Suspected Fluoroquinolone-Induced Exacerbation of Myasthenia Gravis in Dogs.

Acquired myasthenia gravis (MG) in dogs can present with focal or generalized weakness and is diagnosed by the presence of circulating antibodies to the acetylcholine receptor. Megaesophagus is the most common focal form of MG. Although exacerbation of MG has been associated with the use of fluoroquinolones in humans, it has not been previously described in dogs. The medical records of 46 dogs diagnosed with MG based on acetylcholine receptor antibody testing from 1997 to 2021 were retrospectively evaluated to identify any dogs who demonstrated exacerbation of MG after the administration of a fluoroquinolone. Exacerbation of MG, from focal to generalized, occurred in a median of 4.5 days after initiation of fluoroquinolone therapy in six dogs. In addition, one dog with generalized MG and megaesophagus developed pyridostigmine resistance subsequent to fluoroquinolone therapy. Marked improvement in generalized weakness was reported 36 hr after discontinuation of fluoroquinolone therapy alone in one dog and in combination with pyridostigmine in two dogs. Fluoroquinolone therapy was never stopped in three dogs who were euthanized because of severe weakness and one dog who died of respiratory arrest.

Acquired myasthenia gravis with concurrent polymyositis and myocarditis secondary to a thymoma in a dog.

Background: Canine thymomas are associated with multiple paraneoplastic syndromes, among which myasthenia gravis (MG) is the most common. Acquired MG is an autoimmune disease characterized by the presence of antibodies against acetylcholine receptors (ACHRs). ACHRs antibodies are the most commonly formed, but the production of antistriational antibodies binding to skeletal and cardiac muscle proteins has also been recorded both in humans and dogs. An association between the occurrence of antistriational antibodies and a severe form of myocarditis, giant cell myocarditis, has been described in humans. Case Description: A 4-year-old mixed-breed dog was referred because of 1 month history of exercise-induced weakness, hypersalivation, and regurgitation. The neurologic examination was indicative of a neuromuscular junction disease, and MG was suspected. A computed tomographic scan examination showed the presence of a megaoesophagus and a thymic mass. Serum antibodies against ACHRs confirmed the diagnosis of MG. Treatment with pyridostigmine was started, and the thymic mass was surgically excised, and a diagnosis of thymoma was confirmed by histology. 24 hours after surgery, the dog developed a third-degree atrioventricular block. Severe arrhythmia and increased troponin serum levels suggested myocarditis which rapidly led to cardiopulmonary arrest. Histopathologic examination of the heart, esophagus and diaphragm revealed a lymphocytic and macrophagic infiltration, consistent with myocarditis and polymyositis. Scattered rare giant multinucleated cells were also detected in the myocardium. Conclusion: To the author's knowledge, this is the first report of thymoma-associated MG with concurrent polymyositis and giant cell-like myocarditis in a dog.

Clinical features and outcome of acquired myasthenia gravis in 94 dogs.

BACKGROUND: Factors known to be associated with outcome of acquired myasthenia gravis (MG) in dogs are limited. HYPOTHESIS/OBJECTIVES: Of dogs with MG, advancing age and comorbid neoplasia are associated with poor long-term prognosis and low rates of remission. ANIMALS: Ninety-four client-owned dogs with MG diagnosed by acetylcholine receptor antibody (AChR Ab) assay between 2001 and 2019 from a university clinic and 3 private clinics in the United States. METHODS: Cases were retrospectively evaluated and data were collected to determine clinical signs, treatment, and response to therapy defined by means of a clinical scoring rubric. Immunological remission was defined as a return of the AChR Ab concentration to <0.6 nmol/L. Multivariable binary logistic regression analysis was used to identify clinical criteria predicting remission. RESULTS: An anticholinesterase drug was used to treat 90/94 (96%) dogs, which in 63/94 (67%) was the sole treatment; other drugs included immune modulators. Clinical remission (lack of clinical signs ≥4 weeks after treatment cessation) was observed in 29 (31% [95% confidence interval (CI): 22.4-40.8%]) dogs, clinical response (lack of clinical signs on treatment) in 14 (15% [95% CI: 9.0-23.6%]) dogs, clinical improvement (on treatment) in 24 (26% [95% CI: 17.8-35.2%]) dogs, and no clinical improvement in 27 (29% [95% CI: 20.5-38.6%]) dogs. Immunological remission was observed in 27/46 (59%) dogs, with clinical remission in all 27. Younger age (P = .04) and comorbid endocrine disease (P = .04) were associated with clinical remission. Initial AChR Ab concentration (P = .02) and regurgitation (P = .04) were negatively associated with clinical remission. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical remission in MG is less likely in older dogs and dogs presenting with regurgitation or high initial AChR Ab concentration, but more likely in younger dogs and dogs with comorbid endocrine disease.

