxin, but the oesophagus remained dilated for longer. Previous studies have suggested that the abnormalities present in dogs which are developing a distal axonal neuropathy or in some dogs with idiopathic megaoesophagus may be limited to the proprioceptive elements of the oesophageal innervation. The present study suggests that the progressive inefficiency in the transmission of swallows and changes in oesophageal calibre in dogs with evolving megaoesophagus may be a consequence of damage to these proprioceptive elements.     

Adult onset acquired myasthenia gravis in three Great Dane littermates

Acquired canine myasthenia gravis is an autoimmune disease in which autoantibodies are directed against muscle postsynaptic nicotinic acetylcholine receptors. Three adult great dane littermates were evaluated over a four month time period for an acute onset of generalised neuromuscular signs. All three dogs had elevated serum acetylcholine receptor antibody titres, which were considered diagnostic for acquired myasthenia gravis. Identification of three littermates with acquired myasthenia gravis in a breed with a low relative risk of developing the disease suggests a familial and possibly a genetic predisposition to myasthenia gravis in this family of dogs.     

Autoimmune myasthenia gravis and dysautonomia in a dog

A two-year-old male entire border collie dog was evaluated for a short history of mixed bowel diarrhoea, coughing, vomiting and stranguria. Physical examination revealed dyspnoea with increased ventral lung sounds and a flaccidly distended bladder. Neurological examination revealed poor pupillary light reflexes, an absent gag reflex and a poor anal tone. Thoracic radiography was consistent with megaoesophagus and aspiration pneumonia. Clinicopathological testing revealed an elevated muscular nicotinic acetylcholine receptor antibody titre. The dog was euthanased because of clinical deterioration. Cerebrospinal fluid (CSF) collected immediately post-mortem revealed macrophagic pleocytosis. Post-mortem histopathological examination was consistent with dysautonomia. This is the first report of coexisting autoimmune myasthenia gravis and dysautonomia in a non-human species. The concomitant diseases may suggest a common immunopathological aetiology.     

Acquired myasthenia gravis: what we have learned from experimental and spontaneous animal models.

Acquired myasthenia gravis (MG) is a disorder of neuromuscular transmission in which muscle weakness results from an autoantibody mediated depletion of acetylcholine receptors (AChR) at the neuromuscular junction. Experimental autoimmune myasthenia gravis, described in rodents and rabbits, has provided a good model of the effects of the autoimmune response against AChR and has shown that the specificities of the immune response in MG are those that would be obtained by immunization with native AChR. It has provided little information, however, about what initiates and sustains the immune response in MG. Acquired MG occurs spontaneously in dogs and may be the most common neuromuscular disorder that can be diagnosed in this species. As in human MG, an autoimmune response against AChR has been demonstrated and AChR autoantibodies have been implicated in the pathogenesis. The variability in clinical presentation, methods of diagnosis, and occurrence with other autoimmune diseases and neoplasia are identical to that of humans. Future studies of spontaneous canine autoimmune MG may provide clues to the determination of what factors initiate and sustain the autoimmune response to AChR, and in the study of specific suppression of the autoimmune response against AChR.     

Myasthenia gravis associated with thymic neoplasia in a cat

Objective: To describe acute myasthenia gravis (MG) in the postoperative period following removal of a thymoma in an adult cat. Case summary: A 6‐year‐old spayed female domestic short haired cat weighing 6.4 kg was referred for workup and treatment of a cranial mediastinal mass. Thoracoscopic biopsies confirmed the diagnosis of thymoma. Median sternotomy was performed and approximately 95% of the mass was surgically excised. Postoperatively the cat became remarkably weak and hypercapneic. A presumptive diagnosis of MG was made following a positive response to edrophonium injection (Tensilon test). An elevated serum acetylcholine receptor antibody level was consistent with a diagnosis of MG. Initial treatment consisted of neostigmine, followed by corticosteroids and pyridostigmine. The cat responded well to therapy. New or unique information provided: This report describes a rare syndrome of postoperative weakness due to development of MG following incomplete removal of a thymoma. Post‐thymectomy weakness associated with MG has been reported in dogs and is not well described in cats.     

