Myasthenia Gravis. 1

Definition. 1

Aetiology. 1

Epidemiology. 2

Clinical Manifestations. 2

Diagnosis. 3

Treatment 5

Lambert-Eaton Myasthenic Sndrome (LEMS) 6

Clinical manifestations. 7

Diagnosis. 7

Treatment 7

Prognosis. 7

Myasthenia Gravis

Definition

· Autoimmune disorder of neuromuscular transmission

· My – muscle, Asthenia – weakness, Gravis – severe

· Can be divided into generalised and Ocular (see below for discussion of Ocular MG)

Aetiology

· Antibodies to nicotinic ACh receptors (85%)

o Mediate effect in 3 ways:

1. Complement mediated lysis of postsynaptic membrane

2. Cross link AChR and trigger degradation

3. Directly block AChR

o NMJ – develops abnormal shape, immune deposits

· Anti-MuSK antibodies (10%)

· Seronegative MG (5%)

· Thymus

o Abnormal in 85% of people with MG

1. More often in early onset disease

o Hyperplastic in 75%

o Thymoma in 10%

· Role in deletion of self reacting immune cells

· Penacillamine can induce a similar myasthenic syndrome

· Immune checkpoint inhibitors – can induce (?unmask) MG

Epidemiology

· Incidence: ~1 / 100 000

· Prevalence: 4/10 000

· Bimodal distribution

o Early onset <40yrs, female

o Late onset >40yrs, male

Clinical Manifestations

· Fatigable weakness is the hallmark, however not always apparent

· Often worse as day goes by and worse after exertion

· Muscle groups affected

Occular Muscles

· ~2/3 present with ocular disease– 50-80% of which go on to develop generalized disease by 2 years.

· Majority of patients presenting with generalized disease will have ocular symptoms at some stage.

· Ptosis

o Bilateral or unilateral and can vary during disease

o Cogan’s eyelid twitch sign – overshoot of eyelid when opening – rapidly returns to ptotic position

o Curtain sign – lift one ptotic eyelid and the contralateral eyelid becomes more ptotic/closes

o Progressive ptosis on sustained upgaze

o Improvement with cooling (icepack test – see below)

· Diplopia - Extra-occular muscle palsies

o Horizontal or vertical gaze palsies that do not conform to single cranial nerve

o Weakness most frequent and severe in medial rectus (can cause a pseudo-INO)

o Peek sign – patients unable to keep eyes forcibly closed for prolonged period and creep open.

o Pupil always spared (may help differentiate).

Bulbar

· 15% present with bulbar

· Dysarthria- Nasal speech due to paralysis of the palatal muscles, low volume

· Dysphagia – Choking, nasal regurgitation may occur

· Fatigable chewing

Face

· Sneer/myasthenic snarl– mid lip may move up but corner’s of mouth do not.

Limbs

· Neck - flexors > extensors

· Limbs

o Upper greater than lower

o Predominantly proximal

o Deltoid, triceps wrist and finger extensors, ankle dorsiflexors may be preferentially affected

Respiratory

Myasthenic Crisis

• Deterioration in respiratory function requiring intubation and ventilation

• Precipitated by a variety of intercurrent illnesses and drugs

• In particular staring steroid treatment causes deterioration in 50% necessitating intubation in up to 10%.

Natural History

· Symptoms peak within one year in 2/3 of patients

· There is usually a period of active disease with rapid deterioration followed by a prolonged, fluctuating less active phase.

· After 15-20years untreated weakness becomes permanently fixed

· Without treatment:

o 1/3 spontaneously recover

o 1/3 become worse

o 1/3 died

Diagnosis

Examination

· Ocular cooling (“Ice Pack Test”)

o Ice pack over ptotic lid for ~2min

o Remember to hold down frontalis to prevent ‘compensation’ for ptosis and false positive

o Positive if increased MRD1 >2mm

o Sensitivity - 89%

o Specificity - high

· Progressive ptosis on sustained upgaze (positive if >2mm extra ptosis)

· Cogan’s eyelid twitch sign – overshoot of eyelid when opening – rapidly returns to ptotic position

· Curtain sign – lift one ptotic eyelid and the contralateral eyelid becomes more ptotic/closes

Serology

· AChR Antibody

o Sensitivity:

§ Overall MG

§ Generalized MG ~80%

§ Occular MG ~55%

o Very specific

§ Rare false positives with Lambert-Eaton syndrome, motor neurone disease, polymyositis, SLE, autoimmune liver disease, first degree relatives.

o Antibodies can become positive later in disease and repeat testing at 6-12months may be appropriate

o Positive in the majority of patients with co-existent thymoma

o NOT useful to monitor disease progression or severity

o Antibodies can be subcategorised as binding, blocking or modulating. Binding antibody is most common, however blocking antibody is more specific.

· Anti-MuSK Antibody

o Present in 40-50% of those with “seronegative MG”

o Not yet in clinical practice

· Anti-LRP4

o Probably not useful as is generally positive onlyif one of the others is also present.

