Case
7: Myasthenia Gravis
A 67 year old man, who is
complaining of double vision, was found to have bilateral ptosis, covering most
of the pupil on the right side and partially obscuring that on the left. The
ptosis was worse in the evening and almost absent in the morning. He admitted
to tiredness in the arms and legs on exercise, which recovered with resting.
His Tensilon test was positive but electromyography was inconclusive. His serum
contained antibodies to thyroid microsomes (positive at 1/1600) and to
acetylcholine receptors. The patient improved on treatment with pyridostigmine.
Literature
Review Summary
Myasthenia Gravis has an
estimated worldwide prevalence of 150 to 220 million of the population
affecting more women than men, in the United States is currently 53,000 to 59,000
patients and approximately 194 patients in Puerto Rico (Conti-Fine,
et al. 2006). MG
is an autoimmune neuromuscular disease leading to fluctuating muscle weakness
and fatigability caused by the production of antibodies against acetylcholine
receptors at the neuromuscular junction.
In affected persons, there are fewer functional receptors available to
receive ACh because they are blocked by antibodies and eventually destroyed
within the muscle cells. Also, ACh is broken down by acetylcholinesterase
enzyme quickly at the synaptic cleft resulting in a diminished action potential
at the neuromuscular junction that is not forceful enough to generate a
depolarization. The result of this lack to depolarize the nerve cell leads to
muscle weakness that affects daily life activities, such as maintaining the
eyes completely open, or the ability to move the eyes in a synchronized pattern. Epithelial myeloid cells normally present in
the thymus resemble skeletal muscle cells, thus these cells may become
antigenic and the system itself creates an autoimmune response on the muscular
endplate by molecular mimicry. Because
of that, scientists believe the thymus gland may give incorrect instructions to
developing immune cells, ultimately resulting in an impaired chemical
transmission and muscle excitation. (McGrogan, 2010).
This disease is a Type II –
non-cytotoxic hypersensitivity reaction where antibodies binds to tissue
eliciting a complement-mediated destruction of
junctional folds of the postsynaptic membrane. The most common pathology is hyperplasia of thymus
stromal cells or thymoma.
Imaging
Studies
A chest X-ray is frequently
performed; it may point towards alternative diagnoses (e.g., Lambert-Eaton
syndrome due to a lung tumor) and comorbidity. It may also identify widening of
the mediastinum suggestive of thymoma.
Thymectomy, the surgical
removal of the thymus, is essential in cases of thymoma in view of the following
potential neoplastic effects of the tumor. However, the procedure is more
controversial in patients who do not show thymus abnormalities. Although some
of these patients improve with thymectomy, others experience severe
exacerbations.
How
to test for MG
The patient is injected
with edrophonium
(Tensilon test), a reversibly acetylcholinesterase
inhibitor which prevents the breakdown of ACh. Patients will temporarily have
an increase amount of ACh levels at the synaptic cleft which will improve
muscle weakness at sight such as the eyelids and fingers. If the drug improves your muscle strength a
positive diagnosis is made
Another test used is the single-fiber
electromyography (SFEMG) which allows identification of action potentials from
individual muscle fibers (Martinez, 2008).
In a recent study this technique proved very sensitive for diagnosing
generalized MG (93% of patients showed abnormal SFEMG), but in patients with
ocular myasthenia gravis only 38% showed abnormal SFEMG readings (Losen, et al. 2008).
Questions
What
neurological functions/structures are affected in the patient?
Impairment
of Neurologic Functions
Myasthenia Gravis causes
significant skeletal muscle weakness affecting the neuromuscular junctions. The
most common muscles affected are the muscles that control eye movement, facial
expression and swallowing especially after repeated use of the muscles. Common
symptoms include double vision, ptosis, lack of facial expression, waddling
gait, weakness of the extremities, difficulty chewing, swallowing and talking.
Muscles of the face and head are involved early stages of the disease and in
about 85% of the cases the weakness will progress generally to affect large muscle
groups. About 12% of patients will
experience a crisis episode, in which the weakness becomes so severe that
breathing is compromised and respiratory assistance is required.
What type of immunological
mechanisms can explain the alterations observed in the patient?
Immunological
Mechanisms Involved
Reduction of achetycholine
receptors is from an autoimmune process.
The reduced number of available AChR receptors becomes unregulated as
they try to bind free ACh (Scherer, et
al. 2005). MG can be considered a B
cell mediated disease, because the antibodies are a product of an activated
B-cell. The antibody subclass present in this disease is the IgG antibody. The main
mechanism in which AChR antibodies works is that they are able to cross link
nearby AChRs blocking them and making them unfunctional, which eventually will induce
complement mediated destruction of the receptors.
