What are the differential diagnoses and initial management for leg pain in a patient with a complex medical history?

Differential Diagnoses for Leg Pain

Begin with characterizing the pain pattern—specifically whether it occurs with exertion and resolves with rest—then measure ankle-brachial index (ABI) to establish or exclude peripheral arterial disease, which is the most critical life-threatening cause requiring immediate intervention. 1

Vascular Causes (Highest Priority for Mortality Risk)

Peripheral Arterial Disease (PAD)

• Intermittent claudication: Exertional leg muscle pain that occurs predictably at a reproducible walking distance and resolves within 10 minutes of rest 2, 1, 3
• Critical limb ischemia (CLI): Chronic ischemic rest pain, non-healing ulcers, or gangrene indicating severe perfusion decrease and impending limb loss without revascularization 2, 1
• Acute limb ischemia: Sudden onset leg pain with the five "Ps"—pain, pulselessness, pallor, paresthesias, and paralysis—representing a vascular emergency 2

Other Vascular Conditions

• Popliteal artery entrapment syndrome: Exertional leg pain in athletes due to arterial compression 4, 5, 6
• Arterial endofibrosis: Exertional claudication in high-level endurance athletes 6
• Deep vein thrombosis: Constant pain with swelling, warmth, and tenderness 5

Musculoskeletal Causes

Bone and Periosteum

• Medial tibial stress syndrome: Most common cause of chronic leg pain in athletes, with pain along posteromedial tibial border during and after activity 4, 5, 6
• Tibial stress fracture: Focal bone tenderness with pain during weight-bearing that worsens with activity 4, 5, 6

Muscle and Fascia

• Chronic exertional compartment syndrome: Tight, bursting pain during exercise that resolves 10-30 minutes after stopping activity, unlike claudication which resolves within 10 minutes 4, 5, 6
• Inflammatory myopathy: Proximal muscle weakness and pain, elevated creatine kinase 7

Neurologic Causes

• Common peroneal nerve entrapment: Lateral leg pain with possible foot drop 5, 6
• Superficial peroneal nerve entrapment: Anterolateral leg pain with sensory changes 5, 6
• Saphenous nerve entrapment: Medial leg pain with dysesthesias 5, 6
• Complex regional pain syndrome: Disproportionate pain with autonomic changes 5

Neurologic Mimic (Non-Vascular)

• Restless legs syndrome: Urge to move legs that worsens with inactivity and rest, improves with movement, and is worse in evening/night—distinct from claudication which is triggered by walking 3

Initial Management Algorithm

Step 1: Immediate Risk Stratification

• Assess for acute limb ischemia (sudden onset with five "Ps"): Obtain emergent vascular consultation for immediate revascularization 2
• Screen for CLI features (rest pain, non-healing wounds, gangrene): Arrange urgent vascular evaluation within 24-48 hours 2, 1

Step 2: Characterize Pain Pattern

• Exertional pain resolving within 10 minutes of rest: Suspect vascular claudication—proceed to ABI measurement 1, 3
• Exertional pain resolving 10-30 minutes after stopping: Consider chronic exertional compartment syndrome 4, 5, 6
• Pain at rest worsening with inactivity, relieved by movement, worse at night: Consider restless legs syndrome 3
• Focal bone tenderness with weight-bearing pain: Consider stress fracture—obtain X-ray initially 2, 4

Step 3: Objective Vascular Testing

• Obtain resting ABI in all patients with suspected PAD based on exertional symptoms or risk factors (age >70, age 50-69 with smoking/diabetes, age <50 with diabetes plus one other risk factor) 2, 1
• Interpret ABI: ≤0.90 = PAD confirmed; 0.91-0.99 = borderline; 1.00-1.40 = normal; >1.40 = noncompressible vessels (obtain toe-brachial index) 1
• Perform exercise ABI testing if resting ABI is normal/borderline but exertional symptoms persist 1

Step 4: Risk Factor Assessment and Simple Testing

• Document atherosclerotic risk factors: Smoking, diabetes, hypertension, dyslipidemia, family history 2, 1
• Perform focused physical examination: Palpate all lower extremity pulses, auscultate for femoral bruits, assess for pallor with leg elevation 2, 3
• Obtain simple initial tests only: X-rays for suspected trauma/stress fracture, ESR for suspected inflammatory disease 2

Step 5: Biopsychosocial Assessment

• Identify psychosocial factors that may prolong pain: Employment issues, mental health deterioration, medication failure 2
• Avoid continuous investigation cycles: Use biopsychosocial assessment rather than repeated imaging for non-vascular causes 2

Critical Pitfalls to Avoid

• Diabetic patients with CLI may have no pain due to neuropathy but still have severe tissue loss requiring urgent evaluation 1
• Do not obtain anatomic imaging (CTA, MRA, angiography) unless revascularization is being considered 1
• Do not rely on ABI alone in diabetics or chronic kidney disease patients due to noncompressible arteries—obtain toe-brachial index instead 1
• Recognize that "atypical" leg pain (exertional but not consistently resolving with rest) still requires ABI measurement to exclude PAD 2

Treatment Priorities for Confirmed PAD

• Immediate smoking cessation 2
• Antiplatelet therapy for cardiovascular risk reduction 2, 3
• Supervised exercise therapy as first-line treatment for claudication 3
• Treat hypertension, hyperlipidemia, and diabetes to target (HbA1c <7%) 2
• Consider revascularization only for CLI or severe claudication unresponsive to conservative therapy 2, 3