· Antistriational muscle antibodies

o React with the contractile elements of muscle

o Not pathogenic and non-specific (occur in patients with thymoma, liver disease, lung cancer)

o Perhaps useful in predicting thymoma: If positive in patient with MG (<50yrs age) – 60% chance of thymoma

Nerve Conduction Studies

· Withhold anti-cholinesterase medications for >12hours prior if safe

· Repetitive nerve stimulation

o Stimulated 6-10 times at 2 or 3Hz

o Should be done distally (which is easier) and proximally (which is more specific).

§ Paper looking at best combination of muscles (Bour Ali et al. 2016) – Orbicularis oculi (or nasalis), Trapezius, Anconeus – gave best sensitivity with lowest number of muscles

§ Most importantly try to test a clinically weak muscle

o There is an immediate store of ACh and a secondary store which takes some time to mobilise

§ By the 4-5^th stimulation the secondary store starts to mobilise

§ In a normal muscle this does not result in any change as all stimuli are well above threshold

§ In MG this will create repair that takes place from the 5^th stimulus – creating a U-shaped response

o A 10% decrement (in amplitude or area) from 1^st-4^th CMPA is significant.

o Exercise

§ Consider this if the initial decrement is not clearly >10% (i.e. increased sensitivity)

§ 10secs of maximal contraction

· Immediate repeat – should see repair of decrement

· Repeat at 1min interval to 4min – in MG should see gradual increase in decrement (via mechanism that is not definitively know)

§ A further 10sec maximal contraction – decrement should again repair

Single fibre EMG

· Positive in all NMJ disorders

· Not specific

o Can be positive in axonal neuropathies and a variety of other NM diseases

· Sensitivity

o 90% if affected muscle tested

o 60% if limb muscle tested in patient with only ocular symptoms

· If RNS is normal, but SFEMG is abnormal consider congenital myasthenia syndrome

· Aim for 20 pairs

o Normal <2 with jitter

Tensilon Test

· Edrophonium – Ach-Esterase inhibitor

o Rapid onset 1 min

o Short duration 5-10min

· Need to have a clinically measurable endpoint, therefore best reserved for patients with ocular disease.

· Also effects mACh junctions.

o Increased salivation, abdo cramping

o Bradycardia and bronchospasm

· Contraindications: Cardiac disease, asthma

· Monitored with atropine ready (or give prophylactic atropine dose)

· 2mg titrations up to 10mg IV

Test performance in ocular MG

Neurol clinic 2018 Ocular Myasthenia

Treatment

Avoid exacerbating factors

Medications and other exacerbating factors

Main concerns (longer list in uptodate):

· Antibiotics

o Aminoglycoside antibiotics

o Fluroquinolones

o Clindamycin, lincomycin

· Cardiac medications:

o Beta-blockers

o Quinine/quinidine

· Anti-seizure medications

o Phenytoin

· Prednisone – used for treatment but caution needed

· Lithium

· Neuromuscular blockade drugs (anaesthetics – particular concern if need for thymectomy)

Other exacerbating factors:

· Stress

· Systemic illness

· Thyroid dysfunction

· Pregnancy

· Menstrual cycle

· Surgery

Symptomatic

Anticholinesterases

· Pyridostigmine (Mestinon)

· Short acting 30-60mg TDS or QID

· Long acting BD or nocte dosing

· May relive ptosis but not EOM weakness

· Cholinergic SE: Abdominal cramping and diarrhoea, increased salivation, bradycardia

· Alleviate SE with mAChR antagonists

i. Glycopyrrolate, Probanthine, Hyoscyamine

ii. Cholinergic crisis

· Not helpful in MusK?

· Paradoxical weakening with treatment (depolarization block)

· Difficult to distinguish from myasthenic crisis

· Slowly titrate up dose

Mestinon 10mg:

Mestinon 60mg:

