What is the approach for evaluating and treating peripheral neuropathy?

Peripheral Neuropathy: Evaluation and Treatment

Initial Clinical Assessment

Begin by determining the temporal pattern (acute vs. chronic), distribution (symmetric vs. asymmetric), and fiber type involvement (large vs. small fiber) through focused neurological examination including 10-g monofilament testing, 128-Hz tuning fork vibration assessment, pinprick sensation, and ankle reflexes. 1, 2

Key History Elements to Elicit

• Duration and progression of symptoms (numbness, tingling, burning pain, weakness) with specific attention to whether symptoms are progressive or episodic 1, 3
• Diabetes history and glycemic control (most common treatable cause), including fasting glucose and HbA1c values 4, 5
• Medication exposure, particularly chemotherapy agents (taxanes, platinums, vinca alkaloids, bortezomib), as these are common neurotoxic drugs 6
• Alcohol consumption, vitamin supplementation history, and occupational toxin exposures 4, 5
• Family history of neuropathy to identify potential hereditary causes 3, 7

Physical Examination Priorities

• Perform comprehensive sensory testing with 10-g monofilament (loss of protective sensation), vibration with 128-Hz tuning fork, pinprick, and temperature sensation in stocking-glove distribution 1, 2
• Assess motor strength distally in foot dorsiflexion and toe extension, looking for distal weakness or atrophy 5
• Check ankle reflexes bilaterally, as these are often diminished or absent in peripheral neuropathy 2, 5
• Inspect feet thoroughly for ulcers, deformities, calluses, and skin integrity, particularly in diabetic patients 2
• Evaluate for autonomic dysfunction including orthostatic blood pressure changes and signs of gastroparesis 1

Laboratory Evaluation

Order initial screening tests including complete blood count, comprehensive metabolic panel, fasting glucose, HbA1c, vitamin B12, thyroid-stimulating hormone, and serum protein electrophoresis with immunofixation to identify the most common treatable causes. 4, 5

First-Tier Laboratory Tests

• Fasting blood glucose and HbA1c to diagnose or assess control of diabetes mellitus 1, 2, 4
• Vitamin B12 level as deficiency is a common and reversible cause 1, 2, 4
• Thyroid function tests (TSH, free T4) to exclude hypothyroidism 1, 2, 4
• Complete blood count to evaluate for anemia or hematologic disorders 2, 4
• Serum protein electrophoresis with immunofixation to screen for paraproteinemia and monoclonal gammopathy 5
• Erythrocyte sedimentation rate as a nonspecific inflammatory marker 4

Additional Testing When Clinically Indicated

• Hepatitis B, C, and HIV serologies if risk factors present or clinical suspicion exists 1
• Anti-ganglioside antibodies if Guillain-Barré syndrome suspected 1
• Cerebrospinal fluid analysis for suspected Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy 4

Electrodiagnostic Studies

Refer for nerve conduction studies and electromyography to differentiate axonal from demyelinating neuropathy, as this distinction dramatically narrows the differential diagnosis and identifies potentially treatable causes. 3, 5, 7

• Primary demyelinating patterns suggest acquired immune-mediated conditions (chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome) or hereditary demyelinating neuropathies 3, 7
• Axonal patterns are more common and associated with metabolic, toxic, or nutritional causes 3, 7

Pharmacological Treatment of Neuropathic Pain

For Diabetic Peripheral Neuropathy

Duloxetine 60 mg once daily is the first-line pharmacological treatment for painful diabetic peripheral neuropathy, with the option to increase to 120 mg daily if needed for additional benefit. 6, 8, 9

• Duloxetine demonstrated statistically significant pain reduction in two 12-week randomized controlled trials, with some patients experiencing pain relief as early as week 1 9
• Pregabalin 150-300 mg/day (titrated to 300-600 mg/day) is an alternative first-line option approved by the European Medicines Agency, with benefits seen as early as week 1 8, 10
• Gabapentin 300-2400 mg/day is an effective alternative to pregabalin with similar efficacy but may require higher doses 8
• Tricyclic antidepressants (amitriptyline 25-75 mg/day, starting at 10 mg in elderly patients) are effective with low number-needed-to-treat (1.5-3.5) but have significant anticholinergic side effects 6, 8

