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Jun.14.2021

Diabetic Peripheral Neuropathy

Synopsis

Key Points

  • Diabetic peripheral (somatic) neuropathy is peripheral nerve dysfunction caused by diabetes mellitus; it may be accompanied by sensation loss, motor dysfunction, pain, and paresthesia, and it may demonstrate concurrent autonomic dysfunction
  • Neuropathy develops in up to 90% of patients with diabetes r1
  • Chronic sensorimotor polyneuropathy occurs most commonly, accounting for 80% of clinical cases of diabetic neuropathy; other forms include: r2
    • Acute sensory neuropathy
    • Cranial neuropathy
    • Radiculoplexus neuropathy (cervical, thoracic, lumbosacral)
    • Mononeuropathy (ie, entrapment neuropathy)
  • Diagnosis requires exclusion of other causes of neuropathy that occur more commonly in patients with diabetes than in those without (eg, hypothyroidism, vitamin B₁₂ deficiency, uremia); diagnosis also requires consideration of whether trauma, neurotoxins, inflammatory disease, infectious disease (eg, HIV), or malignancy might be present (evaluate accordingly)
  • Screening questionnaires may assist in diagnosis and aid in defining the severity of chronic sensorimotor polyneuropathy; nerve conduction velocity and EMG tests are occasionally but not usually required to determine or confirm diagnosis; nerve biopsies are rarely necessary for diagnosis
  • Acute sensory neuropathies, as well as mononeuropathies, radiculoplexus neuropathies, and cranial neuropathies, usually resolve spontaneously over time, assisted by optimal glycemic control
  • Distal sensory polyneuropathy is lifelong and requires long-term management
    • Healthy diet and moderate exercise are indicated
    • Management of pain is essential and includes the use of anticonvulsants, antidepressants, and, if needed, opioid analgesics; local therapies (eg, capsaicin) are effective for some adults and are first line treatments for children
  • Complications include foot ulcers and joint degeneration; amputation of toes or feet may result

Pitfalls

  • Results of electrodiagnostic studies are not conclusive without clinical context
  • Up to 50% of patients with diabetic peripheral neuropathy are asymptomatic and are consequently at greater risk of injuries, especially to their feet r2

Terminology

Clinical Clarification

  • Diabetic peripheral neuropathy is peripheral nerve dysfunction caused by diabetes mellitus; it may be accompanied by sensation loss, motor dysfunction, pain, and paresthesia r3
  • Distal symmetrical polyneuropathy is the dominant peripheral manifestation, being present in up to 50% of all patients with diabetes mellitus r1
  • Focal, multifocal, and radiculoplexus neuropathies, as well as mononeuropathies (eg, entrapment neuropathies), also occur in patients with diabetes, albeit less frequently (usually in older patients with type 2 diabetes) r4

Classification

  • Diabetic neuropathies can be classified according to type of nerve involved, site of nerve damage, and time course r5
    • Typical diabetic neuropathy (ie, diffuse neuropathy)
      • Distal sensorimotor polyneuropathy (ie, distal symmetric polyneuropathy) r5r6
        • Most common type of diabetic neuropathy in adults and childrenr7 (75% of diabetic neuropathies) and the major cause of diabetic foot ulceration r6
          • Associated with a wide range of symptoms; up to 50% of patients are asymptomatic, particularly early in course of neuropathy r2r6
          • Involves peripheral sensory and motor fibers to varying degrees r5
            • Primarily small-fiber neuropathy
            • Primarily large-fiber neuropathy
            • Mixed small- and large-fiber neuropathy (most common form)
      • Autonomic neuropathy
        • Cardiovascular
        • Gastrointestinal
        • Urogenital
      • Sudomotor dysfunction
      • Hypoglycemia unawareness
      • Abnormal pupillary function
    • Atypical forms of diabetic neuropathy r5
      • Asymmetrical (focal and multifocal) neuropathies are rare and typically are associated with type 2 diabetes in patients older than 50 years r2
      • Radiculopathy or polyradiculopathy
        • Radiculoplexus neuropathies usually affect patients who have mild diabetes, and most cause pain followed by weakness; they are associated with concurrent weight loss r8
          • Lumbosacral radiculoplexus neuropathy (ie, diabetic amyotrophy, Bruns-Garland syndrome) r8
            • Associated with type 2 diabetes and older age (median age: 65 years) r8
            • Causes severe lower extremity pain, particularly in proximal thigh muscles, and weakness with atrophy
          • Thoracic radiculoplexus neuropathy
            • Causes severe pain and dysesthesias involving trunk, chest, and abdominal wall
          • Cervical radiculoplexus neuropathy r8
            • Occurs in patients with type 2 diabetes
            • Causes pain and sensory loss in upper extremities
            • Relatively rare
      • Mononeuropathy
        • Entrapment neuropathies (more common in people with diabetes) r8
          • Peroneal neuropathy at fibular head is most common
          • Median neuropathy at wrist
          • Ulnar neuropathy at elbow
          • Radial neuropathy with entrapment of nerve in spiral groove of humerus r9
        • Cranial neuropathy
          • Third and sixth cranial nerves are primarily affected (fourth cranial nerve is also affected, to a lesser extent), causing unilateral oculomotor nerve palsies r2
          • Facial (seventh) nerve involvement may cause Bell palsy r10
    • Treatment-induced neuropathy r11
      • Typically takes form of acute or subacute painful peripheral sensory neuropathy
      • Complication of aggressive glycemic control, particularly with hemoglobin A1C reduction of 1% or more per month

