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Motor Neurons, the Neuromuscular Junction, and Muscle
University of Calgary Medical School
Neurosciences Course
Cory Toth
August 27, 2007
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Objectives
1) Define muscle disease (myopathy) and discuss their clinical presentation
2) Discuss common forms of muscle disease3) Review of the neuromuscular junction
(NMJ)4) Define myasthenia gravis and discuss
their clinical presentation5) Discuss other forms of NMJ disease
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Objectives
6) Describe motor neuron diseases (MND) and discuss their clinical presentation
7) Describe how MND is diagnosed8) What is available for the patient
with MND?
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The Motor Unit
• The motor unit is a group of muscle fibers and the single motor nerve that activates the fibers
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Muscle
NMJ
Motor Neuron
Peripheral Nerve
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Muscle Contraction
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Muscle Contraction
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Muscle Contraction
1) Peripheral nerve impulse is required, with the impulse transferred from an axon to the SARCOLEMMA of a muscle cell
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Muscle Contraction
2) The impulse travels along the SARCOLEMMA and down the T-TUBULES. From the T-TUBULES, the impulse passes to the SARCOPLASMIC RETICULUM
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Muscle Contraction
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Muscle Contraction
3) As the impulse travels along the Sarcoplasmic Reticulum (SR), the calcium gates in the membrane of the SR open. As a result, CALCIUM diffuses out of the SR and among the myofilaments.
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Muscle Contraction
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Muscle Contraction
• Calcium fills the binding sites in the TROPONIN molecules. As noted previously, this alters the shape and position of the TROPONIN which in turn causes movement of the attached TROPOMYOSIN molecule
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Muscle Contraction
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Muscle Contraction
5) Movement of TROPOMYOSIN permits the MYOSIN HEAD to contact ACTIN6) Contact with ACTIN causes the MYOSIN HEAD to swivel
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Muscle Contraction
7) During the swivel, the MYOSIN HEAD is firmly attached to ACTIN. So, when the HEAD swivels it pulls the ACTIN (and, therefore, the entire thin myofilament) forward (Many MYOSIN HEADS are swivelling simultaneously with a collective effort)
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Muscle Contraction
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Muscle Contraction
8) At the end of the swivel, ATP fits into the binding site on the cross-bridge & this breaks the bond between the cross-bridge (myosin) and actin. The MYOSIN HEAD then swivels back. As it swivels back, the ATP breaks down to ADP & P and the cross-bridge again binds to an actin molecule
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Muscle Contraction
9) As a result, the HEAD is once again bound firmly to ACTIN. However, because the HEAD was not attached to actin when it swivelled back, the HEAD will bind to a different ACTIN molecule (i.e., one further back on the thin myofilament). This action continues…
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Muscle Disease (Myopathy)
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Muscle Appearance
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How do we generate an action potential in skeletal muscle?
-in the muscle, away from the neuromuscular junction- the AP is again all-or-nothing
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Recordings in the junction reveal local potential changes before a regenerative action potential is produced.
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If we block the ability of the postsynaptic receptor channels to open, we can observe local currents, but no action potential.
These local currents are called end plate potentials (epps).
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The Neuromuscular Junction (NMJ)
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The Neuromuscular Junction (NMJ)
The NMJ is an example of fast chemical transmission
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The Neuromuscular Junction (NMJ)
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The Neuromuscular Junction (NMJ)
There are many ways that we manipulate the NMJ, or in which disorders manipulate the NMJ
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1. An action potential arrives at the presynaptic terminal causing voltage gated Ca2+ channels to open, increasing the Ca2+ permeability of the presynaptic terminal.
Ca2+
Ca2+
channelPresynapticterminal
Actionpotential
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NeuromuscularNeuromuscular Transmission:Transmission:
Step by StepStep by StepNerve actionpotential invadesaxon terminal
-
+-
-
-
-
--
+
+
+
+
+
++
--
-
+ +
Depolarizationof terminalopens Ca channels
Lookhere
+ +
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Ca2+
Ca2+
channel
2. Ca2+ enters the presynaptic terminal and initiates the release of a neurotransmitter, acetylcholine (ACh), from synaptic vesicles in the presynaptic terminal.
