7 - Neuromuscular Junction Flashcards
Pathophysiology MG vs LEMs vs Botulism ππ EXAM
MG
ABx against postsynaptic ACh receptors
Decreased ACh quantal response
LEMS
Abx against voltage gated calcium channels
Decreased quantal content leaving the presynaptic cleft
Botulism
Botulinum toxin inhibiting presynaptic release of ACh
Myasthenia gravis (MG) ππ Pathophysiology - Course - PEx - Characteristics - Diagnostic Invx - EDX (EXAM) - Treatment
Pathophysiology
- Postsynaptic membrane
- Antibodies against the ACh Receptors
- Antibodies against Muscle Specific Tyrosine Kinase (MuSK)
- Associated with thymic disorder or thymic tumor
Course
- Bimodal distribution First Peak: 20β30 years, Second Peak: 60β80 years
Clinical Presentation
- Ocular: Ptosis - Diplopia
- Bulbar: Dysphagia - Dysarthria
- Limb/girdle: Painless proximal fatigue and weakness
- Normal MSR & Sensation
Characteristics
- Fatigable muscle weakness that worsens with activity and improves on rest
- Exacerbated with exercise, heat, or time of day (evening)
- Edrophonium (Tensilon) Test: 2-mg followed by 8-mg, improvement begins in 1 minute
Investigation
- Muscle biopsy: Loss of junctional folds and receptors
- Anti-Ach receptor antibodies
- Anti-MuSK antibodies
NCS of Neuromuscular Junction Disorder
- Normal SNAP and CMAP (we need sustained contraction/stimulation)
- Low repetitive RNS (2-3 Hz) shows >10% decrement
EMG of Neuromuscular Junction Disorder
- Spontaneous activity (Fibs)
- Unstable MUAP, drop-off with sustained contraction (neuromuscular junction blocking)
- Single-fiber EMG Increased Jitter & Blocking (most sensitive test)
Treatment
- Thymectomy
- Anticholinesterase, Mestinon (Pyridostigmine) 30 mg q 4 to 6 hours
- Immunosuppressive: Corticosteroids
- Emergency: Plasmapheresis, IVIg
Cuccurollo 4th Edition Chapter 5 EDX pg431Table 5-43
List 4 cranial nerve symptoms in MG π
π‘ Look at the right eye, ptosis and pupils is shifted to right (diplopia).
- Ocular weakness (Ptosis)
- Diplopia
- Dysphagia
- Dysarthria
Cuccurollo 4th Edition Chpater 5 EDX pg431 Table 5-43
Myasthenia Gravis. Electrodiagnostic findings 4 marks ππ
EXAM 2021
List 2 Important EDX tests for MG and their findings. ππ
π‘ Most Important:
- Repetitive nerve stimulation (Low rate 2-3 Hz): >10% Decrementing CMAP
- Single-fiber EMG (most sensitive): Increased jitter
NCS
- Normal SNAP (Myopathy)
- Normal CMAP (We need repetitive stimulation, single stimulation is normal)
- RNS: CMAP >10% decrement on low rate repetitive stimulation 2-3Hz
EMG β Myopathy & MND
- Abnormal spontaneous activity
- Early recruitment (Help from other motor neuron)
- Short duration, low amp, unstable MUAP (Weak NMJ)
Single fiber EMG
- Increase fiber density
- Jitter & blocking
Cuccurollo 4th Edition Chapter 5 EDX pg432 Table 5β43
List 2 investigation to be monitored in MG patient. What could kill them? ππ
- Swallowing assessment (aspiration)
- Pulmonary function test (bulbar dysfunction β respiratory failure)
- Malignancy β CT Chest
What is Edrophonium (Tensilon) test?
Edrophonium
Reversible acetylcholinesterase inhibitor with rapid onset and short duration of action resulting in an increase of acetylcholine in the neuromuscular junction (NMJ)
How
IV Tensilon given at 2mg bolus doses with max of 10mg.
Patient should notice improvement (increased strength) within 30 seconds to 5-10 minutes
Small risk of precipitating cardiac arrhythmia β Atropin should be available
PMR Secrets 3rd Edition Chapter 19 NMJ pg162 Q13
LambertβEaton myasthenic syndrome (LEMS) ππ Location - Etiology - Onset - Clinical presentation - Characteristics - Labs - EDX - Treatment
Location
- Presynaptic
Etiology
- Antibodies against voltage-gated Ca+ channels
- Decreases Ca++ entry into the cell β decreased release of ACh into the synaptic cleft.