Diagnosis

Clinical Presentation

History

  • Symptoms, when present, are as follows:
    • Symmetrical polyneuropathies
      • Chronic sensorimotor neuropathy (ie, diabetic distal sensory polyneuropathy) r2
        • 50% of patients with chronic sensory neuropathy are asymptomatic r6c1
        • Insidious onset of symptoms is typical r6
          • Generally appears many years after type 1 diabetes is first diagnosed
          • May be present at time of diagnosis of type 2 diabetes (often discovered when patients present with a nonhealing foot ulcer) c2
          • Present in 10% to 30% of patients with prediabetes (ie, impaired glucose tolerance) r6c3
          • More than 50% of children with chronic sensorimotor neuropathy are asymptomatic early in disease and are discovered by annual screening
        • Symptomatic patients may experience sensory loss, neuropathic pain, or both r2
          • Pain and stabbing sensations r6c4c5
            • Pain is neuropathic, exacerbated at night, and described by patients variously as burning/hot (like "walking on burning coals"), electric, sharp (like "bees stinging through socks"), achy, and/or tingling r12c6c7c8c9c10
              • Average pain intensity is moderate r12c11
              • Allodynia, hyperesthesia, and/or hyperalgesia may be present c12c13c14
            • 96% of symptomatic patients experience pain in their feet; pain tends to occur most frequently in toes and ball of foot r12c15
            • 39% of symptomatic patients experience pain in their hands r12c16
            • 37% of symptomatic patients experience pain in their calves r12c17
          • Hand and foot sensory loss (ie, stocking-and-glove distribution pattern) r13c18
            • Fingertips often are involved if lower extremity sensory changes have reached the knee
          • Unsteadiness or gait ataxia from disturbed proprioception c19c20
            • Tripping over curbs, difficulty using stairs, or unsteadiness when walking at night may be reported
            • Hand coordination may decrease, causing problems with fine manipulations and/or difficulty with opening car doors or jars c21
      • Acute sensory neuropathy r14
        • Usual presentation is treatment-induced neuropathy with rapid onset of acute symptoms occurring after an episode of glycemic instability (eg, ketoacidosis) or after sudden improvement in glycemic control (typically occurs within 8 weeks after medication initiation or dietary change)r15c22
          • Continuous burning pain, especially in soles of feet, but may progress to involve upper extremities; also may have deep, achy pain. Worse at night c23c24c25c26
            • Electric shock–like sensations (eg, sharp, sudden, stabbing) are experienced by many c27c28
            • Patients often complain of pins and needles sensation; may complain of feet feeling cold c29c30
            • Characteristic feature is hypersensitivity to cutaneous contact with clothes and sheets (ie, severe allodynia) c31
          • May be associated with symptoms of autonomic dysfunction (eg, early satiety and postprandial fullness with gastroparesis, resting tachycardia with cardiac autonomic neuropathy) c32c33c34
        • Presents (rarely) at time of diabetes diagnosis as diabetic neuropathic cachexia involving profound unintentional weight loss and bilateral sensory polyneuropathy with severe pain of soles of feet that may progress to involve entirety of both lower extremities, hands, abdomen, and lower trunk r15
          • Almost always occurs in men, who also present with depression and erectile dysfunction c35c36c37c38c39c40c41c42
            • Only a few cases of diabetic neuropathic cachexia and bilateral sensory polyneuropathy involving women have been reported
          • Autonomic dysfunction other than erectile dysfunction may be reported (eg, lightheadedness or syncope on standing, early satiety with meals) c43c44
          • Weight loss exceeds 10% of baseline weight (up to 60% of premorbid weight) r16
    • Asymmetrical polyneuropathies
      • Focal/multifocal neuropathies
        • Cranial neuropathy
          • Often presents with acute onset of diplopia (with involvement of third, fourth, or sixth cranial nerves) c45c46
            • Fleeting frontal cephalalgia heralds disease in 50% of cases, with abrupt onset over 1 or 2 days r2
          • Facial nerve involvement causes Bell palsy, which in patients with diabetes is associated with preservation of taste r10c47
        • Radiculoplexus neuropathies are usually associated with weight loss, which can occur before onset of pain r8c48
          • Thoracic radiculoplexus neuropathy affects a band of the chest or abdominal wall on 1 or both sides
            • Motor weakness can be present c49
            • Usually presents with severe pain in a bandlike pattern involving back or flank, radiating anteriorly toward chest c50c51c52
            • Sensation of tightness and so-called "asleep" or prickly numbness and allodynia are located along abdominal or chest wall, making clothing uncomfortable c53c54c55c56
          • Lumbosacral radiculoplexus neuropathy (ie, diabetic amyotrophy)
            • Associated with weight loss r8c57
            • Severe pain in lower extremity is main initial feature, followed by weakness and paresthesias that usually begin either unilaterally or asymmetrically; pain eventually becomes bilateral r8c58c59c60
              • Mean time from onset to bilateral involvement is 3 months
              • Pain is described as sharp and lancinating, deep aching, or burning; allodynia often is noted c61c62c63c64c65
            • After pain develops, muscle weakness and wasting occur c66
            • Often associated with autonomic symptoms; majority have sexual disturbances, sweating abnormalities, and blood pressure dysregulation c67c68c69
          • Cervical radiculoplexus neuropathy (ie, brachial plexopathy caused by diabetes)
            • Distal upper extremity sensory loss and pain, initially unilateral, develop into bilateral but asymmetrical involvement c70c71
              • Pain is initial symptom, followed by weakness c72
              • Majority experience unilateral onset, progressing to bilateral involvement c73c74
      • Mononeuropathies r14
        • Peroneal neuropathy at fibular head
          • Typically causes foot dorsiflexion weakness and footdrop c75c76
          • Impaired foot eversion may be present c77
          • Sensory loss over dorsum of foot without pain or paresthesia c78
        • Carpal tunnel syndrome (median neuropathy)
          • Painful paresthesia in first 3 digits and lateral surface of fourth digit; most commonly occurs at night, but may occur with repetitive wrist flexion/extension; may progress to deep-seated ache c79c80c81c82c83c84
          • Pain may radiate into wrist and forearm c85
        • Ulnar neuropathy at elbow
          • Painful paresthesias in fourth and fifth fingers c86
        • Radial neuropathy
          • Inability to extend wrist, thumb, or fingers that have decreased or absent sensation and/or paresthesia along radial and dorsal side of hand c87c88c89c90c91

Physical examination

  • Chronic sensorimotor neuropathy (ie, diabetic distal sensory polyneuropathy)
    • Absent or reduced Achilles tendon reflexes; possibly reduced patellar tendon reflexes c92c93c94
    • Weakened toe and foot dorsiflexion; weakness may progress to frank footdrop c95c96c97
    • Mild distal symmetrical sensory loss to pinprick, light touch, temperature, or pressure changes in a stock-and-glove distribution; may extend to ankles and involve hands c98
      • Test sensation to pinprick with a new (ie, non-reused) safety pinr17 or Wartenberg wheelr1
      • Light touch is initially tested with cotton against dorsum of large toe with patient's eyes closed r17
      • Semmes-Weinstein monofilament is widely used to assess pressure sensation, particularly the 5.07 monofilament, which exerts 10 g of force, touching apex of large toe and first, third, and fifth metatarsal heads r14
        • For children, the smaller 0.98 g monofilament is recommended r7
        • A biothesiometer, which records vibratory threshold, can be used in place of a tuning fork and may be superior in determining vibratory sensation loss, especially in children r18
      • Temperature perception (using a warmed or cooled tuning fork) is tested on dorsum of foot
    • Vibratory sensation loss is tested with 128-Hz (less commonly 256-Hz) tuning fork on dorsum of toes, malleoli, and knees; in upper extremities, vibration sensation at distal digits, wrist, and elbows is tested r17
    • Small muscle wasting in feet and hands in advanced cases c99
    • Loss of position sense in large toe is a late sign of severe peripheral neuropathy and is usually associated with a positive Romberg sign c100c101
  • Acute sensory neuropathy
    • Treatment-induced neuropathy
      • Examination findings are usually normal, although mild sensory loss at feet and/or allodynia may be present c102c103
      • Occasionally, Achilles tendon reflex is diminished c104
      • Dysautonomia, sometimes severe, may be present (eg, resting tachycardia, postural hypotension, postural tachycardia without hypotension) c105c106c107
    • Diabetic neuropathic cachexia
      • Generalized wasting and weakness; most prominent in proximal lower extremities c108c109c110c111c112
      • Sensory loss in feet usually absent or very mild c113
      • Reduction or loss of ankle reflexes c114c115
  • Focal/multifocal neuropathies
    • Cranial neuropathy
      • Third nerve palsy causes almost complete oculomotor dysfunction
        • Ptosis c116
        • Inability to elevate or adduct the involved eye (causing a down and out position at rest) c117c118
        • Pupil is often spared in diabetic neuropathy; when pupil is affected (14%-18% of patients with diabetes), it presents as Argyll Robertson pupil (ie, bilateral small pupils that reduce in size when fixating on a near object but that do not respond to direct light) c119
      • Sixth nerve palsy causes loss of ability to turn out the eye (ie, abduct) c120
      • Fourth nerve palsy is occasionally seen in conjunction with third nerve palsy, causing limitation in downgaze when eye is adducted c121
      • Seventh (facial) nerve palsy, resulting in a Bell palsy r10c122
    • Radiculoplexus neuropathies
      • Thoracic radiculoplexus neuropathy
        • Diminished touch sensation and allodynia in a dermatomal distribution c123c124
        • Weakness and outpouching of abdominal wall in distribution of sensory disturbance may be present c125
      • Lumbosacral radiculoplexus neuropathy (ie, diabetic amyotrophy)
        • Initially appears as proximal lower extremity muscular weakness (typically thigh muscles), starting unilaterally and spreading to become bilateral and involve distal musculature, causing footdrop c126c127c128c129c130
        • Initially, there is no sensory loss; eventually, diminished sensation occurs in an approximate nerve root distribution c131c132
        • Absent Achilles tendon reflex c133
      • Cervical radiculoplexus neuropathy (ie, brachial plexopathy caused by diabetes)
        • Weakness may involve all of brachial plexus (nerve roots C5-T1), particularly weakness in:
          • Shoulder elevation (trapezius) c134
          • Shoulder external rotation c135
          • Elbow pronation c136
          • Elbow supination c137
          • Finger extension c138
          • Thumb flexion (flexor pollicis longus) c139
    • Mononeuropathies
      • Peroneal neuropathy at fibular head
        • Painless footdrop
        • Ankle dorsiflexion weakness
        • Toe extension weakness c140
        • Ankle eversion weakness
        • Diminished sensation over dorsum of foot
      • Carpal tunnel syndrome (median neuropathy)
        • Thenar atrophy c141
        • Positive Phalen test result (high false-positive) c142
        • Positive Tinel sign (high false-positive) c143
        • Diminished sensation in first, second, third, and half of fourth digit
        • Weakness in median-innervated muscles is uncommon c144
      • Ulnar neuropathy at elbow
        • Anesthesia involving fourth and fifth fingers
        • Medial proximal forearm tenderness near medial epicondyle c145
      • Radial neuropathy
        • Inability to extend metacarpophalangeal joints of fingers and thumb or to extend at wrist
        • Decreased sensation along radial side of dorsum of hand c146

