Neuromuscular disease, GBS, CIDP, myasthenia gravis and motor neuron disease

Definition / Overview

• Neuromuscular disease encompasses disorders affecting the lower motor neuron, peripheral nerve, neuromuscular junction (NMJ), and muscle.
• For the FRACP clinical exam, four conditions demand deep command: Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), and motor neuron disease (MND).
• Each occupies a distinct anatomical compartment but all can present with weakness, and distinguishing them in a long case requires synthesis of tempo, pattern of weakness, reflex status, sensory involvement, and electrophysiology.

Guillain-Barré Syndrome (GBS)

Pathophysiology

• GBS is an acute immune-mediated polyneuropathy triggered by molecular mimicry following infection (classically Campylobacter jejuni, CMV, EBV, SARS-CoV-2, influenza vaccination in a small minority).
• Antibodies cross-react with peripheral nerve gangliosides or nodal/paranodal proteins.
• The classic variant is acute inflammatory demyelinating polyneuropathy (AIDP); axonal variants (AMAN, AMSAN) are more common in Asia and following Campylobacter infection and carry greater risk of residual disability.
• The Fisher variant (anti-GQ1b antibodies) produces the triad of ophthalmoplegia, ataxia, and areflexia without prominent limb weakness.

Clinical Features

• Onset: Ascending, symmetric weakness beginning distally over days to 4 weeks; nadir at 4 weeks by definition
• Reflexes: Areflexia or hyporeflexia, a cardinal feature that distinguishes GBS from most myopathies
• Sensory: Variable; paraesthesiae common at onset but motor features dominate
• Autonomic: Present in ~70%; life-threatening arrhythmias, blood pressure lability, urinary retention
• Respiratory: ~30% require mechanical ventilation; monitor with serial forced vital capacity (FVC) and NIF
• Pain: Neuropathic back and radicular pain is common and often undertreated

Prognostic Tool, EGOS/mEGOS

The modified Erasmus GBS Outcome Score uses age, preceding diarrhoea, and GBS disability score at 2 weeks to predict ambulation at 6 months, useful for counselling.

Investigation

Management

Acute phase, ICU-level care if any of the "20-30-40 rule": FVC <20 mL/kg, NIF $<{-}30\,\text{cmH}_2\text{O}$, or MEP $<40\,\text{cmH}_2\text{O}$.

1. Immunotherapy: Intravenous immunoglobulin (IVIg) 2 g/kg over 5 days OR plasma exchange (PE), equivalent efficacy; IVIg preferred for logistics; combination confers no additive benefit
2. Corticosteroids are NOT indicated: randomised evidence shows no benefit and potential harm
3. Continuous cardiac monitoring; treat dysautonomia with short-acting agents (labetalol, esmolol for hypertension; atropine or pacing for bradyarrhythmia)
4. Thromboprophylaxis, pressure area care, nasogastric nutrition if bulbar affected
5. Analgesia: gabapentin or pregabalin; opioids for severe pain
6. Early physiotherapy and rehabilitation planning

Prognosis

~85% achieve independent walking by 6 months; 5-10% have severe residual disability; mortality ~5% in high-income settings (mainly autonomic complications and respiratory failure).

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Pathophysiology

• CIDP shares pathogenic mechanisms with GBS but is defined by a course exceeding 8 weeks.
• It is the most common treatable acquired neuropathy.
• Autoantibodies (including anti-contactin-1, anti-CASPR1, anti-NF155) target paranodal structures.
• Classical CIDP produces symmetric proximal and distal weakness with sensory loss; atypical variants include multifocal acquired demyelinating sensory and motor neuropathy (MADSAM/Lewis-Sumner), pure motor, and distal-predominant CIDP.

Diagnostic Criteria

Diagnosis requires electrodiagnostic evidence of demyelination (prolonged distal latency, slowed NCV, conduction block, prolonged F-waves) in ≥2 nerves, with supportive clinical and CSF findings.

