What is the differential diagnosis for sharp unilateral leg pain in an otherwise healthy individual?

Differential Diagnosis for Sharp Unilateral Leg Pain in Otherwise Healthy Individuals

The differential diagnosis for sharp unilateral leg pain in an otherwise healthy person must prioritize life-threatening and limb-threatening conditions first, followed by common musculoskeletal causes, with deep vein thrombosis (DVT), peripheral arterial disease (PAD), and lumbar radiculopathy being the most critical diagnoses to consider.

Life-Threatening and Limb-Threatening Conditions (Must Exclude First)

Deep Vein Thrombosis (DVT)

• Classic presentation includes unilateral extremity swelling (80%), pain (75%), and erythema (26%) 1
• Look for heaviness in the extremity, unexplained persistent calf cramping, and warmth 1
• Venous ultrasound is the preferred initial diagnostic test 1
• Risk is particularly high with sudden onset, especially in the left leg (May-Thurner syndrome) 1
• Requires immediate anticoagulation if confirmed 1

Peripheral Arterial Disease (PAD)

• Measure ankle-brachial index (ABI) in all patients with leg pain 1
• Sharp pain with exertion that resolves with rest suggests vascular claudication 1
• ABI <0.90 confirms PAD; normal ABI (1.00-1.39) helps exclude it 1, 2
• If resting ABI is normal but symptoms suggest PAD, measure post-exercise ABI 1
• Critical limb ischemia presents with rest pain (ankle pressure <50 mmHg, toe pressure <30 mmHg) 1

Neurogenic Causes (Most Common in Healthy Adults)

Lumbar Radiculopathy/Sciatica

• Pain radiating below the knee in sciatic nerve distribution suggests nerve root compression 3, 4
• Perform straight leg raise (SLR) test: 91% sensitivity but only 26% specificity for disc herniation 3, 4
• Crossed SLR (pain when raising unaffected leg) is more specific: 88% specificity, 29% sensitivity 3, 4
• Assess specific nerve root involvement: L4 (knee strength/reflexes), L5 (great toe/foot dorsiflexion), S1 (plantarflexion/ankle reflexes) 3
• MRI indicated only if severe/progressive neurological deficits or symptoms persist >4-6 weeks despite conservative management 3

Lumbar Spinal Stenosis

• Neurogenic claudication: activity-related pain worsening with prolonged standing/walking, relieved by sitting or forward flexion 5
• Progressive limitation in walking distance distinguishes this from vascular claudication 5
• More common in older adults but can occur in younger patients with congenital stenosis 5

Musculoskeletal Causes

Hip-Related Pain

• Hip pathology can present as sharp leg pain without groin pain 1
• Consider femoroacetabular impingement (FAI) syndrome, acetabular dysplasia, or labral tears 1
• Pain may be felt in buttock, lateral thigh, or anterior thigh rather than groin 1
• Negative flexion-adduction-internal rotation test helps rule out hip-related pain 1

Stress Fractures and Overuse Injuries

• Sharp, localized pain with weight-bearing activities 6, 7
• Medial tibial stress syndrome (shin splints) presents with diffuse medial tibial pain 6, 7
• Chronic exertional compartment syndrome causes pain during activity that resolves with rest 7

Critical Diagnostic Algorithm

Step 1: Exclude emergent vascular conditions

• Assess for DVT signs (swelling, warmth, erythema) → venous ultrasound if positive 1
• Measure ABI to exclude PAD → <0.90 confirms PAD 1

Step 2: Localize pain pattern

• Pain below knee in dermatomal distribution → likely radiculopathy 3, 4
• Pain with walking relieved by rest → vascular vs. neurogenic claudication 1, 5
• Pain with standing/walking relieved by sitting/forward flexion → spinal stenosis 5

Step 3: Perform targeted physical examination

• SLR test for radiculopathy (high sensitivity) 3
• Crossed SLR for disc herniation (high specificity) 3
• Neurological examination for motor/sensory deficits 3
• Hip examination if pain in buttock/lateral thigh 1

Step 4: Imaging only when indicated

• Immediate MRI only for severe/progressive neurological deficits 3
• Delayed imaging (4-6 weeks) for persistent symptoms despite conservative treatment 3
• Avoid imaging with normal post-exercise ABI unless entrapment syndromes suspected 1

Common Pitfalls to Avoid

• Do not assume "sharp" pain excludes vascular causes—PAD can present with various pain qualities 2
• Do not rely solely on pain location—DVT may present with calf pain mimicking musculoskeletal injury 1
• Do not order MRI immediately for radicular symptoms without red flags—most resolve with conservative treatment 3, 4
• Do not miss bilateral symptoms or temperature differences suggesting Charcot neuroarthropathy in diabetics 1
• Low-normal ABI (0.91-0.99) may still represent borderline PAD and cause symptoms 2