Causes and Risk Factors

Causes

  • Acute neuropathies
    • Rapid improvement in glycemic control after initiation of insulin, hypoglycemic agents, or dietary change may prompt an acute painful sensory neuropathy c147
      • Cause is not clear, but neovascularization with an arteriovenous shunt causing endoneurium ischemia has been described
      • Also may be related to acute degeneration and regeneration of nerve fibers
    • Ketoacidosis may precipitate acute sensory neuropathy, related to poor metabolic control c148
  • Chronic neuropathies
    • Poor glucose control is associated with development of diabetic neuropathy, especially in patients with type 1 diabetes c149c150
    • Many patients with type 2 diabetes develop neuropathy despite good glucose control, related at least in part to metabolic derangements affecting microvasculature causing neural ischemia and oxidative stress-induced nerve damage due to hyperglycemia c151
    • Other risk factors for chronic neuropathies in patients with diabetes include:
      • Elevated triglycerides c152
      • Smoking c153
      • Hypertension c154
      • High BMI; in obese patients, each increase of 1 kg of weight increases the likelihood of neuropathic pain developing by 3% r19c155
      • Vitamin D deficiency r20r21

Risk factors and/or associations

Age
  • Diabetic peripheral neuropathies become more prevalent with increasing age r22
    • Aged 20 to 29 years: prevalence is 5% (combined type 1 and type 2 diabetes) c156
    • Aged 70 to 79 years: prevalence is 44.2% (combined type 1 and type 2 diabetes) c157c158c159
  • Focal/multifocal neuropathies typically are seen at relatively older ages r4c160c161c162c163c164c165
Sex
  • Overall prevalence of diabetic peripheral neuropathy is similar in males and females r22
  • Diabetic neuropathic cachexia (an acute neuropathy) occurs almost exclusively in males r15c166c167
  • Thoracic radiculoplexus neuropathy is more common in older males r14c168c169c170
Genetics
  • Inheritance of single-nucleotide polymorphisms of genes for superoxide dismutase 2 and 3—extracellular (SOD3; OMIM *185490)r23 and mitochondrial (SOD2; OMIM *147460),r24 respectively—have been implicated in development of diabetic neuropathy c171
Ethnicity/race
  • Compared with White patients, relative odds of early diabetic neuropathy are 1.3 in Black patients and 1.5 in Native American patients r25c172c173c174
Other risk factors/associations
  • Duration of diabetes is associated with prevalence of peripheral neuropathy c175
    • Fewer than 5 years: 21% of patients r22
    • More than 10 years: 37% of patients r22
    • More than 25 years: over 40% of patients r14
  • Taller patients are more likely to develop lower extremity peripheral sensory neuropathy than shorter patients (height may be proxy for nerve length) r26c176c177
  • Problematic alcohol consumption occurs more frequently in patients with diabetes who develop lower extremity peripheral sensory neuropathy compared with those who do not r26c178
  • Smoking increases odds of developing diabetic peripheral neuropathy by 42% r27c179
  • Peripheral arterial disease (ie, ankle-brachial index lower than 0.9) increases the likelihood of painful peripheral neuropathy developing in patients with diabetes more than 9-fold r19c180
  • Low serum cholesterol levels have been associated with an increased incidence of nerve lesions in patients with diabetic peripheral neuropathy r21

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis of diabetic peripheral neuropathy relies heavily on clinical assessment at routine follow-up visits and during focused screening at prescribed intervals; specific testing is selected when findings are atypical or an additional contributing factor is suspected r4c181
    • Signs are more predictive of neuropathy than symptoms r1
    • In patients with diabetes who present with characteristic symptoms and physical signs of peripheral neuropathy, extensive laboratory and electrodiagnostic testing are not essential; testing is prompted by atypical signs or symptoms or by failure to improve with initial treatment r6
      • Consider clinical likelihood and rule out neuropathies that occur more often in patients with diabetes, such as hypothyroidism (TSH level), uremia (BUN and creatinine levels), vitamin B₁₂ deficiency (serum vitamin B₁₂ level); note or obtain recent blood glucose levels and/or hemoglobin A1C
      • Consider trauma, neurotoxic drugs, inflammatory disease, infectious diseases (eg, HIV), and malignancy as cause of peripheral neuropathy, and obtain CBC, erythrocyte sedimentation rate, folic acid level, liver function studies, HIV serology, and serum immunoelectrophoresis as clinically indicated (ie, clinical suspicion of another cause of neuropathy or absence of adequate response to initial treatment)
      • Most patients receive much of this testing as part of routine diabetes management (eg, vitamin B₁₂ with metformin use, liver function studies to monitor statins/thiazolidinediones, annual BUN/creatinine levels) with the exception of HIV testing, folic acid level, sedimentation rate, and serum immunoelectrophoresis
  • Chronic sensorimotor neuropathy (ie, diabetic distal sensory polyneuropathy) affecting peripheral nervous system r28
    • Initial clinical examination is of primary importance, especially of lower extremities c182
      • Validated scoring systems assist in diagnosis of adults (use is limited in children given that most are asymptomatic)r7 and in defining severity of chronic sensorimotor polyneuropathy, with serial usage recommended to assess treatment response. Examples include:
        • Michigan Neuropathy Screening Instrument: screens for likelihood of neuropathy r29
        • Modified Neuropathy Disability Score: determines severity of sensory deficits and predicts foot ulcer risk
    • Nerve conduction velocity/EMG testing can generally confirm diagnosis r1
      • Test usually not necessary in typical diabetic peripheral neuropathy
      • Appropriate when:
        • Diagnosis is unclear
        • A different cause is suspected
        • Features are atypical (eg, rapid onset, motor greater than sensory deficit, asymmetrical presentation), causing suspicion of a rarer diagnosis
  • Acute sensory neuropathy r16
    • Clinical examination demonstrating findings consistent with peripheral neuropathy, combined with recent hemoglobin A1C or blood glucose measurements documenting a drop in hemoglobin A1C (more than 2% within 3 monthsr15) or rapid control of blood glucose levels in a patient with type 1 or type 2 diabetes, support the diagnosis of treatment-induced neuropathyr16c183c184c185
    • Patients presenting with cachexia, painful lower extremity paresthesia, and signs or symptoms of autonomic dysfunction (eg, resting tachycardia, erectile dysfunction, orthostatic hypotension) who are subsequently diagnosed with diabetes mellitus (type 1 or 2) may be diagnosed with diabetic neuropathic cachexia when other more common causes of unintentional profound weight loss have been eliminated (eg, pancreatic carcinoma, celiac disease) r15
  • Cranial neuropathy r4
    • Physical examination identifies and defines cranial neuropathy c186
  • Radiculoplexus neuropathies r14
    • Thoracic radiculoplexus neuropathy
      • Denervation potentials in intercostal muscles, muscles of anterior abdominal wall, and paraspinal muscles can be detected by EMG tests
    • Lumbosacral radiculoplexus neuropathy (ie, diabetic amyotrophy)
      • Femoral nerve conduction velocity is reduced as detected by EMG and nerve conduction velocity testing
    • Cervical radiculoplexus neuropathy (ie, brachial plexopathy caused by diabetes) r30
      • EMG testing finds frequent fibrillation potentials with decreased recruitment of motor units
  • Mononeuropathies
    • EMG testing can confirm diagnosis of peroneal, median, radial, and ulnar nerve neuropathies r14

