Myopathies, NMJ disorders Flashcards by Shannon O'Connor

Notes on neuromuscular junction:

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

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Notes on background/epidemiology myasthenia gravis

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

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Notes on myasthenia gravis aetiology

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

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Notes on antibodies found in Myasthenia Gravis

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

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Additional notes on Anti-MUSK Antibodies

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

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Clinical features of myasthenia gravis

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

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Triggers or exacerbating factors in myasthenia gravis:

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

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Notes on myasthenic crisis

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

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Investigations for suspected myasthenia gravis

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

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Differential diagnosis for myasthenia gravis

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

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

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

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Notes on use of acetylcholinesterase inhibitors in MG → pyridostigmine

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)

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Notes on immunosuppressants in treatment of myasthenia gravis

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

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Role of thymectomy in Myasthenia Gravis

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

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Definition of refactory myasthenia gravis

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

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Notes on eculizumab in myasthenia gravis

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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

Notes on prognosis in myasthenia gravis

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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

Notes on immune checkpoint inhibitor mediated myasthenia gravis

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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%

Notes on Lambert-Eaton Myasthenic Syndrome

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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

Notes on botulism

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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

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

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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)

Distinguishing MG from LEMS on nerve conduction studies

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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

Differentiating myopathies from NMJ disorders

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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

Examples of metabolic myopathies

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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

Laboratory tests in Muscle and NMJ disorders

* **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

Notes on electrodiagnostic testing in muscle and NMJ disorders

**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

Causes of toxic myopathies

**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

Notes on rhabdomyolysis

* 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

Notes on Dystrophinopathies

* 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

Notes on Myotonic Dystrophy

* 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

Notes on mitochondrial myopathies

**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

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

* 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

Notes on Primary Periodic Paralysis

* 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

Myopathies, NMJ disorders Flashcards

(33 cards)