Classification of myasthenia gravis and congenital myasthenic syndromes in dogs and cats

Myasthenia, a syndrome of impaired neuromuscular transmission, occurs as either an acquired or congenital condition. Myasthenia gravis (MG) is an acquired autoimmune disorder with autoantibodies against the neuromuscular junction (NMJ) of skeletal muscle whereas congenital myasthenic syndromes (CMSs) are a clinically heterogeneous group of genetic disorders affecting the NMJ with a young age of onset. Both conditions are diseases for which recognition is important with regard to treatment and outcome. We review the published literature on MG and CMSs in dogs and cats, and by comparison with published classification used in humans, propose a classification system for MG and CMSs in dogs and cats. Myasthenia gravis is first classified based on focal, generalized, or acute fulminating presentation. It then is subclassified according to the autoimmune disease mechanism or seronegativity. Autoimmune disease mechanism relates to the presence or absence of a thymoma, or administration of thiourylene medication in cats. Congenital myasthenic syndromes are classified according to the affected NMJ component, the mechanism of the defect of neuromuscular transmission, the affected protein, and ultimately the mutated gene responsible. In proposing this categorization of MG and CMSs, we hope to aid recognition of the disease groups for both conditions, as well as guide treatment, refine prognosis, and provide a framework for additional studies of these conditions.     

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.     

Application of therapeutic plasma exchange in dogs with immune-mediated thrombocytopenia

Therapeutic plasma exchange (TPE) is an emerging treatment for dogs with immune-mediated diseases, but reports for treatment of immune-mediated thrombocytopenia (IMT) are lacking. These case reports illustrate the application of centrifugal TPE in 4 dogs with IMT. All dogs presented with severe hemorrhage requiring ≥1 blood transfusions, were unresponsive to conventional treatment or both. Dogs were treated with 3 sequential centrifugal TPE sessions, totaling 4.0 to 4.9 total plasma volumes exchanged per dog. In 3 dogs, TPE was associated with improvement in clinical manifestations of bleeding and platelet count in combination with immunosuppressive drugs. One dog was euthanized after 3 treatments because of persistent severe thrombocytopenia and hemorrhage. Preliminary observations indicate that TPE is safe and may be a useful adjunct in the management of IMT that is severe or refractory to traditional treatment.     

Preliminary investigation of blood concentrations of insulin‐like growth factor,insulin, lactate and β‐hydroxybutyrate in dogs with lymphoma as compared with matched controls

It is well established that tumour cells have metabolic differences when compared with normal cells. This is particularly true for energy metabolism in which dogs with cancer have been reported to have higher blood insulin and lactate concentrations than control dogs. Moreover, some human and animal studies suggest that the insulin‐like growth factor 1 (IGF‐1) signalling pathway may play a role in tumorigenesis and tumour progression. At present, IGF‐1 has not been evaluated in dogs with multicentric lymphoma. In this prospective, cross‐sectional study, blood levels of IGF‐1, as well as other markers of energy metabolism—insulin, glucose, lactate, and β‐hydroxybutyrate—were measured in 16 dogs with histologically or cytologically confirmed treatment‐naïve lymphoma. These results were compared with 16 age‐, sex‐ and weight‐matched healthy controls. Dietary histories were collected, and protein, fat and carbohydrate intake were compared between groups. Results demonstrated that IGF‐1, insulin, glucose and insulin:glucose ratio were not different between groups. However, lactate and β‐hydroxybutyrate were higher in the dogs with lymphoma than that in the control dogs (1.74 ± 0.83 mmoL/L vs 1.08 ± 0.27 and 2.59 ± 0.59 mmol/L vs 0.77 ± 0.38 mmol/L, respectively). Median dietary protein, fat and carbohydrates did not differ between the groups. This preliminary study suggests that higher insulin and IGF‐1 levels relative to controls may not be a consistent finding in dogs with lymphoma. The significance of increased β‐hydroxybutyrate in dogs with lymphoma warrants further investigation in a larger prospective study.     