Laboratory r6

  • Consider in all patients with diabetes and possible or likely neuropathy when diagnosis is not clear or after an inadequate response to initial treatment, if not already obtained for disease management
    • TSH level c187
    • BUN and creatinine levels c188
    • Serum vitamin B₁₂ level c189
    • CBC c190
    • Erythrocyte sedimentation rate c191
    • Folic acid level c192
    • Liver function studies c193
    • Serum immunoelectrophoresis c194

Functional testing

  • EMG/nerve conduction velocity tests of affected region r14c195c196c197c198c199c200c201c202c203c204c205c206
    • Performed by consulting neurologist when diagnosis is not clear from clinical examination or when alternative diagnosis is suspected
      • Results of electrodiagnostic studies are not conclusive without clinical context
    • Typically required when clinical features are atypical (eg, motor involvement more than sensory, development of symptoms is rapid [days to weeks], or presentation is asymmetrical)
    • Test affected extremities and appropriate body regions for peripheral sensory neuropathy r14
      • Femoral nerve if lumbosacral radiculoplexus neuropathy (diabetic amyotrophy) is suspected
      • Intercostal muscles, anterior abdominal wall muscles, and paraspinal muscles if thoracic radiculoplexus neuropathy is suspected
      • Lateral antebrachial cutaneous nerve, median nerve, superficial radial nerve, and ulnar nerve if cervical radiculoplexus neuropathy (ie, brachial plexopathy caused by diabetes) is suspected
      • Localized areas for mononeuropathies (eg, nerve conduction study across carpal tunnel)

Procedures

Nerve biopsy r2c207
General explanation
  • When lower extremities are involved, typically sample superficial peroneal nerve with peroneus brevis muscle or sample sural nerve with vastus lateralis or gastrocnemius muscle
  • When upper extremities are involved, typically sample superficial radial nerve or a branch of ulnar nerve in dorsum of hand
  • Examine neural cross-section microscopically
Indication
  • Previous testing inconclusive for diabetic neuropathy
Complications
  • Nerve damage with long-term numbness, pain, or paresthesias
Interpretation of results
  • Axonal loss is associated with diabetic neuropathy
  • Degeneration and loss of myelin consistent with demyelinating neuropathy (ie, chronic inflammatory demyelinating neuropathy) r3

Other diagnostic tools

  • Michigan Neuropathy Screening Instrument r29c208
    • Consists of inspection of feet, ankle reflexes, and vibratory perception threshold at lateral malleolus; score as follows:
      • Foot appearance
        • Normal: 0
        • Abnormal: 1
      • Ulceration
        • Absent: 0
        • Present: 1
      • Ankle reflex
        • Absent: 1
        • Present with reinforcement: 0.5
        • Present: 0
      • Vibration perception using a 128-Hz tuning fork
        • Absent: 1
        • Reduced: 0.5
        • Present: 0
    • Cutoff point of 2 (for a single foot) predictive of neuropathy r29
  • Modified Neuropathy Disability Score r28c209
    • Evaluates ankle reflexes, vibration perception, pinprick awareness, and temperature sensation at big toe; score as follows: r14
      • Vibration perception threshold using a 128-Hz tuning fork
        • Normal (can distinguish vibration): 0
        • Abnormal: 1
      • Test temperature perception on dorsum of foot using ice water and warm water to chill and warm handle of tuning fork before applying to foot
        • Normal (can distinguish temperature change): 0
        • Abnormal: 1
      • Pinprick
        • Normal (can distinguish sharp versus blunt pricks): 0
        • Abnormal: 1
      • Achilles reflex
        • Present: 0
        • Present with reinforcement: 1
        • Absent: 2
    • Score of 6 or more out of 10 is predictive of foot ulcer risk due to disrupted sensation; score of 10 indicates complete loss of sensation and reflexes r28

