Download ACh - Calgary Emergency Medicine

Motor Neurons, the
Neuromuscular Junction,
and Muscle
Cory Toth
August 27, 2007
University of Calgary
Medical School
Neurosciences Course
Objectives
1) Define muscle disease (myopathy) and
discuss their clinical presentation
2) Discuss common forms of muscle disease
3) Review of the neuromuscular junction
(NMJ)
4) Define myasthenia gravis and discuss
their clinical presentation
5) Discuss other forms of NMJ disease
Objectives
6) Describe motor neuron diseases
(MND) and discuss their clinical
presentation
7) Describe how MND is diagnosed
8) 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
Peripheral Nerve
Muscle
Motor
Neuron
NMJ
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 TTUBULES. 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 ACTIN
6) 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 crossbridge (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
Ca2+
Ca2+
Presynaptic
channel terminal
Action
potential
1. An action potential arrives at the presynaptic terminal
causing voltage gated Ca2+ channels to open, increasing
the Ca2+ permeability of the presynaptic terminal.
Depolarization
Nerve
action
of terminal
opens Cainvades
channels +
potential
+
axon terminal
-
-
-
-
Neuromuscular
Transmission:
+
Step by Step
-
+
+
+
Look - +
here + -
-+
+
-++
-
Ca2+
Presynaptic
Ca2+
channel terminal
ACh
2. Ca2+ enters the presynaptic terminal and initiates the
release of a neurotransmitter, acetylcholine (ACh), from
synaptic vesicles in the presynaptic terminal.
Synaptic cleft
Na+
ACh
Na+
Receptor
molecule
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.
Binding
ofreleased
ACh
opens
Ca+2binds
induces
fusion
ACh
to its
ACh
is
and of
channel
pore
that
is
vesicles
with
receptor
on
the nerve
diffuses
across
+ and K+.
permeable
to
Na
terminal
membrane.
postsynaptic
membrane
synaptic cleft.
ACh ACh
ACh
Ca+2
Ca+2
Na+
Na+
Na+
K+
Na+
K+
Na+
K+
ACh
Na+
Na+
K+
Na+
Na+
K+
Outside
Muscle membrane
Na+
K+
Na+
K+
Na+
K+
Inside
K+
Na+
K+
K+
K+
K+
Na+
Na+
Action
potential Na+
Action
potential
4. The increase in Na+ permeability results in depolarization
of the postsynaptic membrane; once threshold has been
reached a postsynaptic action potential results.
End Plate Potential (EPP)
Presynaptic
terminal
VNa
Muscle Membrane
Voltage (mV)
The movement of Na+ and K+
depolarizes muscle membrane
potential (EPP)
0
EPP
Threshold
-90 mV
VK
Presynaptic
AP
Time (msec)
Outside
Muscle membrane
Inside
ACh Receptor Channels
Na Channels
ACh
Synaptic ACh
receptor
cleft
site
Postsynaptic
membrane
Na+
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.
ACh
Choline Acetic
acid
ACh
receptor
site
Acetylcholinesterase
6. ACh is rapidly broken down in the synaptic cleft by
acetylcholinesterase to acetic acid and choline.
Presynaptic
terminal
ACh
Acetic
acid
Synaptic
vesicle
Choline
ACh
Choline
7. The choline is reabsorbed by the presynaptic terminal
and combined with acetic acid to form more ACh, which
enters synaptic vesicles.
Choline Acetic
acid
8. Acetic acid is taken up by many cell types.
ACh
Choline
ACh ACh
Choline
Meanwhile ...
ACh
isthe
by
Choline
Choline
ishydrolyzed
taken
upfrom
ACh
unbinds
soresynthesized
channel
closes
AChE
into
Choline
into
ACh
and
repackaged
into
nerve
terminal
its
receptor
acetate
into and
vesicle
ACh
Acetate
ACh
Outside
Muscle membrane
Inside
The Neuromuscular
Junction (NMJ)
Structural Reality
By John Heuser and Louise Evans
University 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 molecules
associated with
the NMJ are
numerous and
complex – too
much to know
The Neuromuscular
Junction (NMJ)
• Weakness occurs when the nerve impulse to
initiate or sustain movement does not adequately
reach muscle cells
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
Neuromuscular Presentation
• 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
Examination
General examination:
GA: Alert, looked unwell
VS: T 37 C, BP 120/70mmHg,HR 88/m- regular
.