Evaluation of initial plasma lactate values as a predictor of gastric necrosis and initial and subsequent plasma lactate values as a predictor of survival in dogs with gastric dilatation‐volvulus: 84 dogs (2003–2007)

Objective – To test whether an initial plasma lactate≥6.0 mmol/L is associated with the presence of macroscopic gastric wall necrosis and overall survival in dogs presenting with gastric dilatation‐volvulus (GDV). Additionally, if no association was identified we sought to identify a different predictive initial plasma lactate concentration and to examine whether serial plasma lactate concentrations provide better prediction of survival. Design – Retrospective study over a 5‐year period (2003–2007). Setting – Urban private referral small animal teaching hospital. Animals – Eighty‐four client‐owned dogs with a diagnosis of GDV and plasma lactate measurements. Interventions – None. Measurements and Main Results – There was no statistically significant relationship found between survival and the presence of macroscopic gastric wall necrosis with the initial plasma lactate≥6 mmol/L. There was a significant relationship between the initial plasma lactate >2.9 mmol/L for predicting necrosis and <4.1 mmol/L for predicting survival to discharge. Forty dogs that had an increased initial plasma lactate (>2.5 mmol/L) also had a subsequent plasma lactate measured within 12 hours of presentation, with 37/40 dogs surviving and 70% of these surviving dogs having the subsequent lactate decrease by≥50% within 12 hours. The 3/40 that died failed to decrease their plasma lactate by≥50% from the initial blood lactate. Conclusion – The results of this study indicate that an initial presenting plasma lactate concentration≥6.0 mmol/L is not predictive of macroscopic gastric wall necrosis or survival in dogs presenting with GDV. A decrease in plasma lactate concentrations≥50% within 12 hours may be a good indicator for survival. Limitations to the study include its retrospective nature, the small number of patients, and the number of dogs that were euthanized rather than allowed to progress to a natural outcome.     

Congenital Myasthenic Syndrome in the Dog Breed Gammel Dansk Hønsehund: Clinical,Electrophysiological, Pharmacological and Immunological Comparison with Acquired Myasthenia gravis

The effect of anticholinesterase drugs on the clinical and electrophysiological features in a canine congenital myasthenic syndrome is compared with findings in acquired myasthenia gravis in dogs. Anticholinesterase treatment had no effect on muscle weakness or electrophysiological parameters in the congenital myasthenic syndrome in contrast to its effect on clinical signs and electrophysiological parameters in acquired myasthenia gravis. The lack of effect of anticholinesterase in congenital myasthenia suggests a presynaptic defect as the aetiological factor. No antibodies to acetylcholine receptors were found in the Danish dog breed Gammel Dansk Hønsehund with the myasthenic syndrome. This classifies the disease in the group of canine and human congenital myasthenic diseases.     

Myasthenia gravis in dogs with an emphasis on treatment and critical care management

Objective – To review the human and veterinary literature on the pathophysiology of myasthenia gravis (MG) and describe treatment options for clinical use in people and animals. Data Sources – Human and veterinary clinical reports, studies and reviews, textbooks, and recent research findings in MG from 1996 present, with a focus on treatment and patient management. Human Data Synthesis – MG is a well‐described condition in people with new research and treatment options available. Many of the newest therapeutic options available in veterinary medicine for MG are based on current strategies used in people with this condition. Seronegative MG is well described in people and provides insight to clinical cases encountered in veterinary medicine when the index of suspicion is high though serologic tests are negative. Veterinary Data Synthesis – Previous studies in veterinary medicine focused on the use of acetylcholinesterase inhibitors as the main form of treatment in canine MG. Recent studies, mainly case series and case reports, emphasize the use of immunomodulatory treatments as an alternative for long‐term treatment. However, there are no randomized, controlled studies on treatment with immunomodulatory therapy for MG in dogs available to assess the efficacy of this treatment strategy. Conclusions – Although early recognition of clinical signs is most important in the outcome of patients with MG, further understanding the pathophysiology of MG may lead to earlier diagnosis and novel treatment strategies. The discovery of additional autoantibodies against striated muscle proteins in dogs, should enhance our understanding of diseases affecting the neuromuscular junction. In addition, clinical data for canine MG could be applied to other autoimmune disorders.     