Titin and ryanodine receptor autoantibodies in dogs with thymoma and late-onset myasthenia gravis

Similar to human autoimmune myasthenia gravis (MG), canine MG occurs spontaneously and is associated with autoantibodies against the nicotinic acetylcholine receptor (AChR). In addition to AChR, human MG patients with thymoma or late-onset MG have antibodies against titin and ryanodine receptor (RyR). The objective of this study was to establish if dogs with confirmed MG (AChR antibody titer >0.6 nmol/l) also developed titin and RyR antibodies and identify possible associations with thymoma, late age of onset, or severity of clinical signs. Sera from dogs (n=430) with previously diagnosed autoimmune MG (N=415), other immune-mediated neuromuscular disorders including polymyositis (PM) and masticatory muscle myositis (N=5), and control dogs (N=10) were evaluated for the presence of titin antibodies in ELISA using MGT-30 as antigen, a peptide representing the main immunogenic region (MIR) for human titin antibodies. Titin antibody positive sera were further examined for RyR antibodies in Western blots using a RyR fusion protein (pc2-RyR) as antigen, which covers the MIR for human MG sera. Titin antibodies were found in sera of 80/430 dogs. Thymoma was present in 11/80 and age of onset was after 4 years in 66/80 titin positive dogs. Two of the titin positive dogs had PM. RyR antibodies were found in 13/80 sera (8/13 thymoma, 12/13 age of onset after 4 years, and 1/13 PM). Neither titin nor RyR antibodies were found in sera of healthy control dogs. Acute fulminating MG was described in five dogs with both titin and RyR antibodies. From these studies we conclude that titin and RyR antibodies in canine and human MG have a similar association with thymoma, late-onset MG, and possibly with more severe forms of MG.     

Myasthenia gravis and disorders of neuromuscular transmission.

Myasthenia gravis is a disorder of neuromuscular transmission that occurs in congenital and acquired autoimmune forms. Acquired myasthenia gravis is probably the most common neuromuscular disorder in dogs that can be diagnosed and treated. An early, accurate diagnosis and appropriate therapy is of utmost importance to a good clinical outcome in this disorder. This article focuses on the diagnosis and treatment of acquired myasthenia gravis in dogs and cats with brief discussions of other disorders of neuromuscular transmission, including congenital myasthenia gravis, tick paralysis, botulism, and organophosphate intoxication.     

Diseases of the horse: the centennial of a great book

A 7-year-old Saint Bernard developed muscular weakness 1 year after right forelimb amputation and adjuvant cisplatin chemotherapy for osteogenic sarcoma. Clinical and laboratory findings supported a diagnosis of myasthenia gravis, and the dog had clinical improvement in response to prednisone treatment. Two additional dogs with myasthenia gravis and osteogenic sarcoma were identified by review of the medical records of the University of California Veterinary Medical Teaching Hospital. Findings indicated that myasthenia gravis or other neuromuscular transmission disorders may be associated with muscular weakness in dogs with osteogenic sarcoma.     

Myasthenia gravis: lessons from the past 10 years

Over the past 10 years, significant advances have been made in our understanding of acquired myasthenia gravis (MG) in companion animals. The broad spectrum of presenting clinical signs has been defined and an accurate and sensitive diagnostic test is available. Even with these advances, the mortality rate in dogs with acquired MG remains unacceptably high. While an understanding of the genetic basis for susceptibility to autoimmune disease has started to be developed, the trigger for the initiation of this disease is not known and a mechanism for specific suppression of the aberrant immune response against the acetylcholine receptor remains a mystery.     

Azathioprine therapy for acquired myasthenia gravis in five dogs.

