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 ^r5c1
      • Insidious onset of symptoms is typical ^r5
        • 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) ^r5c3
        • 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 ^r5c4c5
          • 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 ^{r10c6c7c8c9c10}
            • Average pain intensity is moderate ^r10c11
            • 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 ^r10c15
          • 39% of symptomatic patients experience pain in their hands ^r10c16
          • 37% of symptomatic patients experience pain in their calves ^r10c17
        • Hand and foot sensory loss (ie, stocking and glove pattern) ^r11c18
          • 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 ^r12
      • 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)^r13c22
        • 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 ^r13
        • 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) ^r14
  • 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 ^r7c47
      • 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 ^r12
      • 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 stocking distribution; may extend to ankles and involve hands ^c98
    • Test sensation to pinprick with a new (ie, non-reused) safety pin^r15 or Wartenberg wheel^r1
    • Light touch is initially tested with cotton against dorsum of large toe with patient's eyes closed ^r15
    • 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 ^r12
      • For children, the smaller 0.98 g monofilament has been recommended ^r6
      • A biothesiometer, which records vibratory threshold, has been used in place of a tuning fork and may be superior in determining vibratory sensation loss, especially in children ^r16
    • 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 ^r15
  • 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 ^r7c122
  • 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

• 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% ^r17c155

Risk factors and/or associations

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 ^r5
    • 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), and 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 lack 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 ^r24
  • 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)^r6 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 ^r25
      • Modified Neuropathy Disability Score: determines severity of sensory deficits and predicts foot ulcer risk
  • Nerve conduction velocity/EMG testing can generally confirm the diagnosis ^r1
    • This test usually is not necessary in typical diabetic peripheral neuropathy
    • This test is appropriate:
      • When diagnosis is unclear
      • When a different etiology is suspected
      • When features are atypical (eg, rapid onset, motor greater than sensory deficit, asymmetrical presentation), causing suspicion of a rarer diagnosis
• Acute sensory neuropathy ^r14
  • Clinical examination demonstrating findings consistent with a peripheral neuropathy, combined with a recent hemoglobin A1C or blood glucose measurements documenting a drop in hemoglobin A1C (more than 2% within 3 months^r13) or rapid control of blood glucose levels in a patient with type 1 or type 2 diabetes, support the diagnosis of treatment-induced neuropathy^{r14c183c184c185}
  • 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) ^r13
• Cranial neuropathy ^r4
  • Physical examination identifies and defines cranial neuropathy ^c186
• Radiculoplexus neuropathies ^r12
  • 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) ^r26
    • 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 ^r12

Laboratory ^r5

• 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 ^{r12c195c196c197c198c199c200c201c202c203c204c205c206}
  • 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 ^r12
    • 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

Other diagnostic tools

• Michigan Neuropathy Screening Instrument ^r25c208
  • Consists of inspection of feet, ankle reflexes, and vibratory perception threshold at lateral malleolus
    • 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 ^r25
• Modified Neuropathy Disability Score ^r24c209
  • Evaluates ankle reflexes, vibration perception, pinprick awareness, and temperature sensation at big toe ^r12
    • 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 ^r24

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 ^{r12c210c211c212}
    • 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 ^r27c216c217
    • 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 metformin^r28
      • 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 ng/L), which has a sensitivity allowing diagnosis of 97% of patients with true vitamin B₁₂ deficiency ^r27
      • 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 the diagnosis ^r27
      • 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 ^r27
      • Plasma homocysteine level also increases (higher than 15 μmol/L) with vitamin B₁₂ deficiency and may assist in confirming the diagnosis, but it is nonspecific given that it increases in folate deficiency, renal failure, hypothyroidism, and vitamin B₆ deficiency ^r27
  • Tumors (benign or malignant) or masses (neuromas) affecting peripheral nerves ^r29c218c219
    • 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: ^r29
      • 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 ^r30
    • 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 ^r30
      • Antiretroviral agents
      • Cholesterol-lowering statins
      • Anticonvulsants
      • Thalidomide
    • Ethyl alcohol ^r30
      • 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 ^r30
      • Lead ^d3
      • Mercury
      • Arsenic
      • Thallium
      • Germanium
    • Chemotherapy-induced peripheral neuropathy (affects 30%-40% of patients receiving chemotherapy) ^r31
      • 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: ^r32
      • 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 ^r33d4
      • 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 ^r32d5
      • 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 ^r32d6
      • 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 the course of illness) and 2-tiered serologic testing of symptomatic patients (ie, enzyme immunoassay or rarely, indirect immunofluorescence assay, with Western blot to confirm), the standard testing in North America ^r34
        • 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 ^r35
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) ^r36c228
    • 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 ^r37
      • Also, usually not painful; autonomic features are rare ^r36
    • Diagnosed by presence of a monoclonal plasma cell dyscrasia and at least 1 other major criterion for POEMS syndrome ^r36
      • Serum protein electrophoresis and immunofixation are required
      • λ light chain is most usual monoclonal protein
    • Major diagnostic criteria ^r36
      • Presence of both a (sensorimotor) ascending, symmetrical peripheral polyneuropathy and a monoclonal plasma cell dyscrasia
    • Other major diagnostic criteria (1 required) ^r36
      • 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 the diagnosis
          • Serum levels above 1920 pg/mL support the diagnosis
    • Other supportive findings ^r36
      • 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 ^r38c229d7
    • 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 (in mid-30s) in endemic areas or in patients with family history of familial amyloid polyneuropathy (ie, familial case)
      • Late onset (at age 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) ^r38
      • 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: ^r38
      • 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
      • There is eventual involvement of fingers and forearms
      • 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 ^r39
    • Diagnosis in sporadic cases usually requires biopsy to confirm amyloid deposition in tissues: ^r39
      • 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 the 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 the 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-glove distribution pattern; decrease in light touch, proprioception, and vibration
    • Diagnosis is confirmed by:
      • EMG to determine whether the 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

