NMJ Disorders

Describe Myasthenia Gravis:

• STATs

• Associated w/ what other diseases?

• Clinical Presentation?

• Pathogenesis?

STATs:

• most common disorder of neuromuscular transmission

  • 200 cases per million people

• Bi-modal distribution: women < 40 or men > 65

• Etiology Stats

  • Generalized MG-85% have AchRAb and 8-10% have muscle specific tyrosine kinase receptor antibodies (MuSK)

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Associated w/ other autoimmune disorders:

• Autoimmune thyroid disease

  • 60-70%: have thymic hyperplasia

  • 10-12% have thymoma

• SLE

• rheumatoid arthritis

• neuromyelitis optica spectrum disorder (NMO-SD)

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Clinical Presentation:

• Fluctuating, intermittent symptoms sometimes w/ periods of spontaneous improvement

• Appearing with repetitive activity; worsening as day progresses

• Muscle fatigue and weakness

• Characteristically affects extra-ocular, bulbar or proximal limb muscles

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Pathogenesis:

• Autoantibodies against the AChR (post synaptic)-> receptor destruction (complement)

  • Decreases # of active Ach binding

  • Destruction of post-synaptic folds

List the types of presentation in MG

Describe Ocular Onset MG

• STATs

• Symptoms

Ocular Onset MG

STATs

• Most common

• Eventually 90% of MG patients have ocular symptoms

• 15% continue to have isolated ocular symptoms

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Symptoms:

• Ptosis 

• Extraocular weakness 

  • Begins asymmetrically

  • Mimics 3rd 4th and 6th nerve palsies and, rarely INO-(InterNuclear Ophthalmoplegia)

• NOTE:  Unlike true 3rd nerve palsies MG never affects pupillary function

Describe the normal measurements for eyelids and palpebral fissure

What does the Ptosis-primary gaze look like?

What does the upward gaze w/ ptosis look like in pts w/ mg?

Describe Bulbar-onset MG

• STATs

• Symptoms

• STATs

  • next most common type of MG

• Symptoms:

  • Dysphagia

  • Dysarthria

    • nasal speech, slurred and hypophonic

  • Mastication Fatigability/weakness

    • inability to keep the jaw closed after chewing.

  • Nasal regurgitation

1. Describe the Facial muscles involvement in MG

2. Describe limb involvement in MG\

3. Describe Resp. Involvement in MG

Facial muscles involvement in MG

• Characteristics:

  • Freq. involved

  • Pts appear expressionless

  • "myasthenic sneer

    • attempting to smile where the mid- lip rises but the outer corners of the mouth fail to move

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Limb involvement in MG

• Characteristics:

  • Limb weakness

    • Symmetric + prox.

  • Affects  Wrist and finger extensors and foot dorsiflexors 

  • RARELY:

    • Isolated + no eye/bulbar weakness

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Respiratory Involvement in MG

• Characteristics:

  • Difficulty breathing, SOB

  • Obstructive sleep apnea

  • Difficulty sleeping on flat bed

What does the Myasthenic sneer look like?

Describe the Diagnostic Tests for MG

• Bed Side Tests

• Serologic testing

• Other Tests

Bed side tests:

• Tensilon test: 

  • Inject edrophonium (AcHE inhibitor) -> improvement in ptosis/ ophthalmoparesis 

• Ice pack test

  • Cooling -> reduce AcHE act. By making more Ach available @ NMJ

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Serologic testing:

• Acetylcholine receptor antibodies (AChR-Ab)

  • 80-90% of generalized MG have AChR-Ab

  • 50% of ocular MG have AChR-Ab

•  Lrp4-Low density lipoprotein-related protein 4

  • 3-50% of AchR-Ab NEG patients

• Anti Muscle-specific kinase antibodies (MuSK-Ab)

  • 38-50% of generalized MG who are AChR-Ab —NEG

  • Much lower frequency of thymic pathology

  • More common in females

  • Usually present with severe oculobulbar weakness along or neck, shoulder, and respiratory weakness

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Other Tests

• Repetitive nerve stimulation studies

  • Single-fiber electromyography (EMG) = most sensitive test

• Ct Scan of Chest

Describe the Treatment of MG

• In Crisis

• Ongoing Treatment

Crisis

• Plasma Exchange (1.5 total blood volume)

• IVIG

  • Efficacy equal but fewer side effects 

• IV Rituxan for refractory cases

  • More efficacious in Musk positive patients

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Ongoing Treatment

• Pyridostigmine 

• Oral steroids

• Oral immunosuppressants

  • Azathioprine

  • Cellcept-Avoid in pregnancy

Describe Soliris 

• AKA?

• Uses besides MG

• MOA?

• Req. to Prescribe?

• Costs?

Soliris 

• AKA:

  • (Eculizumab)

• Uses besides MG

  •  Paroxysmal Nocturnal Hemoglobinuria 

  • Typical Hemolytic Uremic Syndrome

• MOA

  • binds + inhibits cleavage of C5 

• Req. to Prescribe:

  • generalized MG

  • AChR-Ab POSITIVE

  • Failed other immunosuppressants

• Costs:

  •  $500,000 annually

Describe Ultomiris 

• AKA?

• MOA?

• Req. to Prescribe

• Cost

• Dose

Ultomiris 

• AKA: ravulizumab-cwvz

• MOA:

  • Long acting C5 complement inhibitor

• Req. to prescribe:

  • AChR-Ab positive

• Cost:

  • $458,000 annually

• Dose:

  • Loading dose based on weight then Infusion every 8 weeks

Describe Vyvgart 

• AKA?

• MOA?