Differential Diagnosis

Most common

  • Exclude the following causes of peripheral sensory neuropathies before diagnosing a peripheral (somatic) diabetic neuropathy r2
    • Trauma or injury to extremities or repetitive stress r14c210c211c212
      • Nerve compression, entrapment, or injury may cause neuropathy, as in carpal tunnel syndrome or ulnar neuropathy c213c214c215d1
      • Can also cause pain and paresthesia in and around injured region
      • Resulting neuropathy is locally stable and not progressive
      • Often differentiated by patient history of the following:
        • Falls or injuries
        • Repetitive actions, often occupational exposure
    • Vitamin B₁₂ deficiency r31c216c217
      • Peripheral nerve dysfunction as a neurologic complication of vitamin B₁₂ deficiency; in diabetes mellitus, vitamin B₁₂ deficiency is seen more often in patients treated with metforminr32
        • Prevalence increases with age in the general population in the United States and United Kingdom: approximately 6% in people younger than 60 years and 20% in people aged 60 years or older
        • More common in vegetarians and vegans
      • Psychiatric symptoms such as irritability, depression, and dementia may be present
      • CBC may find macrocytosis and/or anemia
      • Differentiated by levels of serum vitamin B₁₂ lower than 148 pmol/L (200 nanogram/L), which has a sensitivity allowing diagnosis of 97% of patients with true vitamin B₁₂ deficiency r31
        • If vitamin B₁₂ levels are low, obtain serum level of holotranscobalamin (so-called active B₁₂); a low level is an early indicator of low vitamin B₁₂ levels and supports diagnosis r31
        • If serum holotranscobalamin level is intermediate, obtain serum level of methylmalonic acid; an elevated level is consistent with vitamin B₁₂ deficiency except when there is renal insufficiency or when patients are older than 65 years r31
        • Plasma homocysteine level also increases (higher than 15 μmol/L) with vitamin B₁₂ deficiency and may assist in confirming diagnosis, but it is nonspecific given that it increases in folate deficiency, renal failure, hypothyroidism, and vitamin B₆ deficiency r31
    • Tumors (benign or malignant) or masses (neuromas) affecting peripheral nerves r33c218c219
      • Can cause a conduction block or trauma to affected nerve
      • Single nerve is more likely to be affected than multiple nerves
      • Differentiated by prior diagnosis of malignancy (if present) and diagnosis confirmed by: r33
        • Ultrasonogram or MRI showing presence of solid mass
        • Biopsy results showing exact nature of tumor
    • Toxic neuropathies caused by ethyl alcohol or other drugs, heavy metals, or chemotherapy c220
      • Neurotoxins cause axonal degeneration and demyelination r34
      • May cause pain and paresthesia as in diabetic sensory polyneuropathy
      • Onset is likely to be more sudden from time of first exposure compared with onset of typical diabetic sensory polyneuropathy
      • Common drugs implicated in peripheral neuropathies r34
        • Antiretroviral agents
        • Cholesterol-lowering statins
        • Anticonvulsants
        • Thalidomide
      • Ethyl alcohol r34
        • Associated with malnutrition, nutrient deficiencies (thiamine in particular), and direct neurotoxicity of ethyl alcohol
        • Differentiated by history of excessive chronic alcohol consumption d2
      • Heavy metals associated with neuropathy r34
        • Lead d3
        • Mercury
        • Arsenic
        • Thallium
        • Germanium
      • Chemotherapy-induced peripheral neuropathy (affects 30%-40% of patients receiving chemotherapy) r35
        • Large number of chemotherapeutic agents—including platinum drugs, taxanes, epothilones, vinca alkaloids, bortezomib, and lenalidomide—have been implicated
        • Peripheral nerves are structurally damaged, causing abnormal somatosensory processing
        • Differentiated by patient history of chemotherapy before development of neuropathy symptoms
    • Infection
      • Peripheral neuropathy may develop secondary to infection by a host of viruses, bacteria, parasites, and spirochetes, especially in patients who are immunocompromised r36
        • HIV: may cause a distal, symmetrical sensory-dominant peripheral neuropathy in 20% to 60% of patients who are HIV positive c221
          • Mean time to appearance of neuropathy is 9.5 years after HIV diagnosis
          • Exposure to older dideoxynucleoside antiretroviral agents (ie, didanosine, stavudine, zalcitabine) may cause distal, symmetrical sensory polyneuropathy not distinguishable from HIV-induced polyneuropathy
            • Drug exposure neuropathy begins 2 to 3 months after drug initiation and may involve upper extremities earlier than HIV-induced polyneuropathy
        • Hepatitis C: may cause a length-dependent sensory (peripheral) neuropathy and a sensory predominant sensorimotor (peripheral) polyneuropathy; neuropathy affects 10% of infected patients, increasing to 26% to 86% in patients with concurrent cryoglobulinemia c222c223
        • Lyme disease c224c225c226c227
          • Early disease (within days to 1-2 months of onset) is associated with cranial nerve neuropathies (usually seventh cranial nerve) and radiculoneuritis (ie, cervical, thoracic, lumbosacral)
          • Later disease (months to years from onset) is associated with focal or multifocal radiculoneuropathy or mononeuropathy (may be symmetrical or asymmetrical)
      • HIV-induced neuropathy r37d4
        • Increased risk with coexistent diabetes mellitus
        • Motor symptoms are usually absent; sensory symptoms include paresthesia, neuropathic pain (eg, burning, stabbing, tingling), imbalance, and numbness
        • Autonomic dysfunction may occur (eg, orthostatic hypotension, sweating dysfunction)
        • Differentiated by positive HIV serology preceding development of length-dependent loss of pinprick and temperature sensation, and diminished or absent ankle jerk (often with hyperactive patellar reflexes), impaired balance, and reduced distal vibratory sensation
      • Hepatitis C–induced neuropathy r36d5
        • Presents with sensory loss, ataxia, paresthesia, neuropathic pain, hyporeflexia, and sometimes mild weakness
        • Patients usually can state the time of onset
        • Differentiated by positive hepatitis C serology with examination finding a length-dependent sensory or sensorimotor neuropathy
      • Lyme disease r36d6
        • Infection with the spirochete Borrelia burgdorferi or related Borrelia species (eg, Borrelia afzelii and Borrelia garinii in Europe and Asia)
        • With early-onset neuropathy (usually occurs from early spring to late fall), peripheral nerve involvement may occur; most commonly, cranial neuropathy or radiculopathy
        • With late-onset neuropathy, a milder focal or multifocal radiculoneuropathy or mononeuropathy may develop
          • Usually symmetrical, or asymmetrical with neuropathic pain (eg, burning, stabbing, tingling) or radicular pain, diminished reflexes, decreased sensation or numbness
          • Only slight weakness if any
        • Differentiated by recognition of clinical syndrome (especially when characteristic rash is described early in course of illness) and 2-tiered serologic testing of symptomatic patients (ie, enzyme immunoassay or rarely, indirect immunofluorescence assay, with Western blot or second enzyme immunoassay to confirm), the standard testing in North America r38r39
          • Testing for the VlsE C6 (VMP-like sequence, expressed) lipoprotein by ELISA and Western blot analysis detects other Borrelia species in addition to Borrelia burgdorferi and can be used to diagnose infection acquired outside North America by these other species r40
    • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) r41c228
      • A plasma cell dyscrasia, characterized by peripheral neuropathy, organomegaly (hepatomegaly and splenomegaly), endocrinopathy, M protein (monoclonal M-spike), and skin changes
        • Clinically differentiated by the fact that neuropathy in POEMS syndrome is severe, often beginning with sensory symptoms and then developing into a predominantly motor neuropathy r42
        • Also usually not painful; autonomic features are rare r41
      • Diagnosed by presence of a monoclonal plasma cell dyscrasia and at least 1 other major criterion for POEMS syndrome r41
        • Serum protein electrophoresis and immunofixation are required
        • λ light chain is most usual monoclonal protein
      • Major diagnostic criteria r41
        • Presence of both a (sensorimotor) ascending, symmetrical peripheral polyneuropathy and a monoclonal plasma cell dyscrasia
      • Other major diagnostic criteria (1 required) r41
        • Concurrent Castleman disease (11%-30%)
        • Osteosclerotic bone lesions, best detected by CT scan (27%-97%)
        • Vascular endothelial growth factor (plasma or serum)
          • Very elevated during POEMS syndrome, and levels correlate with disease activity
          • Plasma levels may be more specific than serum levels
            • Plasma levels higher than 200 pg/mL support diagnosis
            • Serum levels above 1920 pg/mL support diagnosis
      • Other supportive findings r41
        • At least 1 endocrine abnormality (eg, hypogonadism, hypothyroidism) (67%-84%)
        • Skin changes (eg, hyperpigmentation, hypertrichosis) (68%-89%)
        • Splenomegaly (22%-70%), hepatomegaly (24%-78%), or lymphadenopathy (26%-74%)
        • Papilledema (29%-64%)
        • Extracellular volume overload (29%-87%); includes peripheral edema, ascites, pleural effusion, or pericardial effusion
        • Thrombocytosis (54%-88%)
        • Clubbing (5%-49%)
    • Transthyretin familial amyloid polyneuropathy r43c229d7
      • Life-threatening autosomal dominant polyneuropathy due to nerve lesions caused by amyloid fibril deposits, most often owing to mutated TTR gene (transthyretin)
      • Age of onset
        • Early onset (aged mid-30s) in endemic areas or in patients with family history of familial amyloid polyneuropathy (ie, familial case)
        • Late onset (aged 50 years or older) in nonendemic areas and in patients with no family history (ie, sporadic case)
      • 2 main patterns of initial sensorimotor deficit; both have autonomic disturbances (eg, orthostatic hypotension, gastroparesis, erectile dysfunction), although they are more prominent in early-onset disease, and extraneurologic manifestations (eg, cardiac involvement [arrhythmias, conduction disorders], progressive renal failure, visual loss) r43
        • Most common: nerve length–dependent progressive sensorimotor polyneuropathy
        • Focal neurologic deficits at onset due to local amyloid deposits
          • Carpal tunnel syndrome is the most common presentation (typically severe in degree of symptoms and impairment)
          • Other focal lesions are rare
          • Length-dependent progressive sensorimotor polyneuropathy may also be present or develop
      • In patients with length-dependent progressive sensorimotor familial amyloid polyneuropathy: r43
        • Early-onset disease typically begins with foot discomfort (numbness and spontaneous pain); late-onset disease often begins with leg paresthesias or pain
          • Initial examination finds impaired pinprick and thermal sensation with intact light touch and proprioception, and normal muscle strength and reflexes
        • Sensory loss to above both ankles occurs within a few months, and there is subsequent relentless progression to loss of sensation up the legs and development of burning pain; motor deficits occur in feet and lower legs and walking becomes difficult
        • Eventual involvement of fingers and forearms occurs
        • Life-threatening autonomic dysfunction develops, along with weight loss and wasting of muscles
      • Diagnosis in familial cases can be confirmed by a DNA test (often polymerase chain reaction) that detects TTR gene mutations r44
      • Diagnosis in sporadic cases usually requires biopsy to confirm amyloid deposition in tissues: r44
        • Abdominal fat pad or rectal biopsy (most common sites)
        • Sural nerve biopsy
        • Labial salivary gland
    • Chronic inflammatory demyelinating polyneuropathy r3c230
      • Multifocal demyelination that usually affects spinal roots, major plexuses, and proximal nerve trunks
        • Immune-mediated disorder of peripheral nervous system; most common from ages 40 to 60 years
      • In most patients, it causes a gradual onset of progressive sensory loss over several weeks, paresthesia, and symmetrical limb weakness with spontaneous pain, usually starting in proximal leg muscles; it also may involve upper extremities
        • In lower extremity involvement, patients report difficulty rising from chair, climbing stairs, or walking, as well as having falls
        • In upper extremity involvement, patients report problems tying shoes, gripping objects, and using utensils
      • Peak deficit occurs after at least 8 weeks, compared with acute form (ie, Guillain-Barré syndrome), which peaks within 4 weeks
        • Weakness in proximal and distal leg muscles (most common) or in proximal and distal arm muscles; proximal weakness is a core feature, along with discrepancy between degree of weakness and absence of atrophy (consistent with demyelination)
        • Generalized hyporeflexia or areflexia
        • Decreased sensation distally in a stocking-and-glove distribution pattern; decrease in light touch, proprioception, and vibration
      • Diagnosis is confirmed by:
        • EMG test to determine whether disorder is a peripheral neuropathy and whether it is demyelinating
        • Cerebrospinal fluid analysis showing elevated protein levels (above 45 mg/dL)
          • In some cases, mild lymphocytic pleocytosis and increased γ-globulin fraction
        • Peripheral nerve biopsy, if diagnostic evaluation is otherwise inconclusive

