Motor Neuron Diseases & Disorders of the NMJ Flashcards
Disorders that cause degeneration of the anterior horn cells in the spinal cord with or without similar lesions in the lower brainstem motor nuclei and/or Betz cells of the brain and associated tracts
Motor neuron diseases
Motor neuron diseases are characterized clinically by progressive _____ and _____ of the affected muscles without accompanying sensory, cerebellar, or mental changes
Wasting; weakness
4 main types of adult motor neuron disease
Amyotrophic lateral sclerosis (most common)
Progressive bulbar palsy
Progressive (spinal) muscular atrophy
Primary lateral sclerosis
T/F: Aside from the 4 main types of adult motor neuron disease (ALS, progressive bulbar palsy, progressive SMA, and primary lateral sclerosis), there are rarer, more benign, and limited forms of adult motor neuron diseases that exist
True
[these include brachial amyotrophic diplegia, leg amyotrophic diplegia, isolated bulbar ALS, monomelic amyotrophy (Hirayama’s disease), etc]
Clinical features of ALS in terms of gender distribution, upper vs lower motor neuron disease, and risk factors
Slightly more common in males
Mixed upper and lower motor neuron signs, especially in same limb [upper = spasticity, hyperreflexia, babinski sign; lower = atrophy, fasciculations]
May also be bulbar involvement of the upper or lower motor neuron type
No definite risk factors related to occupation, trauma, diet, SES, etc.!
The pathophysiology of ALS involves degeneration of _____ cells, ______ ____ nuclei, descending _________ tracts, and ______ horn cells
Betz; lower brainstem; corticospinal; anterior
The clinical presentation of ALS is highly variable, but what are some commonalities in terms of age of onset and presenting signs/symptoms?
Age 20-60, most common after age 50
First sign is often hand clumsiness or impaired dexterity with mild wasting/weakness of hand intrinsics
Eventually other hand/arm becomes involved and weakness/atrophy spreads proximally in arms
Later the legs become involved, followed by atrophic weakness in tongue, pharynx, and muscles of respiration
Accompanying symptoms include fasciculations, cramps, drooling, and weight loss
Prognosis of ALS
Relentlessly progressive without remissions, relapses, or stable plateaus
Death from respiratory failure, aspiration PNA, or PE
Mean duration of symptoms = 4 years, death within 2-5 years
[treatment is supportive — feeding tubes, ventilatory support, various assistive devices, symptomatic meds, riluzol (glutamate inhibitor)]
Adult motor neuron disease characterized by selective involvement of the motor nuclei of the lower cranial nerves; clinical presentation includes dysarthria, dysphagia, dysphonia, chewing difficulty, drooling, and respiratory difficulty
Progressive bulbar palsy
Progressive bulbar palsy rarely runs its course as an isolated syndrome, and it almost always progresses to generalized disease (i.e., ______).
The earlier the onset of ______ symptoms in ALS, the shorter the course of the disease
ALS
Bulbar
Adult motor neuron disease affecting M>F, mean age at onset 64, and lower motor neuron deficits predominate due to degeneration of anterior horn cells. There is NO upper motor neuron involvement
Progressive spinal muscular atrophy
Clinical features of progressive spinal muscular atrophy
Often begins with symmetric upper extremity involvement
Weakness, atrophy, respiratory difficulty
Can progress to ALS but usually does not
Survival rate >15 yrs — better with earlier age of onset
Adult motor neuron disease typically affecting pts 50-55 y/o, and upper motor neuron (corticospinal) deficits prevail — causing weakness, spasticity, hyperreflexia, Babinski signs with a slow progression that can evolve into ALS, but with a better survival rate
Primary lateral sclerosis
Acquired motor neuron disease associated with asthma
Hopkins syndrome
Describe the anatomy and physiology of the NMJ
A nerve AP arrives at the motor nerve terminal and depolarizes the nerve terminal membrane
This initiates influx of calcium into the motor axon, leading to fusion of vesicles containing ACh with the presynaptic membrane and release of ACh which diffuses across the synaptic cleft, binds post-synaptic receptors on the muscle membrane, and generates a localized endplate potential (EPP)
If the EPP reaches threshold, the muscle membrane undergoes an increase in sodium conductance and a muscle AP is generated. Propagation of the AP through the muscle fiber ultimately results in muscle contraction.
Neuromuscular transmission is terminated by diffusion of ACh from the synapse and its rapid cleavage by AChE
3 classifications of disorders of the NMJ
Presynaptic
Synaptic
Postsynaptic
How are the following disorders classified?
