9 - Neuromuscular Junction disorders Flashcards

Question

Lambert-Eaton myasthenic syndrome (LEMS)

Answer 1

Subacute weakness Weakness may improve with exercise Depressed reflexes Autonomic Sx & signs

Answer 2

Males > Females 5:1 Middle-age -> elderly 50% assoc w/ malignancy * SCLC most common In patients <40, malignancy uncommon

Answer 3

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.

Answer 4

3,4 Di-aminopyridine Treat malignancy 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.

Answer 5

Acute onset Antecedent GI illness Usually involves eyes early and prominently Significant bulbar dysfunction Loss of reflexes Autonomic instability

Answer 6

Subtypes A – H * A, B, E most common pathogen -produced by Clostridium botulinum -2 ng may cause death

Answer 7

**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.

Answer 8

* Heptavalent anti-BTX * Supportive -Airway / Intubation -DVT prophylaxis -Nutrition -positioning -pulmonary * Autonomic complications

Answer 9

**Foodborne botulism:** When a person ingests the preformed toxin. ***Infant botulism:** children under the age of 1 year who have C. botulinum colonization in their gastrointestinal tract. **Wound botulism:** When infected wounds contain C. botulinum, and they secrete the toxin. **Iatrogenic botulism:** This occurs when cosmetic or therapeutic procedures that use the C. botulinum toxin cause systemic intoxication. **Intestinal colonization:** When a person over the age of 1 year harbors the C. botulinum toxin within the gastrointestinal tract (infantile botulism in children and adults).

Answer 10

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.

Answer 11

In botulism, nerve connection reestablishment is a slow process and depends on the regeneration of nerve terminals and the synthesis of new proteins involved in neurotransmitter release. Botulinum toxin, produced by the bacterium Clostridium botulinum, prevents the release of acetylcholine, a neurotransmitter, at the neuromuscular junction. This inhibition leads to muscle paralysis. The process of nerve connection reestablishment involves several steps: **Toxin Degradation:** The effect of botulinum toxin is not permanent. Over time, the toxin is broken down and cleared from the body. **Regeneration of Nerve Terminals:** -Once the toxin is cleared, nerve terminals begin to regenerate. -New nerve endings form, and axons extend toward their target muscles. **Protein Synthesis:** -The synthesis of new proteins, including those involved in the formation of the SNARE complex (syntaxin, synaptobrevin, and SNAP-25), is essential for the reestablishment of normal neurotransmitter release. **Formation of Functional SNARE Complex:** -As nerve terminals regenerate, the proteins involved in neurotransmitter release gradually regain their normal function. -The formation of a functional SNARE complex is crucial for vesicle fusion and the release of acetylcholine. **Recovery of Neuromuscular Function:** -As nerve connections are reestablished and the SNARE complex functions properly, the neuromuscular junction begins to recover. Muscle function improves over time, and paralysis diminishes.