ACh
Presynapticterminal
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Na+
Synaptic cleft
Na+
ACh
Receptormolecule
3. Diffusion of ACh across the synaptic cleft and binding of ACh to Ach receptors on the postsynaptic muscle fiber membrane causes an increase in the permeability of ligand-gated Na+ channels.
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K+
Outside
Inside
Na+
Na+
Na+Na+
Na+
Na+
Na+ Na+Na+
Na+
Na+
Na+
K+ K+
K+
K+
K+
K+
K+K+
K+
K+ K+
ACh
ACh
ACh
Ca+2 induces fusion ofvesicles with nerveterminal membrane.
ACh is released anddiffuses acrosssynaptic cleft.
ACh
ACh binds to itsreceptor on thepostsynaptic membrane
Binding of ACh openschannel pore that ispermeable to Na+ and K+.
Na+
Na+
K+
Muscle membrane
Nerveterminal Ca+2
Ca+2
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4. The increase in Na+ permeability results in depolarization of the postsynaptic membrane; once threshold has been reached a postsynaptic action potential results.
Na+
Actionpotential
Actionpotential
Na+
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End Plate Potential (EPP)
Outside
Inside
Muscle membrane
Presynapticterminal M
usc
le M
em
bra
ne
Vo
ltage
(m
V)
Time (msec)
-90 mV
VK
VNa
0
Threshold
Presynaptic AP
EPP
The movement of Na+ and K+
depolarizes muscle membranepotential (EPP)
ACh Receptor Channels Na Channels
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5. Once ACh is released into the synaptic cleft it binds to the receptors for ACh on the postsynaptic membrane and causes Na+ channels to open.
Synapticcleft
Postsynapticmembrane
Na+
ACh
AChreceptorsite
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AChreceptorsite
Acetylcholinesterase
Aceticacid
CholineACh
6. ACh is rapidly broken down in the synaptic cleft byacetylcholinesterase to acetic acid and choline.
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Presynapticterminal
Synapticvesicle
ACh
Aceticacid
Choline
CholineACh
7. The choline is reabsorbed by the presynaptic terminal and combined with acetic acid to form more ACh, which enters synaptic vesicles.
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Choline
8. Acetic acid is taken up by many cell types.
Aceticacid
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Meanwhile ...
Outside
Inside
ACh
ACh unbinds fromits receptor
Muscle membrane
ACh
so the channel closes
ACh
AChNerveterminal
ACh is hydrolyzed byAChE into Cholineand acetate
Choline
Acetate
Choline is taken upinto nerve terminal
Choline
Choline resynthesizedinto ACh and repackagedinto vesicle
ACh
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Structural Reality
By John Heuser and Louise EvansUniversity of California, San Francisco
The Neuromuscular Junction (NMJ)
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Structure-function of neurotransmitter postsynaptic receptors.1. Nicotinic acetylcholine receptor of the neuromuscular junction.
- composed of five subunits, composing a functional ligand-gated ion channel.- each subunit has four transmembrane spanning regions
The Neuromuscular Junction (NMJ)
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The Neuromuscular Junction (NMJ)
The molecules associated with the NMJ are numerous and complex – too much to know
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• Weakness occurs when the nerve impulse to initiate or sustain movement does not adequately reach muscle cells
The Neuromuscular Junction (NMJ)
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ID: 29 yrs old RH Male
CC: Abrupt onset of profound quadriparesis
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Neuromuscular Presentation
HPI:
• Sore Muscles and felt fatigued after 40 minutes of working out in gym
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• Developed quadriparesis over next 20 hours
• No sensory symptoms
Neuromuscular Presentation
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Review of Systems:
• Denied numbness, pain, diplopia, dysarthria, dysphagia, bowel/bladder symptoms, shortness of breath.
• Denies fever, rash, arthralgia, diarrhea, or vomiting prior to the onset.
Neuromuscular Presentation
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Past history
• Denies past history of weakness
• But had episode of feeling like “Jello” after working out in gym previously
• Exercise-induced cramps, lasting over 2-3 days.