Lambert-Eaton myasthenic syndrome, botulism, steroids, Mg, Black Widow venom, congenital myasthenic syndrome, aminoglycosides, tetanus, tick paralysis, 4-aminopyridine
A. Presynaptic NMJ Disorders
B. Synaptic NMJ Disorders
C. Postsynaptic NMJ Disorders
A. Presynaptic NMJ Disorders
How are the following disorders classified?
Myasthenia gravis, Neonatal myasthenia, Congenital myasthenia, Succinylcholine, D-penicillamine, Curare, Classic slow-channel syndrome
A. Presynaptic NMJ Disorders
B. Synaptic NMJ Disorders
C. Postsynaptic NMJ Disorders
C. Postsynaptic NMJ Disorders
How are the following disorders classified?
Organophosphates, Edrophonium, Neostigmine, Congenital end-plate AChE deficiency, Nerve agents (Sarin, VX)
A. Presynaptic NMJ Disorders
B. Synaptic NMJ Disorders
C. Postsynaptic NMJ Disorders
B. Synaptic NMJ Disorders
The etiology of _____ _____ is a defect of neuromuscular transmission due to an antibody-mediated attack upon nicotinic acetylcholine receptors (AChR) on the muscle membrane; mostly sporadic but there is a high frequency of HLA B8 and DR3 as well as several other autoimmune disorders
Myasthenia gravis
Clinical symptoms of myasthenia gravis include 3 general characteristics:
- Fluctuating weakness — “excessive fatigueability”
- Distribution of weakness
- Clinical response to cholinergic drugs
What is important to know about the distribution of weakness in MG?
Ocular muscles are affected first in 40% of pts and ultimately involved in 85%. Often see ptosis and diplopia
Other common symptoms include dysarthria, dysphagia, limb weakness, and neck weakness
MG is diagnosed based on clinical hx and exam findings. What are lab findings in terms of antibodies?
Acetylcholine receptor antibodies (anti AChR Abs) — note that up to 10% of cases may be antibody negative
MUSK antibodies
EMG findings and special test performed in dx of MG
EMG findings — decremental response on repetitive stimulation. Increased “jitter” on single fiber EMG
Tensilon (edrophonium) test —positive in 90% of pts. Be aware of side effects — bradycardia, ventricular arrhythmias
About 10% of pts with MG have no detectable anti-AChR Abs. About 40% of these have MUSK (muscle specific tyrosine kinase) Abs.
The MUSK syndrome has 3 general types, mainly seen in women. What are the 3 types?
Oculopharyngeal (+/- tongue, face) weakness
Neck, shoulder, respiratory weakness
Indistinguishable from antibody-positive MG
[note: these have poor response to AChE medications and thymectomy; PLEX, IVIG, and rituximab are best; remission possible]
Pathophysiology of Lambert-Eaton Myasthenic Syndrome
Autoimmune attack against voltage-gated Ca++ channels on the presynaptic nerve terminal
Presynaptic abnormality of ACh release at NMJ —> weakness
Lambert-Eaton Myasthenic syndrome (LEMS) is often associated with ______
Cancer — especially SCCL
Clinical presentation of Lambert-Eaton Myasthenic syndrome
Proximal weakness, loss of DTRs, myalgias, dry mouth, impotence
Oropharyngeal and ocular muscles may be mildly affected but not to the degree seen in MG
Strength may improve after exercise
May see slight (but usually not dramatic) improvement with edrophonium test
Lab and EMG findings in Lambert Eaton Myasthenic Syndrome
Labs — anti-VGCC antibodies
EMG — low amplitude motor responses that facilitate (increase) after a brief period of exercise; incremental response on fast repetitive stimulation (often greater than 100%)
MOA of botulinum toxin at NMJ
Blocks presynaptic mechanisms for release of ACh
[tx with antitoxin and guanidine hydrochloride]
MOA of nerve gases like Sarin and VX at NMJ
Act by inhibiting AChE at NMJ to cause end organ overstimulation (i.e., cholinergic crisis)
What is the most significant antibiotic known to exacerbate or unmask myasthenia gravis?
Aminoglycosides
What antibiotic may cause a disorder identical to autoimmune MG?
D-penicillamine
Drugs other than abx that can exacerbate or unmask MG
Neuromuscular blockers — succinylcholine, pancuronium, etc
Excess anticholinesterase medication
Corticosteroids and ACTH (large doses)
Thyroid supplements
BOTOX
Magnesium salts (MOM, antacids)
Antiarrhythmics — lidocain, quinine, procainamide, verapamil, B-blockers