Management

• First-line: IVIg (2 g/kg loading, then 1 g/kg every 3 weeks), or prednisolone (starting ≥1 mg/kg/day), or PE, all proven effective
• Monitoring response: Disability scales (ONLS, INCAT), grip strength dynamometry, serial NCS
• Steroid-sparing agents: Azathioprine (2-3 mg/kg/day) or mycophenolate if steroid-dependent or intolerant
• Refractory: Rituximab (particularly if anti-NF155 or anti-CASPR1 positive, these patients often respond poorly to IVIg alone)
• Screen for associated conditions: diabetes, monoclonal gammopathy (MGUS, myeloma), HIV, hepatitis

Myasthenia Gravis (MG)

Pathophysiology

• MG is an antibody-mediated NMJ disorder.
• In ~85% of generalised MG, IgG antibodies against the acetylcholine receptor (AChR) reduce receptor availability by complement-mediated destruction and receptor internalisation.
• Anti-muscle-specific kinase (MuSK) antibodies (~5-8%) impair AChR clustering and tend to cause more prominent bulbar and facial weakness with relative preservation of limb strength.
• A small seronegative subset may have anti-LRP4 antibodies.
• The result is fatigable, fluctuating weakness that worsens with activity and improves with rest.

Clinical Features

• Ocular: Ptosis (often asymmetric), diplopia, present in >50% at onset; ~15% remain purely ocular
• Bulbar: Dysarthria (nasal quality), dysphagia, dysphonia, fatigue on chewing
• Limb: Proximal > distal; shoulder abduction and hip flexion commonly tested
• Fatigability: Ice pack test for ptosis (ptosis improves after 2 min ice application, sensitivity ~80%); sustained upgaze fatigue; repetitive task weakness
• Thymus: Thymoma in ~15% (any age, AChR-Ab positive); thymic hyperplasia in ~65% of young AChR-Ab positive patients

Investigation

Management

Symptomatic

• Pyridostigmine (acetylcholinesterase inhibitor): starting 30-60 mg orally 3-4 times daily, titrated to effect; max ~120 mg per dose; muscarinic side effects (diarrhoea, salivation) managed with propantheline; avoid in MuSK-MG where it is poorly tolerated

Immunosuppression

1. Prednisolone: Start low (10-25 mg/day) and escalate slowly to avoid initial steroid-induced exacerbation; maintenance ≥6-12 months; bone protection mandatory
2. Azathioprine: 2-3 mg/kg/day; onset 12-18 months; check TPMT before starting; steroid-sparing agent of choice
3. Mycophenolate mofetil: Alternative if azathioprine intolerant; 1-1.5 g twice daily
4. Rituximab: Particularly effective in MuSK-MG; consider after failure of two immunosuppressants

Thymectomy

• Recommended for all thymoma patients regardless of MG severity
• In non-thymomatous AChR-positive MG: thymectomy improves clinical outcome and reduces steroid burden, evidence from the MGTX randomised trial; best results in young patients within 5 years of diagnosis; role in MuSK-MG is uncertain

Rescue and Hospitalisation

• IVIg 2 g/kg over 2-5 days OR plasma exchange (PE), for rapid deterioration, pre-operatively, or myasthenic crisis
• PE generally faster onset (~3-5 days) than IVIg; prefer PE if IgA deficiency or fluid-overloaded

Myasthenic Crisis

Definition: Respiratory failure due to MG weakness requiring ventilatory support.

Triggers: Infection (most common), aspiration, surgery, medications (aminoglycosides, fluoroquinolones, beta-blockers, magnesium, neuromuscular blocking agents), rapid steroid reduction, pregnancy.

1. Admit to HDU/ICU; monitor FVC and NIF serially
2. Intubate if FVC <15-20 mL/kg or rapidly deteriorating
3. Initiate PE or IVIg
4. Withhold or reduce pyridostigmine during crisis (increased secretions may worsen respiratory status)
5. Identify and treat precipitant

Novel Therapies

• Eculizumab (complement C5 inhibitor): approved for refractory AChR-positive MG; requires meningococcal vaccination ≥2 weeks prior
• Efgartigimod (FcRn antagonist): reduces IgG levels including pathogenic antibodies; approved for generalised AChR-positive MG; administered as IV infusion cycles
• Rozanolixizumab, nipocalimab: Further FcRn antagonists in use/emerging

Motor Neuron Disease (MND) / ALS

Pathophysiology

• MND encompasses a spectrum of disorders characterised by progressive degeneration of upper motor neurons (UMN) and lower motor neurons (LMN).
• Amyotrophic lateral sclerosis (ALS) is the most common form (~80%), combining UMN and LMN features.
• Primary lateral sclerosis (PLS) is pure UMN; progressive muscular atrophy (PMA) is pure LMN.
• Frontotemporal dementia (FTD) co-occurs in ~15%.
• Most cases are sporadic; ~10% familial with mutations in SOD1, C9orf72, FUS, TDP-43.
• Pathophysiology involves protein aggregation, RNA processing errors, and glutamate excitotoxicity.

