First step: differentiate true weakness from general fatigue, dizziness, lightheadedness, etc.

Second step: locate the lesion. The differential diagnosis can be broken down based on potential locations of lesions

Differential Diagnosis

  • Central nervous system
    • Brain
      • Infarct (thrombotic, embolic, or hemorrhagic)
        • Acute onset, may have a history of trauma, atrial fibrillation, or atherosclerotic disease
      • Neoplasm
        • Insidious onset, associated symptoms include fevers, chills, night sweats, weight loss
      • Progressive Multifocal Leukoencephalopathy
        • Etiology: JC Virus in immunosuppressed patients
      • Multiple Sclerosis
        • Classically presents in young women, ~age 30. May have a history of other non-specific neurologic complaints
        • Lesions disseminated in space and time (classically juxtacortical, infratentorial, or periventricular)
        • Oligoclonal bands on CSF analysis
    • Spinal cord
      • Transverse Myelitis
        • Usually acute in onset, may be a result of infection, systemic autoimmune disease, paraneoplastic syndrome, or idiopathic
        • Treatment: High-dose IV glucocorticoids (PLEX if refractory)
      • Multiple Sclerosis
        • Classically presents in young women, ~age 30. May have a history of other non-specific neurologic complaints
      • Poliomyelitis
        • In patients who did not receive childhood vaccinations
      • Amyotrophic Lateral Sclerosis (ALS)
        • Asymmetric findings of both upper and lower motor neuron defects
        • Ranolazine may slow disease progression
      • Guillain-Barré Syndrome
        • Ascending weakness, paresthesias
        • Typically following infection (most notably: campylobacter, mycoplasma, Haemophilus, or CMV)
        • Typically self-limited, but may cause respiratory failure if severe enough
        • Treatment: IVIG, PLEX (no steroids)
  • Peripheral nervous system
    • Peripheral neuropathy
      • Diabetes
        • Diabetic amyotrophy
          • Severe pain of usually thigh muscles (L2-L4 distribution), followed by weakness and numbness of unilateral thigh area over weeks to months
        • Diabetic polyneuropathy
          • Distal lower extremity weakness, “stocking/glove distribution” sensory loss, paresthesias
      • B12 deficiency
        • Inadequate consumption (vegan/vegetarian diet), reduced absorption (gastrectomy, pernicious anemia, Celiac disease, IBD, pancreatic insufficiency, PPI use, etc.)
        • May also present with macrocytic/megaloblastic anemia
      • Guillain-Barre Syndrome
        • Acute inflammatory demyelinating polyradiculoneuropathy classically following an infection such as campylobacter, non-specific viral illness, or zika virus
        • Characterized by ascending weakness, radicular symptoms, and diffuse areflexia. Symptoms can ascend to bulbar and diaphragmatic neurons
        • CSF: elevated protein with normal leukocyte count
        • Nerve conduction studies: demyelinating changes studies
        • Management: IVIG or plasma exchange (NO steroids)
      • Radiculopathy
        • Compression of nerve from osteoarthritis, trauma, etc.
      • Porphyria
        • Very rare, may present with cutaneous findings or alterations in mental status
      • Alcohol Use
  • Motor end plate
    • Neuromuscular junction disease
      • Myasthenia Gravis
        • Antibodies for post-synaptic acetylcholine receptors -> competitively inhibit acetylcholine binding to post-synaptic neuron
          • Acetylcholine receptor antibodies in 90% of patients
          • Anti–muscle-specific kinase [MuSK] antibodies in 95%
        • Weakness worsens with repetitive use
      • Lambert-Eaton Syndrome
        • Antibodies to pre-synaptic voltage-gated calcium channels -> inhibit calcium influx to pre-synaptic neuron -> inhibit release of acetylcholine
        • Weakness improves with repetitive use
        • Highly-associated with small cell lung carcinoma
  • Muscle
    • Myositis
      • Polymyositis
        • Typically, will be symmetric and proximal muscles
      • Dermatomyositis
        • Weakness findings similar to those in polymyositis, will have associated skin findings such as Gottron papules (papules over the dorsal hands), shawl sign (rash over the upper back, neck, and top of chest), and heliotropic rash (periorbital region)
      • Inclusion Body Myositis
        • Similar findings as polymyositis, however, this may be more insidious in onset and may have characteristic findings of asymmetric distal upper extremity weakness (1)
      • Drug-induced Myositis
        • History of statin, fibrate, interferon, corticosteroids, amiodarone, colchicine, vincristine, or chloroquine use (2)
    • Immune-Mediated Necrotizing Myopathy
      • May be related to statins but symptoms persist despite statin discontinuation
      • Diagnosis: Elevated CK, Hydroxymethylglutaryl coenzyme A reductase, evidence of necrosis without inflammation on biopsy
      • Treatment: Glucocorticoids
  • Systemic
    • Electrolyte derangements


