After reading this note you will be able to describe the clinical approach to Myasthenia gravis, recognise its presentation, interpret key investigations and outline immediate and definitive management – remembering to verify drug doses and local protocols against the Kenya MoH guideline and your hospital formulary.
Definition
Myasthenia gravis (MG) is a chronic, autoimmune neuromuscular junction disorder characterised by fluctuating skeletal muscle weakness that worsens with activity and improves with rest.
Anatomy and physiology you need
| Structure | Role in normal transmission | Relevance to MG |
|---|---|---|
| Motor nerve terminal | Releases acetylcholine (ACh) into synaptic cleft | Target of auto‑antibodies |
| Motor end‑plate (post‑synaptic membrane) | Contains nicotinic ACh receptors (nAChR) that bind ACh → depolarisation | Site of receptor loss or blockade |
| Acetylcholinesterase (AChE) | Hydrolyses ACh, terminating signal | Inhibition prolongs ACh action, useful therapeutically |
| Muscle fibre | Generates contraction when depolarised | Weakness results when insufficient ACh‑receptor activation |
Causes and risk factors
- Primary autoimmune MG – idiopathic, most common.
- Thymic abnormalities – thymoma or thymic hyperplasia (important in Kenyan patients; thymoma prevalence similar to global data).
- Infections prevalent in Kenya – HIV infection (immune dysregulation), chronic hepatitis B/C, tuberculosis (immune activation), malaria (periodic immune stimulation).
- Other tropical conditions – sickle cell disease (chronic inflammation), rheumatic fever (molecular mimicry).
- Genetic predisposition – HLA‑DR3, HLA‑B8 associations reported worldwide; familial cases are rare.
- Medications – quinidine, fluoroquinolones, β‑blockers, and some antibiotics can exacerbate MG; awareness needed when prescribing in Kenya.
Pathophysiology
- Loss of tolerance → auto‑reactive B‑cells produce antibodies
- Antibody types → anti‑nAChR (≈80 %); anti‑MuSK; anti‑LRP4 (less common)
- Binding to post‑synaptic receptors →
- Receptor blockade (antibodies occupy nAChR)
- Complement‑mediated lysis (membrane attack complex damages end‑plate)
- Receptor internalisation (antibody‑induced endocytosis)
- Reduced functional receptor density → fewer ACh binding sites
- Impaired end‑plate depolarisation → insufficient Na⁺ influx → muscle fibre fails to contract adequately
- Clinical weakness → manifests as fatigable, fluctuating weakness that improves with rest
(Arrows indicate progression: loss of tolerance → antibodies → receptor loss → impaired transmission → weakness.)
Clinical features
| Aspect | Key questions / findings | Why it occurs |
|---|---|---|
| Onset & course | “When did the symptoms start?” “Did they get worse during the day or after activity?” | Auto‑antibody‑mediated loss of acetylcholine receptors produces fatigue that worsens with use and improves with rest (fluctuating weakness). |
| Pattern of weakness | Ptosis, diplopia, difficulty chewing, swallowing, speaking, neck flexion, proximal limb weakness, respiratory effort. Ask about “drooping eyelids”, “trouble holding objects”, “climbing stairs”, “getting up from a chair”. | Extra‑ocular muscles have a high firing rate and few reserve fibers, making them early targets. Bulbar and proximal muscles are similarly vulnerable. |
| Fluctuation & fatigability | “Do symptoms improve after a short rest or after sleeping?” “Do they worsen in hot weather or after infections?” | Reduced safety factor at the neuromuscular junction becomes more pronounced with sustained activity or metabolic stress. |
| Cranial nerve involvement | “Any change in voice, difficulty swallowing liquids or solids, choking, nasal speech?” | Impaired transmission at the neuromuscular junction of muscles innervated by cranial nerves (IX, X, XII). |
| Respiratory symptoms | “Shortness of breath when climbing stairs or lying flat?” “Any episodes of sudden breathlessness at night?” | Weakness of diaphragm and intercostals can precipitate myasthenic crisis, especially when supine. |
| Associated autoimmune disease | “History of thymoma, thymic hyperplasia, other autoimmune conditions (e.g., lupus, rheumatoid arthritis)?” | Thymic pathology is a common source of auto‑antibody production. |
| Triggers / exacerbating factors | Recent infection (TB, malaria, HIV), fever, pregnancy, certain antibiotics (e.g., aminoglycosides), β‑blockers, magnesium, stress. | Infections and drugs that impair neuromuscular transmission lower the already compromised safety factor. |
| Medication history | Use of quinine, penicillamine, procainamide, or other known precipitants. | These agents can worsen neuromuscular transmission. |
| Family history | Any relatives with MG or other autoimmune disease. | Rare familial forms exist; helps in counseling. |
| Systemic symptoms | Weight loss, fatigue unrelated to muscle use, fever. | May indicate concurrent infection (TB, HIV) that can mimic or aggravate MG. |
Examination findings
- Ptosis & variable diplopia – intermittent because extra‑ocular muscles fatigue quickly.