Neuromuscular Presentation
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• Family Hx : unremarkable
• Social Hx: unremarkable
Neuromuscular Presentation
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ExaminationGeneral examination:
GA: Alert, looked unwell
VS: T 37 C, BP 120/70mmHg,HR 88/m- regular
.
CVS, Respiratory, Abdomen: Unremarkable
Neuromuscular Presentation
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Neurological ExaminationCranial nerves: normal, no facial weakness.
Motor– No fasciculation or myotonia– Flaccid tone– Normal muscle bulk– Power: quadriparesis grade 1-2/5, worse
proximally to arms and legs– Areflexic; plantars downgoing
Neuromuscular Presentation
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• Sensation: normal to pin, touch, temperature, JPS and vibration to all limbs
Neuromuscular Presentation
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Neuromuscular Presentation
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Investigations
Neuromuscular Presentation
Chemistry and Hematology Blood Tests ECG
Electrophysiology Chest X-Ray
Lumbar Puncture Stool Culture
Antibody Testing Neuroimaging
Other Blood Tests
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Investigations• CBC : normal profile
• BS: 7.6 mmol/L
• BUN 5.3 mmol/L
• Cr 75 umol/L
• Electrolyte: Na 144, K 1.5, Cl 106, CO2 25
• Mg 0.77, PO 0.65, Ca 2.40
Neuromuscular Presentation
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• TSH: <0.01 UTU/ml
• Free T4: 59.1 (8.0-22.0) pmol/L
• Total T3: 5.3 (1.1-2.8) nmol/L
• Antithyroid peroxidase Ab: 3516.7 (0-60.0)
Neuromuscular Presentation
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Neuromuscular Presentation
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Neuromuscular Presentation
CXR Normal
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Neuromuscular Presentation
Lumbar Puncture not performed
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Neuromuscular Presentation
Stool Culture not performed
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Neuromuscular Presentation
Antibody testing not performed
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Neuromuscular Presentation
Neuroimaging not performed
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Nerve Latency (ms)
Amplitude (mV) CV (m/s) Minimal F wave (ms)
Rt. MedianWristElbow
4.37.7
9.4019.114
56 25.0
Rt .tibialAnklePop fossa
4.812.4
12.7110.77
53 46.2
Rt . peronealAnkleFibular headKnee
4.29.811.9
7.2457.1206.771
5248
45.6
Motor nerve conductions
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Nerve Latency (ms) Amplitude(μV) CV (m/s)
Rt. Median sensoryWristElbow
2.85.9
0.0280.018
61
Rt superficial peroneal 2.5 3.4 49
Rt sural 3.0 3.6 47
Sensory conductions
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Exercise test in Rt Median Nerve over APB
DL CMAP
Baseline 4.3 9.401
20 mints after prolonged exercise
3.7 6.23
Neuromuscular Presentation
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Needle Electromyography
Fib PSW Polyphasia Amp Duration Firing rate
Recruitment
Effort
Triceps - - 2+ -1 -1 N Full Full
TA - - 2+ N -1 N Full Full
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Treatment
• Oral K, intravenous saline with K+• Supportive Rx – admitted for observation
to 112• Propanolol 40 mg po bid started until
euthyroid state is reached
>>No new attacks, follow up with endocrinologist with radioiodine treatment planned
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• Myasthenia gravis (MG) is the most common NMJ disorder by far
• Immune-mediated disease which targets the Acetycholine receptor (AchR) or related structures with antibodies (Ab)
• Called gravis initially because of its bad prognosis when no therapies were available. Now, it is rare for anyone with MG to directly die of the disease
Myasthenia Gravis
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5 minutes of ice
applied
Myasthenia Gravis
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Famous People with Myasthenia Gravis
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Myasthenia Gravis
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• Prevalence of 50-400 cases per million • Annual incidence: 2.5 to 20 per million • Onset age has a bimodal pattern:
Myasthenia Gravis
Age Prevalence: 20 40 60 80 years
Late peak 6th-8th
decade, male
Early peak 2nd-4th decade, female
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• Ocular (>50%): Ptosis; Diplopia
Myasthenia Gravis
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Myasthenia Gravis
Eyelid Fatiguability
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Bulbar:Dysarthria, Dysphagia, Weak mastication Signs: Poor palatal elevation; Weak tongue May result in aspiration pneumonia
Myasthenia Gravis
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Myasthenia Gravis
• Weakness (>35%) – Distribution: Variable; Bulbar, Legs, or
Arms; Painless • Fatigue (Common)
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Respiratory failure • life-threatening!• Diaphragmatic and Intercostal muscle weakness• Strong indication for rapidly-acting therapeutic intervention (NEED TO HOSPITALIZE)• May require intubation and ventilation
Myasthenia Gravis
• Progression: insidious, weeks-months
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• MG patients will have normal muscle bulk, normoreflexia, and normal sensory exams• Aggravating factors: Systemic disease: Infections;Thyroid disease, stress, pregnancy, and Medications:certain antibiotics immune mediators
(prednisone; chloroquine)
Botox quinidineProcainamide Magnesium; β-blockers
Myasthenia Gravis
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• Consistent history and physical examination AND two positive diagnostic tests, preferably serological and electrodiagnostic• Diagnostic investigations of MG should usually include both:• Testing for serum anti-AChR antibodies• Repetitive nerve stimulation studies (part of EMG)
How is MG diagnosed?