Clinical Features and Diagnostic Criteria

The revised El Escorial criteria require UMN and LMN signs in specific body regions (bulbar, cervical, thoracic, lumbosacral):

Key examination findings:

• LMN: Fasciculations, wasting, flaccidity, depressed reflexes
• UMN: Spasticity, brisk reflexes, Babinski sign, jaw jerk
• Bulbar: Fasciculating tongue ("bag of worms"), nasal dysarthria, dysphonia, dysphagia, LMN (bulbar palsy) or slow spastic speech, brisk jaw jerk, UMN (pseudobulbar palsy)
• Cognitive: FTD features in ~15%; affects decision-making capacity
• Spared: Eye movements (until late), bladder/bowel function (typically), sensation

Investigation

• EMG/NCS: LMN evidence (fibrillations, fasciculations, chronic denervation/reinnervation); NCS rules out mimicking neuropathies
• MRI brain and spine: to exclude structural causes (cervical myelopathy is a critical mimic)
• Genetic testing: C9orf72 repeat expansion, SOD1, relevant for familial cases and clinical trials
• Pulmonary function tests: FVC, SNIP, for respiratory monitoring and timing of NIV
• Neuropsychological assessment: FTD screening

Management

MND management is multidisciplinary (neurologist, respiratory physician, gastroenterologist, palliative care, speech pathology, occupational therapy, physiotherapy, social work).

Disease-Modifying Therapy

• Riluzole 50 mg twice daily: glutamate antagonist; modest survival benefit (~2-3 months median); monitor LFTs; well tolerated in most
• Edaravone (IV formulation): free radical scavenger; approved in some jurisdictions for rapidly progressing ALS; evidence of modest functional slowing in selected patients

Respiratory Management

• Serial FVC and SNIP every 3 months; when FVC <50% predicted or SNIP $<40\,\text{cmH}_2\text{O}$, initiate discussion about non-invasive ventilation (NIV)
• NIV (bilevel positive airway pressure) prolongs survival and improves quality of life; goal of care discussion essential
• Invasive ventilation: discuss early; some patients with FTD may lack capacity for advance care planning

Nutritional Management

• Percutaneous endoscopic gastrostomy (PEG) should be placed while FVC >50% predicted (anaesthetic risk increases below this threshold)
• Radiologically inserted gastrostomy (RIG) can be used when FVC is lower

Symptom Management

• Sialorrhoea: hyoscine patch, glycopyrrolate, or small doses of amitriptyline; botulinum toxin to salivary glands
• Pseudobulbar affect: dextromethorphan/quinidine or low-dose SSRIs
• Spasticity: baclofen, tizanidine
• Pain: multidisciplinary approach; opioids in advanced disease
• Palliative care: early referral; advance care planning including decisions about NIV, PEG, and end-of-life preferences

Comparative Overview for the Clinical Exam

Long-Case Framing and Multimorbidity Considerations

• GBS in pregnancy: PE preferred over IVIg (IVIg crosses placenta); close fetal monitoring; risk of relapse postpartum
• MG and thymoma: Thymoma may co-occur with other paraneoplastic syndromes; exclude Lambert-Eaton myasthenic syndrome (which presents with proximal weakness that improves with repeated activity, the opposite of MG, and autonomic features)
• Immunosuppression risks: Opportunistic infection screening before initiating high-dose steroids or rituximab; tuberculosis (IGRA), hepatitis B/C serology, varicella immune status; avoid live vaccines
• Medication triggers in MG: Counsel patients explicitly, aminoglycosides, fluoroquinolones, magnesium, beta-blockers, iodinated contrast, and neuromuscular blocking agents can all precipitate crisis; document and communicate to surgical teams
• Advance care planning in MND: Initiate early; patients with FTD may lose capacity; explore goals of care regarding NIV, PEG, and resuscitation; acknowledge that most patients die of respiratory failure within 3-5 years of symptom onset
• Health equity: Indigenous Australians and patients from rural areas face significant delays in specialist neurology access; MND and MG carry disproportionate burden when multidisciplinary services are unavailable; advocate for telehealth and coordinated care pathways