The clinical utility of neostigmine administration in the diagnosis of acquired myasthenia gravis.

OBJECTIVE: To assess the clinical utility of neostigmine methylsulfate administration in the diagnosis of suspected acquired myasthenia gravis (MG) in dogs and cats. DESIGN: Retrospective study (2017-2019). SETTING: Five university teaching hospitals and 2 private referral hospitals. ANIMALS: Twenty-two dogs and 3 cats. Criteria for inclusion were clinical signs consistent with acquired MG, performance of a neostigmine challenge and acetylcholine receptor antibody titers. INTERVENTIONS: None. MEASUREMENTS & MAIN RESULTS: The route of neostigmine administration was recorded. Response to neostigmine challenge was determined via sequential evaluation of muscle strength and ambulation following administration of neostigmine methylsulfate. Response to neostigmine challenge was compared to acetylcholine receptor antibody titers, which were used as the biochemical gold standard in this study. Sixteen out of 22 dogs were diagnosed with acquired MG. Thirteen of 16 had a strong positive response to neostigmine challenge whereas 3 of 16 had no response. Two out of 3 dogs with polymyositis also had a strong positive response to neostigmine challenge. Weak positive results were seen with intracranial neoplasia (n = 1) and a dog with dilated cardiomyopathy and coxofemoral joint disease (n = 1). One cat was diagnosed with acquired MG and had a positive response to neostigmine challenge. Two cats had no response to neostigmine challenge and were diagnosed with alternate conditions. Two cats were premedicated with glycopyrrolate, one of which had a mild adverse response to neostigmine challenge (sialorrhea and mild transient tremors). Three out of 22 dogs had minimal adverse effects (sialorrhea and 1 dog with muscle tremors). CONCLUSIONS: The neostigmine challenge appears to be safe and viable alternative to the previously utilized edrophonium challenge, particularly when weak positive responses are considered negative for acquired MG. Polymyositis cases may have a false positive response to neostigmine challenge.

Therapeutic plasma exchange as adjunct therapy in 3 dogs with myasthenia gravis and myasthenia-like syndrome.

OBJECTIVE: To describe the use of therapeutic membrane-based plasma exchange (TPE) for treatment of clinical signs associated with suspected acquired myasthenia gravis (MG) in 3 dogs. CASE SERIES SUMMARY: Three dogs presented with clinical signs consistent with acquired MG. All 3 dogs were medically managed prior to being treated with TPE. Two of the 3 dogs had increased acetylcholine receptor antibody titers that decreased after TPE. One dog diagnosed with primary MG became clinically normal after 2 sessions of TPE and continued to do well with medical management several months later. The second dog was diagnosed with a suspect thymoma, and TPE was performed as a bridge to surgery, with marked improvement of clinical signs after TPE. The dog was ultimately diagnosed with a thymic carcinoma. The third dog had a positive acetylcholine antibody titer and was ultimately diagnosed with hemangiosarcoma (spleen and liver) and invasive mediastinal thymoma. This dog developed severe pneumonia, was ventilator dependent, and died of multiple organ dysfunction. No immediate complications were observed secondary to TPE. All 3 dogs were concurrently treated with either immunosuppressive agents, anticholinesterase drugs, or both. NEW OR UNIQUE INFORMATION PROVIDED: The use of TPE in dogs with MG appears to be well tolerated and safe. It may be a reasonable adjunct therapy to acetylcholinesterase drugs in cases that are not responding to medical management alone. Therapeutic plasma exchange might also be considered preoperatively to prevent postoperative complications in dogs with severe MG, although further studies should be performed.