- Facial weakness – reduced smile, difficulty puffing cheeks; reflects cranial nerve VII involvement.
- Bulbar signs – dysarthria, dysphagia, nasal speech; due to weakness of palate and pharyngeal muscles.
- Neck flexor weakness – difficulty holding head up; proximal neck muscles are affected early.
- Proximal limb weakness – difficulty rising from a chair, climbing stairs; limb girdle muscles have high demand.
- Fatigability on repeated testing – e.g., sustained upgaze or repeated hand‑grip leads to worsening weakness, confirming a use‑dependent defect.
- Respiratory assessment – reduced vital capacity, shallow breathing; indicates diaphragmatic involvement.
- Absence of sensory loss – helps separate from peripheral neuropathies.
- No reflex abnormalities – reflexes are usually preserved, distinguishing from central motor lesions.
Differential diagnosis
| Condition | Points to it | What separates it from MG |
|---|---|---|
| Lambert‑Eaton myasthenic syndrome | Proximal weakness, autonomic symptoms, associated malignancy | Weakness improves with repeated effort; reflexes are reduced and may increase after exercise. |
| Ocular myopathies (e.g., chronic progressive external ophthalmoplegia) | Isolated ptosis, diplopia | Progressive, non‑fluctuating; no bulbar or respiratory involvement; negative acetylcholine‑receptor antibodies. |
| Botulism | Acute descending paralysis, dry mouth, pupillary dilation | Rapid onset, gastrointestinal prodrome, toxin exposure; EMG shows presynaptic block. |
| Stroke / brainstem infarct | Sudden focal neurological deficit, sensory loss | Acute onset, imaging shows infarct; weakness does not fluctuate with use. |
| Multiple sclerosis | Variable neurological signs, optic neuritis | MRI shows demyelinating lesions; sensory and motor signs often dissociated. |
| Myopathies (e.g., polymyositis) | Proximal weakness, elevated CK | Weakness is constant, CK markedly raised, EMG shows myopathic changes. |
| Thyroid eye disease | Proptosis, lid retraction, restrictive ophthalmopathy | Eye signs are due to tissue expansion, not fatigable weakness; thyroid function abnormal. |
Investigations
| Test | What it answers | Interpretation |
|---|---|---|
| Acetylcholine‑receptor (AChR) antibody assay | Presence of pathogenic auto‑antibodies | Positive in majority of generalized MG; high titres correlate with disease severity. |
| Muscle‑specific kinase (MuSK) antibody assay | Auto‑antibodies in seronegative AChR cases | Positive in a subset, often with bulbar‑predominant disease; guides therapy choice. |
| Repetitive nerve stimulation (RNS) | Electrophysiological evidence of decremental response | >10 % decrement at 3 Hz supports MG; more sensitive in generalized disease. |
| Single‑fiber EMG (SF‑EMG) | Most sensitive test for neuromuscular transmission defect | Increased jitter or blocking confirms MG; useful when antibodies are negative. |
| Chest CT/MRI | Detect thymic hyperplasia or thymoma | Thymoma present in ~15 % of adults; hyperplasia common in younger patients; influences surgical decision. |
| Pulmonary function tests (spirometry) | Baseline respiratory reserve, risk of crisis | Reduced forced vital capacity (< 1 L) or maximal inspiratory pressure signals need for close monitoring. |
| Basic labs (CBC, electrolytes, renal & liver function) | Identify infection, electrolyte disturbances, drug safety | Hyponatraemia, hypermagnesemia, renal impairment can exacerbate MG or limit medication choices. |
Diagnosis and severity
Diagnostic criteria (adapted for our setting)
- Clinical picture consistent with fluctuating, fatigable weakness affecting ocular, bulbar, respiratory or proximal muscles.
