Myasthenia gravis

Myasthenia gravis is the rare clinical disease that results

from impaired neuromuscular transmission at the synapse
between the termination of the axon of the lower motor
neuron and the muscle, at the motor end plate.
It is an auto immune disorder, with a prevalence of 5 per
100,000.
The epidemiology of MG demonstrates 2 peaks. The first
peak, mainly in women, occurs between ages 10 and 40
years. The second peak has
a male predominance and occurs from ages 50 to 75
years.
MG is characterized by: weakness and fatiguing of some or
all muscle groups; weakness worsening on sustained or
repeated exertion, or towards the end of the day, relieved
by rest. E.g. chewing and swallowing may be much more
difficult towards the end of a meal than they were at the
start.
Neuromuscular transmission depends on normal synthesis
and release of acetylcholine into the gap substance of the
synapse, and its uptake by healthy receptors on the
muscle membrane.

Pathophysiology
The etiology or initial event that begins the onset of MG
remains unknown. However, the weakness results from 3
factors.
The most important one is circulating antibodies directed
against the AchR on the postsynaptic membrane of the
neuromuscular junction. Some of these antibodies attach
 to the AchR located on key parts of the sodium/potassium
channel, thereby interfering with opening the
sodium/potassium channel. When sufficient AchRs are
blocked by antibodies, the muscle will not depolarize
sufficiently to trigger
contraction of the muscle fiber.

A second factor contributing to the weakness is that AchR

molecules have as faster rate of degeneration. When AchR
antibodies simultaneously attach to two adjacent AchRs, a cell
signal initiates internalization of both receptors and degrades
them. The turnover rate is faster than replacement of new
membrane AchRs, resulting in a net loss of available AchRs at
the synapse.
The third factor develops because the antibody attached to
the AchR triggers serum complement activation, producing
secondary damage to the synaptic membrane. As a
consequence of years of complement damage, the
postsynaptic membrane loses its rich invaginations and
becomes simplified in structure (Figures 5-2a and 5-2b).
In severe chronic cases, the postsynaptic membrane may
have a 2/3 reduction in the normal number of AchR molecules,
a number insufficient to initiate depolarization and contraction
of the muscle fiber even if no acetylcholine antibodies were
present. In these patients, pyridostigmine usage does not
improve the probability of muscle fiber contraction.

Of these patients, 75% have an associated abnormality of the

thymus gland. About 85% of these patients have thymic
hyperplasia with germinal center lymphocyte proliferation,
and 15% have a thymoma. The role of the thymus gland in
producing the abnormal antibodies is poorly understood. The
current hypothesis is that the AchR antibody is a T-cell
mediated antibody response. Surgical removal of the thymus
gland often results in clinical improvement and a reduction of
the number of circulating antibodies.

MG can occur in infants. Infants born to mothers with MG may

have sufficient circulating antibodies to cause the infant to
become floppy, weak,
and have a poor suck. This transient syndrome lasts for
several weeks until the maternal antibody disappears. Other
infants have congenital MG that
is due to genetic mutations in the AchR. These infants remain
persistently weak and do not respond to immunosuppressive
drugs.
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