What is the differential diagnosis for an adult patient with no significant past medical history presenting with a swollen and painful leg?

Differential Diagnosis for Swollen Leg with Pain

The differential diagnosis for an adult with a swollen, painful leg must prioritize life-threatening conditions first: deep vein thrombosis (DVT), acute limb ischemia (ALI), and compartment syndrome, followed by common causes like venous insufficiency, cellulitis, and less common entities like diabetic muscle infarction or Charcot neuro-osteoarthropathy in diabetic patients.

Immediate Life-Threatening Conditions to Exclude

Deep Vein Thrombosis (DVT)

• DVT is the most critical diagnosis to exclude given its potential for pulmonary embolism, which carries 25-30% mortality if untreated 1
• Calculate Wells score or similar clinical prediction rule to stratify pretest probability based on risk factors: recent immobility, surgery, cancer, prior DVT, pregnancy, or oral contraceptive use 2
• For moderate-to-high pretest probability, proceed directly to proximal compression ultrasound (CUS) without D-dimer testing 1, 2
• For low pretest probability, obtain D-dimer first; if negative, DVT is excluded 2
• Proximal DVT (above-the-knee) carries high risk for pulmonary embolism, while distal DVT (below-the-knee) rarely causes pulmonary embolism but may extend proximally in one-sixth of cases 1
• If proximal CUS is negative but suspicion remains high, repeat CUS in 1 week or perform whole-leg ultrasound 1

Acute Limb Ischemia (ALI)

• Presents with the "6 P's": pain, pallor, paresthesia/paralysis, poikilothermia (coldness), and pulselessness 1
• This is a vascular emergency requiring immediate multidisciplinary consultation before imaging 1
• Differentiate from venous thrombosis: ALI presents with a cold, pale leg versus DVT with a warm, swollen leg 1
• Rare presentation of phlegmasia cerulea dolens (massive venous thrombosis) causes dusky discoloration, massive swelling, and pain but maintains distal arterial pulses 1
• Arteriography is preferred if clinical suspicion is intermediate-to-high; CTA is appropriate if suspicion is lower and renal function permits 1

Compartment Syndrome

• Manifests with acute ischemia via tissue pressurization, often following trauma or injury 1
• Should be excluded clinically before pursuing imaging modalities 1

Common Non-Life-Threatening Causes

Chronic Venous Insufficiency

• Most common cause of leg edema in older adults 3
• Characterized by sensation of heavy or swollen legs, itching, worsened by hot environment, improved by cold environment, and not worsened by walking 4
• Differentiated from arterial disease by presence of distal pulses 1
• Treated with leg elevation, compression stockings, and sometimes diuretics 3

Cellulitis/Soft Tissue Infection

• Requires at least two of the following: local swelling/induration, erythema >0.5 cm around wound, local tenderness/pain, local warmth, or purulent discharge 5
• Systemic antibiotics should be initiated promptly if infection is confirmed 1
• Ultrasound can identify abscess formation requiring drainage 2

Congestive Heart Failure

• Typically presents with bilateral leg edema rather than unilateral 6, 3
• Associated with dyspnea, orthopnea, and elevated jugular venous pressure 3

Special Considerations in Diabetic Patients

Charcot Neuro-osteoarthropathy (CNO)

• Suspect in diabetic patients with neuropathy presenting with unilateral red, warm, swollen foot with intact skin 5
• Temperature difference ≥2°C between affected and unaffected foot strongly suggests active CNO 5
• Initiate knee-high immobilization/offloading immediately while awaiting diagnostic confirmation—delayed treatment leads to catastrophic consequences including fractures, deformity, and amputation 5
• Plain radiographs may be normal in early stages; MRI is preferred advanced imaging showing bone marrow edema 5
• Pain may be minimal or absent due to sensory neuropathy—do not assume absence of pain rules out serious pathology 5

Diabetic Muscle Infarction

• Rare complication presenting as severely painful mass in lower limb with high ESR in poorly controlled longstanding Type 1 diabetes with microangiopathy 7
• MRI shows diffuse muscle enlargement and edematous pattern 7
• Creatine kinase typically normal, distinguishing it from rhabdomyolysis 7

Less Common Causes to Consider

Ruptured Baker's Cyst

• Can mimic DVT with acute calf pain and swelling 2
• Ultrasound readily identifies this diagnosis 2

Lymphedema

• Chronic progressive swelling, typically painless unless infected 6, 3
• Skin changes include thickening and hyperkeratosis in advanced stages 6

Hematoma or Tumor

• History of trauma or anticoagulation suggests hematoma 2
• Ultrasound or MRI can identify mass lesions 2

Idiopathic Edema

• Most common cause in women between menarche and menopause 3
• Initial treatment is spironolactone 3

Pulmonary Hypertension with Secondary Leg Edema

• Under-recognized cause, often associated with sleep apnea 3
• Evaluate patients with daytime somnolence, loud snoring, or neck circumference >17 inches with echocardiogram 3

Critical Pitfalls to Avoid

• Never delay anticoagulation in moderate-to-high probability DVT patients while awaiting imaging—this increases risk of pulmonary embolism and mortality 2
• Do not use D-dimer as standalone test in moderate-to-high pretest probability patients—insufficient negative predictive value 1, 2
• In diabetic patients with neuropathy and hot swollen foot, never delay immobilization while waiting for imaging to confirm CNO 5
• Do not assume bilateral edema excludes DVT—bilateral DVT can occur 8
• Exclude gout, trauma, and fracture in appropriate clinical contexts 5

Diagnostic Algorithm Summary

For acute presentation (<72 hours) or symptomatic patients:

1. Assess for life-threatening conditions: check pulses (ALI), calculate Wells score (DVT), evaluate for compartment syndrome 1, 2
2. If high probability DVT: immediate CUS and anticoagulation 2
3. If cold/pulseless leg: immediate vascular surgery consultation 1
4. If diabetic with neuropathy and warm swollen foot: immediate immobilization and imaging for CNO 5

For chronic presentation (>72 hours) in stable patients:

1. Assess for venous insufficiency, heart failure, lymphedema 3
2. Consider age and sex: venous insufficiency in elderly, idiopathic edema in premenopausal women 3
3. Basic laboratory evaluation: CBC, urinalysis, electrolytes, creatinine, glucose, TSH, albumin 3