Treatment

Goals

  • Maximize glycemic control
  • Reduce symptoms
  • Improve functional status
  • Avoid complications

Disposition

Admission criteria

  • Marked glycemic instability
  • Management of complications (eg, nonhealing foot ulcers)
  • Inadequate outpatient management of pain

Recommendations for specialist referral

  • Refer to neurologist if needed to assist in diagnosis of a peripheral neuropathy, especially when 1 or more of the following are encountered: r45
    • Motor deficits predominate over sensory deficits
    • Symptoms rapidly develop and progress
    • Significant asymmetry of deficits
    • Mononeuropathy
    • Cranial nerve dysfunction
    • Symptom progression despite optimal glycemic control
    • Initial symptoms occur in upper extremity
    • Other neurologic syndromes
    • Family history of nondiabetic neuropathy
  • Additional referrals may be needed to help manage various manifestations and complications of diabetic neuropathy (eg, pain specialist, orthopedic or general surgeon, physical medicine and rehabilitation specialist, ophthalmologist, podiatrist, dietitian)

Treatment Options

In all patients

  • Monitor blood glucose levels regularly r6
  • Provide optimal glycemic control r46
    • There is good evidence that good glycemic control delays progression of neuropathy in type 1 diabetes; the effect in type 2 diabetes appears to be lesser r47
    • There is no evidence, however, that good glycemic control improves neuropathic pain once it occurs r48
  • Maintain optimal blood pressure and lipid levels r4
    • In patients with type 1 diabetes, use of an ACE inhibitor with or without a calcium channel blocker has been shown to benefit peripheral neuropathy r47
    • Statins and fibrates appear to delay progression of neuropathy and reduce incidence of diabetic foot infection and amputation in type 1 diabetes r47
  • Advise patients to eat a healthy diet (rich in nonstarchy vegetables with minimal added sugars, refined grains, and highly processed foods) and to exercise regularly r49r50
    • There is some evidence that regular aerobic exercise can improve nerve function and symptoms related to neuropathy in patients with type 2 diabetes r51
  • Counsel patients to avoid (or quit) smoking and excess alcohol use r4

Chronic distal sensory polyneuropathy r6

  • Manage pain and discomfort, which may require topical preparations, antidepressants, anticonvulsants, and/or opioid analgesics
    • Topical preparations, including capsaicin and nitroglycerin for children and adults and lidocaine patch for adults, help control neuropathic pain in some patients r52
      • In children, consider these preparations as first line therapy, before or in concert with oral medications r7
      • In adults, these preparations are generally used when response to oral medications is inadequate, or when minimizing risks of polypharmacy in elderly patientsr53
        • Capsaicin r54
          • Low-dose (0.025% or 0.075%) cream applied directly over painful area has questionable efficacy in adults; however, 8% patch (applied to affected area for 1 hour once) has demonstrated long-term efficacy (about 12 weeks) for diabetic neuropathic pain in adultsr56, and a network meta-analysis comparing data from trials on capsaicin with that of studies on various oral agents (eg, antidepressants, anticonvulsants) indicates that high-dose capsaicin may have similar efficacyr57r55
            • Patch may be reapplied every 12 weeks, if needed r56
            • 27% of patients who used patch in 1 study showed significant improvement r56
            • Patch requires use of local anesthetic before placement to control burning pain from skin irritation r56
            • There are concerns that capsaicin may alter underlying neurophysiology and increase the risk for ulceration r48
          • Capsaicin cream (0.025%, 0.075%) has reported efficacy in children, although tolerability is an issue due to local irritation r7
        • Nitroglycerin r55
          • Nitroglycerin spray (childrenr7 and adults), applied over affected area, and patchesr58 (adults) or transdermal ointment, applied to a hairless area of skin, have demonstrated efficacy; pain is significantly reduced in up to 70% of patients, although adverse effects (primarily headache) limit use of nitroglycerinr58
        • Lidocaine r54r55
          • Lidocaine 5% patch,r59 applied over affected area, is effective for adults with painful diabetic peripheral neuropathy (65% response rater60)
            • Most useful for focal, more localized pain
    • Oral medications r6r61
      • Adults
        • First line antidepressants found effective for relief of neuropathic pain:
          • Venlafaxine r62
          • Duloxetine r62
          • Tricyclic antidepressant (eg, amitriptyline)
        • Anticonvulsant analgesics are also appropriate first line agents r62
          • Pregabalin (has strongest evidence for efficacy)
          • Gabapentin
        • Can add opioid analgesics to manage neuropathic pain if other treatments are inadequate (third line therapy)
          • Tramadol and oxycodone in long-acting form have the most documented efficacy in neuropathic pain treatment r63
          • Tapentadol extended-release has been approved to treat neuropathic pain r6r64
        • Studies are underway to determine whether there are biologic or genomic markers that can be used to select the medication(s) most likely to benefit an individual patient r47
      • Children
        • NSAIDs may be useful in children, with or without pain-modulating medications (ie, antidepressants, anticonvulsant analgesics); usually, avoid opioids in children r7
    • Antioxidant therapy with α-lipoic acid may improve symptoms of diabetic peripheral neuropathy r65
      • Although current evidence is insufficient to support or disprove its usefulness, some clinicians add oral therapy with α-lipoic acid to the treatment regimen when other therapies do not adequately control symptoms r66
    • Actovegin, an antioxidant derived from calf blood, has been shown to improve symptoms in painful diabetic neuropathy; however, further investigation is required to establish any place in therapy r61r65
    • A Cochrane review of pregabalin for treatment of neuropathic pain found the following results among patients with painful diabetic neuropathy: r67
      • At a dose of 300 mg, 47% experienced at least a 30% reduction in pain, compared with 42% receiving placebo; 31% had at least 50% reduction in intensity, compared with 24% receiving placebo (moderate-quality evidence)
      • At a dose of 600 mg, 63% experienced at least a 30% reduction in pain, compared with 52% receiving placebo; 41% had at least 50% reduction in intensity, compared with 28% receiving placebo (low-quality evidence)
    • A Cochrane review of gabapentin for neuropathic pain found that among patients with painful diabetic neuropathy, a dose of 1200 mg/day: r68
      • 52% experienced at least 30% reduction in pain intensity, compared with 37% with placebo (moderate-quality evidence)
      • 38% experienced at least 50% reduction, compared with 21% with placebo (moderate-quality evidence)
    • A systematic review evaluating various classes of pharmacologic treatments for diabetic neuropathic pain reached the following conclusions: r69
      • Duloxetine and venlafaxine are more effective than placebo (moderate-quality evidence)
      • Pregabalin, oxcarbazepine, tricyclic antidepressants, atypical opioids (tramadol, tapentadol) and botulinum toxin are more effective than placebo (low-quality evidence)
        • Pooled subject numbers were less than 100 for studies of both botulinum toxin and tricyclic antidepressants
      • Gabapentin, typical opioids, low-dose topical capsaicin (0.025%, 0.075%), dextromethorphan, and mexiletine were found to be no more effective than placebo (low-quality evidence)
      • There was insufficient evidence to compare drugs
    • A study comparing the combination of duloxetine and pregabalin with high-dose monotherapy of each agent did not find a significant difference between combination therapy and monotherapy at the doses prescribed, although a subsequent analysis indicated that the subgroup with mild to moderate pain (versus severe pain) may derive more benefit from the combination r48
  • Foot care r70
    • Perform clinical foot examinations to look for ulcers or deformities
    • Cold water immersion may relieve pain in a neuropathic foot by reducing arteriovenous shunting caused by the neuropathy r1

