Practice Essentials
Diabetic neuropathy is the most common complication of diabetes mellitus (DM), affecting as many as 50% of patients with type 1 and type 2 DM. Diabetic peripheral neuropathy involves the presence of symptoms or signs of peripheral nerve dysfunction in people with diabetes after other possible causes have been excluded.
Essential update: Screening tools for diabetic neuropathy may lack diagnostic usefulness
In a systematic review of 5 studies of noninvasive screening tools for detecting peripheral neuropathies in pediatric patients with type 1 diabetes, Hirschfeld and colleagues found that the diagnostic utility of the Rydel-Seiffer tuning fork and 10-g Semmes-Weinstein monofilament was low, while that of biothesiometry and a finer (1-g) monofilament was acceptable. Sensitivities and specificities of these screening tools were as follows[1, 2] :
- Tuning fork: 87-99% (sensitivity); 1-19% (specificity)
- Coarse monofilament: 16% (sensitivity); 64% (specificity)
- Fine monofilament: 73% (sensitivity); 87% (specificity)
- Biothesiometer: 61-80% (sensitivity); 64-76% (specificity)
Signs and symptoms
In type 1 DM, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia, whereas in type 2, it may be apparent after only a few years of known poor glycemic control or even at diagnosis. Symptoms include the following:
- Sensory – Negative or positive, diffuse or focal; usually insidious in onset and showing a stocking-and-glove distribution in the distal extremities
- Motor – Distal, proximal, or more focal weakness, sometimes occurring along with sensory neuropathy (sensorimotor neuropathy)
- Autonomic – Neuropathy that may involve the cardiovascular, gastrointestinal, and genitourinary systems and the sweat glands
Physical examination should include the following assessments:
- Peripheral neuropathy testing – Gross light touch and pinprick sensation; vibratory sense; deep tendon reflexes; strength testing and muscle atrophy; dorsal pedal and posterior tibial pulses; skin assessment; Tinel testing; cranial nerve testing
- Autonomic neuropathy testing – Objective evaluation of cardiovagal, adrenergic, and sudomotor function in a specialized autonomic laboratory; may be preceded by bedside screening to assess supine and upright blood pressure and heart rate, with measurement of sinus arrhythmia ratio
Two classification systems for diabetic neuropathy are the Thomas system and the symmetrical-versus-asymmetrical system. The Thomas system (modified) is as follows:
- Hyperglycemic neuropathy
- Generalized symmetrical polyneuropathies
- Sensory neuropathy
- Sensorimotor neuropathy
- Autonomic neuropathy
- Focal and multifocal neuropathies
- Superimposed chronic inflammatory demyelinating polyneuropathy
Distal symmetrical sensorimotor polyneuropathy is commonly defined according to the following 3 key criteria:
- The patient must have diabetes mellitus consistent with a widely accepted definition
- Severity of polyneuropathy should be commensurate with duration and severity of diabetes
- Other causes of sensorimotor polyneuropathy must be excluded
Pure autonomic diabetic neuropathy is rare.
Asymmetrical neuropathies include the following:
- Median neuropathy of the wrist (carpal tunnel syndrome)
- Other single or multiple limb mononeuropathies
- Thoracic radiculoneuropathy
- Lumbosacral radiculoplexus neuropathy
- Cervical radiculoplexus neuropathy
Diabetic polyneuropathy is commonly staged as follows:
- NO – No neuropathy
- N1a – Signs but no symptoms of neuropathy
- N2a – Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic symptoms; patient is able to heel-walk
- N2b – Severe symptomatic diabetic polyneuropathy; patient is unable to heel-walk)
- N3 – Disabling diabetic polyneuropathy
See Clinical Presentation for more detail.
Diagnosis
Laboratory tests that may be helpful include the following:
- Fasting plasma glucose
- Hemoglobin A1c
- Complete blood count
- Complete metabolic panel (electrolytes and liver function panel)
- Vitamin B-12 and folate levels
- Thyroid function tests
- Erythrocyte sedimentation rate
- C-reactive protein
- Serum protein electrophoresis with immunofixation electrophoresis
- Antinuclear antibody
- Anti-SSA and SSB antibodies
- Rheumatoid factor
- Paraneoplastic antibodies
- Rapid plasma reagin
- Genetic screens
- Hematology screen (for anemia)
- Sequential multiple analysis-7 (renal function and electrolyte imbalances)
Other diagnostic modalities that may be considered are as follows:
- Electromyography and nerve conduction velocity testing
- Electrophysiologic studies
- Magnetic resonance imaging
- Computed tomography (including single-photon emission computed tomography)
- Nuclear imaging
- Doppler imaging
- Microdialysis
- Electrocardiography
- Nerve and skin biopsy (now rarely recommended for clinical purposes)
See Workup for more detail.