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Edrophonium (Tensilon) Testing:• Action - Inhibits acetylcholinesterase• Prolongs presence of acetylcholine in NMJ• Enhances muscle strength• Duration: few minutes, short acting• Response seen in patients with NMJ dysfunction (not specific for MG)
How is MG diagnosed?
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How is MG diagnosed?
tensilon
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The Acetylcholine
Receptor Antibody
How is MG diagnosed?
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Modulation of post-synaptic AChRs by anti-
AChR antibodies - Increased AChR degradation
Anti-AChR antibodies cross-link post-synaptic AChRs
Cross-linked AChRs are endocytosed more rapidly than normal
Internalized AChRs are degraded. Fewer AChRs remain on the post-synaptic membrane
How is MG diagnosed?
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Complement binds to the Antibody-AChR complex. Membrane-attack complex (MAC) forms on the membrane
The post-junctional membrane is damaged, with fewer post-synaptic membrane folds, areduced numbers of AChRs, and widened synaptic clefts
How is MG diagnosed?
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Anti-AChR antibody presence: Most common in adults with generalized MG: 85-90% Less common in Childhood MG: 50% and Ocular MG: 50-70%
How is MG diagnosed?
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Repetitive Nerve Stimulation (RNS):• shows a repetitive decrement
How is MG diagnosed?
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Pyridostigmine (Mestinon)• 60 mg tid to 120 mg q3h or SR 90-180 mg qhs• First line treatment in most MG patients• Advantages: Few serious side effects• Disadvantages: cholinergic symptoms & ?crisis; not effective in all patients; ?does not treat disease, only symptoms
How is MG treated?
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Other treatments:PrednisoneAzathioprineIntravenous ImmunoglobulinPlasma ExchangeCyclophosphamideCyclosporineMycophenolate mofetil (Cellcept)
How is MG treated?
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Prednisone side effects:• Cushingoid features and weight gain• Bone: Avascular necrosis; Osteoporosis• Myopathy: Type II atrophy• Diabetes• Hypertension • Skin: Acne; Striae• Psychosis & Mood Disorders• Glaucoma• Infection
How is MG treated?
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Thymectomy:• Indications: generalized MG in < 55y, Thymoma• Only indicated as elective procedure (not emergent)• Advantages: Low morbidity• Disadvantages of thymectomy: benefits not understood, very-long term benefit only, very good and experienced surgeon necessary
How is MG treated?
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How is MG treated?
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• Transient neonatal myasthenia• Congenital forms of MG• Drug-induced forms of MG
Other forms of MG
Other NMJ Disorders
• Lambert-Eaton Myasthenic Disorder• Botulism
RARE!