Five dogs with acquired myasthenia gravis (MG), verified via positive serum acetylcholine (ACh) receptor antibody concentrations, were treated with a drug protocol including azathioprine (AZA). Four of the five dogs were concurrently treated with pyridostigmine. Azathioprine was used as the sole immunosuppressive agent in four dogs. One dog was temporarily treated with a combination of an immunosuppressive dose of prednisone and AZA, then maintained on AZA as the sole immunosuppressive drug. Three patients experienced complete remission of clinical signs within three months of therapy. In the four dogs for which follow-up serum ACh receptor antibody concentrations were available, initial versus final concentrations decreased substantially (81%), coincident with clinical improvement. One dog died suddenly due to a suspected myasthenic crisis before attaining the target dose of AZA. Two of the four surviving dogs were euthanized approximately one and seven years after diagnosis. One of these two dogs was euthanized because of a rib osteosarcoma, and the other dog was euthanized because of paraparesis of undetermined cause. The remaining two dogs were alive and doing well at the time of final follow-up evaluation, approximately six months and one year after diagnosis. The use of AZA as a therapeutic agent for acquired canine MG has not been investigated. The cases presented in this report suggest a potentially important role for AZA in the treatment of acquired MG in dogs.     

Acquired myasthenia gravis associated with a non-invasive thymic carcinoma in a dog

An 8 1/2-year-old neutered male Beagle was diagnosed with acquired myasthenia gravis associated with a non-invasive thymic carcinoma. The thymic mass was surgically excised and the dog was treated with pyridostigmine, prednisolone and azathioprine. Serial acetylcholine receptor antibody titres were increased initially but slowly declined to normal values over a period of 24 weeks. Improved exercise tolerance was seen following therapy, however, oesophageal dysfunction persisted. The dog was euthanased 26 weeks after initial presentation due to a complicating illness. A necropsy showed no regrowth or metastasis of the thymic carcinoma.     

Mitogen stimulation of canine normal and myasthenia gravis lymphocytes

Responses of canine lymphoid tissues to mitogens were studied in five normal dogs and in two dogs with acquired myasthenia gravis (MG). In the normal dogs, lymph-node-derived lymphocytes gave the most consistent proliferative responses to concanavalin A (Con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM), as determined by thymidine incorporation; and in most cases PHA, lipopolysaccharide (LPS), and PWM stimulated total IgG production, as determined by ELISA. Splenic lymphocytes had the greatest capacity for increased total IgG production. In the myasthenic dogs total IgG production by unstimulated lymph-node-derived lymphocytes was 88 micrograms/ml and 153 micrograms/ml, much higher than that of unstimulated normal dog lymphocytes (mean less than 1.0 microgram/ml). All mitogens resulted in suppression rather than stimulation of IgG production by lymphocytes from dogs with MG. Production of antibodies to acetylcholine receptors (AChRs) was detected in the supernatants of lymphocyte cultures from one of the dogs with MG at a rate of 78 fmol/5 x 10(5) cells per week and was not detected in culture supernatants of control dogs. This study demonstrates that lymph nodes may be an important site of antibody production in myasthenic dogs and provides the necessary groundwork for future studies of the cellular immunology of canine MG.     

Use of mycophenolate mofetil as a rescue agent in the treatment of severe generalized myasthenia gravis in three dogs

Objective – To describe the use of IV and oral mycophenolate mofetil (MMF) as adjunctive therapy in 3 dogs with severe generalized myasthenia gravis.
Case Series Summary – Three dogs suffering from severe generalized myasthenia gravis as confirmed by acetylcholine antibody titers were treated with MMF as part of their treatment regimens. All 3 dogs had radiographic evidence of megaesophagus and suffered from severe regurgitation. Each dog was initially treated with pyridostigmine and supportive agents. When clinical remission was not achieved, IV MMF was administered to all dogs. Signs of clinical remission were apparent within 48 hours and all dogs were later maintained on oral MMF following resolution of regurgitation.
New or Unique Information Provided – This is the first report of the use of IV MMF as adjunctive treatment in dogs with severe generalized myasthenia gravis. Outcome was favorable in all 3 dogs and no adverse effects were noted from the MMF.