Management
Key components of the management of diabetic neuropathy include the following:
- Foot care, including regular follow-up, patient education, and referral as appropriate
- Tight, stable glycemic control (most important for slowing progression of neuropathy)
- Pain management (eg, with pregabalin, gabapentin, sodium valproate, dextromethorphan, morphine sulfate, tramadol, oxycodone, duloxetine, topical capsaicin, transdermal lidocaine)
- Treatment of diabetic gastroparesis (eg, with erythromycin, cisapride, metoclopramide, polyethylene glycol 3350, tegaserod [currently available only on an emergency basis])
- Experimental therapies include aldose reductase inhibitors, alpha-lipoic acid, actovegin, and spinal cord stimulators.
Treatment of autonomic dysfunction must address the following:
- Erectile dysfunction
- Orthostatic hypotension
- Gustatory sweating
Surgical treatment may be considered as follows:
- Aggressive debridement or amputation for recalcitrant foot necrosis or infection
- Jejunostomy for intractable gastroparesis
- Implantation of a penile prosthesis for ongoing impotence
- Bracing, special boots, or, in some cases, surgery for Charcot foot
Pancreatic transplantation for diabetes with end-stage renal disease
History
In type 1 diabetes mellitus, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia. Conversely, patients with type 2 diabetes mellitus may present with distal polyneuropathy after only a few years of known poor glycemic control; sometimes, these patients already have neuropathy at the time of diagnosis.
Since diabetic neuropathy can manifest as a wide variety of sensory, motor, and autonomic symptoms, a structured list of symptoms can be used to help screen all diabetic patients for possible neuropathy.
Sensory symptoms
Sensory neuropathy usually is insidious in onset and shows a stocking-and-glove distribution in the distal extremities. Sensory symptoms may be negative or positive, diffuse or focal. Negative sensory symptoms include feelings of numbness or deadness, which patients may describe as being akin to wearing gloves or socks. Loss of balance, especially with the eyes closed, and painless injuries due to loss of sensation are common. Positive symptoms may be described as burning, prickling pain, tingling, electric shock–like feelings, aching, tightness, or hypersensitivity to touch.
Motor symptoms
Motor problems may include distal, proximal, or more focal weakness. In the upper extremities, distal motor symptoms may include impaired fine hand coordination and difficulty with tasks such as opening jars or turning keys. Foot slapping and toe scuffing or frequent tripping may be early symptoms of foot weakness. Symptoms of proximal limb weakness include difficulty climbing up and down stairs, difficulty getting up from a seated or supine position, falls due to the knees giving way, and difficulty raising the arms above the shoulders.
In the most common presentation of diabetic neuropathy with symmetrical sensorimotor symptoms, minor weakness of the toes and feet may be seen; severe weakness is uncommon and should prompt investigation into other causes, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or vasculitis. More severe weakness may be observed in asymmetrical diabetic neuropathy syndromes. Motor neuropathy may occur along with sensory neuropathy (sensorimotor neuropathy).
Autonomic symptoms
Autonomic neuropathy may involve the cardiovascular, gastrointestinal, and genitourinary systems and the sweat glands. Patients with generalized autonomic neuropathies may report ataxia, gait instability, or near syncope/syncope. In addition, autonomic neuropathies have further symptoms that relate to the anatomic site of nerve damage—gastrointestinal, cardiovascular, bladder, or sudomotor.
Gastrointestinal autonomic neuropathy may produce the following symptoms[39] :
- Dysphagia
- Abdominal pain
- Nausea/vomiting
- Malabsorption
- Fecal incontinence
- Diarrhea
- Constipation
Cardiovascular autonomic neuropathy may produce the following symptoms[40] :
- Persistent sinus tachycardia
- Orthostatic hypotension
- Sinus arrhythmia
- Decreased heart variability in response to deep breathing
- Near syncope upon changing positions from recumbent to standing
Bladder neuropathy (which must be differentiated from prostate or spine disorders) may produce the following symptoms:
- Poor urinary stream
- Feeling of incomplete bladder emptying
- Straining to void
Sudomotor neuropathy may produce the following symptoms:
- Heat intolerance
- Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities
Gustatory sweating
Diagnostic Considerations
Establishing the diagnosis of diabetic neuropathy requires careful evaluation, because in 10-26% of diabetic patients with neuropathy, the neuropathy may have another cause.[29, 53, 54, 55, 56]
The differential diagnoses to consider vary with the presentation.
