Diabetic neuropathy

Diabetic neuropathy is a progressive nerve injury caused by chronic hyperglycemia. Distal symmetric polyneuropathy and autonomic neuropathy are the most common types; less common manifestations include mononeuropathy and radiculopathy. Patients with distal symmetric polyneuropathy typically present with sensory loss of the lower extremities and may also have motor weakness, although many affected individuals are asymptomatic. Diagnosis is typically clinical, and management includes glycemic control and daily foot care. Pharmacological therapy may be considered for pain management. In diabetic autonomic neuropathy, clinical presentation, recommended diagnostic studies, and treatment vary depending on the organ system involved. Annual screening for diabetic neuropathy is recommended for all patients with diabetes, starting at the time of diagnosis for patients with type 2 diabetes mellitus (T2DM) and 5 years after diagnosis for patients with type 1 diabetes mellitus (T1DM).

See also “Diabetic gastroparesis.”

• Diabetic polyneuropathy is the most common form of polyneuropathy in high-income countries. ^[1][2]
• ∼ 50% of patients with diabetes develop peripheral neuropathy. ^[3]
• Up to 90% of patients with diabetes may develop autonomic neuropathy. ^[4]

Epidemiological data refers to the US, unless otherwise specified.

Chronic hyperglycemia causes glycation of axon proteins and subsequent development of progressive sensomotor neuropathy; typically affects multiple peripheral nerves.

• Frequently asymptomatic, but can lead to the development of additional diabetic complications (e.g., diabetic foot) ^[5]
• Types include: ^[6]
  • Distal symmetric polyneuropathy in diabetes
    • A bilateral progressive neuropathy causing sensory loss and/or pain in a stocking glove pattern
    • Most common form of diabetic neuropathy (75%)
  • Mononeuropathy
    • A focal neuropathy that affects a single nerve (e.g., cranial mononeuropathy, mononeuropathy multiplex)
    • Affects < 10% of patients with diabetic peripheral neuropathy ^[3]
  • Diabetic radioculoplexus neuropathy: most commonly diabetic lumbosacral plexopathy, which manifests as thigh pain and proximal muscle weakness
  • Treatment-induced neuropathy in diabetes (insulin neuritis): a rare small-fiber neuropathy triggered by an improvement in blood glucose levels after chronic hyperglycemia

Many individuals with diabetic peripheral neuropathy are asymptomatic and the condition is often detected only during screening or after complications develop. ^[6][7][8]

• Sensory symptoms
  • Common features
    • Distal symmetrical sensory loss; : stocking glove sensory loss pattern with proximal progression
    • Numbness
    • Tingling
    • Dysesthesia (e.g., burning feet syndrome with symptoms that worsen at night)
  • Less common features
    • Allodynia
    • Hyperesthesia
• Motor weakness: e.g., ataxia, balance issues
• Neurological examination may show loss or reduction of:
  • Ankle reflex
  • Vibration sense (using a tuning fork)
  • Sharp/dull discrimination (e.g., pinprick sensation)
  • Light touch (e.g., monofilament test)
  • Proprioception
  • Temperature sensation

Approximately 50% of patients with diabetic peripheral neuropathy are asymptomatic. ^[6]

• The following neuropathies are more common in patients with diabetes: ^[6]
  • Compression neuropathies (e.g., carpal tunnel syndrome)
  • Chronic inflammatory demyelinating polyneuropathy
• See also “Etiology of polyneuropathy.”

• Perform diagnostic studies for polyneuropathy to rule out alternative causes. ^[6][7]
• Referral to a neurologist for electrophysiological testing is only required for: ^[7]
  • Atypical presentations
  • Diagnostic uncertainty

Diabetic peripheral neuropathy is a diagnosis of exclusion. ^[6][7]

• Manage underlying etiologies. ^[5][6]
  • Optimize glycemic control (see “Glycemic targets in diabetes”).
  • Treat dyslipidemia and hypertension, if present.
    • See “Management of hypercholesterolemia.”
    • See “Hypertension management.”
• Educate patients and caregivers on measures to prevent complications (e.g., preventive measures against diabetic foot). ^[5]
• Provide pain relief if necessary (see “Analgesia for peripheral neuropathy”).
  • First-line medications include pregabalin, duloxetine, venlafaxine, and amitriptyline. ^[5]
  • Follow up with patients regularly; adjust medication if pain remains inadequately controlled after 12 weeks of use. ^[9]
  • For patients with severe or refractory symptoms, consider referral to a pain management specialist.
• Refer to neurology in case of diagnostic uncertainty.

