What is the differential diagnosis and treatment approach for a patient presenting with peripheral neuropathy, considering potential underlying causes such as diabetic neuropathy, vitamin B12 deficiency, autoimmune disorders, or toxin exposure?

Differential Diagnosis of Peripheral Neuropathy

Peripheral neuropathy is a diagnosis of exclusion that requires systematic evaluation for treatable causes, with diabetes mellitus being the most common etiology, followed by toxins (including alcohol and medications), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies, infections, autoimmune disorders, and hereditary conditions. 1

Most Common Etiologies by Category

Metabolic and Endocrine Causes

• Diabetes mellitus is the single most common cause, presenting as distal symmetric polyneuropathy affecting both sensory and motor fibers (though motor involvement is typically less prominent), and up to 50% may be asymptomatic 1, 2
• Hypothyroidism should be screened in all patients with peripheral neuropathy 3
• Renal disease can cause uremic neuropathy 1

Nutritional Deficiencies

• Vitamin B12 deficiency is one of the most common treatable causes and must be checked in all patients 1, 4, 3
• Vitamin E, thiamine, nicotinamide, and red-cell folate deficiencies should be excluded, particularly in patients with malabsorption or inflammatory bowel disease 2
• Copper deficiency can cause peripheral neuropathy and should be considered 2

Toxic and Drug-Induced Causes

• Alcohol is a major toxin causing peripheral neuropathy 1
• Chemotherapy agents are common iatrogenic causes:
  • Vincristine causes motor neuropathy in approximately 10% of patients, ranging from grade 1-3 distal weakness to rare life-threatening grade 4 motor neurotoxicity 2, 5
  • Bortezomib causes predominantly sensory neuropathy, but motor impairment occurs in approximately 10% of cases 2, 5
  • Thalidomide is a major cause of treatment-related neuropathy in multiple myeloma patients 2
  • Taxanes (paclitaxel) and platinum compounds (oxaliplatin) primarily affect sensory fibers 2
• Metronidazole is a common antimicrobial cause 2
• Anti-TNF agents can cause peripheral neuropathy 2

Infectious Causes

• HIV infection should be screened in appropriate clinical contexts 1
• Hepatitis C infection (particularly with cryoglobulins) can cause peripheral neuropathy 2

Malignancy-Related Causes

• Multiple myeloma can cause neuropathy through direct nerve compression or associated conditions 1, 2
• Bronchogenic carcinoma and other malignancies should be considered 1
• POEMS syndrome (plasma cell dyscrasia) causes neuropathy through direct effects 2
• Light chain deposits (amyloidosis) lead to neuropathy through nerve infiltration 2
• Monoclonal gammopathies should be screened with serum protein electrophoresis 2, 4

Autoimmune and Inflammatory Causes

• Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable cause that must not be missed 1, 3
• Vasculitis can cause mononeuropathy multiplex or polyneuropathy 1
• Cryoglobulinemia should be screened 2
• Guillain-Barré syndrome presents acutely and requires urgent recognition 1, 3
• Autoimmune mechanisms in the context of inflammatory bowel disease 2

Hereditary Causes

• Charcot-Marie-Tooth type 1A should be ruled out, particularly in cases with predominant motor involvement and distinct deformities (hollow foot, stork legs) 2, 5
• Family history of hereditary peripheral neuropathy predisposes patients to chemotherapy-induced neuropathy 2

Mechanical and Structural Causes

• Direct nerve compression (radicular or medullary) can mimic peripheral neuropathy 2
• Cervical and lumbar disease must be excluded 6

Essential Initial Laboratory Workup

The following tests should be ordered on all patients with peripheral neuropathy to identify treatable causes:

• Complete blood count 4, 3
• Comprehensive metabolic profile (including renal function) 4, 3
• Fasting blood glucose or hemoglobin A1c 1, 4, 3
• Vitamin B12 level 1, 4, 3
• Thyroid-stimulating hormone (TSH) 4, 3
• Serum protein electrophoresis with immunofixation 4
• Erythrocyte sedimentation rate 3

Additional Testing Based on Clinical Context

When initial workup is unrevealing or specific patterns suggest particular etiologies:

For Suspected Autoimmune or Inflammatory Causes

• Lumbar puncture with CSF analysis (elevated protein and WBCs suggest CIDP or GBS; cytology should be sent in cancer patients) 1, 3
• Serum antiganglioside antibody tests for GBS and its subtypes 1
• Vasculitic and autoimmune screening panels 1

For Suspected Hereditary Causes

• Genetic testing for Charcot-Marie-Tooth disease and other inherited neuropathies 2, 7

For Suspected Small Fiber Neuropathy

• Skin biopsy for intraepidermal nerve fiber density assessment 6, 7

Electrodiagnostic Studies

• Nerve conduction studies and electromyography help differentiate axonal from demyelinating neuropathy 6, 3, 7, 8
• Uniform demyelinating features suggest hereditary demyelination, whereas differences between nerves and segments favor acquired demyelination 8
• Electrodiagnostic testing is rarely needed except when clinical features are atypical or diagnosis is unclear 1

Advanced Imaging

• MRI of spine with and without contrast to rule out compressive lesions and evaluate for nerve root enhancement/thickening 1
• MRI of brain if cranial nerve involvement is present 1

Critical Clinical Pitfalls to Avoid

Do not assume diabetic neuropathy in a patient with diabetes without excluding other causes, as nondiabetic neuropathies may be present and treatable 1

Recognize that 25% to 46% of peripheral neuropathy cases remain idiopathic after comprehensive evaluation, but these patients generally have favorable prognosis 4, 8

Screen for reversible causes first: vitamin B12 deficiency, hypothyroidism, and diabetes are the most common treatable causes 3

Consider medication history carefully, as neurotoxic medications are among the most common iatrogenic causes 2, 9

Assess for pre-existing risk factors including prior neuropathy, smoking, retinopathy, nephropathy (particularly dialysis or post-transplant), foot deformities, and prior ulceration or amputation, as these increase susceptibility to additional nerve damage 2