Myopathies, NMJ disorders

Question 1

Notes on neuromuscular junction:

Answer 1

• Consists of presynaptic axon terminal and a postsynaptic muscle end plate
• Presynaptic terminal → vesicles containing ACh, ATP, Mg, Ca - most vesicles bound to actin cytoskeleton by proteins called synapsins
• Action potential → opening Ca channels → increased intracellular Ca → phosphorylation synapsins → release of vesicles from cytoskeleton → vesicles bind to presynaptic membrane terminal by “docking” which allows rapid exocytosis of vesicles
• ‘Docking” mediated by proteins called SNARE complexes - proteins involved in SNARE complex = VAMP, syntaxin, SNAP-25 (all targets of botulinum toxin)
• ACh binds to ACh receptor on post-synaptic membrane → influx of Na → depolarisation of end plate region → muscle fibre action potention → contraction of muscle → remaining ACh in synapse is degraded by acetylcholinesterase to allow muscle repolarisation

Question 2

Notes on background/epidemiology myasthenia gravis

Answer 2

• Autoimmune disease of neuromuscular junction
• Fatigable ocular, limb and/or bulbar weakness
• 80% pathogenetic AChR antibodies
• Some genetic factors identified - CHRNA1 (encodes the AChR alpha-subunit), also HLA associations
• Environmental factors not well established
• All ages affected
  
  • <40 years - more women
  • 40s even distribution B/W men and women
  • >50 years - more men

Question 3

Notes on myasthenia gravis aetiology

Answer 3

• Autoimmune attack on the postsynaptic membrane of the neuromuscular junction
• Antibody mediated, T cell dependent attack
  
  • Damage of post-synaptic membranes, simplification of its highly folded surface, reduced number & density of AChR, abnormal neuromuscular transmission, fatiguable muscle weakness
• Thymus thought to play a role in pathogenesis
  
  • Thymoma in 15%
  • Thymic hyperplasia in 65%
• Associated with hyperthyroidism, SLE, scleroderma, rheumatoid arthritis

Question 4

Notes on antibodies found in Myasthenia Gravis

Answer 4

• Anti-AChR antibodies - pathogenic (the remainder not clearly pathogenic)
  
  • Bind to alpha subunit of AChR, block ACh-AChR binding → increased AChR internalisation & degradation → damage to the post-synaptic membrane
  • Very specific for MG, 80% with generalised MG, 50% with ocular MG
  • Some seroconvert over a 6 month period after an initial -ve test
• Anti-MuSK antibodies (anti-muscle specific tyrosine kinase) - block MuSK-LRP4 binding → reduced AChR clustering at endplate - not clear if pathogenic. Test if AChR negative (often done simultaneously)
  
  • Present in ⅓ of anti-AChR antibody negative generalised MG cases (usually females)
  • Present in 1-10% with MG
• Anti-LRP4 antibody present in 20% of double seronegative MG cases
• Anti-striatonial antibodies → 30% adult onset MG, 80% thymoma without MG

Question 5

Additional notes on Anti-MUSK Antibodies

Answer 5

• More often women
• Can have atypical presentations
  
  • Neck extensor, shoulder and respiratory muscle weakness
  • Severe oculobulbar weakness, fixed facial muscle weakness, weakness of tongue and pharyngeal muscles - poor treatment response
  • More frequently respond to plasma exchange than IVIG
  • Usually less improvement and more side effects (fasciculations) with cholinesterase inhibitors

Question 6

Clinical features of myasthenia gravis

Answer 6

• Fluctuating and fatiguable muscle weakness that worsens with exercise and improves with rest
• Ptosis (often asymmetric) and binocular diplopia (most common presenting symptoms)
• Bulbar weakness - flaccid dysarthria, dysphagia, jaw closure weakness
• Facial weakness - weak, inability to smile
• Neck flexion usually weaker than neck extension
• Limb weakness - usually proximal and symmetric
  
  • Finger and wrist extension, ankle dorsiflexion

Question 7

Triggers or exacerbating factors in myasthenia gravis:

Answer 7

• Surgery
• Pregnancy and postpartum period
• Heat
• Stress
• Infections
• Bone marrow transplantation
• Medications
  
  • Antibiotics → aminoglycosides** (inhibit pre- and postsynaptic transmission) **fluoroquinolones, ketolides, macrolides, nitrofurantoin, clindamycin, metronidazole, tetracyclines, vancomycin
  • D-peniillamine - induce production of AChR antibodies
  • Magnesium and magnesium containing medications
  • Botulinum toxin
  • Antiseizure - carbamazepine, phenytoin (pre- and postsynaptic)
  • Psych - lithium (with chronic use may complete with calcium in presynaptic region and reduce release of ACh)
  • Glucocorticoids
  • Interferon alpha
  • Cardiovascular medications → beta blockers**, calcium channel blockers, **quinine
  • Neuromuscular blockers
  • Checkpoint inhibitors - exacerbates underlying MG and can produce AChR antibodies

Underlined and bold = drugs that can induce/unmask MG.