References
Conti-Fine
BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. 2006. J. Clin. Invest. 116 (11): 2843–54. doi:10.1172/JCI29894. PMC 1626141. PMID 17080188.
McGrogan
A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: a systematic
literature review. 2010. Neuroepidemiology 34 (3): 171–183. doi:10.1159/000279334. PMID 20130418.
Medicine
net. "Myasthenia Gravis Symptoms, Causes, Treatment - What Is the Role of
the Thymus Gland in Myasthenia Gravis? Available at:
http://www.medicinenet.com/myasthenia_gravis/page2.htm. Obtained: May 18, 2012.
Losen M,
Martínez-Martínez P, Phernambucq M, Schuurman J, Parren PW, DE Baets MH. Treatment
of myasthenia gravis by preventing acetylcholine receptor modulation. 2008. Ann
N Y Acad Sci 1132: 174–9. doi:10.1196/annals.1405.034.
PMID 18567867.
Scherer K,
Bedlack RS, Simel DL. Does this patient have myasthenia gravis? 2005. JAMA 293
(15): 1906–14. doi:10.1001/jama.293.15.1906. PMID 15840866.
It is important to understand the mechanism for such autoimmune disease. Even though the cause of many of this conditions is not fully understood we can produce treatments that could help the patient lead a relatively normal life. The mechanism for MG is relatively simple to understand, basically cells produced in the thymus induce the production of autoantibodies. By knowing this relatively simple fact it was deduced that by removing the thymus the disease would exacerbated in a less indirect way.
ResponderBorrarThe way of diagnosing the disease is also a treatment for it. By inhibiting a single enzyme diminishes the effect of the antibodies on muscles. This is why it is important for us as future physicians to understand how each disease behaves and begin to treat it and may be at some point even cure it.
Trabajando en Guatemala como interprete medico, vi varios casos de paralisis muscular en ninos. Me impacto bastante porque soy ninos sin ningun trauma que parecen saludables pero comienzan a experimentar debilidad y despues no pueden caminar sino con mucho esfuerzo. Estos ninos son condenados a cama durante periodos de debilidad extendida. Ojala en el futuro se puedan desarrolar tratamientos mas economicos para ayudar a estos ninos en paises en desarrollo.
ResponderBorrarVisto la teoria que estas enfermedades representan las sequelaes a infecciones bactereogenicas, me tiene sentido que uno encontraria mas casos de debilidades musculares progresivas y autoimunes en Guatemala. Esto seria porque los sistemas de saneamiento son menos desarrollados en Guatemala que en paises mas desarrollados. Me pregunto cual seria la epidemiologia de estas enfermedades en paises en desarrollo vs. el mundo industrialisado. Vi varios casos en Guatemala, pero desconozco la prevalencia en otros paises. Si se fuese a estudiar la epidemilogia, o si ha ya sido estudiado, representaria una fuente posible de apoyo a esta teoria de sequelaes a infecciones bacteriogenicas.
It it also important to mention that it is recommended for women diagnosed with MG that wait at least 2 years after diagnosis, for getting pregnant because of the complications added to the already compromised status. Studies have shown that pregnant patients face risks of exacerbation, respiratory failure, adverse drug response, crisis, and death. Also that serious complications requiring the transfer of the newborn to pediatric intensive care unit occur more frequently in delivery involving mother with MG, one of the causes being that neonatal MG is caused by transfer of MG antibodies between the mother and newborn.
ResponderBorrarhttp://www.neurology.org/content/61/10/1459.full
http://emedicine.medscape.com/article/261815-overview
I feel that MG has been a topic in every subject we have studied during our first year in medical school. It is a presentation that i'm sure none of us will ever forget. However, I was unaware that the NBME could test MS in conjunction with immuno, so it was helpful to see it anew.
ResponderBorrarMost of the cases of myasthenia gravis have been related to the thymus gland. However, myasthenia gravis may also occur in association with other autoimmune diseases. Rheumatoid arthritis, thyroiditis, systemic lupus erythematous (SLE) and certain blood diseases are some autoimmune diseases linked to this disorder. Therefore, the immune system can fail in different ways and can produce errors in distinguishing self from non-self antigen, making them more likely to attack the body’s own cells.
ResponderBorrarBased on research, the immunosuppressive medications have been useful in treating myasthenia gravis. It has increased a person’s susceptibility to infections. However, the main goal of research now is to find new methods that can cure myasthenia gravis specifically. Most of the medications suppress the immune system as a whole, instead of reducing the specific autoantibodies. The objective is to suppress only the destructive immune response affecting acetylcholine receptors, without damaging the remainder of the immune system. The experiment has been done in mice, and researchers are planning to develop this gene-based therapy to patients with myasthenia gravis.
http://www.hopkinsmedicine.org/news/media/releases/researchers_halt_autoimmune_disease_myasthenia_gravis_in_mice