What is the recommended management for polyneuropathy?

Treatment of Polyneuropathy

The treatment of polyneuropathy requires first identifying and treating the underlying cause (such as optimizing glucose control in diabetes or stopping neurotoxic medications), followed by symptomatic management of neuropathic pain with first-line agents including pregabalin, duloxetine, or tricyclic antidepressants, and addressing autonomic dysfunction when present. 1, 2

Identify and Treat the Underlying Cause

The most critical step is determining the etiology, as this directly impacts treatment strategy and prognosis 3:

Common Reversible Causes to Screen For

• Diabetes mellitus – Optimize glycemic control, as well-controlled blood glucose delays progression of diabetic neuropathy 1, 3
• Vitamin B12 deficiency – Measure serum B12 with metabolites (methylmalonic acid ± homocysteine) to increase sensitivity 2
• Hypothyroidism – Check TSH 2
• Alcohol abuse – Cessation is essential, as alcohol-associated polyneuropathy has a prevalence of 22-66% among persons with chronic alcoholism 3
• Medication-induced neuropathy – Review and discontinue neurotoxic drugs, especially chemotherapeutic agents 1, 3, 4
• Monoclonal gammopathy – Obtain serum protein immunofixation electrophoresis 2
• Chronic kidney disease/uremia – Assess renal function 2

Disease-Specific Treatments

For diabetic neuropathy: Strict glycemic control is the only intervention proven to delay progression 1

For inflammatory demyelinating polyneuropathies (Guillain-Barré syndrome, CIDP): Consider intravenous immunoglobulin (IVIG) or plasmapheresis 1, 2, 5. For acute inflammatory demyelinating polyneuropathy with severe or progressing symptoms, use pulse methylprednisolone 1g IV daily for 3-5 days PLUS IVIG 2g/kg over 5 days 5

For vasculitic neuropathy (e.g., polyarteritis nodosa with mononeuritis multiplex): Initiate cyclophosphamide and high-dose glucocorticoids 1

For hereditary transthyretin amyloidosis (ATTRv) polyneuropathy: TTR silencers (patisiran, inotersen, or vutrisiran) slow progression and may reverse disease, with early treatment yielding better outcomes 1. Daily vitamin A supplementation (3,000 IU) is required with these medications 1

For immune checkpoint inhibitor-related polyneuropathy: Corticosteroids may be beneficial 2

Pharmacologic Management of Neuropathic Pain

Approximately half of all polyneuropathy cases are associated with pain 3. Use a stepwise approach:

First-Line Agents (Choose Based on Comorbidities and Tolerability)

Pregabalin – Number needed to treat (NNT) of 4.1 for >50% pain relief 1, 6. Start low and titrate based on efficacy and tolerability 1, 2

Gabapentin – NNT of 4.1, similar efficacy to pregabalin 1, 6. Requires more frequent dosing than pregabalin 1

Duloxetine – An SNRI with proven efficacy in painful diabetic neuropathy 1, 2, 7

Tricyclic antidepressants (TCAs) – NNT of 2.6, making them highly effective 1, 6. However, use caution in patients with autonomic dysfunction (orthostatic hypotension, urinary retention, constipation) or cardiac disease, as TCAs can worsen these conditions 1, 4. TCAs remain drugs of first choice when contraindications are absent 6

Second-Line Agents

Tramadol – NNT of 3.4, a mixed opioid and monoaminergic drug 1, 6

Selective serotonin reuptake inhibitors (SSRIs) – NNT of 6.7, less effective than TCAs but may be preferable in patients who cannot tolerate TCAs 1, 6

Topical capsaicin 8% patch – FDA-approved for painful diabetic neuropathy, with NNT of 5.9 7, 6

Carbamazepine and other sodium channel blockers – NNT of 2.5 for anticonvulsant sodium channel blockers 6, 4

Combination Therapy

When monotherapy provides inadequate relief or adverse effects limit dose escalation, combination therapy is appropriate 1:

• Gabapentin + extended-release morphine – Combination required lower doses of both medications and resulted in better pain relief than either alone in patients with painful diabetic neuropathy 1
• Nortriptyline + gabapentin – Superior to either medication alone 1
• Pregabalin + extended-release oxycodone – Improved pain relief at lower doses with better tolerability 1

Management of Autonomic Dysfunction

Autonomic symptoms occur because autonomic fibers are predominantly small, unmyelinated C-fibers 2:

Orthostatic Hypotension (≥20 mmHg systolic or ≥10 mmHg diastolic drop)

• Non-pharmacologic measures: Increased salt and fluid intake, compression stockings (knee- or thigh-high), abdominal binders 1, 2
• Pharmacologic options:
  • Salt tablets 1
  • Fludrocortisone 1, 2
  • Midodrine 1, 2
  • Droxidopa 1, 2
  • Pyridostigmine – Does not cause fluid retention or supine hypertension, making it safer in patients with heart failure 1

Important caveat: Fludrocortisone, midodrine, and droxidopa may be poorly tolerated in patients with cardiac involvement or heart failure due to restrictive physiology 1

Gastrointestinal Dysfunction

• Early satiety, nausea, vomiting, gastroparesis, alternating diarrhea and constipation require symptomatic management 1, 2

Genitourinary Dysfunction

• Urinary retention and erectile dysfunction may require urologic consultation 1, 2

Non-Pharmacologic Interventions

Exercise – Has emerged as an important therapeutic tool and may improve the underlying polyneuropathy in the setting of obesity, metabolic syndrome, and diabetes 7

Physical therapy and occupational therapy – Beneficial for patients with functional deficits, gait instability, or muscle weakness 1, 8, 3

Foot care and orthopedic shoes – Essential for preventing ulcers and amputations, particularly in diabetic neuropathy 1, 8

Use 10-g monofilament testing – To identify feet at risk for ulceration 2

Monitoring and Follow-Up

• Serial neurologic examinations are preferred over repeated electromyography for monitoring stable peripheral neuropathy 1, 2
• For diabetic neuropathy: Re-evaluate at least once a year with neurologic testing including temperature sensation, pinprick sensation, vibration perception (128-Hz tuning fork), pressure sensation (10-g monofilament), and ankle reflexes 1
• For patients with history of severe polyarteritis nodosa with abdominal involvement: Follow-up abdominal vascular imaging when clinically asymptomatic 1
• Monitor for medication side effects and adjust treatment accordingly 1

Critical Pitfalls to Avoid

• Do not assume neuropathy in a diabetic patient is automatically diabetic neuropathy – It is a diagnosis of exclusion; screen for B12 deficiency, hypothyroidism, monoclonal gammopathy, and other causes 2
• Do not delay corticosteroids in inflammatory cases – This leads to irreversible neurological damage 5
• Do not reduce corticosteroids too rapidly – This causes symptom recurrence requiring restart of higher doses 5
• Avoid medications that worsen neuropathy – Review all current medications for neurotoxic potential 2, 4
• Do not use TCAs indiscriminately in patients with autonomic dysfunction – They can worsen orthostatic hypotension, urinary retention, and constipation 1
• Recognize that older patients with amyloidosis are at greater risk for medication side effects – Consider the Beers Criteria when prescribing 1
• Do not overlook hereditary causes in younger patients or those with family history 2

When to Refer to Neurology

• Atypical presentations (asymmetric distribution, rapid progression, predominant motor weakness) 2
• Suspected vasculitis or amyloidosis requiring nerve biopsy 2
• Suspected hereditary neuropathy requiring genetic counseling and testing 2
• Severe neuropathy of unidentified cause after initial workup 3