9 - Neuromuscular Junction disorders Flashcards
NMJ DISORDERS
Myasthenia gravis
Congenital myasthenic syndromes
Botulism
Lambert Eaton Myasthenic syndrome
Organophosphate poisoning
Neuromuscular Junction (diagram)
Myasthenia gravis (overview)
“grave muscle fatigue“
Fatigable weakness
Prominent eye muscle involvement
Prevalence: ~20 per 100,000
Myasthenia gravis
Epidemiology
Myasthenia gravis (mechanism)
Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness and fatigue, primarily affecting the voluntary muscles. In MG, the immune system mistakenly attacks the acetylcholine receptors (AchR) at the neuromuscular junction, leading to impaired communication between nerves and muscles. The neuromuscular junction is the site where nerve cells communicate with muscle cells, and acetylcholine receptors play a crucial role in this communication.
Neuromuscular Junction in myasthenia gravis
Myasthenia
Clinical features
- Fatigable weakness
- Fluctuations worse with exercise
- Better with rest
- Less symptoms in AM
- Prominent eye muscle involvement
- Spares sensation and autonomic function
MG classification
- Ocular
- Generalized
- Crisis
Ocular MG
Generalized MG
- Weakness of any muscles other than eye movement
- 50-60% of OMG will generalize in 2-3 years
Myasthenic Crises
weakness of respiratory or swallowing muscles
Diagnosis of MG
Clinical Dx
Ice pack
Tensilon test
Electrodiagnosis
* Repetitive Stimulation
* Single Fiber EMG
Antibodies
Ice pack test to confirm myasthenia gravis
Tensilon test (edrophonium) to confirm myasthenia gravis
Anti-AchR Antibodies in myasthenia gravis
other antibodies in myasthenia gravis
Electromyography for myasthenia gravis
Purpose of Electromyography (EMG):
* Detection of Neuromuscular Abnormalities: EMG is employed to detect abnormalities in the neuromuscular system, specifically focusing on the communication between nerves and muscles.
* Confirmation of Myasthenia Gravis: EMG can help confirm the diagnosis of myasthenia gravis by revealing characteristic patterns of muscle response to repetitive nerve stimulation.
Repetitive Nerve Stimulation (RNS) Test:
* Principle: In myasthenia gravis, muscle weakness is often more evident with repeated or sustained muscle activity. The RNS test is a specific type of EMG that assesses muscle response to repetitive nerve stimulation.
* Procedure: During the RNS test, a series of electrical stimuli are delivered to a nerve, and the resulting muscle responses are recorded. In MG, there is a characteristic decrease in the amplitude of muscle responses with repetitive stimulation.
Single Fiber EMG for myasthenia gravis
Single Fiber EMG:
Principle: Single fiber EMG is a more sensitive test that evaluates the electrical activity of individual muscle fibers.
Procedure: A fine needle electrode is inserted into the muscle, and the activity of individual muscle fibers is recorded. In myasthenia gravis, there may be increased jitter (variability in the timing of muscle fiber responses), reflecting the impaired neuromuscular transmission.
MG - symptomatic treatment
MG - Immunosuppression
Thymectomy in MG
Rationale for Thymectomy:
Association with MG: There is a strong association between thymic abnormalities and MG. Many individuals with MG have an enlarged thymus or thymic hyperplasia.
Autoantibody Production: The thymus is thought to contribute to the production of autoantibodies, including those targeting acetylcholine receptors at the neuromuscular junction.
Indications for Thymectomy:
Generalized MG: Thymectomy is often recommended for individuals with generalized MG, where muscle weakness affects multiple muscle groups.
Younger Patients: Thymectomy is considered more beneficial in younger individuals with MG.
Thymoma: If a thymoma (a tumor of the thymus) is present, thymectomy is generally recommended irrespective of age.
Lambert-Eaton myasthenic syndrome
(LEMS) - weakness
Lambert-Eaton myasthenic syndrome (LEMS) - mechanism
Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder characterized by muscle weakness and fatigue. The primary mechanism of LEMS involves an autoimmune attack on the neuromuscular junction, leading to impaired synaptic transmission. Here’s a brief explanation of the key mechanisms:
Autoimmune Response:
LEMS is often associated with an underlying malignancy, commonly small-cell lung cancer, but it can also occur without an identified tumor.
The immune system mistakenly targets components of the neuromuscular junction.