The rest = generally well tolerated but can be associated with flares

Question 8

Notes on myasthenic crisis

Answer 8

• Occurs in 15%
• Respiratory failure secondary to severe weakness of the diaphragm and accessory muscles of breathing
• Emergency
  
  • Ventilation support in ICU
  • Steroid treatment
  • IVIG or plasma exchange

Question 9

Investigations for suspected myasthenia gravis

Answer 9

• Antibody tests - autoantibody positive + weakness = MG
• Electrodiagnostic testing → repetitive stimulation
  
  • CMAP decrement >10% indicates NMJ transmission problem. More sensitive in generalised than ocular MG
• Single-fibre electromyography
  
  • Most sensitive test to confirm a NMJ transmission problem when performed in a weak muscle
  • Normal study in an affected muscle excludes MG
  • Extensor digitorum communis 1st, frontalis or orbicularis 2nd
• Ice pack test
  
  • High diagnostic sp and sn in distinguishing myasthenic ptosis from other causes.
  • Apply ice to eyelid for 5 minutes - positive test if improvement in palpebral fissure of at least 2 minutes
• Edrophonium test
  
  • Fast acting acetylcholinesterase inhibitor - 30 second onset, 5 minute duration of action
  • Administered at intervals of 1-2 minutes to observe for improvement in ptosis +/- ocular movemements
  • Atropine administered pre-emptively to manage possible muscarinic side effects (sweating, lacrimation, nausea, vomiting, diarrhoea, bradycardia, bronchospasm)
• CT Chest
  
  • Look for evidence/recurrence of thymoma
• Thyroid function tests
  
  • Autoimmune thyroid disease often A/W MG

Question 10

Differential diagnosis for myasthenia gravis

Answer 10

Generalised MG

• Lambert-Eaton Myasthenic Syndrome
• Congenital myasthenic syndromes
• Botulism
• Lyme disease
• Bulbar ALS
• Brainstem ischaemia
• GBS - Miller Fisher syndrome
• GBS - Pharyngeal-cervical-brachial variant

Purely ocular MG

• Mitochondrial disorders e.g. chronic progressive external ophthalmoplegia
• Oculopharyngeal muscular dystrophy

Question 11

Notes on use of IVIG and Plasma Exchange in the treatment of Myasthenia Gravis

Answer 11

• Used in generailsed MG treatment
  
  • Rapid onset, short term treatment for acute exacberations or pre-op
  • More chronic use in refactory cases, unable to tolerate immunosuppressants

PLEX

• 5-6 exchanges 2-3 L on alternating days
• Improves strength in majority
• Fast onset in myasthenic crisis - after 2nf or 3rd exchange
• Unable to use if sepsis or hypotension, central venous catheter complications

IVIG

• Divided doses over 2-5 days
• Improves strength in the majority
• For mod→ severe exacberations unable to tolerate immunosupressants
• Improvement after a few days → 2 weeks, effects last weeks to months
• Idiosyncratic reactions, aseptic meningitis, increased thrombosis risk
• Cautious use if risk of volume overload

Question 12

Notes on use of acetylcholinesterase inhibitors in MG → pyridostigmine

Answer 12

• Increase ACh in synaptic cleft
• Used for symptomatic treatment alone → pure ocular MG, mild generalised MG
• Combined w/ immunosuppressants in mod & severe generalised MG
• Effective within 30-60 minutes, last 3-4 hours
• Timing of dose should target symptoms
  
  • Dysphagia → take 30 minutes before meals
  • Diplopia → no need to take prior to sleep in the evening
• Anti-MuSK group does not respond
• No long term side effects
• Adverse effects → abdominal cramping, diarrhoea, increased lacrimation (muscarinic side effects)

Question 13

Notes on immunosuppressants in treatment of myasthenia gravis

Answer 13

Corticosteroids

• Usually 1st choice when pyridostigmine alone insufficienct
• Needed in most cases
• Effective within 2-3 weeks
• Short term exacberations can occur with use - especially if bulbar weakness
• Prednisone → target dose 60-80mg daily until improvement. Usually start at that dose if IP treatment, OP start 10-20mg and uptitrate 5mg/week. Slow taper once significant improvement
• Introduce steroid-sparing agent if symptoms recur at a prednisone dose too high to maintain in the long term