Cranial mononeuropathy includes the following:
- Intracranial aneurysms
- Bell palsy
Thoracoabdominal neuropathy includes the following:
- Herpes zoster
- Spinal tumors
- Myocardial infarction
- Acute cholecystitis
- Acute appendicitis
- Diverticulitis
Lumbosacral radiculoplexopathy includes the following:
- Anterior disk protrusion
- Spinal cord tumors
- Malignant nerve root infiltrations
- Inflammatory neuropathies
Peripheral neuropathy includes the following:
- Pernicious anemia
- Vitamin B-6 intoxication
- Alcoholism
- Uremia
- Chemical toxins
- Nerve entrapment and compression of benign etiology
- Hepatitis
- Idiopathic
- Congenital (various hereditary sensory motor neuropathies)
- Paraneoplastic syndrome
- Syphilis
- HIV/AIDS
- Medication (eg, chemotherapy, isoniazid)
- Spine disease (eg, radiculopathy, stenosis, arteriovenous [AV] fistula)
Cardiovascular autonomic neuropathy (in addition to some listed above) includes the following:
- Myocardial infarction
- Neuropathic arrhythmias (eg, Wolff-Parkinson–White syndrome, sick sinus syndrome)
- Volume depletion
- Drugs
Gastrointestinal neuropathy includes the following:
- Gastrointestinal malignancy
- Peptic ulcer disease
- Postsurgical vagotomy
- Electrolyte imbalance
Bladder dysfunction includes the following:
- Bladder outlet obstruction
- Prostate cancer
- Spinal cauda equine syndrome
Mononeuropathy includes the following:
- Vasculitides
- Acromegaly
- Coagulopathies
- Hypothyroidism
For more information, see Diabetic Lumbosacral Plexopathy.
Differential Diagnoses
- Alcohol (Ethanol) Related Neuropathy
- Amyloid polyneuropathy
- Chronic Inflammatory Demyelinating Polyradiculoneuropathy
- Nutritional Neuropathy
- Sarcoidosis and Neuropathy
- Spinal Cord Tumors
- Thyroid Disease
- Toxic Neuropathy
- Uremic Neuropathy
- Vasculitic Neuropathy
- Vitamin B-12 deficiency
Proceed to Workup
Approach Considerations
Fasting plasma glucose and hemoglobin A1c are important laboratory screening tests for diabetic neuropathy.
Imaging studies rarely help the physician diagnose or manage diabetic neuropathy. However, in the appropriate clinical setting, MRI of the cervical, thoracic, and/or lumbar regions may help exclude another cause for symptoms mimicking diabetic neuropathy.
Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy. An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected.
Hemoglobin A1c and Fasting Plasma Glucose
Hemoglobin A1c and fasting plasma glucose are important laboratory screening tests for diabetic neuropathy. Hemoglobin A1c measurement is useful to assess the adequacy of recent diabetes control; levels are likely to be elevated in patients with diabetic neuropathies. In some cases, especially with asymmetrical syndromes, the severity of the elevation does not always correlate with the severity of the nerve disease.
A 3-hour glucose tolerance test may be more sensitive in borderline cases. A urinalysis is also helpful to screen for nephropathy and proteinuria.
Basic Laboratory Screening Tests
Testing is tailored depending on the clinical presentation. Examples of tests suggested as basic screening tools to exclude common causes of neuropathy other than diabetes include the following:
- Complete blood cell count
- Complete metabolic panel (electrolytes and liver function panel)
- Vitamin B-12 and folate levels
- Thyroid function tests
- Erythrocyte sedimentation rate
- C-reactive protein
- Serum protein electrophoresis with immunofixation electrophoresis
- Antinuclear antibody
- Anti-SSA and SSB antibodies
- Rheumatoid factor
- Paraneoplastic antibodies
- Rapid plasma reagin
- Genetic screens
- Hematology screen to check for anemia
- Sequential multiple analysis-7 (SMA7) to check renal function and electrolyte imbalances
For more information, see Type 2 Diabetes and TCF7L2.