Myeloid-derived suppressor cell and regulatory T cell frequencies in canine myasthenia gravis: A pilot study.

Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated autoimmune disease. Little is known about its cellular pathogenesis in dogs. This study provides the first preliminary assessment of the frequency of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the peripheral blood of dogs with seropositive generalized MG. No alteration in frequency of either MDSCs or Tregs in dogs with MG was observed when compared to those in either seronegative dogs with diagnoses other than MG, or healthy dogs. A longitudinal study in three dogs with MG revealed no correlation between the relative numbers of either population and the clinical course of disease. Neither the frequency of MDSCs nor of Tregs showed a correlation with anti-AChR antibody titer in dogs with MG. These findings suggest that aberrations in the frequency of either immunosuppressive population do not occur in MG, but they need to be validated in large-scale prospective studies.

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.

Long-term outcome of cats with acquired myasthenia gravis without evidence of a cranial mediastinal mass.

BACKGROUND: Acquired myasthenia gravis (AMG) is increasingly recognized in cats, yet information regarding the natural history of the disease, treatment, and outcome including occurrence of immune and spontaneous remission remains limited. OBJECTIVE: To determine the long-term outcome of cats with AMG without evidence of a cranial mediastinal mass (CMM). ANIMALS: Eight cats diagnosed with AMG without evidence of a CMM. METHODS: Retrospective case series. The medical records of cats diagnosed with AMG between 2005 and 2018 from 2 veterinary referral hospitals were reviewed for inclusion. Inclusion criteria consisted of a diagnosis of AMG, thoracic imaging, serum biochemistry including measurement of creatine kinase, and a CBC. Exclusion criteria were the presence of an identifiable CMM, or administration of methimazole or carbimazole. RESULTS: All cats had an excellent long-term outcome, achieving immune remission within 6 months of diagnosis, including 4 cats that did not receive any treatment and whose natural course of disease involved spontaneous remission. Clinical presentation was heterogeneous, and skeletal muscle weakness and fatigability induced or exacerbated by the wheelbarrow exercise stress test were the most consistent abnormalities associated with AMG. CONCLUSION AND CLINICAL IMPORTANCE: Cats diagnosed with AMG without evidence a CMM have a favorable outcome and frequently achieve immune remission. Moreover, the natural history of AMG in cats includes spontaneous remission when there is no evidence of a CMM. Attempting to rule out the presence of a CMM therefore refines prognosis, and treatment is not always necessary in this disease population.

Clinical and serologic remission of acquired myasthenia gravis in a domestic ferret (Mustela putorius furo).

CASE DESCRIPTION: A 4.5-year-old neutered male domestic ferret (Mustela putorius furo) was examined because of clinical signs compatible with neuromuscular disease. CLINICAL FINDINGS: Results of electrophysiologic assessment, including measurement of compound muscle action potentials following repetitive nerve stimulation, and measurement of the anti-acetylcholine receptor antibody titer were consistent with a diagnosis of acquired myasthenia gravis. TREATMENT AND OUTCOME: Medical treatment with pyridostigmine and prednisolone was instituted. The first signs of clinical improvement were observed 2 months later, followed by a slow but steady improvement over the next months. Anti-acetylcholine receptor antibody titer was measured 10 months after initiation of treatment and was markedly decreased, compared with the initial titer. Pyridostigmine and prednisolone dosages were tapered over the following 4 months without any evidence of recurrence of clinical signs. Thirty months after initial examination, the ferret was clinically normal and not receiving any treatment. A follow-up anti-acetylcholine receptor antibody titer was similar to previously published values for healthy ferrets. CLINICAL RELEVANCE: Findings indicated that clinical and serologic remission can be achieved in ferrets with myasthenia gravis. However, owner willingness to provide extensive supportive care was vital to the outcome for this patient, as was the owner's decision to not euthanize the ferret despite an initial lack of response to treatment.

