motor neurons, the neuromuscular junction, and muscle university of calgary medical school...

Motor Neurons, the Neuromuscular Junction, and Muscle

University of Calgary Medical School

Neurosciences Course

Cory Toth

August 27, 2007

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

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?

The Motor Unit

• The motor unit is a group of muscle fibers and the single motor nerve that activates the fibers

Muscle

NMJ

Motor Neuron

Peripheral Nerve

Muscle Contraction

Muscle Contraction

Muscle Contraction

1) Peripheral nerve impulse is required, with the impulse transferred from an axon to the SARCOLEMMA of a muscle cell

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

Muscle Contraction

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.

Muscle Contraction

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

Muscle Contraction

Muscle Contraction

5) Movement of TROPOMYOSIN permits the MYOSIN HEAD to contact ACTIN6) Contact with ACTIN causes the MYOSIN HEAD to swivel

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)

Muscle Contraction

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

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…

Muscle Disease (Myopathy)

Muscle Appearance

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

Recordings in the junction reveal local potential changes before a regenerative action potential is produced.

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).

The Neuromuscular Junction (NMJ)

The Neuromuscular Junction (NMJ)

The NMJ is an example of fast chemical transmission

The Neuromuscular Junction (NMJ)

The Neuromuscular Junction (NMJ)

There are many ways that we manipulate the NMJ, or in which disorders manipulate the NMJ

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

NeuromuscularNeuromuscular Transmission:Transmission:

Step by StepStep by StepNerve actionpotential invadesaxon terminal

-

+-

-

-

-

--

+

+

+

+

+

++

--

-

+ +

Depolarizationof terminalopens Ca channels

Lookhere

+ +

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

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.

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

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+

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

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

AChreceptorsite

Acetylcholinesterase

Aceticacid

CholineACh

6. ACh is rapidly broken down in the synaptic cleft byacetylcholinesterase to acetic acid and choline.

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.

Choline

8. Acetic acid is taken up by many cell types.

Aceticacid

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

Structural Reality

By John Heuser and Louise EvansUniversity of California, San Francisco

The Neuromuscular Junction (NMJ)

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)

The Neuromuscular Junction (NMJ)

The molecules associated with the NMJ are numerous and complex – too much to know

• Weakness occurs when the nerve impulse to initiate or sustain movement does not adequately reach muscle cells

The Neuromuscular Junction (NMJ)

ID: 29 yrs old RH Male

CC: Abrupt onset of profound quadriparesis

Neuromuscular Presentation

HPI:

• Sore Muscles and felt fatigued after 40 minutes of working out in gym

• Developed quadriparesis over next 20 hours

• No sensory symptoms

Neuromuscular Presentation

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

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

• Family Hx : unremarkable

• Social Hx: unremarkable

Neuromuscular Presentation

ExaminationGeneral examination:

GA: Alert, looked unwell

VS: T 37 C, BP 120/70mmHg,HR 88/m- regular

.

CVS, Respiratory, Abdomen: Unremarkable

Neuromuscular Presentation

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

• Sensation: normal to pin, touch, temperature, JPS and vibration to all limbs

Neuromuscular Presentation

Neuromuscular Presentation

Investigations

Neuromuscular Presentation

Chemistry and Hematology Blood Tests ECG

Electrophysiology Chest X-Ray

Lumbar Puncture Stool Culture

Antibody Testing Neuroimaging

Other Blood Tests

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

• 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

Neuromuscular Presentation

Neuromuscular Presentation

CXR Normal

Neuromuscular Presentation

Lumbar Puncture not performed

Neuromuscular Presentation

Stool Culture not performed

Neuromuscular Presentation

Antibody testing not performed

Neuromuscular Presentation

Neuroimaging not performed

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

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

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

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

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

• 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

5 minutes of ice

applied

Myasthenia Gravis

Famous People with Myasthenia Gravis

Myasthenia Gravis

• 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

• Ocular (>50%): Ptosis; Diplopia

Myasthenia Gravis

Myasthenia Gravis

Eyelid Fatiguability

Bulbar:Dysarthria, Dysphagia, Weak mastication Signs: Poor palatal elevation; Weak tongue May result in aspiration pneumonia

Myasthenia Gravis

Myasthenia Gravis

• Weakness (>35%) – Distribution: Variable; Bulbar, Legs, or

Arms; Painless • Fatigue (Common)

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

• 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

• 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?

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?

How is MG diagnosed?

tensilon

The Acetylcholine

Receptor Antibody

How is MG diagnosed?

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?

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?

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?

Repetitive Nerve Stimulation (RNS):• shows a repetitive decrement

How is MG diagnosed?

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?

Other treatments:PrednisoneAzathioprineIntravenous ImmunoglobulinPlasma ExchangeCyclophosphamideCyclosporineMycophenolate mofetil (Cellcept)

How is MG treated?

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?

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?

How is MG treated?

• 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!

Case Discussion

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

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

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

Motor Neuron Disease (MND)

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.

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

Motor Neuron Disease (MND)

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

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

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)

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

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

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

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

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