Azathioprine

• 6MP that blocks nucleotide synthesis & T lymphocyte proliferation
• Effective after 4-8 months
• Adverse effects: myelosupression, toxic hepatitis, pancreatitis
• Pre-screen with TMPT

Mycophenolate

• Inhibits monophosphate dehydrogenase, suppresses cell-mediated immunity & antibody production
• Effective after 1-2 months
• Adverse effects: nausea, diarrhoea, abdominal pain, leukopaenia, anaemia

Rituximab

• Significant improvement/remission in severe or refactory generalised MG
  
  • Especially MuSK positive cases (benefit less clear in refactory AChr antibody positive cases but can be trialled)
• Adverse effects: infusion reactions, hepatitis B reactivation, ulcers (skin and mouth), PML

Question 14

Role of thymectomy in Myasthenia Gravis

Answer 14

Indications

• MG patients with thymoma
• Non-thymomatous generalised MG with +ve AChR antibody
  
  • Aged 18-50 → consider early to improve outcome and minimuse immunosuppressive complications
  • Fail to respond to initial adequate immunotherapy trial or don’t tolerate side effects → strongly consider
  • Generally not indicated > 65 years
• Should be planned as soon as patient has improved with treatment to a level safe to undergo surgery

Question 15

Definition of refactory myasthenia gravis

Answer 15

• Unchanged or worsened symptoms after
  
  • Steroid treatment & at least 2 other immunosuppressants used at adequate doses for adequate durations or until intolerable side effects occurred

Question 16

Notes on eculizumab in myasthenia gravis

Answer 16

• Complement inhibitor
• FDA approved for adults with ACHR antibody positive generalised MG, severe or refactory disease not responded to usual treatment
• Not currently available in Aus/NZ
• Risk of menigococcal & other bacterial infections, vaccinate prior to use

Question 17

Notes on prognosis in myasthenia gravis

Answer 17

• Exacerbations more common in early disease prior to complete treatment implementation
• Maximal severity within first few years from onset
• Generalisation of purely ocular presentations usually occurs within 2 years
• 15% treatment refactory
  
  • RFs: thymoma, anti-MuSK antibody, female, younger age at onset
• Some develop fixed weakness that is no longer treatment responsive
• Mortality <5%
  
  • RFs for morbidity and mortality: thymoma, refactory generalised MG, older age, complex comorbidities

Question 18

Notes on immune checkpoint inhibitor mediated myasthenia gravis

Answer 18

ICI-related MG

• Prominent bulbar & respiratory manifestations
• High rate of associated myocarditis
• Frequently overlaps with other neurologic & non-neurologic immune related adverse events
• Need to discontinue ICI +/- immunosuppression

ICI-related myocarditis

• Large specrum ranging from myalgia to severe generalised weakness w/ respiratory muscle involvement
• Myocarditis present in up to 40%

Question 19

Notes on Lambert-Eaton Myasthenic Syndrome

Answer 19

• 50% paraneoplastic - mainly SCLC. Other 50% autoimmune disorders
• HLA DR3 association
• Pathogenic andt diagnostic IgG P/Q type VGCC antibodies
  
  • Less ACh released from pre-synaptic nerve terminals
  • Failure of neuromuscular transmission
  • Skeletal muscle weakness (usually worse in lower limbs and proximal, not usually fatiguable), areflexia/hyporeflexia & autonomic dysfunction
• Mild sensory symptoms/signs may be present - distal symmetrical sensory neuropathy
• Onset usually in 50s/60S; male predominance
• Investigations
  
  • VGCC antibodies (85% positive overall, 100% positive when paraneoplastic)
  • NCS → low baseline motor amplitudes, increased motor amplitude after brief exercise
  • Repetitive stimulation - decrement with low rates, increment with fast rates
  • Malignancy screening up to 2 years - CT CAP and age and sex appropriate cancer screening
• Treatment
  
  • Symptomatic - 3,4 diaminopyridine (potassium channel blocker that potentiates AP), +/- prydostigmine, autonomic dysfunction management
  • IVIG/PLEX acutely; treat underlying cancer
  • Chronic immunosuppression may be required

Question 20

Notes on botulism

Answer 20

• Caused by botulinum neurotoxin produced by clostridium botulinum bacteria (anaerobic, gram positive)
• Bacterial colonisation of deep wounds or improperly cooked/canned foods
• Presentation: acute descending flaccid weakness & respiratory/autonomic dysfunction
  