Clinical features and prognosis of canine megaesophagus in Japan.

Megaesophagus (ME) is a common esophageal disease in dogs and the prognosis is generally poor, especially with aspiration pneumonia (AP). We retrospectively investigated the clinical features and prognosis of canine ME in Japan. Twenty-eight dogs were included in this study, with the Miniature Dachshund breed being significantly overrepresented (odds ratio: 4.33). Most cases (21 of 28) were diagnosed as idiopathic ME and Myasthenia gravis was the most common cause of secondary ME. The overall median survival time (MST) was not reached and the 3-month survival rate was 85.7%. Ten dogs were diagnosed with AP, at least once during the study period, and the MST of ME dogs with AP was 114 days. The survival time overall and even with AP, was notably more prolonged compared to the previous studies. We hypothesized that treatment for canine ME could prolong the survival time, even in those with both ME and AP.

Evaluation of coexisting polymyositis in feline myasthenia gravis: A case series.

Acquired myasthenia gravis (MG) is relatively uncommon in cats. In humans, MG may be associated with other immune-mediated disorders, in particular polymyositis (PM). In this study, we described in-depth electrodiagnostic findings and pathological changes in muscles of cats diagnosed with MG, and assessed the presence of concurrent PM. Six cats with confirmed acetylcholine receptor antibody seropositive MG, and two suspected cases with clinical signs and electrophysiological changes consistent with MG, were reviewed. All animals presented with severe typical signs of generalized weakness and/or fatigability, resembling late-onset MG in humans, in addition to regurgitation. Five cats presented a cranial mediastinal mass, with 3 confirmed as thymoma. Repetitive nerve stimulation revealed a decrement of the compound muscle action potential in all tested cases, starting from low frequencies of stimulation. Serum creatine kinase activity was increased in 6/8 cats. Muscle biopsies performed in 5 cats revealed varying degrees of mixed mononuclear cell infiltrates, positive for the leukocyte markers CD3/CD4/CD8 and CD11b. Further MHC-1/C5b-9 positive sarcolemmal deposits were identified in all tested cases, with or without thymoma. This study documents an association of MG and PM in cats, and provides further support for feline MG as a relevant animal model of human MG.

Association of early onset myasthenia gravis in Newfoundland dogs with the canine major histocompatibility complex class I.

Acquired Myasthenia Gravis (MG) is an autoimmune neuromuscular disorder whose development in humans has been associated with the Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA). There is a form of early onset MG (EOMG) in Newfoundland dogs that mimics the clinical presentation in humans and appears to have familial inheritance. Genotyping of three classical Dog Leukocyte Antigen (DLA) class II genes, DLA-DRB1, DLA-DQA1 and DLA-DQB1, in 16 Newfoundlands with EOMG and 46 unaffected Newfoundlands, identified DLA-DQB1 *00301 (p-value = 0.0051 OR: 7.41) as a risk locus for the development of EOMG in this breed. In order to further investigate the extent of the association to the entire MHC region, 208 additional SNPs were genotyped in two phases. Both a risk locus for EOMG to the DLA class I (chr12: 458483-506460) and a protective locus for EOMG susceptibility that extends outside of the DLA class I (chr12: 89701-475348) were identified. Four additional dog breeds with an elevated risk for the development of MG were SNP genotyped, but no shared or significant associations were found. MHC involvement in canine MG disease manifestation overlaps with loci identified in human studies and highlights the value of dogs as a model for genetic studies of naturally occurring diseases.

