In a patient presenting with pure motor weakness without sensory deficits, what are the clinical presentation, pathophysiology, etiologies, diagnostic work‑up, and management for proximal myopathy, myasthenia gravis, Lambert‑Eaton myasthenic syndrome, and motor neuron disease?

Pure Motor Weakness Without Sensory Deficits: Diagnostic Approach

Proximal Myopathy

Clinical Presentation

Proximal myopathy presents with symmetric weakness of hip and shoulder girdle muscles, causing difficulty rising from chairs, climbing stairs, and lifting objects overhead, without sensory symptoms or reflex changes. 1

• Patients develop progressive difficulty with activities requiring proximal muscle strength, such as combing hair or standing from a seated position 1
• Muscle pain may be present, particularly in inflammatory myopathies 1
• Cutaneous features (Gottron papules, heliotrope rash, shawl sign) suggest dermatomyositis 1
• Systemic features including fever, Raynaud phenomenon, and interstitial lung disease may accompany antisynthetase syndrome 1

Pathophysiology

• Inflammatory myopathies result from T-cell mediated immune attack on muscle fibers, with specific myositis-specific antibodies (MSAs) targeting different cellular components 1
• Anti-Jo-1 antibody (most common antisynthetase) targets histidyl-tRNA synthetase, while anti-SRP antibody targets signal recognition particle, causing necrotizing myopathy 1
• Non-inflammatory causes include endocrine disorders (thyroid disease, hyperparathyroidism), drug-induced myopathy (statins), and metabolic myopathies 1

Investigation

• Serum creatine kinase (CK) is the initial screening test—elevation confirms muscle involvement, though normal levels do not exclude myopathy 2
• Electromyography demonstrates polyphasic motor unit action potentials of short duration and low amplitude with increased insertional activity, fibrillation potentials, and sharp waves 1
• Muscle biopsy is the gold standard, showing inflammatory infiltrates in inflammatory myopathies versus dystrophic changes or mitochondrial abnormalities in other causes 1
• Test for myositis-specific antibodies (anti-Jo-1, anti-SRP, anti-Mi2) to classify inflammatory myopathy subtype 1
• Screen for thyroid dysfunction (TSH), vitamin deficiencies (B12, folate), and review medications for statin use 2

Management

• Corticosteroids are first-line for inflammatory myopathies, though patients with anti-SRP antibody have poor response to standard immunosuppression 1
• Add steroid-sparing agents (azathioprine, methotrexate, mycophenolate mofetil) for maintenance therapy 1
• Discontinue offending medications if drug-induced myopathy is identified 2
• Treat underlying endocrine disorders appropriately 1

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Myasthenia Gravis

Clinical Presentation

Myasthenia gravis presents with painless, fluctuating, fatigable weakness that worsens with repetitive activity and improves with rest, most characteristically beginning with asymmetric ptosis and binocular diplopia. 3

• Ocular weakness is the most typical initial presentation, with asymmetric ptosis and diplopia 3
• Bulbar weakness causes dysarthria, dysphagia, and difficulty chewing, particularly later in meals 3
• Limb weakness is typically proximal but less common as an initial presentation 3
• Most patients with initial ocular weakness progress to generalized weakness within three years 3
• Weakness characteristically fluctuates throughout the day and worsens with sustained activity 3

Pathophysiology

• Antibody-mediated, T-cell dependent immunologic attack on the postsynaptic membrane at the neuromuscular junction 3
• Acetylcholine receptor (AChR) antibodies are present in most patients, while muscle-specific tyrosine kinase (MuSK) antibodies occur in a subset of seronegative patients 3
• Antibodies reduce the number of functional AChRs, impairing neuromuscular transmission 3

Investigation

• Edrophonium (Tensilon) test produces unequivocal improvement in strength within minutes, supporting the diagnosis 3
• Repetitive nerve stimulation demonstrates decremental response (>10% amplitude reduction) in affected muscles 3
• Single-fiber electromyography is the most sensitive test, showing increased jitter and blocking 3
• Serologic testing for AChR antibodies (positive in 80-85% of generalized MG) and MuSK antibodies (in seronegative patients) 3
• Chest CT or MRI to evaluate for thymoma, present in 10-15% of patients 3

Management

• Pyridostigmine (cholinesterase inhibitor) provides symptomatic improvement, starting at 30-60 mg three times daily 3
• Corticosteroids are first-line immunotherapy, though initial worsening may occur in the first 1-2 weeks 3
• Azathioprine, mycophenolate mofetil, or cyclosporine as steroid-sparing agents 3
• Plasma exchange or intravenous immunoglobulin (IVIg) for myasthenic crisis or severe exacerbations 3
• Thymectomy for patients with thymoma or generalized MG under age 60 3

Common pitfall: Avoid medications that worsen neuromuscular transmission including aminoglycosides, fluoroquinolones, macrolides, beta-blockers, and IV magnesium 2

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Lambert-Eaton Myasthenic Syndrome

Clinical Presentation

Lambert-Eaton syndrome presents with progressive proximal leg weakness (particularly hip muscles), depressed or absent reflexes, and autonomic dysfunction (dry mouth, constipation, erectile dysfunction), with characteristic improvement in strength after brief exercise. 4, 5, 6