Critical caveat: Obtain ECG before starting tricyclic antidepressants in elderly patients or those with cardiovascular disease, as these agents can cause cardiac conduction abnormalities. 8

For Chemotherapy-Induced Peripheral Neuropathy

Duloxetine is the only agent with appropriate evidence to support its use for established painful chemotherapy-induced peripheral neuropathy, though the benefit is limited. 6, 8

• No agents are recommended for prevention of chemotherapy-induced peripheral neuropathy 6
• Acetyl-L-carnitine should be discouraged for prevention of chemotherapy-induced peripheral neuropathy 6
• Consider dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment 6

Second-Line and Adjunctive Therapies

If first-line agents provide inadequate relief after optimization, consider adding a second agent with a different mechanism of action or switching to an alternative first-line medication. 8

• Tramadol or other opioid agonists may be considered as combination therapy for refractory pain, though long-term opioid use should generally be avoided 8
• Topical capsaicin cream or lidocaine patches for localized neuropathic pain 8
• Alpha-lipoic acid 600 mg IV daily for 3 weeks has shown efficacy in reducing diabetic neuropathic pain 8

Important Contraindications and Monitoring

• Avoid tricyclic antidepressants in patients with glaucoma, orthostatic hypotension, cardiovascular disease, or fall risk 8
• Avoid duloxetine in patients with hepatic disease 8, 9
• Monitor for edema and weight gain with pregabalin and gabapentin 8, 10
• Common side effects include dizziness, somnolence, peripheral edema, nausea, and constipation across most agents 8, 9, 10

Disease-Modifying Management

Glycemic Control in Diabetic Neuropathy

Optimize glucose control as the foundational step in managing diabetic peripheral neuropathy to prevent progression, targeting individualized HbA1c goals based on patient factors. 6, 8, 1

• Poor or erratic glycemic control contributes to neuropathic pain genesis, and blood glucose flux may worsen symptoms 6

Cardiovascular Risk Factor Management

Address hypertension and hyperlipidemia aggressively, as cardiovascular risk factors contribute to diabetic peripheral neuropathy progression. 6, 8, 1

• Note that lipid-lowering drugs can rarely cause painful neuropathic syndrome themselves 6

Non-Pharmacological Interventions

• Regular physical activity and walking to improve circulation, though excessive standing should be avoided 8, 1
• Wear loose-fitting shoes and cotton socks for symptom relief 8
• Soak feet in cold water for temporary pain relief 8
• Transcutaneous electrical nerve stimulation for refractory cases 8
• Spinal cord stimulation may be considered in extreme cases unresponsive to pharmacotherapy 6, 8

Monitoring and Follow-Up

Reassess pain intensity using an 11-point numeric rating scale and evaluate quality of life impact at regular intervals, with annual screening for diabetic neuropathy in all type 2 diabetes patients and after 5 years in type 1 diabetes. 6, 8, 1

• Screen for foot ulcers at each visit in patients with diabetic neuropathy and loss of protective sensation 1, 2
• Educate patients with loss of protective sensation about daily foot inspection and proper foot care 2
• If pain relief is inadequate after optimizing one medication, switch to another first-line agent or add a second medication with different mechanism 8

Common Pitfalls to Avoid

• Failing to perform complete foot examination at least annually in diabetic patients 2
• Relying on single test for diagnosis; at least two tests should confirm peripheral neuropathy 2
• Not considering non-diabetic causes even in patients with diabetes, as multiple etiologies can coexist 2
• Overlooking vascular assessment in patients with neuropathic symptoms, as peripheral arterial disease may contribute 2
• Starting tricyclic antidepressants without cardiac evaluation in high-risk patients 8