Differential Diagnosis of Peripheral Neuropathy

Most Common Etiologies by Category

Diabetes mellitus is the single most common cause of peripheral neuropathy, presenting as distal symmetric polyneuropathy affecting both sensory and motor fibers, and up to 50% may be asymptomatic 1, 2, 3
Renal disease can cause uremic neuropathy, a significant concern in patients with peripheral neuropathy 1, 2
Vitamin B12 deficiency is one of the most common treatable causes and must be checked in all patients with peripheral neuropathy 1, 2
Alcohol is a major toxin causing peripheral neuropathy, particularly in patients with a history of excessive alcohol consumption 1, 2
HIV infection should be screened in appropriate clinical contexts, as it is a known cause of peripheral neuropathy 1, 2
Multiple myeloma can cause neuropathy through direct nerve compression or associated conditions, and should be considered in patients with peripheral neuropathy 1, 2, 3
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable cause that must not be missed, and patients with peripheral neuropathy should be screened for this condition 1, 2

Fasting blood glucose or hemoglobin A1c should be ordered on all patients with peripheral neuropathy to identify diabetic causes 1, 2
Vitamin B12 level should be checked in all patients with peripheral neuropathy, as deficiency is a common treatable cause 1, 2

Lumbar puncture with CSF analysis should be performed when suspected autoimmune or inflammatory causes are present, such as CIDP or Guillain-Barré syndrome 4
Serum antiganglioside antibody tests should be ordered for patients with suspected Guillain-Barré syndrome or its subtypes 4
Genetic testing for Charcot-Marie-Tooth disease and other inherited neuropathies should be considered in patients with suspected hereditary causes 3
Skin biopsy for intraepidermal nerve fiber density assessment should be performed in patients with suspected small fiber neuropathy 5
Nerve conduction studies and electromyography can help differentiate axonal from demyelinating neuropathy, and should be ordered when clinical features are atypical or diagnosis is unclear 5
MRI of spine with and without contrast should be ordered to rule out compressive lesions and evaluate for nerve root enhancement/thickening 4

Do not assume diabetic neuropathy in a patient with diabetes without excluding other causes, as nondiabetic neuropathies may be present and treatable 1, 2
Consider medication history carefully, as neurotoxic medications are among the most common iatrogenic causes 3
Assess for pre-existing risk factors, including prior neuropathy, smoking, retinopathy, nephropathy, foot deformities, and prior ulceration or amputation, as these increase susceptibility to additional nerve damage 3

The American Diabetes Association recommends annual screening for diabetic patients with type 2 diabetes at diagnosis, then annually, and for type 1 diabetes 5 years after diagnosis, then annually, to detect peripheral neuropathy 6
The American Diabetes Association suggests documenting key symptoms such as small fiber involvement (burning, tingling, pain) and large fiber involvement (numbness, loss of balance, sensory ataxia) in patients with suspected peripheral neuropathy 6
The American Diabetes Association recommends optimizing glycemic control (target HbA1c 6-7%) to prevent progression of diabetic neuropathy, though this will not reverse existing nerve damage 6

Referral to a neurologist is indicated in patients with atypical clinical features that do not fit the pattern of length-dependent symmetric polyneuropathy (e.g., asymmetric presentation, rapid progression, predominant motor involvement, or upper extremity onset) 6
Referral to a neurologist is also indicated in patients with unclear diagnosis after initial clinical assessment and laboratory workup, requiring electrodiagnostic studies to differentiate axonal from demyelinating neuropathy 6
The American Diabetes Association recommends against assuming diabetic neuropathy in a patient with diabetes without excluding other treatable causes (B12 deficiency, hypothyroidism, alcohol, medications, CIDP) 6
The American Diabetes Association suggests avoiding over-referral of patients with typical length-dependent symmetric polyneuropathy who respond to first-line therapy—electrodiagnostic testing is rarely needed in straightforward cases 6