- Associated with small cell (oat cell) carcinoma of the lung β Monitor with CT
Onset
- Bimodal distribution First Peak: 40 years, Second Peak: 60 years
Clinical presentation
- Proximal fatigue and weakness, mainly lower limbs (quadriceps first)
- Rarely involves the neck, facial, or bulbar muscles in contrast to MG
- Vice like grip βoverly firm handshakeβ
- Abnormal MSR (like Botulism, EXAM Q)
- Autonomic symptoms (like Botulism)
- Mouth: Dry mouth
- GU: Erectile dysfunction
- GI: Constipation
Characteristics
- Exacerbated with rest
- Improved with exercise
Labs
- Overdevelopment of neuromuscular junction
NCS
- SNAP: Normal
- CMAP: Low amplitude (unlike MG, amount of ACh released is low)
- RNS: >10% decrement on low rate 2-5 Hz BUT increased at high rate 50 Hz.
EMG like MG
- Unstable MUAP, drop-off occurs with sustained contraction
- Single-fiber EMG jitter and blocking
Treatment
Treat malignancy
IV Immunoglobulin
Plasmapheresis
Immunosuppressive agents: Corticosteroids
Guanidine: Increases ACh quanta
Side effects: GI, bone marrow suppression, renal tubular necrosis
3,4-diaminopyridine
Cuccurollo 4th Edition Chapter 5 EDX pg431 Table 5-43
List 2 NCS studies to confirm LEMS ππ
- Post Activation/Exercise/Contraction increase in CMAP
- Rapid repetitive nerve stimulation (high frequency)
List 4 clinical differences in LEMS vs MG. ππ EXAM
Cuccurollo 4th Edition Chapter 5 EDX pg431 Table 5-43
Botulism Location - Etiology - Onset - Clinical presentation - Labs - EDX - Treatment
Location
- Presynaptic
Etiology
- Ingestion of contaminated raw meat, fish, canned vegetables, and raw honey.
- Botulinum toxin: Found in stool or blood serum
- Clostridium botulinum toxins blocking presynaptic exocytosis of ACh from the nerve terminal
Onest
- Begins 2β7 days after ingestion
Presentation
- Bulbar symptoms are noted first (look at the picture arrow β)
- Ocular weakness (Ptosis)
- Dysphagia
- Dysarthria
- Respiratory and cardiac dysfunction
- GI symptoms: Diarrhea, N/V
- Widespread paralysis or flaccidity
- Decreased deep tendon reflexes
NCS
- SNAP: Normal
- CMAP: Abnormal amplitude
- RNS Low rate 2-3 Hz >10% decrement
EMG
- Unstable MUAP
- See single-fiber EMG
Treatment
- ABE antitoxin
- Supportive: intubation
- Recovery via collateral sprouting
Cuccurollo 4th Edition Chapter 5 EDX pg431 Table 5-43
How to Distinguishing MG vs. Botulism ππ EXAM
Similarities
- Weakness
- Bulbar Symptoms (Dysphagia, Dysarthria)
- Ocular weakness (Ptosis)
- Flaccid Paralysis (Proximal > Distal, Eyes to Toes)
- Respiratory Failure
- EDX (Same findings of NMJ)
- 10% decrement on low rate repetitive stimulation
- Unstable MUAP
Differences
- Presynaptic
- GI Symptoms: Diarrhea, N/V
- Respiratory and cardiac dysfunction
- Decreased deep tendon reflexes
- Decreased CMAP (low ACh content)
EDX in any NMJ disorders ππ
NCS
- Sensory SNAP: Normal
- Motor CMAP: Decreased AMP
- Post exercise CMAP: Increased amplitudes >100% seen in LEMS (low ACh content)
- RNS
- Low rate 2-3 Hz > 10% decrement in all of them
- High Rate 40-50 Hz 200-300% increment in LEMS > Botulism (low ACh content)
EMG
- Abnormal spontaneous activity: Fibs & PSWs
- Early recruitment (myopathic pattern)
- MUAPs: Shot duration, low amp, unstable (myopathic pattern)
Cuccurollo 4th Edition Chapter 5 EDX pg430
What is the βsafety marginβ for neuromuscular transmission? How is the safety margin for neuromuscular transmission altered in MG?
