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Diabetic Polyneuropathy

Basics

  • Peripheral nerve dysfunction seen in diabetes with several clinical patterns:
  • Symmetric polyneuropathy (distal sensory or sensorimotor)
  • Mononeuropathy, radiculopathy, polyradiculopathy
  • Cranial neuropathy
  • Focal limb or truncal neuropathy
  • Radiculoplexus neuropathy (diabetic amyotrophy)
  • Acute painful small fiber neuropathy
  • Autonomic neuropathies
  • Chronic inflammatory demyelinating polyneuropathy (CIDP)

Epidemiology

  • Generalized polyneuropathy prevalence:
  • 10-30% at diabetes diagnosis
  • 50% at 10 years of diabetes duration
  • Higher prevalence in type 2 diabetes than type 1.
  • Autonomic neuropathy: ~16.7% (UK study)

Etiology and Pathophysiology

  • Metabolic derangements due to hyperglycemia and dyslipidemia:
  • Aldose reductase converts excess glucose to sorbitol causing nerve damage.
  • Nonenzymatic glycation forms advanced glycosylation end products.
  • Protein kinase C activation leads to vascular endothelial changes.
  • Oxidative stress and mitochondrial dysfunction impair neurons.
  • Vasculopathy causes nerve ischemia, especially in mononeuropathies.

Risk Factors

  • Poor glycemic control
  • Long duration of diabetes
  • Hypertension
  • Dyslipidemia
  • Obesity
  • Tobacco and alcohol use

Prevention

  • Maintain good blood glucose control.
  • Exercise and proper diet.

Diagnosis

History

  • Typical distal symmetric sensorimotor neuropathy:
  • Numbness, tingling, pain (worse at night), allodynia, hyperalgesia in legs/feet.
  • Often silent sensory loss; ataxia and falls due to proprioceptive loss.
  • Neuropathic foot ulcers and joint degeneration.

  • Hands involved late.

  • Other patterns:

  • Proximal polyneuropathy: proximal leg weakness, less pain.
  • Mononeuropathies: cranial nerves (3rd, 4th, 6th, 7th), femoral, sciatic, peroneal nerves.
  • Truncal neuropathies: dermatomal pain.
  • Lumbar radiculoplexus neuropathy (diabetic amyotrophy): unilateral thigh pain, weakness.
  • Autonomic neuropathy: GI symptoms (diarrhea, gastroparesis), cardiovascular (orthostatic hypotension), urogenital dysfunction, sudomotor changes.
  • CIDP: progressive motor weakness.
  • Diabetic cachexia: painful small fiber neuropathy with weight loss and depression.

Physical Exam

  • Symmetric distal polyneuropathy:
  • "Stocking-glove" sensory loss.
  • Large fiber: loss of vibration, light touch.
  • Small fiber: loss of temperature, pinprick.
  • Absent ankle reflexes.

  • Muscle wasting and foot deformities.

  • Proximal neuropathy:

  • Proximal limb weakness, loss of patellar reflex.

  • Cranial nerve palsies:

  • 3rd nerve palsy: painful ophthalmoplegia with pupil spared.

  • 6th nerve palsy: lateral gaze palsy.

  • Mononeuropathies:

  • Femoral, sciatic, peroneal neuropathies with sensory and motor deficits.

  • Autonomic neuropathy signs:

  • Resting tachycardia, orthostatic hypotension, gastroparesis signs.

  • CIDP:

  • Motor weakness, elevated CSF protein.

Differential Diagnosis

  • Metabolic: uremia, hypothyroidism
  • Drug-induced: cisplatin, vincristine, isoniazid, amiodarone, alcohol
  • Toxic: arsenic, n-hexane
  • Nutritional deficiencies: B12, pyridoxine, thiamine
  • Paraneoplastic neuropathies

Diagnostic Tests

  • Labs:
  • Fasting glucose, OGTT, HbA1c.
  • Vitamin B12, thyroid function, renal function.
  • Syphilis and HIV testing.
  • Serum protein electrophoresis.
  • Imaging if needed (MRI, CT) for compressive neuropathies.
  • Bedside sensory testing: 128-Hz tuning fork, 10-g monofilament, pinprick, temperature.
  • Electromyography and nerve conduction studies.
  • Skin biopsy for epidermal nerve fiber density (small fiber neuropathy).
  • Corneal confocal microscopy (noninvasive).
  • Lumbar puncture in CIDP.

Treatment

General Measures

  • Optimize glycemic control.
  • Use proper footwear to prevent foot injury.

Medication for Pain

  • First Line:
  • Pregabalin (150–600 mg/day): calcium channel modulator; adverse effects include dizziness, drowsiness, edema.

  • Duloxetine (30–60 mg/day): SNRI; nausea, dizziness.

  • Autonomic symptoms:

  • Orthostatic hypotension: fludrocortisone, midodrine (off-label).
  • Gastroparesis: metoclopramide, domperidone, erythromycin (off-label).
  • Diarrhea: loperamide, clonidine, octreotide (off-label), antibiotics for bacterial overgrowth.

  • Hyperhidrosis: propantheline, topical glycopyrrolate.

  • Second Line:

  • Gabapentin (300–1200 mg TID; off-label).
  • TCAs (amitriptyline, nortriptyline; off-label) with caution for anticholinergic and cardiac side effects.

  • Venlafaxine (SNRI; off-label).

  • Topicals:

  • Capsaicin cream or patch.

  • Lidocaine patches.

  • Opioids:

  • Tramadol, tapentadol (off-label).

Additional Therapies

  • Neuromodulation: TENS, percutaneous nerve stimulation, spinal cord stimulation.
  • Investigational: actovegin, dextromethorphan with quinidine.
  • Surgery: spinal cord stimulation (10 kHz).

Referral

  • Neurology for suspected CIDP or unclear diagnosis.

Prognosis

  • Slow chronic progression for symmetric polyneuropathy.
  • Focal neuropathies may recover over months to years.

Complications

  • Claw foot deformity.
  • Neuropathic ulcers.
  • Charcot arthropathy.

ICD10 Codes:
- E10.42 Type 1 diabetes mellitus with diabetic polyneuropathy
- E11.42 Type 2 diabetes mellitus with diabetic polyneuropathy
- E13.42 Other specified diabetes mellitus with diabetic polyneuropathy

Clinical Pearls:
- Treatment-induced neuropathy can worsen symptoms early after glycemic control improvement but usually stabilizes.
- Combining agents with different mechanisms is common; topical therapies may supplement systemic treatment.
- Limited evidence supports combination oral therapy.