• Req. to Prescribe

• Cost

Vyvgart 

• AKA: (efgartigimod-alpha)

• MOA:

  • IgG Abs to Fc of IgG auto Abs -> degradation

• Req. to Prescribe:

  • general MG patients who are AChR-Ab positive

• Cost: $225,000 annually

Describe the prognosis of MG

• Phases?

MG Prognosis

• Early: Symptoms transient -> worsens/more persistent months later -> max. Weakness w/in 2 yrs 

Phases:

• First phase

  • Active phase w/ fluctuations + more severe symptoms

  • First 5-7 years

  • Most myasthenic crises occur in this early period.

• Second Phase

  • Symptoms stable but persists

    • Can get worst:

      • infection, medication taper, or other perturbations

• Third Phase

  • Remission can occur

Describe Myasthenic Crisis

• Definition

• Cause

Myasthenic Crisis

• Definition: 

  • Weakness from acquired MG that is life threatening and severe enough to necessitate intubation

• Cause:

  • weakness of respiratory muscles

    • Severe oropharyngeal muscle weakness often accompanies or predom. Feature

  • Triggered by infections or certain medications.

List the common medicines to avoid w/ MG pts

Describe Lambert Eaton Myasthenic Syndrome

• STATs

• Pathogensis

• Associated w/

• STATs:

  • Middle age to older people

  • Annual incidence = 0.48 per million population

• Pathogenesis:

  • PRE-synaptic NMJ disorder

  • P/Q type VGCC (Voltage Gated Calcium Channel) antibodies

• Associated w/

  • malignancy (especially small cell lung cancer)

    • 70%

Describe the symptoms and clinical signs for Lambert Eaton Myasthenic Syndrome

• Symptoms

• Signs

Symptoms

• Proximal limb weakness Legs > arms

• Fatigue or fluctuating symptoms

• Difficulty rising from sitting; climbing stairs

• Metallic taste in mouth

• Autonomic dysfunction

  • Dry mouth

  • Constipation

  • Blurred vision

  • Impaired sweating

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Clinical Signs

• Weakness on exam is less demonstrable than patients level of disability

• Hypoactive or absent muscle stretch reflexes

• Lambert’s sign

  • Grip becomes more powerful over several seconds

    • b/c increased influx of calcium in pre-synaptic membrane

• Sluggish pupillary reflexes

List the Laboratory Work-up for LEMS

• Find Neoplasm (Serum tumor markers, CT, PET)

• EMG/NCS

• Serum markers for inflammatory/autoimmune diseases

• Antibodies to voltage-gated calcium channels (VGCCs)

  • 75-100% of LEMS patients who have small cell lung cancer (SCLC) 

  • 50-90% of LEMS patients who do not have underlying cancer.

List the LEMS treatments

LEMS Treatments

• Treat underlying malignancy

• Pyridostigmine

• 3,4-DAP (Di-Amino Pyridine) Trade name=Ampyra

NOTE:

Other possible treatments (plasma exchange, steroids and immunosuppressive agents) have not been tested in randomized controlled trials

Describe Botulism

• What is it?

• Pathogenesis

• STATs

• Key Symptom

Botulism

• What is it?

  • PRE-synaptic NMJ disorder

  • Toxins produced by Clostridium Botulinum

• Pathogenesis:

  • Inhibits release of Ach from the NMJ, sympathetic and parasympathetic ganglia

• STATs

  • 100 cases/year in the US-25% food born/3% wound/ 72% infantile

• Key symptom:

  • Symmetric Descending Flaccid Paralysis 

  • Autonomic disturbance always beginning with the cranial nerves

Describe the transmission and types of botulism and Symptoms

Botulism Transmission/Type

• Transmission

  • Skin Break

    • Toxin can’t pass through intact skin

  • Direct absorption through mucous membranes

  • Lung

  • GI Tract

• Types

  • Food born

  • Wound

  • Inhalation

  • Infantile-infestation through GI tract

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Symptoms

• Diplopia or Blurred Vision ptosis

• Dysphagia

• Dry mouth

• Symmetric Descending Flaccid Paralysis

Describe the MOA of Botulism

List the Diagnosis/Treatment of Botulism

Diagnosis

• Identification of Botox Toxin in serum or stool

• EMG/NCS

• MRI Brain

• CSF

• Tensilon test

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Treatment

• Anti-toxin

• Surgical removal of wound

Describe Neuromyotonia (Isaac's Syndrome)

• STATs

• Variants

• What is it?

• MOA

• Symptoms

• Cause

• STATs

  • 100-200 cases in the US

• Varients:

  • Acquired-80% of all cases/Auto-immune related

  • Paraneoplastic-Small Cell Lung CA, Thymoma or Lymphoma

  • Hereditary

• What is it?

  • Small Cell Lung Cancer or Thymoma involving voltage gated potassium channels (VGKC) @ PRE-synaptic membrane

• MOA:

  • Inhibition of VGKC -> prolongs depolarization -> increases  Ach release -> hyperexcites post-synaptic membrane -> twitching or myokymia

• Symptoms:

  • muscle stiffness

• Cause:

  • Exposure to toxins + autoantibodies

    • gold or mercury or radiation

List the Diagnosis/Treatments for Neuromyotonia (Isaac's Syndrome)

Diagnosis:

• EMG/NCS-High, 

  • irregular single unit discharges

  • fibrillation potentials and fasciculations

• Chest CT

• Serum for VGKC

• Serum for AChR-Ab, immunofixation, TSH, ANA, ESR

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Treatment:

• Immunosuppressive therapy 

  • Plasma exchange 

• Anticonvulsants