π‘ TL;DR In normal condition, we produce so much action potential from EEP (3x more than what we actually need to generate muscle action potential) that even if we repetitively contract the muscle or stimulate it or simply exercise it we will not be that much fatigue, we are still able to generate muscle contraction (muscle action potentials), so we ARE SAFE TO EXERCISE AND SAFE FROM FATIGUE.
In the normal subject, the amount of ACh released from the presynaptic nerve terminal decreases with each repeated nerve depolarization at a slow rate. This means fewer receptors are activated at the muscle endplate, generating fewer MEPPs and a lower EPP. However, the number of receptors is still high enough that this slight decline in ACh output does not drive the EPP below the depolarization threshold for the muscle fiber, and full contraction still occurs. This functional redundancy is known as the safety margin for neuromuscular transmission.
In MG, antibodies decrease the number of functional AChRs. Because fewer AChRs are available for activation, the safety margin for neuromuscular transmission is lowered. Fewer MEPPs are generated when ACh output falls and the EPP is lower. With repeated activation of the nerve and further declines in ACh output, the EPP eventually falls below the threshold necessary to trigger depolarization and contraction of the muscle fiber (blocking of neuromuscular transmission). With continued activation of the nerve, this happens at an increasing number of NMJs and many muscle fibers fail to activate, causing weakness. With extrinsic repetitive electrical stimulation of the nerve at low frequencies, the size of the electrical response accompanying muscle contraction (the compound motor action potential or CMAP) decreases due to this same phenomenon. After a period of rest, ACh content is restored, and these abnormalities may improve
Neurology Secrets 6th Edition Chapter 5 NMJ pg65-67
Explain Repetitive nerve stimulation (RNS)
What are the precautions? π
List 4 muscles that can be evaluated in RNS. ππ
Method
- Repetitive motor study with supramaximal stimulus measuring CMAPs.
Aim of study
- Confirm diagnosis of NMJ
- Depleting ACh store, result in failure of neuromuscular transmission and less APs.
- > 10% decrease in amplitude from the first to fifth waveform
Muscles
- Orbicularis oculi
- Deltoid
- Abductor digiti minimi
- Abductor pollicis brevis
Precautions
- Best performed on the clinically weak muscle(s).
- Cholinesterase inhibitors should be held for 12 hours
Cuccurollo 4th Edition Chapter 5 EDX pg433
Patient suspected MG, explain to patient the steps of RNS (EDX Clinic)
π‘ High-rate repetitive stimulation (HRRS) is uncomfortable and is typically performed if a patient is unable to perform a 30- to 60-second maximal isometric contraction.
- Stop anticholinesterase inhibitors 12 hr prior to the study.
- Preform on weak muscle group
- Optimize limb temperature (approximately 30Β°C)
- Minimize electrode gel
- Immobilize the electrode
- Immobilize the limb
- Stimulate at a supramaximal level
List 3 Parameters measured in single fiber EMG in NMJ disorders. π
π‘ SFEMG is the single most sensitive test for MG and is positive in 95% of generalized cases and 90% of pure ocular cases.
-
Fiber density (Figure 5-126)
- Density increased after denervation and reinnervation process.
-
Jitter (Fig 37.4 B)
- AP variation of two muscle fibers belonging to the same motor unit
- Normally 10-60 ΞΌsec.
- Low safety factor and cause a delay in the time for an EPP to reach threshold for a muscle fiber AP, which increases the jitter between the two neighboring muscle fiber
- Immature NMJs have poor activation, resulting in increased jitter within the first month.
- Reinnervation through collateral sprouting after a nerve injury also can cause a delay.
-
Blocking (Fig 37.4 C)
- If Jitter becomes > 100 ΞΌsec, then single muscle fiber AP fails to appear.
- Take approximately 6 months to resolve.
Cuccurollo 4th Edition Chapter 5 EDX pg436-437
Neurology Secrets 6th Edition Chapter 5 NMJ pg70
Patient suspected MG, Single Fiber EMG (SFEMG) was abnormal. List 2 other DDx. π Think anatomy, other pure motor diseases with normal sensation.
- Myopathies.
- NMJ disorders.
- Axonal neuropathies.
- Motor neuron disorders: ALS
Cuccurollo 4th Edition Chapter 5 EDX pg437