Presynaptic Neuromuscular Junction Involvement:
In contrast to myasthenia gravis (MG), which primarily affects postsynaptic receptors, LEMS predominantly involves the presynaptic region of the neuromuscular junction.
The presynaptic terminal is responsible for releasing acetylcholine, a neurotransmitter essential for muscle contraction.
Voltage-Gated Calcium Channels (VGCCs):
The main target of the autoimmune attack in LEMS is the voltage-gated calcium channels (VGCCs) located on the presynaptic membrane.
VGCCs are crucial for the influx of calcium ions into the nerve terminal, facilitating the release of acetylcholine.
Impaired Acetylcholine Release:
Antibodies generated by the immune system in LEMS patients bind to and interfere with the function of VGCCs. This immune-mediated disruption leads to a reduction in the normal influx of calcium ions into the nerve terminal.
Reduced Acetylcholine Release:
The diminished calcium influx results in a decreased release of acetylcholine into the synaptic cleft. Acetylcholine is essential for transmitting signals from the nerve to the muscle, initiating muscle contraction.
Muscle Weakness and Fatigue:
The impaired acetylcholine release leads to weakened nerve impulses reaching the muscle fibers, causing muscle weakness and fatigue.
Symptoms are often more evident during repetitive or sustained muscle activity.
Post-Activation Potentiation:
One characteristic feature of LEMS is the phenomenon known as post-activation potentiation. Contrary to MG, LEMS symptoms may temporarily improve with repetitive muscle use, likely due to the gradual accumulation of intracellular calcium, which enhances acetylcholine release.
Treatment:
Treatment strategies for LEMS often involve addressing the autoimmune component with immunosuppressive medications.
Symptomatic relief can be achieved through medications like 3,4-diaminopyridine (3,4-DAP), which enhances acetylcholine release.
LEMS
Diagnosis
botulinum mechanism
Neurotransmitter Release:
Normal muscle contraction involves the release of acetylcholine, a neurotransmitter, from nerve endings at the neuromuscular junction.
SNARE Complex Formation:
* The process of neurotransmitter release relies on the formation of a complex of proteins called the SNARE complex.
* Key proteins in this complex include syntaxin and synaptobrevin (also known as VAMP) on the vesicle membrane, and SNAP-25 on the cell membrane.
Vesicle Fusion:
* The SNARE complex facilitates the fusion of synaptic vesicles containing acetylcholine with the cell membrane.
* This fusion allows the release of acetylcholine into the synaptic cleft, where it binds to receptors on the muscle cell membrane.
Acetylcholine Release:
The binding of acetylcholine to its receptors triggers a series of events that lead to muscle contraction.
Botulinum Toxin Action:
Botulinum toxin interferes with the release of acetylcholine by cleaving specific proteins involved in the SNARE complex.
The toxin has protease activity and targets proteins like SNAP-25, a critical component of the SNARE complex.
Cleavage of SNAP-25:
Botulinum toxin cleaves SNAP-25, preventing its proper function in the SNARE complex.
This cleavage disrupts the normal formation of the SNARE complex, inhibiting the fusion of synaptic vesicles with the cell membrane.
Inhibition of Acetylcholine Release:
* Without a functional SNARE complex, the vesicles containing acetylcholine cannot properly fuse with the cell membrane.
* As a result, the release of acetylcholine into the synaptic cleft is significantly reduced.
Muscle Paralysis:
* With insufficient acetylcholine release, the muscle is unable to receive the necessary signals for contraction.
* This leads to temporary muscle paralysis in the treated area.
Therapeutic Applications:
Botulinum toxin is used therapeutically for various conditions characterized by muscle overactivity, such as cosmetic procedures to reduce wrinkles, treatment of muscle spasms, and management of certain neurological disorders.
Anti-cholinesterase toxins
The mechanism of action (MOA) of anti-cholinesterase toxins involves inhibiting the activity of acetylcholinesterase (AChE), an enzyme responsible for breaking down acetylcholine, a neurotransmitter. By inhibiting AChE, these toxins lead to an accumulation of acetylcholine in the synapses, causing prolonged stimulation of cholinergic receptors. This results in overstimulation of the nervous system, leading to symptoms such as muscle twitching, paralysis, and, in severe cases, respiratory failure.
diagrams of typical NMJ disorders compared to normal cholinergic transmission