Acute sensory neuropathy r4

  • Provide adequate treatment of neuropathic pain as per chronic distal sensory polyneuropathy

In focal neuropathies, including cranial nerve palsy, the disease is self-limited r45

  • Consider analgesic therapy for neuropathic pain, especially with a radiculoplexus neuropathy, which is associated with severe pain
  • Short course of a corticosteroid may be helpful when treating facial neuropathy r10
  • IV corticosteroids and other immune therapies (eg, IV immunoglobulin) have been used to treat radiculoplexus neuropathies; however, evidence-based therapy has not been established
  • Patients with cranial nerve palsies involving eye movements may require surgery to reposition or transpose extraocular muscles r10

Drug therapy c231

  • Antidepressant r6c232c233
    • Venlafaxine c234c235
      • Venlafaxine Hydrochloride Oral tablet, extended-release; Adults: Initiate at 75 mg PO once daily and titrate to effectiveness and as tolerated. Effective daily dose range: 75 to 225 mg PO once daily. For some patients, it may be desirable to start at 37.5 mg PO once daily for 4 to 7 days to allow adjustment to the medication before increasing to 75 mg PO once daily. According to the American Academy of Neurology treatment guidelines, venlafaxine is probably effective and should be considered for the treatment of painful diabetic neuropathy (level B evidence). The recommendation is based on several trials showing improvements in Visual Analog Scale (VAS) and severity of pain scores compared to placebo, or when combined with other accepted therapies (e.g., gabapentin).
    • Duloxetine c236c237
      • Duloxetine Oral capsule, gastro-resistant pellets; Adults: 60 mg PO once daily is the initial and target dose. A lower starting dose may be more appropriate in some patients (e.g., renal dysfunction).
    • Amitriptyline c238c239
      • Amitriptyline Hydrochloride Oral tablet; Children and Adolescents 11 years and older: Initially, 0.1 mg/kg/dose PO at bedtime; titrate as tolerated if needed over 2 to 3 weeks to 0.5 to 2 mg/kg/dose at bedtime r71
      • Amitriptyline Hydrochloride Oral tablet; Adults: Initially, 25 mg PO given once daily 1 to 2 hours before bedtime. Titrate in 10 mg to 25 mg increments once or twice a week, if needed, until pain is controlled or side effects are limiting. Per the American Academy of Neurology (AAN) a dosage range of 25 mg to 100 mg/day is probably effective in lessening the pain of peripheral diabetic neuropathy.
    • Imipramine c240c241
      • Imipramine Hydrochloride Oral tablet; Children and Adolescents 6 years of age and older: Initially, 0.2 to 0.4 mg/kg/dose PO at bedtime; titrate if needed by increasing by 50% every 2 to 3 days, with a maximum of 3 mg/kg/dose at bedtime r71
        • Manufacturer recommends not exceeding 2.5 mg/kg/day; ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount r72
      • Imipramine Hydrochloride Oral tablet; Adults: In a clinical trial, patients received 50 mg PO once daily at bedtime for 1 week; daily dose was titrated by 50 mg increments on a weekly basis. Other regimens have titrated daily dosage by 25 mg increments once weekly. Titrate to efficacy and tolerance. Max: 150 mg PO once daily. The American Academy of Neurology guidelines do not support or refute the use of imipramine for the treatment of painful diabetic neuropathy due to inadequate or conflicting data.
  • Anticonvulsant r6c242c243
    • Pregabalin c244c245
      • Pregabalin Oral capsule; Adults: 50 mg PO 3 times daily, initially. May increase dose to 100 mg PO 3 times daily after 1 week based on efficacy and tolerability.
      • Titrate dose to effect
    • Gabapentin c246c247
      • Gabapentin Oral solution; Children and Adolescents: Day 1: give 5 mg/kg/dose (Max: 300 mg/dose) PO at bedtime; Day 2: give 5 mg/kg/dose (Max: 300 mg/dose) PO twice daily; Day 3: give 5 mg/kg/dose (Max: 300 mg/dose) PO 3 times daily, then titrate dose to effect, ranging from 8 to 35 mg/kg/day, in 3 divided doses. Max: 3,600 mg/day r71
      • Gabapentin Oral capsule; Adults: Initially, 300 mg PO three times per day. Titrate dosage based on clinical response and drug tolerance up to a maximum of 3600 mg/day PO, given in divided doses. In clinical trials, a mean effective and tolerated daily dosage of approximately 1500 mg/day, in divided doses, has been reported. The American Academy of Neurology considers gabapentin probably effective for the treatment of painful diabetic neuropathy. The guideline stance is based on one higher quality trial where gabapentin-treated patients' mean daily pain score was significantly lower (p < 0.001) than placebo. Additional statistically significant differences favoring gabapentin were observed in secondary measures of pain and with measures of quality of life. Published randomized, controlled trials and meta-analyses suggest that gabapentin is efficacious for the treatment of PDN and has a favorable safety profile.
    • Carbamazepine c248c249
      • Carbamazepine Oral tablet; Adults: Initially, 100 mg PO twice daily. Titrate dose to 600 to 800 mg/day or until side effects are intolerable.
  • Opioid analgesic r6
    • Tramadol c250c251
      • Tramadol Hydrochloride Oral tablet; Adults: 50 mg/day PO, initially. Titrate by 50 mg/day every 3 days up to 200 mg/day in divided doses. Further increase by 50 mg/day if needed to obtain optimal pain relief. Max: 400 mg/day. May titrate more rapidly if pain relief is inadequate at any time.
    • Oxycodone c252c253
      • Oxycodone Hydrochloride Oral tablet, extended-release; Adults: 10 mg PO every 12 hours initially. Titrate dosage every 2 to 7 days up to a maximum of 120 mg/day PO, given in divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The American Academy of Neurology guidelines consider extended-release oxycodone as probably effective in lessening the pain of diabetic neuropathy.
    • Tapentadol extended-release c254c255
      • Tapentadol Oral tablet, extended-release; Adults: Initially, 50 mg PO twice daily. Titrate dose by no more than 50 mg/dose twice daily every 3 days within the range of 100 to 250 mg PO twice daily. Max: 500 mg/day. Consider lower doses in geriatric patients.
  • Antioxidant
    • Alpha-lipoic acid r73c256c257
      • Alpha-Lipoic Acid Oral Capsule; Adults: 600 mg PO once daily for 5 weeks r73
  • Topical preparations r74
    • Capsaicin r56c258c259
      • Topical cream
        • Capsaicin Topical cream; Adults, Adolescents, and Children 10 years and Older: Apply 2 to 4 times daily.
      • Transdermal patch
        • Capsaicin Medicated topical patch; Adults: Apply up to 4 patches for 60 minutes every 3 months PRN.
    • Lidocaine c260
      • Lidocaine Transdermal patch - 24 hour; Adults: Optimal dosage is not established. Apply up to 4 patches topically to the most painful area. (Max recommended by manufacturer: 3 patches to the most painful area). Wear for up to 12 hours within a 24-hour period; some studies allowed patches to remain in place for up to 18 hours. American Academy of Neurology clinical practice guidelines consider the lidocaine patch as possibly effective in lessening the pain of diabetic neuropathy; use as a treatment option may be considered.
    • Nitroglycerin c261c262
      • Transdermal patch
        • Nitroglycerin Transdermal patch - 24 hour; Adults: 1 transdermal patch (0.2 mg/hour), applied topically every 24 hours. To prevent tolerance, leave patch on for 12 to 14 hours, then remove for 10 to 12 hours before applying next patch. Rotate application site daily to reduce local irritation r58
      • Topical sprays
        • Off-label indication
        • Nitroglycerin Sublingual/Translingual spray (used topically); Adults: Apply 1 metered spray (400 mcg) to dorsum of both feet at bedtime r75
        • Isosorbide dinitrate spray; Adults: Apply 1 metered spray (30 mg) to dorsum of both feet at bedtime r76
          • Requires special compound
      • Topical ointment
        • Nitroglycerin (glyceryl trinitrate) 2% Topical ointment; Adults: Apply to 1 to 2 inches of skin every 4 to 8 hours; suspending use for 8 hours daily is recommended to avoid tolerance r55