Mestinon timespan (SR) 180mg

Disease Modifying

Treatment	Comment
Prednisolone	High doses may worsen disease initially and should be used with caution Start 5-10mg daily (or 10mg every second day) and increase every 7-10 days up to 60-80mg or until symptom control is achieved Then taper slowly every month towards 15mg/day. Reduce by 1mg/month thereafter. Remission in 30%
Traditional steroid sparing agents
Azathioprine	Most patients benefit however onset of benefit usually 6-12 months with peak at 1-2 years
Mycophenolate	Slow onset, possibly less side effects PROMISE-MG trial found similar efficacy to azathioprine
Methotrexate	Mixed evidence
Cyclophosphamide	IV lupus protocol trialled for 6 months – small RCT with positive results (Buzzard et al 2015) Onset of action 3-4 months Probably does not help in MuSK
Cyclosporine	Slightly more rapid onset than azathioprine but significant toxicity
Anti CD20
Rituximab	Thought to be particularly helpful in MuSK Evidence in AChRA + disease – variable. - Beat MG – no steroid sparing effect - RINOMAX – minimal disease outcome achieved in 71% vs 29%
Complement inhibitors	High risk of meningococcal meningitis – vaccination against Neisseria meningitidis recommended at least 2 weeks before treatment and again at 2-5 years, otherwise antibiotic prophylaxis.
Eculizumab (Soliris)	Antibody which blocks cleavage of C5 into C5a and C5b REGAIN trial – negative primary endpoint, positive in some secondary endpoints
Ravulizumab (Ultomiris)	Similar mechanism to Eculizumab, longer half-life CHAMPION MG study – MG-ADL improved, QOL measure not improved at 26 weeks
Zilucoplan (Zilbrysq)	A synthetic macrolide which binds C5 and prevents cleavage. RAISE study – Positive MG-ADL outcomes
FcRN Inhibitors	FcRN extend the life of IgG by protecting it from degradation in lysosomes. Use of inhibitors may lead to hypogammaglobulinamia
Efgartigimod (Vyvgart)	IgG fragment that binds to FcRn. ADAPT trial MG-ADL scores improved 68% vs 30%
Rozanolixizumab (Rystiggo)	Mycarin G clinical trial S/C weekly injection Positive primary endpoints Very effective in MuSK subgroup High rate of adverse effects – headache, diarrhoea, fever and nausea
Proteosome inhibitors
Bortezomib	Still not tested in large clinical trials High rate of peripheral neuropathy 30-40%, some permanent
CAR-T cell therapy	Descartes 08 phase 2 trial showed positive results
CAAR-T cell therapy
Immunoglobulin removal
Plasmapheresis	Remove antibodies from circulation Effect seen in days but only lasts 3-4weeks Used in critically ill patients
IVIG	Effect seen within a week Benefit can last 3-6weeks Expensive Maintenance – benefit capped at 1g/kg

Surgery - Thymectomy

· Thymoma removal

· Surgery +/- radiation and chemo

· 70% 5 year survival

· ‘Normal’ thymus removal

· MGTX trial (NJEM 2016) demonstrated benefit in AChRA positive patients <50 years age.

i. Significant reduction in prednisolone and azathioprine use.

· Role in elderly and ocular MG unclear

Perioperative management

· Risk of deterioration from surgery small with correct management

· Very rough figures suggest 1-2% serious complication (prolonged ICU stay etc), 15-20% have mild exacerbation of disease.

· Anaesthetics

· Succinylcholine – patients are resistant because there are not enough nAChRs to allow depolarisation. However inactivation of drug takes longer in presence of pyridostigmine.

· Non-depolarising agents – patients have increased sensitivity due to reduced number of receptors.

· If needed a dose reduction of 50% is usually necessary

· Trying to reverse neuromuscular blockade with pyridostigmine is less effective if patient is already being treated.

· Inhalation anaesthetics recommended – due to increased sensitivity patients may also get extra muscle relaxant effect.

· Trial of Four monitoring recommended

· There is no pre-operative risk score that has proven consistently effective

· Previous respiratory problems and bulbar symptoms are risk factors for complication.

· Patients needing high pre-op doses of pyridostigmine may also have higher risk.

· It is important that patients continue to get normal pyridostigmine dose up time of surgery.

· Sufficient spontaneous breathing prior to extubation is essential – various respiratory and consciousness parameters have been proposed for this.

· Pain management is important as pain may precipitate deterioration.

· References:

· Anaesthesia and MG Acta Anaesth Scand 201,256:17

· Standardized protocol for perioperative management Acta Anaesth Scand 2012, 56:66

Ocular Myaesthenia Gravis

• Conversion to generalised MG

o Very variable figues

o Traditionally said to be 80%

o More recent study ~20%

o Study from Singapore ~10%

o 80% convert within first 2 years.

o Predictors of conversion – positive AChRA, Positive repepitive stimulation study, thymoma

o Immunosuppression does not seem to prevent conversion

Lambert-Eaton Myasthenic Sndrome (LEMS)

Aetiology

· Antibodies to P/Q calcium channels at the motor nerve terminals

· Present in 85%

· Antibodies result in impaired release of AcH from nerve terminals

Association with malignancy

· Majority of patients have malignancy

· Most commonly small cell lung cancer – the cells of which express simular proteins and induce immune response

Clinical

· Similar to MG with some differences

· Proximal muscles of the lower limb are most commonly affected

· Reflexes are often absent or reduced (c.f. MG)

· Cranial nerve involvement – ptosis or diplopia (70%)

· Autonomic symptoms – dry mouth, impotence

Investigations

· Serology

· NCS

· Incremental increase in repetitive nerve stimulation

Treatment

· Cancer removal

· Plasmapheresis

· Immunosupression

· 3,4-DAP or pyridostigmine may help

Botulism

Pathology

Clostridium botulinum, gram positive, rod shaped, spore forming obligate anaerobic bacteria
8 toxin subtypes, 5 cause no human disease
Toxin binds to presynaptic acetylcholine nerve terminals
Phagocytosed and irreversibly inhibits neurotransmission
Ingestion of preformed toxin or spores with subsequent toxin