What are the differential diagnoses and treatment options for a patient in their 30s with uncontrolled Diabetes Mellitus (DM) presenting with symmetric bilateral foot burning?

Symmetric Bilateral Burning Feet in a 30-Year-Old with Uncontrolled Diabetes

This patient most likely has diabetic peripheral neuropathy (DPN) with painful small fiber involvement, and first-line treatment should be pregabalin (300-600 mg/day), duloxetine (60-120 mg/day), or gabapentin (900-3600 mg/day), while aggressively optimizing glycemic control. 1, 2

Differential Diagnoses

Most Likely: Diabetic Peripheral Neuropathy (Painful DPN)

• Burning pain in a symmetric, bilateral, distal distribution is the hallmark presentation of painful diabetic peripheral neuropathy affecting small nerve fibers 1, 2
• The pain characteristically worsens at night and may be accompanied by "electrical shock" sensations, stabbing pains, and uncomfortable tingling 2
• Patients often describe altered temperature perceptions, with feet feeling abnormally warm or cold 2
• Up to 50% of patients with diabetes develop DPN, and among symptomatic patients, 16-20% experience neuropathic pain that significantly impacts quality of life 1, 3
• The symmetric nature of symptoms is critical—asymmetrical symptoms should prompt investigation for other etiologies 2, 4

Critical to Exclude: Charcot Neuro-Osteoarthropathy (CNO)

• CNO must be immediately excluded as it presents with unilateral (not bilateral) red, warm, swollen foot with intact skin, potentially with minimal pain due to neuropathy 5, 4
• If CNO is suspected, initiate knee-high immobilization/offloading promptly while performing diagnostic studies 5
• CNO left untreated presents high risk for bone fractures, dislocations, deformity, ulceration, infection, and amputation 5
• The bilateral symmetric presentation in this case makes CNO less likely, but unilateral CNO should always be considered in diabetic patients with a hot, swollen foot 5

Other Causes to Consider

• Vitamin B12 deficiency, hypothyroidism, renal disease, and medication-induced neuropathy must be ruled out, as diabetic neuropathy remains a diagnosis of exclusion 1
• Peripheral arterial disease (PAD) is present in up to 40-50% of diabetic foot complications and must be evaluated through palpating dorsalis pedis and posterior tibial pulses 1, 4
• Infection must be excluded by assessing for at least two signs of inflammation: redness, warmth, induration, pain/tenderness, or purulent secretions 4

Diagnostic Approach

Immediate Clinical Assessment

• Perform 10-g monofilament testing at multiple plantar sites to confirm loss of protective sensation (LOPS)—inability to perceive the monofilament at any site confirms the diagnosis 1
• Use a 128-Hz tuning fork at the dorsum of the great toe to assess vibration sense (large fiber function) 1
• Test pinprick or temperature sensation to evaluate small fiber function 1
• Check ankle reflexes, which are typically diminished or absent in DPN 1
• Palpate dorsalis pedis and posterior tibial pulses bilaterally to assess vascular status 1, 4

Laboratory Evaluation

• Screen for diabetes mellitus with fasting glucose and HbA1c 2
• Rule out vitamin B12 deficiency, hypothyroidism, and renal disease 1
• Standard nerve conduction studies may be completely normal in small fiber neuropathy, as these tests only evaluate large myelinated fibers 2
• Electrophysiological testing is rarely needed except when clinical features are atypical or suggest a non-length-dependent pattern 1

Comprehensive Foot Examination

• Inspect feet for skin integrity, calluses, deformities, pre-ulcerative signs, and any existing ulceration 1
• Assess capillary refill time and look for dependent rubor or pallor on elevation 1
• Perform probe-to-bone test for any open wound to help diagnose or exclude osteomyelitis 4

Treatment Options

Optimize Glycemic Control (Foundation of Treatment)

• Tight glycemic control effectively prevents DPN in type 1 diabetes and modestly slows progression in type 2 diabetes 1
• Aggressively optimize glycemic control, as addressing the underlying etiology is crucial in managing neuropathic pain 2
• Target blood pressure <130/80 mmHg, as blood pressure control slows retinopathy and likely neuropathy progression 1
• Initiate statin therapy for cardiovascular risk reduction 1
• Smoking cessation is crucial, as smoking significantly increases amputation risk 1

First-Line Pharmacologic Treatment for Neuropathic Pain

• Pregabalin 300-600 mg/day (divided three times daily) is established as effective first-line therapy 1, 6
• Duloxetine 60-120 mg/day is specifically recommended for neuropathic pain, numbness, and tingling 1, 2
• Gabapentin 900-3600 mg/day is another first-line option 1, 7
• These medications achieve ≥50% pain reduction in 38% of patients at optimal dosing 2
• Pregabalin 100 mg and 200 mg three times daily statistically significantly improved pain scores in clinical trials, with some patients experiencing pain decrease as early as Week 1 6

Additional Pharmacologic Options

• Amitriptyline (tricyclic antidepressant) is a first-line option 7
• Second-line options include nortriptyline, imipramine, venlafaxine, carbamazepine, oxcarbazepine, topical lidocaine, and topical capsaicin 7
• Opioids should generally be avoided 7

Non-Pharmacologic Treatment

• Physical activity and exercise are recommended as adjunctive approaches, with early evidence suggesting protective effects on neuropathy progression 1, 2, 7
• Peripheral transcutaneous electrical nerve stimulation (TENS) is well tolerated and inexpensive, but benefits are modest 7
• Neuromodulation with spinal cord stimulation has low- to moderate-quality evidence 7

Preventive Care and Patient Education

• Refer to podiatry or foot care specialist for ongoing preventive care and surveillance 1
• Prescribe therapeutic footwear with adequate cushioning and depth to accommodate any deformities and redistribute plantar pressures 1
• Educate patients on daily foot self-examination using a mirror to inspect plantar surfaces for cuts, blisters, redness, or calluses 1
• Instruct patients to never walk barefoot, even indoors, and to check inside shoes before wearing for foreign objects 1
• Advise patients to avoid extreme temperatures, such as testing bath water with the elbow, not the foot 1
• Patients should report any skin breaks, color changes, swelling, or warmth to their healthcare provider immediately 1

Monitoring and Follow-Up

• Monitor for depression and anxiety, as over two-thirds of patients with painful neuropathy develop anxiety and/or depression, and addressing psychological comorbidities improves overall pain outcomes 2
• Periodic, objective monitoring of medication response is critical because patients may not obtain desired pain reduction, adverse effects are common, and serious adverse effects can occur 7
• Screen for symptoms of cardiac autonomic neuropathy, such as resting tachycardia >100 bpm and orthostatic hypotension, as these often coexist with DPN 1
• Inspect feet at every clinical visit 1

Critical Pitfalls to Avoid

• Do not overlook asymmetrical symptoms—painful DPN is invariably symmetrical, and asymmetry should prompt investigation for other etiologies 2, 4
• Do not miss Charcot neuro-osteoarthropathy in diabetic patients with unilateral foot inflammation—failure to immobilize can lead to permanent deformity 4
• Do not use prolonged cold water immersion or ice application for symptom relief, as it can lead to immersion foot, skin ulceration, and infection risk 2
• Do not rely solely on nerve conduction studies to diagnose small fiber neuropathy, as they may be completely normal 2