Temporal deterioration of neurological symptoms and increase of serum acetylcholine receptor antibody levels after thymectomy: a case report of a cat with myasthenia gravis.

Neurological signs and serum acetylcholine receptor antibody (AChR-Ab) levels before and after thymectomy were monitored in a 6-year-old male cat with acquired Myasthenia Gravis (MG) as a paraneoplastic syndrome of thymoma. Soon after surgery, the neurological symptoms relapsed, and the cholinesterase inhibitor was administered to control them. The AChR-Ab levels increased postoperatively until 90 days after surgery. This is the first report on long term measurements of serum AChR-Ab levels in a cat with MG. Although thymectomy is valuable for the removal of thymoma, it may not resolve MG symptoms, neurological signs and serum AChR-Ab levels, without medication early after surgery. Also, this case report indicates that the AChR-Ab level might be a guide to detect a deterioration of MG symptoms.

Video-Assisted Thoracoscopic Resection of a Noninvasive Thymoma in a Cat with Myasthenia Gravis Using Low-Pressure Carbon Dioxide Insufflation.

OBJECTIVE: To report the use of low-pressure carbon dioxide insufflation during video-assisted thoracoscopic surgery for resection of a noninvasive thymoma in a cat with secondary myasthenia gravis. STUDY DESIGN: Clinical case report. ANIMAL: Client-owned cat. METHODS: An 11-year-old castrated male domestic shorthair cat was examined for generalized weakness, voice change, hypersalivation, hyporexia, vomiting, coughing, and gagging. Thoracic ultrasound revealed a cranial mediastinal mass for which cytology was consistent with a thymoma (or lymphoid tissue). Acetylcholine receptor antibody concentration was elevated at 3.16 mmol/L (reference interval < 0.3 mmol/L). Thoracic computed tomography showed two round, contrast-enhancing structures in the cranioventral mediastinum identified as the sternal lymph node and a cranial mediastinal mass (11 × 17 × 24 mm). A presumptive diagnosis of thymoma with paraneoplastic myasthenia gravis was made and surgical resection of both mediastinal masses was recommended. RESULTS: Video-assisted thoracoscopic resection of the cranial mediastinal mass and sternal lymph node were performed with low-pressure carbon dioxide insufflation maintained at an intrathoracic pressure of 2-3 mmHg. The cat recovered from surgery without serious complications. Nineteen months after surgery, the cat developed hind limb stiffness. Thoracic radiographs ruled out a cranial mediastinal mass or megaesophagus. Acetylcholine receptor antibody concentration remained elevated at 2.72 mmol/L. CONCLUSION: Low-pressure thoracic insufflation facilitated video-assisted thoracoscopic resection of cranial mediastinal masses in this cat.

Acute idiopathic polyradiculoneuritis concurrent with acquired myasthenia gravis in a West Highland white terrier dog.