  • Typical presentation → blurred vision, diplopia/ophthalmoplegia, facial weakness, dysarthria & dysphagia
  • → Loss of head control, limb weakness (proximal → distal) and resp muscle weakness
  • Autonomic - fixed & dilated pupils, dry mouth, GI symptoms, heart rate & BP abnormalities
• Investigations
  
  • Serum and stool samples - PCR testing to identify organism
  • NCS → low baseline motor amplitudes, increased motor amplitudes after brief exercise
  • Repeititve stimulation - decrement with low rates, increment with fast rates
• Treatment
  
  • ICU admission
  • IV human botulism immunoglobulin or heptavalent antitoxin
  • Low mortality, recovery can be prolonged
  • Notifiable disease

Question 21

When to think of ICU referral +/- early intubation in myasthenia gravis

Answer 21

• SOB/suffocating/drowning when lying supine
• Severe dysphagia, difficulty clearing secretions
• FVC <30ml/kg, counting out loud to 20

Neuromuscular respiratory failure

• Development insidious, often underrecognised
• Aterial hypoxaemia - due to hypoventilation and microatelectasis
• Hypercapnia is late - heralding impending arrest
• Bulbar involvement may prevent clearing of secretions and sign of aspiration
• Other causes of acute neuromuscular respiratory faliure
  
  • GBS, ALS, muscular dystrophies (with exacberating factors)

Question 22

Distinguishing MG from LEMS on nerve conduction studies

Answer 22

• LEMS and MG → at low frequency (1-5 Hz), there is decrement with repetitive motor stimulation
• In LEMs but not MG → at high frequency (20-50Hz) repetitive stimulation there is an incremental response
• Incremental response in LEMs also seen with preceding voluntary activity

Question 23

Differentiating myopathies from NMJ disorders

Answer 23

Features of NMJ disorders

• Ptosis
• Diplopia
• Ophthalmoplegia
• Dysarthria
• Limb weakness
• Fatigue
• Paraesthetsia (LEMS)

Fluctuating in symptoms and signs and ocular manifestations help to distinguish from myopathies

Features of myopathies

• Negative symptoms
  
  • Weakness, fatigue, exercise intolerance, muscle atrophy
• Positive symptoms
  
  • Cramps, stiffness/myotonia, contracture, muscle hypoertrophy, myalgia, myoglobinuria

Question 24

Examples of metabolic myopathies

Answer 24

• Glycogen storage defects
• Lipid metabolism disorders
• Mitochondrial myopathies
• Periodic paralysis
• Electrolyte imbalance
• Endocrine myopathies
• Toxic myopathies
• Amyloid myopathy
• Inflammatory myopathies
  
  • Inclusion body myositis
  • Dermatomyositis
  • Necrotisind myopathy
  • Infectious myositis

Question 25

Laboratory tests in Muscle and NMJ disorders

Answer 25

• CK
  
  • Elevated levels may not be seen in all myoapthies, degree of weakness may not correlate with level
• AST/ALT/LDH - can be high in muscle disease
• Electrolytes
• TFTs
• ESR/ANA/ENA/inflammatory myositis antibody panel
• Serum immunofixation (?amyloid)
• AChR antibodies/MuSK antibodies
• VGCC antibodies (LEMS)
• Molecular genetic studies - hereditary muscle and NMJ diseases

Question 26

Notes on electrodiagnostic testing in muscle and NMJ disorders

Answer 26

Nerve Conduction Studies

• Motor NCS normal or low amplitude
• Sensory NCS usually normal

Repetitive Stimulation

• Help distinguish B/W NMJ disorders and myopathies
• Decrement in MG with slow rates
• LEMS & Botulism - decrement slow rates, increment fast rates

EMG

• Myopathic features - motor unit action potential has small amplitude & duration
• Single fibre EMG - may be useful for diagnosis of myasthenia gravis

Question 27

Causes of toxic myopathies

Answer 27

Inflammatory

• Immune checkpoint inhibitors, D-penicillamine, levodopa, cimetidine, phenytoin, interferon alpha, TNF inhibitors, imatinib, hydroxyurea

Non-inflammatory necrotising or vacuolar

• Cholesterol lowering meds (statins, other), chloroquine, colchicine, labetalol, cyclosporin, tacrolimus, vincristine, isoretinoic acid, alcohol, propofol

Rhabdomyolysis and myoglobinuria

• Statins, alcohol, heroin, amphetamine, cocaine

Myosin loss

• Steroids, non-depolarising neuromuscular blocking agents

Management

Identify and cease offending agent & provide supportive care until recovery

Question 28

Notes on rhabdomyolysis

Answer 28

• Breakdown & necrosis of muscle tissue and release of intracellular contents into blood
• Presentation
  
