What workup should be performed for a patient with sudden unilateral swelling below the knee, a negative deep vein thrombosis study, and a normal knee X‑ray without osteoarthritis?

Workup for Unilateral Below-Knee Swelling with Negative DVT and Normal X-ray

The workup should focus on identifying alternative causes of unilateral leg swelling, including Baker's cyst (ruptured or intact), cellulitis, lymphedema, chronic venous disease, and musculoskeletal disorders, as these commonly mimic DVT clinically. 1

Immediate Clinical Assessment

Key History Elements to Obtain

• Recent trauma or calf strain history, as musculoskeletal injuries can present with isolated swelling and may progress to severe symptoms even after initial resolution 2
• Presence of fever or skin changes suggesting infectious etiology such as cellulitis 1
• History of prior DVT or chronic venous insufficiency, as these predispose to recurrent swelling and chronic venous disease 1
• Timing and acuity of onset, particularly whether swelling developed after prolonged immobility or travel 2

Physical Examination Findings to Document

• Skin temperature, erythema, and tenderness to differentiate cellulitis from other causes 1
• Palpation of popliteal fossa for Baker's cyst, which can rupture and cause acute calf swelling mimicking DVT 1
• Assessment for pitting edema versus firm swelling to distinguish lymphedema from venous or inflammatory causes 1
• Range of motion and joint examination to identify musculoskeletal pathology 2

Recommended Imaging Strategy

If Symptoms Persist or Worsen

• Repeat duplex ultrasound in 5-7 days if initial DVT study was negative but symptoms persist or worsen, as this can detect propagating distal DVT that was initially below detection threshold 1
• Consider whole-leg ultrasound if not already performed, as standard proximal compression ultrasound has lower sensitivity (63.5%) for distal calf DVT 1

Alternative Diagnoses Requiring Specific Imaging

• Musculoskeletal ultrasound or MRI to evaluate for Baker's cyst (intact or ruptured), muscle tears, hematoma, or other soft tissue pathology not visible on plain radiographs 1
• Consider MRI of the knee and calf if Baker's cyst rupture is suspected, as this provides superior soft tissue characterization compared to ultrasound alone 1

Laboratory Testing

D-dimer Considerations

• D-dimer testing has limited utility after negative imaging, as it cannot diagnose alternative conditions and may remain elevated in cellulitis, trauma, or other inflammatory states 1
• Elevated D-dimer with negative ultrasound warrants consideration of repeat imaging or alternative diagnoses rather than treatment for DVT 1

Additional Laboratory Work

• Complete blood count and inflammatory markers (ESR, CRP) if cellulitis or other inflammatory process is suspected
• Blood cultures if febrile to evaluate for systemic infection

Common Pitfalls to Avoid

• Do not dismiss persistent unilateral swelling as benign edema without identifying a specific cause, as DVT can initially be missed and propagate proximally 1
• Do not assume all below-knee swelling is distal DVT even with negative proximal ultrasound, as Baker's cyst rupture (pseudothrombophlebitis) is a common DVT mimic 1, 2
• Avoid relying solely on clinical prediction scores after negative imaging, as numerous pathologic conditions mimic DVT presentation 1
• Do not overlook musculoskeletal causes in athletic or active patients, as severe DVT-like presentations can occur from muscle injuries 2

Follow-up Strategy

If No Diagnosis Established

• Serial ultrasound at 5-7 days is mandatory if symptoms persist or worsen with initially negative complete duplex ultrasound 1
• Consider cross-sectional imaging (MRI or CT) if ultrasound remains negative but clinical suspicion for pathology remains high 1

When to Escalate Care

• Immediate vascular surgery consultation if compartment syndrome is suspected based on severe pain, tense swelling, or neurovascular compromise
• Infectious disease consultation if cellulitis is severe, rapidly progressive, or patient is immunocompromised