Case 4: Ivan Netter

Neuromuscular Junction (NMJ): Description

Synapse between LMN + skeletal muscle

Involved in excitation-contraction coupling

NMJ: LMN

Presynaptic neuron

1. Receive AP from axon = Presynapatic membrane depolarize = Open voltage-gated Ca2+ channels

2. Ca2+ influx into presynaptic terminal = Vesicles containing ACh fuse with presynaptic membrane = Release ACh into synaptic cleft

NMJ: Skeletal Muscle

1. ACh bind cholinergic nicotinic receptors on postsynaptic membrane (muscle motor end plate) = Na+ enter muscle

2. Muscle sarcolemma depolarize = End-plate potential (EPP) → T-tubules

3. Voltage-sensitive dihydropyridine receptors (DHPR) in T-tubules + ryanodine receptors in SR open = Release Ca2+ from SR into sarcoplasm (intracellular)

4. Tropomyosin unbind myosin-binding site on actin = Crossbridge cycling + muscle contraction

NMJ: Synaptic Cleft

1. Acetylcholinesterase (AChE) breaks down ACh → Acetate + choline

2. Choline reuptake into presynaptic membrane = Resynthesize ACh

NMJ Disorders: Etiology

Autoimmune: Myasthenia gravis

Paraneoplastic: Lambert-Eaton myasthenic syndrome (LEMS)

• Autoimmune condition = Abs against presynaptic Ca2+ channels = Inhibit ACh release

• From small cell lung cancer

Toxic:

• Botulism

• Cholinergic poisoning (organophosphates)

• Tick paralysis

• Snake venom

NMJ Disorders: Clinical Presentation

Muscle weakness: Lack of strength

Muscle fatigue: Inability to continue after multiple repetitions

Neuromuscular weakness: Impaired motor function (strength or ROM)

• Paresis: Mild-moderate

• Paralysis: Severe or complete

NMJ Disorders: Management

Autoimmune + Paraneoplastic: Immunosuppressants

• Corticosteroids (prednisone)

• Steroid-sparing immunosuppressants (MTX, axathioprine)

• Biologics (rituximab)

Toxic:

• Respiratory support

• Remove source

• Administer antitoxin

Myasthenia Gravis (MG): Description

Autoimmune NMJ disorder → Muscle weakness

• Ocular: Affects only extraocular + eyelid muscles

• Generalized: Affects all skeletal muscles

MG: Epidemiology

More common in women

Risk factors…

• Other autoimmune conditions

• Thymoma (tumor in anterior mediastinum)

• Thymic hyperplasia

• Allogenic stem cell transplantation

MG: Etiology

Autoantibodies against postsynaptic ACh receptors (AChR) or receptor-associated proteins (muscle-specific tyrosine kinase = AChR formation)

MG: Pathophysiology

1. Autoantibodies target postsynaptic AChR on muscle cells =

• Competitive AChR inhibition

• AChR internalization/degradation

• Complement activation

2. Impair signal transduction at NMJ (AChR inhibition + internalization) OR muscle cell lysis (complement) = Skeletal muscle weakness + fatigue

• Thymus: Muscle-like (myoid) cells express AChR = T cells target AChR = Produce AChR autoantibodies

MG: Clinical Presentation

Muscle fatigue + weakness

• Worse with use

• Improves with rest

Eye muscles

• Diplopia

• Blurred vision

• Ptosis: Drooping eyelids

Bulbar (face + neck) muscles

• Dysarthria (impaired speech)

• Dysphagia

Proximal muscles

• Difficulty standing + climbing stairs

• Difficulty brushing hair

Respiratory muscles

• Dyspnea

• Resp failure

MG: Investigations

Physical exam

Lab tests

EMG study

Chest CT

Tensilon/Edrophonium test

MG Investigations: Physical Exam

Normal deep tendon reflexes

Plantar responses

• Down going

Ocular Tests:

• Ice-Pack Test: Ice pack on affected eyelid for 5 mins = Improve ptosis

• Curtain Sign: Lifting more ptotic eyelid = Worsens ptosis in contralateral eyelid

• Cogan Lid Twitch Sign: Eyelid twitching after 10-20 sec downward gaze

• Simpson Test: Looking up for > 1 min = Eyelid fatigue

MG Investigations: Lab Tests

Anti-AchR abs

Anti-MuSK abs: Negative anti-AChR abs

MG Investigations: EMG Study

Negative anti-AChR abs

Decremental response on repetitive stimulation

MG Investigations: Chest CT

Assess thymoma or thymic hyperplasia

MG Investigations: Tensilon/Edrophonium Test

Process:

1. Administer rapid-acting short-duration AChE inhibitor

2. Assess symptoms improvement

Not performed

MG: Treatment

Pharmacological

Surgery

MG Treatment: Pharmacological

AChE inhibitor

• MOA: Inhibit ACh breakdown = Increase ACh action at NMJ = Improve muscle contraction + strength

• First-Line: Pyridostigmine

Immunosuppressants

• Indication: Pyridostigmine inadequacy/intolerance

• Ex: Glucocorticoids, azathioprine

MG Treatment: Surgery

Thymectomy

Indications:

• Thymoma

• Immunotherapy unsuccessful/intolerance

MG: Complications

Myasthenic Crisis: Acute symptom exacerbation → Resp failure

MG: DDX

Lambert-Eaton myasthenic syndrome (LEMS)