  • Asymptoamtic, increase in CK
  • Volume depletion, metabolic and electrolyte abnormalities, AKI
• Diagnosis
  
  • CK > 1000 or at least 5x ULN
• Investigations
  
  • Serum CK, myoglobin, electrolytes, creatinine
  • Urinalysis - check for myoglobinuria
• Causes
  
  • Acquired - trauma (crush injuries, compression, electrical, surgery), coma/prolonged immobilisation, strenuous exercise, seizures, extreme heat, NMS, toxins, infection
  • Genetic - disorders of lipid metabolism, disorders of carbohydrate metabolism, mitochondrial disorders
• Treatment
  
  • Treat underlying cause
  • Fluid replacement
  • Treat electrolyte disturbance
• Generally good prognosis if early and agressive treatment

Question 29

Notes on Dystrophinopathies

Answer 29

• Absence/decrease in function of dystrophin protein found in skeletal muscle (X chromosome)
  
  • Males affected, female carriers
• Spectrum of disease
  
  • Progressive skeletal muscle weakness - proximal lower limb initially → proximal upper limb later, symmetrical
  • Respiratory muscle and dysphagia later in illness
  • Cardiomyopathy
  • Duchenne - most severe, onset within 1st year, loss of ambulation by 12-13 years
  • Becker - milder/variable, more severe cardiac involvement
• Investigations
  
  • CK, genetic testing, muscle biopsy (dystrophin absent in Duchenne MD & present in small amounts in Beckers)
• Management
  
  • Oral steroids - commenced B/W 4→ 7 year in Duchenne, prolonged ambulation, preserved UL strength, reduced scoliosis risk
  • MDT
  • Carrier testing → female carriers may have cardiomyopathy

Question 30

Notes on Myotonic Dystrophy

Answer 30

• AD inheritance
• Triad of:
  
  • Progressive weakness
  • Myotonia (impaired muscle relaxation)
  • Early onset cataracts
• Myotonic dystrophy type 1 = most common MD
• Percussion myotonia → direct percussion of muscle leads to pronounced contraction with delayed relaxation
• Facial weakness, frontal balding, temporal muscle atrophy & weakness, hatchet face
• Investigations
  
  • CK, EMG (dive bomber sound of waxing and waning myotonia), genetic testing
• Management
  
  • Screen/treat other organ involvement
    
    • Cardiac (arrhythmias, CCF → leading cause of death in Type 1)
    • Respiratory failure, sleep apnoea
    • Cataracts
    • IBS, bacterial overgrowth syndrome
    • Hypothyroidism
    • dm
    • Increased cancer risks
    • GA risks
  • Supportive and symptomatic care
    
    • Myotonia Rx - medications targeting skeletal muscle sodium channels e.g. mexeletine

Question 31

Notes on mitochondrial myopathies

Answer 31

MELAS

• Mitochondrial encephalomyopathy, alctic acidosis and stroke like syndrome
• Stroke and stroke like events in non-vascular territories (typically parieto-occipital), varying degrees of cognitive impairment, epilepsy, myopathy, elevated lactate in blood and csf

Question 32

Notes on Glycogen Storage Disease Myopathies - Pompe Disease (Glycogen Storage Disease Type 2)

Answer 32

• AR inheritance
• Mutations in GAA gene → enzymatic acid maltase deficinecy
• Myopathy
• Baseline CK usually elevated
• Diagnosis confirmed on enzyme testing/genetic sequencing
• Management
  
  • High protein diets with complex carbohydrates, avoid strenuous exercise
  • Enzyme replacement therapy with
  • Monitor and treat cardiomyopathy

Question 33

Notes on Primary Periodic Paralysis

Answer 33

• AD inheritance
• Onset early childhood, also adulthood
• Presentations
  
  • Complete paralysis of all four limbs, absent reflexes
  • Abortive episodes: weakness of one or more limbs usually lasting several minutes → hours. May not be recognised if brief and subtle
  • Episodes may be triggered by specific factors or more common at certain times of day
• Hypokalaemic periodic paralysis - mutations in calcium channel, triggered by carbohydrate rich meals and prolonged rest
• Hyperkalaemic ‘’’ - mutations in sodium channel, triggered by fasting or exercise, myotonia eyes and hands, often painful
• Investigations
  
  • CK, potassium and EMG may be helpful acutely, genetic testing
• Treatment and management
  
  • Avoid triggers, stabilise potassium level