- Objective confirmation by at least one of:
- Positive AChR or MuSK antibodies, or
- Electrophysiological evidence (RNS decrement or abnormal SF‑EMG).
- Exclusion of mimics through history, exam and targeted investigations.
When both clinical and laboratory criteria are met, the diagnosis is definite MG. If clinical suspicion is high but antibodies/electrophysiology are negative, a trial of anticholinesterase and observation is acceptable before labeling as seronegative MG.
Severity grading (for initial management planning)
| Grade | Clinical picture | Management implication |
|---|---|---|
| I (ocular) | Isolated ptosis/diplopia, no bulbar or limb weakness | Anticholinesterase ± low‑dose steroids; monitor for generalisation. |
| II (mild generalized) | Limb or bulbar weakness but able to sit upright, normal respiration | Anticholinesterase + steroids; consider early immunosuppressant; outpatient follow‑up. |
| III (moderate) | Marked limb/bulbar weakness, may need assistance for ADLs, vital capacity > 1 L | Higher‑dose steroids, add steroid‑sparing agent (azathioprine, mycophenolate); consider thymectomy if indicated. |
| IV (severe) | Severe weakness, respiratory compromise (vital capacity ≤ 1 L), may need ventilatory support | Admit to high‑dependency unit, start IV immunoglobulin or plasma exchange, aggressive immunosuppression, plan for definitive thymectomy if thymoma present. |
| V (crisis) | Acute respiratory failure requiring intubation | Immediate airway protection, plasma exchange or IVIG, high‑dose steroids, treat precipitating factors (infection, drugs). |
Severity assessment should be repeated after any change in therapy or after an infection, as patients can shift rapidly between grades. Early recognition of respiratory decline (fall in vital capacity or negative inspiratory force) is critical to prevent crisis.
Management
| Phase | Goal | Key Interventions | Monitoring / Safety |
|---|---|---|---|
| Immediate stabilisation | Secure airway, maintain ventilation | • Assess for respiratory fatigue (vital capacity, negative inspiratory force) <br>• Give supplemental O₂ if SpO₂ < 94 % <br>• Prepare for non‑invasive ventilation or intubation if VC < 1 L or rapid decline | Continuous pulse‑oximetry, bedside spirometry every 30 min, cardiac monitoring; have senior anaesthetist on standby |
| Definitive medical therapy | Reduce auto‑antibody activity | • Acetylcholinesterase inhibitor (e.g., pyridostigmine) – start low, titrate to symptom control <br>• Rapid‑acting immunotherapy for crisis or severe disease: plasma exchange or intravenous immunoglobulin (IVIG) <br>• Long‑term immunosuppression – corticosteroids (prednisone‑type) → steroid‑sparing agents (azathioprine, mycophenolate mofetil, cyclosporine) <br>• Thymectomy for patients < 60 yr with generalized MG, especially if thymoma present | Baseline CBC, LFT, renal function before immunosuppressants; weekly weight & blood pressure on steroids; screen for infections; repeat antibody titres only for research, not routine |
| Adjuncts | Symptom control, prevent exacerbations | • Avoid medications that worsen MG (e.g., aminoglycosides, fluoroquinolones, certain β‑blockers) <br>• Counsel on stress, infection, pregnancy, and vaccination timing | Review medication list at each visit; educate patient/family |
| Follow‑up | Assess disease control, taper steroids, monitor complications | • Clinic review 4‑6 weeks after any change, then 3‑6 monthly <br>• Repeat pulmonary function tests if respiratory symptoms recur <br>• Monitor for steroid‑related adverse effects (glucose, bone density, cataract) | Use standardized MG‑ADL score to track functional status |
Contra‑indications / safety notes
- Plasma exchange is contraindicated in severe coagulopathy or uncontrolled bleeding.
- IVIG should be avoided in patients with severe renal insufficiency or known IgA deficiency with antibodies.
- Thymectomy is not performed in patients with advanced thymic carcinoma invading mediastinum.
- Chronic high‑dose steroids demand prophylaxis for osteoporosis, gastric protection, and glucose monitoring.
Complications and prognosis
- Myasthenic crisis – acute respiratory failure; mortality reduced with early ventilation and plasma exchange/IVIG.