Definitive‐intent intensity‐modulated radiation therapy provides similar outcomes to those previously published for definitive‐intent three‐dimensional conformal radiation therapy in dogs with primary brain tumors: A multi‐institutional retrospective study

Radiotherapy with or without surgery is a common choice for brain tumors in dogs. Although numerous studies have evaluated use of three‐dimensional conformal radiotherapy, reports of definitive‐intent, IMRT for canine intracranial tumors are lacking. Intensity‐modulated radiation therapy has the benefit of decreasing dose to nearby organs at risk and may aid in reducing toxicity. However, increasing dose conformity with IMRT calls for accurate target delineation and daily patient positioning, in order to decrease the risk of a geographic miss. To determine survival outcome and toxicity, we performed a multi‐institutional retrospective observational study evaluating dogs with brain tumors treated with IMRT. Fifty‐two dogs treated with fractionated, definitive‐intent IMRT at four academic radiotherapy facilities were included. All dogs presented with neurologic signs and were diagnosed via MRI. Presumed radiological diagnoses included 37 meningiomas, 12 gliomas, and one peripheral nerve sheath tumor. One dog had two presumed meningiomas and one dog had either a glioma or meningioma. All dogs were treated in the macroscopic disease setting and were prescribed a total dose of 45‐50 Gy (2.25‐2.5 Gy per fraction in 18‐20 daily fractions). Median survival time for all patients, including seven cases treated with a second course of therapy was 18.1 months (95% confidence of interval 12.3‐26.6 months). As previously described for brain tumors, increasing severity of neurologic signs at diagnosis was associated with a worse outcome. Intensity‐modulated radiation therapy was well tolerated with few reported acute, acute delayed, or late side effects.     

Proof-of-concept study: Evaluation of plasma and urinary electrolytes as markers of response to L-asparaginase therapy in dogs with high-grade lymphoma

Response to chemotherapy is one of the most important prognostic factors in dogs with lymphoma. The objective of this feasibility study was to evaluate if clinical responses to a specific cytotoxic agent (L-asparaginase) could be anticipated by measuring analyte concentrations in plasma and urine concentrations of lymphoma-bearing dogs. We hypothesized that potassium and phosphate concentrations in plasma and urine would be higher in dogs that completely responded to therapy. Plasma and urine samples of dogs with lymphoma were obtained before 12 and 24 hours after intramuscular L-asparaginase injections. Peripheral lymph node volumes were evaluated according to the Veterinary Cooperative Oncology Group standardized criteria. Plasma and urine electrolyte, calcium, phosphate, creatinine, urea, total protein, and albumin concentrations were measured, and the fractional excretions of each electrolyte were calculated. Statistical analyses compared complete vs partial responders using a linear regression model. Contrast analyses were also performed to differentiate the mean of each group, with adjustments made with the Benjamini-Hochberg procedure. Fourteen dogs were included, eight with complete responses, and six with partial responses. Plasma phosphate concentrations were significantly higher at 12 hours (P = .0003) and 24 hours (P = .009) after complete responses to therapy. This study demonstrates the potential use of plasma and urine analyte monitoring after chemotherapy induction. Plasma phosphate measurements represent a potential indicator of early responses to L-asparaginase therapy. Larger population studies are warranted to confirm these preliminary results.     

Therapeutic effects of vitamin E supplementation in 4 dogs with poor semen quality and low superoxide dismutase activity in seminal plasma

Four dogs with poor semen quality, low seminal plasma superoxide dismutase (SOD) activity and low blood plasma testosterone (T) levels were orally administered one vitamin E tablet containing 50 mg α-tocopheryl acetate per dog daily for 4 weeks. The mean values of semen quality were temporarily improved after the start of vitamin E treatment and the values of 4, and 5 weeks after that were significantly different from those before the treatment (P<0.05–0.001). The mean blood plasma T and seminal plasma SOD activity values slightly increased in the 4 dogs after the treatment. The results of the present study indicate that poor semen quality in dogs with low seminal plasma SOD can be improved by vitamin E treatment.