The most important aspect in the approach to weakness is the history and physical exam. Labs and imaging will not be necessary in all patients, but they may be used as confirmatory tests for suspicions raised during the patient interview.

  • History
    • Systemic vs localized, symmetric vs asymmetric, acute vs subacute vs chronic
    • Associated symptoms: “B”-symptoms (fever, night sweats, weight loss), numbness/paresthesias, rashes, dietary habits, pains, alcohol use, recent illnesses
    • Past medical history: Cancer, immunosuppression, osteoarthritis, trauma, atherosclerotic disease, diabetes
    • Medications
  • Physical Exam
    • Characterize the symmetry and severity of weakness (3)
      • 0: No muscle activation
      • 1: Muscle twitch, does not achieve full ROM
      • 2: Full ROM with gravity eliminated
      • 3: Full ROM against gravity
      • 4: Full ROM against SOME resistance
      • 5: Full ROM against FULL resistance
    • Does weakness improve or worsen with repetitive stimulation?
    • Assess for associated loss of sensation
    • Assess for skin changes
  • Labs
    • CK (muscle breakdown)
    • CRP/ESR (inflammatory etiology)
    • CMP (electrolyte derangements, elevated AST/ALT in muscle breakdown)
    • Hemoglobin A1C
    • Vitamin B12/Folate
    • Anti-CaR Antibody (Lambert-Eaton Syndrome)
    • Anti-AchR Antibody, Anti-MuSK Antibody (Myasthenia Gravis)
    • Lumbar puncture (Guillain-Barre syndrome will result in elevated protein levels with normal cell counts)
    • Muscle Biopsy (to determine underlying etiology of myositis)
      • Polymyositis: CD8+ predominant inflammation, perivascular/perimysial/endomysial inflammation (4)
      • Dermatomyositis: CD4+ predominant inflammation, perifascicular atrophy (5)
      • Inclusion Body Myositis: Endomysial inflammation (6)
  • Imaging
    • CT head without contrast (to evaluate for infarct, hemorrhagic CVA)
    • MRI (Neoplasm, abscess, Multiple Sclerosis, Transverse Myelitis, radiculopathy)


  1. Dimachkie, M., & Barohn, R. (2012, July). Inclusion body myositis. Retrieved January 02, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535450/
  2. Valiyil, R., & Christopher-Stine, L. (2010, June). Drug-related myopathies of which the clinician should be aware. Retrieved January 02, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092639/
  3. Naqvi, U. (2020, September 03). Muscle Strength Grading. Retrieved January 02, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK436008/
  4. RJ;, A. (n.d.). Evaluation and treatment of inflammatory myopathies. Retrieved January 02, 2021, from https://pubmed.ncbi.nlm.nih.gov/19762898/
  5. KW;, K. (n.d.). Microvascular deposition of complement membrane attack complex in dermatomyositis. Retrieved January 02, 2021, from https://pubmed.ncbi.nlm.nih.gov/3945256/
  6. Lloyd TE;Mammen AL;Amato AA;Weiss MD;Needham M;Greenberg SA;. (n.d.). Evaluation and construction of diagnostic criteria for inclusion body myositis. Retrieved January 02, 2021, from https://pubmed.ncbi.nlm.nih.gov/24975859/

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