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: ^r40
  • 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)

Drug therapy ^c231

• Antidepressant ^r5c232c233
  • 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; lower dose may be appropriate in patients who cannot tolerate the higher initial dose.
  • 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. ^r58
    • 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 ^r58
      • 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. ^r59
    • 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 ^r5c242c243
  • Pregabalin ^c244c245
    • Pregabalin Oral capsule; Adults: Initially, 50 mg PO 3 times daily; may increase to 100 mg PO 3 times daily in 1 week based on efficacy and tolerability.
  • Gabapentin ^c246c247
    • Gabapentin Oral solution; Children and Adolescents: Day 1: 5 mg/kg/dose (Max: 300 mg/dose) PO at bedtime; Day 2: 5 mg/kg/dose (Max: 300 mg/dose) PO twice daily; Day 3: 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. ^r58
    • 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 ^r5
  • Tramadol ^c250c251
    • Tramadol Hydrochloride Oral tablet; Adults: In one study, the initial dose was 50 mg/day PO, with increases in 50 mg increments every 3 days up to 200 mg/day by Day 10 (i.e., 50 mg PO four times daily). During Days 14 through 28, patients could increase their dose by 50 mg/day to obtain optimal pain relief, not to exceed 400 mg/day in divided doses. A more rapid titration was permitted for inadequate pain relief at any time. The mean effective dose in clinical trials was 210 mg/day, in divided doses. The American Academy of Neurology considers tramadol probably effective in lessening the pain of diabetic neuropathy.
  • 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 ^r60c256c257
    • Alpha Lipoic Acid Oral Capsule; Adults: 600 mg PO once daily for 5 weeks. ^r60
• Topical preparations ^r61
  • Capsaicin ^r48c258c259
    • 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 q3 months PRN.
  • Lidocaine ^c260
    • Lidocaine Medicated topical patch; Adults and Adolescents: Apply to affected area every 8 to 12 hours. Leave patch in place for up to 8 but no more than 12 hours.
  • 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. ^r50
    • 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 ^r62
      • Isosorbide dinitrate spray; Adults: Apply 1 metered spray (30 mg) to dorsum of both feet at bedtime ^r63
        • 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. ^r47

Nondrug and supportive care

• Foot care ^r64r65c263
  • 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 ^r61c264
• Dietary change may reduce neuropathy symptoms, although no consensus has been reached on a specific treatment diet
  • In general, a low-fat diet or Mediterranean diet, which improves glycemic control, is recommended ^r44c265c266
  • Low-fat, plant-based (vegetarian) diet has been shown to improve symptoms of painful diabetic neuropathy ^r66
• Regular exercise ^c267
  • At least 150 minutes of moderate exercise weekly^r67r68 has been recommended for most patients with diabetes
    • It has been associated with nerve fiber regeneration in patients with type 2 diabetes with neuropathy ^r69
    • Those with severe peripheral neuropathy are advised to perform non–weight-bearing exercise ^r67
• Procedures

Comorbidities ^c268

Special populations

• Pregnancy
  • Most medications indicated or commonly used for diabetic neuropathy are not appropriate during pregnancy ^r70
  • 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 ^r70

At-risk populations

• Patients with diabetes mellitus ^r5

Screening tests

• Screen all patients with diabetes as follows: ^r71
  • 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 ^{r25r71c272c273c274}
    • 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 ^r75
    • Use of more than 1 test increases sensitivity to more than 87% ^r24
  • 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