• Proximal lower extremity weakness predominates, causing difficulty rising from chairs and climbing stairs 4, 6
• Depressed or absent muscle stretch reflexes that may transiently improve after brief muscle activation 4, 6
• Autonomic symptoms are nearly universal: dry mouth (most common), constipation, erectile dysfunction, orthostatic hypotension 4, 5, 6
• Ocular and bulbar weakness occur but are less prominent than in myasthenia gravis 4, 5
• Post-exercise facilitation: strength temporarily improves after 10-15 seconds of maximal voluntary contraction 4

Pathophysiology

• Autoantibodies against presynaptic P/Q-type voltage-gated calcium channels (VGCCs) impair acetylcholine release at the neuromuscular junction 5
• 50-60% of cases are paraneoplastic, most commonly associated with small cell lung cancer (SCLC-LEMS) 4, 5
• Remaining cases are idiopathic (NT-LEMS), associated with other autoimmune diseases 5

Investigation

• Electromyography shows low-amplitude compound muscle action potentials (<5 mV) that increase dramatically (>100%) after 10 seconds of maximal voluntary contraction or high-frequency (20-50 Hz) repetitive nerve stimulation 4
• Anti-VGCC antibody testing is positive in 85-95% of patients 4, 5
• LEMS diagnosis mandates intensive oncological screening, particularly chest CT for small cell lung cancer, especially in older patients with smoking history 4, 5
• Repeat cancer screening every 3-6 months for 2 years if initial workup is negative 5

Management

• 3,4-diaminopyridine (amifampridine) is first-line symptomatic treatment, producing clinically significant benefit in >85% of patients, with marked improvement in over half 4, 5
• Treat underlying malignancy if present—successful cancer treatment leads to improvement in many patients 4, 5
• Add immunosuppression (prednisone plus azathioprine or cyclosporine) if severe weakness persists despite amifampridine 4, 5
• Plasma exchange or IVIg for acute severe weakness, though improvement is transient and rarely complete 4

Critical distinction from myasthenia gravis: LEMS has predominant lower extremity weakness, depressed reflexes, and post-exercise facilitation, whereas myasthenia gravis has prominent ocular/bulbar weakness, normal reflexes, and worsening with exercise 3, 4

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Motor Neuron Disease

Clinical Presentation

Motor neuron disease presents with progressive, asymmetric weakness combining upper motor neuron signs (spasticity, hyperreflexia, Babinski sign) and lower motor neuron signs (muscle atrophy, fasciculations, flaccid weakness) without sensory loss.

• Limb-onset ALS typically begins with asymmetric distal hand weakness (difficulty with fine motor tasks) or foot drop [@general medical knowledge@]
• Bulbar-onset ALS presents with dysarthria, dysphagia, and tongue atrophy with fasciculations [@general medical knowledge@]
• Progressive muscle atrophy and fasciculations are prominent, particularly in the tongue, shoulders, and thighs [@general medical knowledge@]
• Hyperreflexia in atrophic, weak muscles is pathognomonic for ALS [@general medical knowledge@]
• Respiratory muscle weakness develops as disease progresses, causing dyspnea and orthopnea [@general medical knowledge@]
• Frontotemporal dementia occurs in 15% of patients [@general medical knowledge@]

Pathophysiology

• Progressive degeneration of upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord [@general medical knowledge@]
• Etiology remains unclear, with contributions from glutamate excitotoxicity, oxidative stress, protein aggregation, and neuroinflammation [@general medical knowledge@]
• 5-10% of cases are familial, with mutations in SOD1, C9orf72, TARDBP, and FUS genes [@general medical knowledge@]

Investigation

• Electromyography demonstrates widespread denervation (fibrillation potentials, positive sharp waves) with chronic reinnervation (large polyphasic motor units) in multiple body regions [@general medical knowledge@]
• Nerve conduction studies show normal sensory responses with reduced motor amplitudes in advanced disease [@general medical knowledge@]
• MRI brain and spine to exclude structural lesions mimicking motor neuron disease [@general medical knowledge@]
• Exclude ALS mimics: check vitamin B12, TSH, serum protein electrophoresis, anti-GM1 antibodies (multifocal motor neuropathy), HIV, Lyme serology [@general medical knowledge@]
• Genetic testing for familial ALS genes if family history or young age at onset [@general medical knowledge@]

Management

• Riluzole 50 mg twice daily modestly prolongs survival by 2-3 months and should be started at diagnosis [@general medical knowledge@]
• Edaravone (antioxidant) may slow functional decline in early-stage patients [@general medical knowledge@]
• Multidisciplinary care including neurology, pulmonology, nutrition, physical therapy, occupational therapy, and palliative care [@general medical knowledge@]
• Non-invasive ventilation (BiPAP) when forced vital capacity falls below 50% or symptoms of nocturnal hypoventilation develop [@general medical knowledge@]
• Percutaneous endoscopic gastrostomy for nutritional support when swallowing becomes unsafe [@general medical knowledge@]
• Treat spasticity with baclofen or tizanidine; manage sialorrhea with anticholinergics or botulinum toxin [@general medical knowledge@]

Critical diagnostic pitfall: Marked sensory loss, sphincter dysfunction at onset, or prominent autonomic failure should prompt reconsideration of the diagnosis away from motor neuron disease [@general medical knowledge@]