Nondrug and supportive care

  • Foot care r77r78c263
    • Regular foot care and prompt attention to foot lesions is essential
    • Advise daily self-inspection, regular skin cleansing, and moisturizing, but avoidance of self-treatment of foot abnormalities
    • Recommend protection of feet, including supportive, comfortable, well broken-in footwear; proper nail cutting; and avoidance of walking barefoot
  • Use of a bed cradle to hold sheets off of feet or wearing silk pajamas may reduce allodynia r1
  • Percutaneous nerve stimulation, 3 to 4 times weekly, has evidence of efficacy; consider it for treatment of painful diabetic neuropathy r74c264
  • Dietary change may reduce neuropathy symptoms, although no consensus has been reached on a specific treatment diet
    • In general, a diet that emphasizes nonstarchy vegetables and minimizes added sugar, refined grains, and highly processed foods is recommended r49r50c265c266
    • Low-fat, plant-based (vegetarian) diet has been shown to improve symptoms of painful diabetic neuropathy r79
  • Regular exercise c267
    • At least 150 minutes of moderate to vigorous aerobic exercise weekly is recommended for most patients with diabetes r80
      • Associated with nerve fiber regeneration in patients with type 2 diabetes with neuropathy r81
      • Patients with peripheral neuropathy should wear proper footwear and examine feet daily; advise to perform non–weight-bearing exercise in presence of foot injury or open sore r80

Comorbidities c268

Special populations

  • Pregnancy
    • Most medications indicated or commonly used for diabetic neuropathy are not appropriate during pregnancy r82
    • Treatment of neuropathy in pregnancy is limited to α-lipoic acid, judicious use of common analgesics and supportive, nondrug approaches, as well as establishing and maintaining glycemic control r82

Monitoring

  • Patients with diabetic peripheral neuropathy require regular monitoring, at least annually, for the development of neuropathic complications (eg, Charcot foot, ulcerations) as part of typical diabetic monitoring (eg, glycemic control, medication management, comorbidity management)
    • International Working Group on the Diabetic Foot recommends: r78
      • Evaluation (focus on feet and lower extremities) every 6 to 12 months for patients with loss of protective sensation
      • Evaluation every 3 to 6 months for patients with loss of protective sensation and with peripheral artery disease and/or a foot deformity
      • Evaluation every 1 to 3 months for patients with loss of protective sensation and history of foot ulceration, end stage renal failure, or lower extremity amputation
    • American Diabetes Association recommends at least annual evaluation for diabetic peripheral neuropathy including: r83
      • Inspection of the skin
        • Perform at every visit for patients with known sensory loss or previous ulceration or amputation
      • Examination for deformities
      • Assessment of either temperature or pinprick sensation, assessment of vibration sensation using 128-Hz tuning fork, and 10-g monofilament sensation testing
      • Assessment of pulses in legs and feet, with follow-up ankle-brachial index if pedal pulses are reduced or nonpalpable
    • Up to 50% of patients with diabetic peripheral neuropathy are asymptomatic and are consequently at greater risk of injuries, especially to their feet r2

Complications and Prognosis

Complications

  • Foot ulcers c269d8
    • Lifetime risk of developing foot ulcers is approximately 15% in patients with diabetes r84
    • More than 7% of all patients with diabetes will develop 1 or more ulcers r84
  • Amputation of injured or damaged extremities, usually feet c270
    • Approximately 5 amputations per 1000 patients with diabetes r84
    • The majority of foot or toe amputations follow foot ulcer or injury
    • One multicenter series demonstrated almost 30% of patients with neuropathic diabetic foot ulcers require amputation r85
  • Charcot joint (ie, neuropathic arthropathy) is chronic progressive joint degeneration, frequently reported in the foot c271
    • 0.2% incidence in all patients with diabetes, but 29% in patients diagnosed with peripheral neuropathy (ie, diabetic distal sensory polyneuropathy) r86

Prognosis

  • Symptoms of acute sensory neuropathy typically resolve in less than a year, although some patients experience residual distal paresthesiasr16r14
  • Chronic sensorimotor neuropathy is a lifelong condition
  • Overall prognosis of radiculoplexus neuropathies is fair to good; symptoms improve over several months, but may not completely resolve r87
  • Prognosis for focal diabetic neuropathies is generally good r10
    • Extraocular palsies generally resolve over time
    • Facial palsy prognosis relates to severity of the palsy
      • 85% of patients recover normal function within 3 weeks, and the other 15% recover over 3 to 5 months; sequelae are severe in 4%, mild in 13%, and slight in 12% of patients

Screening and Prevention

Screening

At-risk populations

  • Patients with diabetes mellitus r6

Screening tests

  • Screen all patients with diabetes as follows: r83
    • Distal symmetrical polyneuropathy: use neurologic testing, including pinprick, temperature, vibration (128-Hz tuning fork), 10-g monofilament pressure sensation at large toe, and ankle reflexes r29r83c272c273c274
      • Accuracy of monofilament testing has been widely studied, with varying results. A recent systematic review found pooled sensitivity and specificity of 0.53 and 0.88, respectively, compared with nerve conduction studies r88
      • Use of more than 1 test increases sensitivity to more than 87% r28
    • Start screening at diagnosis of type 2 diabetes and continue at least annually thereafter
    • Start screening 5 years after diagnosis of type 1 diabetes and continue at least annually thereafter

Prevention

  • Glycemic control r46c275
    • Risk of peripheral neuropathy (ie, chronic sensorimotor neuropathy) is dramatically reduced in patients with type 1 diabetes who have enhanced glucose control (78% relative risk reduction with near-normal glycemia) r6
    • Risk of peripheral neuropathy is modestly reduced in patients with type 2 diabetes who have enhanced glucose control (5%-9% relative risk reduction) r6
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