Weakness

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The best source is clearly Bradley and Daroff's Neurology. Let me read the main differential diagnosis section.

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Weakness as a Symptom: Differential Diagnosis

Weakness is a complaint that requires careful anatomical localization before a differential diagnosis can be constructed. The key principle: identify where along the neuraxis the lesion lies, then narrow by pattern, time course, and associated features.

Step 1 — Localize the Lesion

The neurological exam divides weakness into:

Level	Key Signs
Upper motor neuron (UMN) — cortex, corticospinal tract	Spasticity, hyperreflexia, extensor plantar (Babinski), weakness of upper-limb extensors + lower-limb flexors
Lower motor neuron (LMN) — anterior horn cell, nerve root, peripheral nerve	Flaccidity, hyporeflexia/areflexia, fasciculations, atrophy
Neuromuscular junction (NMJ)	Fatigable weakness, prominent ocular/bulbar/proximal muscles, reflexes preserved until severe
Muscle (myopathy)	Proximal > distal weakness, no sensory loss, normal or reduced reflexes, no fasciculations

By Anatomical Level

🧠 Central Nervous System (UMN)

Stroke — sudden-onset hemiplegia/monoplegia
Multiple sclerosis — relapsing-remitting or progressive; often with sensory, visual, cerebellar signs
Brain or spinal cord tumor — progressive; often with localizing signs
Cervical/thoracic myelopathy — bilateral leg weakness, spasticity, sphincter dysfunction
Transverse myelitis — acute, often with sensory level and bladder involvement
CNS vasculitis, ALS (UMN component)

🔬 Anterior Horn Cell

Amyotrophic lateral sclerosis (ALS) — mixed UMN + LMN, no sensory loss, relentlessly progressive
Progressive muscular atrophy (PMA) — pure LMN variant of ALS
Spinal muscular atrophy (SMA) — genetic; proximal > distal; childhood or adult onset
West Nile virus, poliomyelitis — acute flaccid paralysis

🔀 Nerve Root / Plexus

Radiculopathy (cervical or lumbar) — dermatomal sensory loss + myotomal weakness, reflex loss
Brachial plexopathy (Parsonage-Turner, trauma, neoplastic)
Lumbosacral plexopathy

🔌 Peripheral Nerve

Guillain-Barré syndrome (GBS) — ascending flaccid weakness, areflexia, post-infectious
Chronic inflammatory demyelinating polyneuropathy (CIDP) — slowly progressive or relapsing
Vasculitic neuropathy — multifocal, painful
Charcot-Marie-Tooth (CMT) — hereditary, distal weakness, pes cavus
Mononeuropathies (median, ulnar, peroneal nerve compression)
Multifocal motor neuropathy with conduction block (MMNCB) — pure motor, anti-GM1 antibodies

⚡ Neuromuscular Junction

Myasthenia gravis (MG) — fatigable ptosis, diplopia, bulbar and proximal limb weakness; AChR antibodies in 80–85%; MuSK antibodies in 4–6%
Lambert-Eaton myasthenic syndrome (LEMS) — proximal weakness that briefly improves with activity; associated with small-cell lung cancer; calcium channel antibodies
Botulism — descending paralysis, pupil involvement, constipation; foodborne or wound source

💪 Muscle (Myopathy)

Inflammatory:

Polymyositis, dermatomyositis, inclusion body myositis (IBM)
IBM: classically distal finger flexors + quadriceps; poor response to immunotherapy

Genetic (Muscular Dystrophies):

Duchenne/Becker — dystrophinopathy; proximal, Gowers' sign, very elevated CK
Facioscapulohumeral (FSH) — face + shoulder girdle; scapular winging; normal/mildly elevated CK
Myotonic dystrophy — distal > proximal, myotonia, ptosis, cataracts
Limb-girdle muscular dystrophies (LGMD)
Oculopharyngeal MD (OPMD) — late-onset ptosis + dysphagia

Metabolic Myopathies:

Glycogen storage diseases (McArdle disease — exercise intolerance + myoglobinuria)
Mitochondrial myopathies — ptosis, external ophthalmoplegia, exercise intolerance

Toxic/Drug-induced:

Statins — proximal myalgia + weakness, elevated CK
Steroids — proximal weakness, normal CK
Alcohol, colchicine, hydroxychloroquine

Endocrine:

Hypothyroidism (proximal weakness, elevated CK), hyperthyroidism
Cushing's syndrome, Addison's disease
Hypokalemia, hypophosphatemia, hypercalcemia

Differential by Pattern of Weakness

Pattern	Likely Diagnosis
Ocular weakness (ptosis, diplopia)	MG, mitochondrial myopathy, OPMD, botulism
Facial + bulbar	MG, GBS, brainstem lesion, motor neuron disease
Proximal arm + shoulder girdle	FSH dystrophy, LGMD, polymyositis, LEMS
Proximal leg + hip girdle	LGMD, polymyositis, Duchenne/Becker, spinal canal stenosis
Distal > proximal	CMT, myotonic dystrophy, IBM, peroneal neuropathy
Respiratory weakness	GBS, MG, ALS, Pompe disease
Fluctuating weakness	MG, periodic paralysis, LEMS, MS
Exacerbated by exercise	MG, LEMS, metabolic myopathies (McArdle), periodic paralysis

Constant vs. Fluctuating

Constant and progressive → muscular dystrophy, ALS, motor neuron disease, neoplasm
Fluctuating/fatigable → MG, LEMS, periodic paralysis, MS
Episodic with exercise → metabolic myopathies, channelopathies

Key Investigations

Test	Use
CK (creatine kinase)	Markedly elevated in Duchenne, polymyositis, rhabdomyolysis; normal/mild in FSH, IBM, OPMD
EMG/nerve conduction	Distinguishes myopathy vs. neuropathy vs. NMJ disorder
AChR antibodies	MG (80–85% sensitivity for generalized disease)
MuSK antibodies	MG seronegative for AChR (4–6%)
Anti-GM1 antibodies	MMNCB
Myositis panel (anti-Jo-1, etc.)	Inflammatory myopathies; predicts ILD and malignancy association
Genetic testing	Hereditary neuropathies, muscular dystrophies
Muscle/nerve biopsy	When diagnosis remains unclear after above workup
Repetitive nerve stimulation	NMJ disorders (decremental response in MG; incremental in LEMS)

Practical Approach (Bedside)

UMN or LMN? — Check tone, reflexes, plantar response
Sensory loss? — Present → nerve root or peripheral nerve; Absent → anterior horn cell, NMJ, or muscle
Fatigable? — Strongly suggests NMJ (MG, LEMS, botulism)
Proximal or distal? — Proximal → myopathy/NMJ; Distal → neuropathy
Acute or chronic? Genetic or acquired?
Associated features — rash (dermatomyositis), cardiac (certain muscular dystrophies), cataracts (myotonic dystrophy), autonomic (LEMS, botulism)

Sources: Bradley and Daroff's Neurology in Clinical Practice (Chapter: Differential Diagnosis by Affected Region and Other Manifestations of Weakness)

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