CVS, Respiratory, Abdomen: Unremarkable
Neuromuscular Presentation
Neurological Examination
Cranial 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
Chemistry and Hematology
Blood Tests
Other Blood Tests
Electrophysiology
Lumbar Puncture
Antibody Testing
ECG
Chest X-Ray
Stool Culture
Neuroimaging
Neuromuscular Presentation
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
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
Motor nerve conductions
Nerve
Rt. Median
Wrist
Elbow
Rt .tibial
Ankle
Pop fossa
Rt . peroneal
Ankle
Fibular head
Knee
Latency
(ms)
Amplitude (mV) CV (m/s) Minimal F wave
(ms)
4.3
7.7
9.401
9.114
56
25.0
4.8
12.4
12.71
10.77
53
46.2
4.2
9.8
11.9
7.245
7.120
6.771
52
48
45.6
Sensory conductions
Nerve
Latency (ms)
Amplitude(μV)
CV (m/s)
Rt. Median sensory
Wrist
Elbow
2.8
5.9
0.028
0.018
61
Rt superficial peroneal
2.5
3.4
49
Rt sural
3.0
3.6
47
Neuromuscular Presentation
Exercise test in Rt Median Nerve over APB
DL
CMAP
Baseline
4.3
9.401
20 mints after prolonged
exercise
3.7
6.23
Needle Electromyography
Fib
PSW
Polyphasia
Amp
Duration
Firing
rate
Recruitm
ent
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
• 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
Myasthenia Gravis
5
minutes
of ice
applied
Famous People with
Myasthenia Gravis
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:
Early peak
2nd-4th decade, female
Late peak
6th-8th
decade,
male
Age Prevalence:
20
40
60
80 years
Myasthenia Gravis
• Ocular (>50%): Ptosis;
Diplopia
Myasthenia Gravis
Eyelid
Fatiguability
Myasthenia Gravis
Bulbar:
Dysarthria, Dysphagia,
Weak mastication
Signs: Poor palatal
elevation; Weak tongue
May result in aspiration
pneumonia
Myasthenia Gravis
• Weakness (>35%)
– Distribution: Variable; Bulbar, Legs, or
Arms; Painless
• Fatigue (Common)
Myasthenia Gravis
• Progression: insidious,
weeks-months
Respiratory failure
• life-threatening!
• Diaphragmatic and Intercostal
muscle weakness
• Strong indication for rapidlyacting therapeutic intervention
(NEED TO HOSPITALIZE)
• May require intubation and
ventilation
Myasthenia Gravis
• 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
Procainamide
quinidine
Magnesium; β-blockers
How is MG
diagnosed?
• 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?
tensilon
How is MG
diagnosed?
The
Acetylcholine
Receptor
Antibody
How is MG
diagnosed?
Anti-AChR antibodies
cross-link post-synaptic
Internalized AChRs are
AChRs
degraded. Fewer AChRs
remain on the postsynaptic membrane
Cross-linked AChRs are
endocytosed more rapidly
than normal
Modulation of post-synaptic AChRs by antiAChR antibodies - Increased AChR
degradation
How is MG
diagnosed?
Complement binds to
the Antibody-AChR
complex. Membraneattack complex (MAC)
forms on the membrane
The post-junctional
membrane is damaged, with
fewer post-synaptic
membrane folds, a
reduced 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 treated?
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:
Prednisone
Azathioprine
Intravenous Immunoglobulin
Plasma Exchange
Cyclophosphamide
Cyclosporine
Mycophenolate 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?
Other forms of MG
• Transient neonatal myasthenia
• Congenital forms of MG
• Drug-induced 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 mimics
Differential Diagnosis of ALS
Spinal 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
•Infectious
Polio and post-polio syndrome West Nile Virus neuromyelitis
HIV
•Hereditary
Familial forms of ALS (i.e. superoxide dismutase, or SOD)
Spinal Muscular Atrophy
Kennedy’s syndrome
Friedrich’s Ataxia
• Toxic
Lead Intoxication
• Other
Tay-Sachs disease (adult form)
Guam complex
Immune-mediated motor neuropathies
Paraneoplastic neuropathies/MND