Mignan, Thomas
(2023)
Studies on myasthenia gravis in dogs and cats.
MRes thesis, University of Nottingham.
Abstract
Myasthenia is a term used to describe impairment of neuromuscular transmission. Its etymology is derived from the Greek “myasthenia” meaning muscle weakness. Both a congenital and an acquired form exist, each with a different pathophysiology, clinical presentation, list of differential diagnoses, diagnostic approach, treatment, and outcome. Myasthenia is considered one of the most completely understood neuromuscular diseases in dogs and cats, however there are several aspects which warrant further investigations.
The long-term outcome of cats with myasthenia gravis (MG) remains incompletely understood with conflicting results published to date, although it has generally been unfavourable in recent studies. Furthermore, the natural course of MG in cats has not been investigated to date.
Myasthenia gravis is currently classified in dogs and cats according to generalisation, progression, and severity of skeletal muscle weakness and fatigability based on a previous classification system used for humans which has not been updated in over twenty-five years. However, factors such as the presence or absence of a thymoma, or administration of thiourylene medication in cats, can influence treatment, outcome, or both, frequently leading to the division of affected dogs and cats into separate disease groups based on these factors.
Historically, congenital myasthenic syndromes (CMSs) were termed congenital MG which was thought to solely be the result of a postsynaptic deficiency of acetylcholine receptors (AChRs) in the absence of antibodies directed against them. However, it is now clear a congenital post-synaptic acetylcholine receptor (AChR) deficiency is only one of several clinically heterogeneous congenital myasthenic syndromes affecting the neuromuscular junction (NMJ), resulting in skeletal muscle weakness and fatigability. These syndromes are collectively referred to as CMSs and considered as a separate disease entity from MG. There is currently no established classification system for CMSs in dogs and cats.
A significantly higher incidence of MG associated megaoesophagus (88%) is reported in dogs compared to cats (40%), or even humans in which there are only a few cases reported. This has been attributed to the tunica muscularis of the canine oesophagus being described as solely composed of skeletal muscle as opposed to that of cats or humans in which the distal third and two thirds are respectively reported to contain smooth muscle. Recently, however, the distal third of the tunica muscularis was reported to be composed of smooth muscle in a population of eight Iraqi dogs.
From this, the aims of the present thesis were the following:
• Evaluate the long-term outcome of cats with MG without evidence of a cranial mediastinal mass (CMM).
• Evaluate the natural course of the disease in cats with myasthenia gravis without evidence of a CMM.
• Update the classification system used for MG in dogs and cats based on comparison with published classification systems in human beings.
• Establish a classification system for CMSs in dogs and cats.
• Evaluate the tunica muscularis composition of the oesophagus in dogs.
A set of hypotheses were proposed:
• The long-term outcome of cats with MG without evidence of a CMM is often favourable.
• The natural course of the disease can involve spontaneous remission in cats with MG without evidence of a CMM.
• The tunica muscularis of the canine oesophagus is solely composed of skeletal muscle.
To address these questions, two studies, one retrospective, one prospective, and a literature review, were undertaken.
Study 1 – Long term outcome of cats with myasthenia gravis without evidence of a cranial mediastinal mass.
Eight cats diagnosed with MG without evidence of a CMM. Retrospective case series. The medical records of cats diagnosed with MG between 2005 and 2018 from two veterinary referral hospitals were reviewed for inclusion. Inclusion criteria consisted of a diagnosis of MG, as well as for thoracic imaging, serum biochemistry including measurement of creatine kinase activity, and a haematology profile to have been performed. Exclusion criteria were the presence of an identifiable CMM, or administration of methimazole or carbimazole. All cats had an excellent long-term outcome, achieving immune remission within six months of diagnosis, including four 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 MG. Cats diagnosed with MG without evidence a CMM have a favourable outcome and frequently achieve immune remission. Moreover, the natural history of MG 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.
Study 2 – Classification of myasthenia gravis and congenital myasthenic syndromes.
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, generalised, 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 categorisation 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.
Study 3 – Composition of the tunica muscularis of the oesophagus in dogs.
A population of thirty dogs comprising ten small, ten medium, and ten large breed dogs without any history or pathological evidence of oesophageal disease were prospectively recruited. Samples of the cervical, thoracic, and abdominal region of the oesophagus were collected from all dogs. Phosphotungstic acid haematoxylin staining (PTAH) was consistent across all thirty dogs, and throughout the cervical, thoracic, and abdominal regions of the oesophagus, revealing strong positive staining of the entire tunica muscularis layer, revealing cross-striations consistent with skeletal muscle. Smooth muscle actin (SMA) staining was consistent across all thirty dogs and throughout the cervical, thoracic, and abdominal regions of the oesophagus, revealing strong positive staining in the mucosal layer consistent with the smooth muscle layer that is the muscularis mucosa but no staining of the tunica muscularis. These findings support the theory that MG associated megaoesophagus incidence is negatively correlated with the amount of smooth muscle in the tunica muscularis layer of the oesophagus. Given the lack of smooth muscle in the tunica muscularis, medications targeting the skeletal muscle should be prioritised in management of MG associated megaoesophagus.
In conclusion, the results of this thesis strengthen the understanding of treatment and outcome of MG and CMSs, and highlight future research avenues as well as provide a framework for such studies.
| Item Type: |
Thesis (University of Nottingham only)
(MRes)
|
| Supervisors: |
Targett, Mike
Lowrie, Mark
West, Winsome |
| Keywords: |
Myasthenia, neuromuscular diseases, cats, dogs |
| Subjects: |
S Agriculture > SF Animal culture |
| Faculties/Schools: |
UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science |
| Item ID: |
76655 |
| Depositing User: |
Mignan, Thomas
|
| Date Deposited: |
16 Feb 2024 10:37 |
| Last Modified: |
13 Mar 2024 15:42 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/76655 |
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