- Chronic immunosuppression – infections (TB, opportunistic fungi, hepatitis), metabolic derangements, cataract, avascular necrosis.
- Thymoma‑related – local invasion, paraneoplastic syndromes, recurrence after resection.
- Pregnancy – risk of neonatal transient myasthenia; maternal disease often stable with careful drug selection.
- Long‑term outlook – > 80 % achieve minimal symptoms with combined therapy; early thymectomy improves remission rates, especially in younger patients.
High‑yield exam points
- Look‑alike conditions: Lambert‑Eaton syndrome (presynaptic, improves with use), botulism (descending weakness, autonomic signs), hypothyroid myopathy, motor neuron disease.
- Common wrong first step: Starting high‑dose steroids without confirming airway safety in a patient with fatigable breathing.
- Bedside examiner questions:
- “Demonstrate the ice‑pack test and explain its physiology.”
- “What muscles would you test to differentiate ocular from generalized MG?”
- “List three drugs you must avoid in this patient and why.”
- “How would you assess for impending respiratory failure?”
Clinical case
Case: A 28‑year‑old Kenyan female university student presents with 3 weeks of painless drooping of both eyelids, worsening at the end of the day, and difficulty chewing her meals. She reports mild shortness of breath after climbing two flights of stairs. On exam, ptosis is present, extra‑ocular movements are limited horizontally, and a “fatigable” grip strength test shows a 30 % drop after 30 seconds of sustained squeezing. Vital capacity is 1.8 L (normal > 2.5 L).
Questions
- What is the most appropriate next investigation?
Answer: Perform a bedside ice‑pack test (apply ice to the eyelids for 2 minutes; improvement supports MG).
- Which immediate management step is mandatory before any immunosuppressive therapy?
Answer: Assess and secure the airway – obtain vital capacity and be prepared for ventilation because respiratory muscles may be compromised.
- What long‑term treatment strategy offers the best chance of remission in this patient?
Answer: Thymectomy combined with acetylcholinesterase inhibitor and a steroid‑sparing immunosuppressant, given her age, generalized symptoms, and likely thymic hyperplasia.
Practice questions
Question 1
A 55‑year‑old man with known generalized MG presents with sudden dyspnoea, SpO₂ = 88 % on room air, and a vital capacity of 0.9 L. What is the next best step?
A. Increase pyridostigmine dose
B. Start oral prednisone
C. Initiate non‑invasive ventilation and arrange plasma exchange
D. Order a CT chest
Answer: C. Initiate non‑invasive ventilation and arrange plasma exchange
Explanation: The patient is in myasthenic crisis; airway support and rapid immunomodulation are priorities.
Question 2
A 40‑year‑old woman with MG reports worsening weakness after starting a new antibiotic for a urinary tract infection. Which drug is the most likely culprit?
A. Amoxicillin
B. Ciprofloxacin
C. Azithromycin
D. Metronidazole
Answer: B. Ciprofloxacin
Explanation: Fluoroquinolones can exacerbate MG by interfering with neuromuscular transmission.
Question 3
Which feature distinguishes Lambert‑Eaton syndrome from Myasthenia gravis?
A. Improvement with rest
B. Ptosis that worsens with use
C. Incremental response on repetitive nerve stimulation
D. Positive anti‑AChR antibodies
Answer: C. Incremental response on repetitive nerve stimulation
Explanation: LEMS shows a characteristic increase in CMAP amplitude with rapid stimulation, opposite to the decrement seen in MG.
Question 4
A 22‑year‑old male with newly diagnosed MG is started on azathioprine. Which baseline test is essential before initiation?
A. Serum calcium
B. TPMT activity or genotype
C. Serum ferritin
D. Urine protein‑creatinine ratio
Answer: B. TPMT activity or genotype
Explanation: Low TPMT activity predisposes to azathioprine toxicity; testing guides safe dosing.
Question 5
In a pregnant woman with well‑controlled MG on pyridostigmine, which medication should be avoided if she develops a severe flare?
A. Intravenous immunoglobulin
B. Plasma exchange
C. High‑dose corticosteroids
D. Azathioprine
Answer: D. Azathioprine
Explanation: Azathioprine is category D in pregnancy and generally avoided; IVIG or plasma exchange are safer acute options.
Drafted with AI assistance from standard references and reviewed for structure. Check details against your lecture notes and the Kenya MoH guideline.