Good glycemic control can prevent the onset and progression of diabetic neuropathy, but it cannot reverse existing nerve damage. ^[5]

• Diabetic foot ulcers
• Diabetic neuropathic arthropathy (Charcot foot)
• See also “Diabetic foot.”

Diabetic neuropathy is a major risk factor for diabetic foot ulcers. ^[5]

Diabetic autonomic neuropathy is a type of diabetic neuropathy characterized by damage to small fiber autonomic nerves; multiple organ systems are susceptible. ^[6]

Genitourinary autonomic neuropathy ^[5]

• Sexual dysfunction (e.g., erectile dysfunction)
• Neurogenic bladder, e.g.:
  • Urinary retention
  • Incomplete bladder emptying
  • Bladder distention
  • Overflow incontinence
  • Poor urinary stream

Cardiovascular autonomic neuropathy ^[5]

• Early: decreased heart variability ^[6]
• Late:
  • Orthostatic hypotension
  • Tachycardia at rest

Patients with cardiovascular autonomic neuropathy are at increased risk for silent myocardial infarction, arrhythmias, and death. ^[5][6]

Gastrointestinal autonomic neuropathy ^[5]

• Diabetic gastroparesis
• Stool changes (e.g., diarrhea, fecal incontinence, constipation)
• Esophageal dysmotility

Other autonomic neuropathies ^[6]

• Impaired pupillary tone ^[10]
• Sudomotor dysfuncton
  • Dry skin
  • Heat intolerance
  • Abnormal sweating (e.g., anhidrosis, gustatory sweating)
• Hypoglycemia unawareness

• Perform a focused history based on the suspected affected organ. ^[5][6]
• Obtain diagnostic studies as needed to rule out alternative etiologies and confirm the diagnosis.
  • Genitourinary
    • Urodynamic testing: to assess for neurogenic bladder dysfunction ^[5]
    • Sex hormone panel: in patients with hypogonadism or sexual dysfunction ^[6]
  • Cardiovascular ^[6]
    • Orthostatic vital signs: to assess for orthostatic hypotension
    • ECG: to assess for resting tachycardia and decreased HR variability
  • Gastrointestinal ^[5][6]
    • Stool diagnostic studies: in patients with diarrhea
    • Esophageal barium swallow: to assess for esophageal hypermotility disorders
    • Upper gastrointestinal endoscopy: to rule out gastric outlet obstruction and peptic ulcer disease
    • Colonoscopy: in case of diarrhea or red flags in patients with constipation
    • See also “Diagnostics for diabetic gastroparesis.”

• Optimize diabetes management to achieve glycemic targets in DM. ^[6]
• Treat dyslipidemia and hypertension, if present. ^[6]
  • See “Management of hypercholesterolemia.”
  • See “Hypertension management.”
• If possible, discontinue medications that may contribute to symptoms. ^[5][6]
• Consider specialist referral. ^[6]
• Treatment varies depending on the organ system(s) affected:
  • Genitourinary symptoms: See “Treatment of urinary incontinence” and “Sexual dysfunction.”
  • Symptoms of diabetic gastroparesis, see “Management of diabetic gastroparesis.”
  • Manage orthostatic hypotension. ^[5]
    • Nonpharmacological management of orthostatic hypotension and syncope, including regular exercise
    • Pharmacological management (e.g., fludrocortisone, midodrine) ^[6]
    • Use of short-acting drugs at bedtime for patients with supine hypertension

• Educate patients on symptoms of diabetic neuropathies.
• Optimize diabetes management to achieve glycemic targets in DM.
• Encourage smoking cessation.
• Initiate ASCVD prevention.

Screening for diabetic neuropathy

Perform annually, starting at the time of diagnosis for patients with T2DM and 5 years after diagnosis for patients with T1DM (earlier if symptoms develop). ^[5]

Screening for diabetic peripheral neuropathy ^[6]

• Inquire about subjective symptoms of diabetic peripheral neuropathy.
• Assess ankle reflexes and perform a focused examination of sensation.

Screening for diabetic autonomic neuropathy ^[5][6]

• Inquire if patient is experiencing:
  • Symptoms of diabetic gastroparesis
  • Symptoms of erectile dysfunction or female sexual dysfunction
  • Recurrent urinary tract infections and/or symptoms of urinary incontinence
  • Peripheral dry and/or cracked skin
  • Symptoms of hypotension or syncope
• Record resting heart rate: A resting heart rate > 100 bpm suggests cardiovascular autonomic neuropathy.
• Check orthostatic vital signs.
• Assess for decreased heart rate variability by recording an ECG either:
  • When the patient rises from seated to standing
  • Continuously while the patient takes deep breaths for 1–2 minutes