BACKGROUND: Acute Idiopathic Polyradiculoneuritis, an animal model for the axonal form of the Guillain - Barre Syndrome in humans and the acquired myasthenia gravis are different autoimmune disorders affecting the peripheral nerves and the neuromuscular junction, respectively. Both lead to muscle weakness and possible respiratory failure. The coexistence of these two entities combined in the same patient is rare in humans and, to our knowledge, the present case is the first reported in dogs. CASE PRESENTATION: An 11-year-old West Highland WhiteTerrier female dog was referred to our clinic with a history of symmetrical weakness beginning with the pelvic limbs and evolving cranially, progressing to non-ambulatory flaccid tetraparesis over the preceding week. The history did not reveal signs of a recent other illness, trauma or exposure to a neurotoxin or raccoon bite. The last vaccination was carried out 5 months before presentation. Upon clinical examination, spinal reflexes and postural reactions were decreased in all four limbs and became absent within the following 24 h; perineal reflex was normal, and loss of voice was observed. The patient maintained its ability to urinate and defecate and it had no difficulty to eat or to drink. There were no cerebellar or sensory deficits. The electrophysiological findings revealed positive sharp waves and complex repetitive discharges on the electromyogram, temporal dispersion of compound muscle action potentials associated with polyphasia and a slow motor nerve conduction velocity as signs of demyelination, and an increased latency of F-waves. The cerebrospinal fluid had a normal cellularity with increased protein content. A reduction by 18 % in the amplitudes of the third compound muscle action potential as compared to the first one was observed during a repetitive nerve stimulation, indicating a postsynaptic disturbance. Only the motor electrophysiology was considered in this study. The diagnosis was based on clinical and electrophysiological findings associated with a positive titer for acetylcholine receptor antibodies. CONCLUSION: The diagnosis of MG was based on the typical clinical findings such as dysphonia and dysphagia, decremental response of RNS and positive AChRs antibody titre. Flaccid tetraparesis associated with diminished reflexes, increase of the distal latencies and temporal dispersion which caused lower MNCV, along with the increase of the F wave latencies supported the diagnosis of AIP. A cerebrospinal fluid tap indicated an albuminocytologic dissociation sustaining the radicular implication of AIP. As such, a diagnosis of MG and AIP co-occurrence syndrome was established.

Myasthenia gravis and congenital myasthenic syndromes in dogs and cats: A history and mini-review.

Myasthenia gravis (MG) is a disorder of neuromuscular transmission in which muscle weakness results from an autoantibody mediated depletion of acetylcholine receptors (AChRs) at the neuromuscular junction. Myasthenia gravis occurs spontaneously in dogs and cats, and as in human MG, an autoimmune response against nicotinic AChRs has been demonstrated and autoantibodies against AChRs implicated in the pathogenesis. While both species are affected with MG, there are distinct differences in clinical presentations and frequency of spontaneous remission. Congenital myasthenic syndromes (CMSs) are hereditary disorders of neuromuscular transmission resulting in structural or functional defects of the neuromuscular junction. The clinical presentation and pathogenesis of a CMS in Jack Russell terriers was first described in the 1970's and 1980s and has since been reported in a few other breeds. Mutations have been reported in CHRNE, COLQ and CHAT in canine CMS. A form of COLQ deficient CMS has recently been reported in cats.

Risk Factors and Outcomes in Cats with Acquired Myasthenia Gravis (2001-2012).

BACKGROUND: Acquired myasthenia gravis (MG) in cats most commonly causes generalized weakness without megaesophagus and is more often associated with a cranial mediastinal mass, compared to dogs. HYPOTHESIS/OBJECTIVES: To extend the clinical findings described in the report of 2000 on MG in cats (J Am Vet Med Assoc 215:55-57). ANIMALS: Two hundred and thirty-five cats with MG. METHODS: Retrospective case study to evaluate the long-term outcome and incidence of spontaneous remission in myasthenic cats. Information including signalment, clinical presentation, presence of and type of cranial mediastinal mass, treatment including surgical versus medical, survival time, and outcome including spontaneous remissions was collected and analyzed in cats diagnosed at the Comparative Neuromuscular Laboratory, University of California San Diego by detection of acetylcholine receptor antibody titers >0.3 nmol/L by immunoprecipitation radioimmunosassay. RESULTS: Acquired MG in cats is associated with a euthanasia rate of 58%. Abyssinian and Somali cats had an increased incidence of MG compared to mixed breed cats or cats of other breeds. A cranial mediastinal mass, most commonly thymoma, was observed in 52% of the cats, which is higher than in the previous report. Spontaneous remission is not a characteristic of MG in cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Myasthenia gravis in cats is a chronic disease associated with a high incidence of a cranial mediastinal mass. Spontaneous remission is not common and clinicians should warn owners of the necessity for long-term treatment. The clinical outcome with a cranial mediastinal mass did not differ between surgical or medical treatment.