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Case Discussion
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Motor Neuron Disease (MND)
• MND is a disease which targets the lower and/or upper motor neurons (LMNs, UMNs)
• The most common form of disease is Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s Disease
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Motor Neuron Disease (MND)
• ALS is a progressive disorder without known cure or cause
• Onset is insiduous and can present in different manners
• Incidence of ~1/100,000
• Typically presents between ages 30-80, with increasing incidence in later decades, with male=female
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Motor Neuron Disease (MND)
• Presents with either limb or bulbar-onset
• Limb onset will begin with progressive weakness of limb muscles with muscle atrophy and fasciculations
• Fasciculation is a sporadic contraction of muscle fibers in a motor unit due to an unstable motor neuron
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Motor Neuron Disease (MND)
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Motor Neuron Disease (MND)
• Weakness develops based upon both UMN and LMN disease
• Therefore, a mixture of signs can be seen on exam demonstrating both UMN and LMN dysfunction
• Spasticity may be seen in one arm with flaccidity in one leg
• Hyperreflexia may be seen in one leg, with hyporeflexia in one arm, etc.
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Motor Neuron Disease (MND)
• Along with weakness of limbs, bulbar dysfunction occurs as well (Bulbar onset form)
• Bulbar brainstem motor nuclei and their motor neurons, important for speech and swallowing
• Bulbar-onset ALS patients have their bulbar functions affected first
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Motor Neuron Disease (MND)
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Motor Neuron Disease (MND)
• Weight loss is often prominent in ALS
• In <10% of cases, cognitive changes can occur leading to dementia or behavioral changes
• In patients with bulbar dysfunction, a pseudobulbar affect may occur
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Motor Neuron Disease (MND)
• Other features of ALS include fatigue, cramps, pain due to immobility, and respiratory failure
• Features not part of ALS include sensory loss, eye movement abnormality, and sphincter disturbance
• Overall survival averages ~2 years from diagnosis, and ~3 years after symptom onset, but it is important to emphasize that this is an average
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Motor Neuron Disease (MND)
• One of the most important things to do is not to misdiagnose, and to rule out mimicsDifferential Diagnosis of ALSSpinal cord lesions (tumor, syrinx)Infections (HIV, syphilis, myelitis, poliomyelitis, Lyme disease)Endocrine (hyperthyroidism, hyperparathyroidism, diabetic radiculoneuropathy)Toxins (lead, mercury)Other (postpolio syndrome, Friedreich's ataxia, Kennedy’s syndrome, sarcoidosis, multiple sclerosis, polymyositis, myasthenia gravis, muscular dystrophies)
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How is ALS diagnosed?
Definite ALS -- progressive LMN and UMN signs in 3-4 body regions
Probable ALS -- progressive LMN and UMN signs in at least 2 regions with
Possible ALS --LMN and UMN in 1 region --UMN in two regions --LMN and UMN signs without progression
Suspected ALS--LMN signs in 2-3 regions
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How is ALS diagnosed?
• Although clinical findings are the most important method of diagnosis of ALS, EMG testing is necessary for assessment of muscles in ALS patients and uses El Escorial criteria
• EMG shows fibrillations, positive sharp waves and fasciculations
• EMG is also necessary to rule out other disorders
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What is avaliable for the ALS patient?
• While there are no cures, there are mechanisms to assist the ALS patient
• Riluzole is a glutamate receptor antagonist which has proven efficacy in ALS with prolongation of life by ~2-3 months
• Gastric tube placement can help maintain weight and quality of life in bulbar-affected ALS patients
• CPAP/BIPAP machines can help with nighttime respiratory functions in patients with respiratory failure or sleep apnea
•Ventilation can be an option in particular patients
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Other forms of MND
•ALS Variants Progressive Lateral Sclerosis (PLS)
- UMN form of ALS, which may develop into ALS in later stages Progressive Muscular Atrophy (PMA)
- LMN form of ALS, which also may develop into ALS in later stages
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Other forms of MND
•InfectiousPolio and post-polio syndrome West Nile Virus neuromyelitis HIV•HereditaryFamilial forms of ALS (i.e. superoxide dismutase, or SOD)Spinal Muscular AtrophyKennedy’s syndrome Friedrich’s Ataxia• ToxicLead Intoxication• OtherTay-Sachs disease (adult form)Guam complex Immune-mediated motor neuropathiesParaneoplastic neuropathies/MND