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.
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: [70, 71]
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Tuning fork: 87-99% (sensitivity); 1-19% (specificity)
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Coarse monofilament: 16% (sensitivity); 64% (specificity)
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Fine monofilament: 73% (sensitivity); 87% (specificity)
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Biothesiometer: 61-80% (sensitivity); 64-76% (specificity)
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:
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Complete blood cell count
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Complete metabolic panel (electrolytes and liver function panel)
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Vitamin B-12 and folate levels
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Thyroid function tests
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Erythrocyte sedimentation rate
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C-reactive protein
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Serum protein electrophoresis with immunofixation electrophoresis
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Antinuclear antibody
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Anti-SSA and SSB antibodies
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Rheumatoid factor
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Paraneoplastic antibodies
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Rapid plasma reagin
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Genetic screens
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Hematology screen to check for anemia
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Sequential multiple analysis-7 (SMA7) to check renal function and electrolyte imbalances/complete metabolic panel (CMP)
For more information, see Type 2 Diabetes and TCF7L2.
Electromyography and Nerve Conduction Studies
Nerve conduction studies (NCS) and electromyography (EMG) can document the characteristics of the neuropathy (eg, axonal, demyelinating) and the localization (eg, mononeuropathy versus radiculopathy or distal neuropathy) and, possibly, the severity and even prognosis for morbidity. Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy. These same panels recommend the use of nerve conduction velocity (NCV)/EMG procedures in clinical research studies. An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected.
Conventional nerve conduction velocity studies
Conventional NCV testing includes measurement of the speed of both motor and sensory conduction. The amplitude of the distal response is also measured. The proximal component of conduction can be investigated with H-reflex (S1 root) or F-wave (motor pathways only) response.
Needle electromyography
Needle EMG is performed in the distal muscles in cases of generalized neuropathy and entrapment, in the proximal limb muscles in amyotrophy, and in the paraspinal and limb muscles in suspected radiculopathy. The examiner searches for abnormal spontaneous potentials, voluntary motor unit recruitment, and motor unit configuration. In weak patients, the recruitment characteristics can often help distinguish a neuropathic from a myopathic process.
Nerve conduction study findings
Findings on nerve conduction studies depend on the pattern of nerve damage. Patients with distal symmetrical sensorimotor polyneuropathy from predominant axonal loss have reduced or absent sensory nerve action potentials, especially in the legs. With progression of neuropathy, compound motor action potential amplitudes may also be reduced and abnormalities may be observed in the hands. These changes reflect length-dependent degeneration of large-diameter myelinated nerve fibers.
Conduction velocities are generally within the normal range or only mildly slowed in distal symmetrical polyneuropathy. If conduction velocities are less than 70% of the lower limit of normal, or if conduction block is present, the patient may have superimposed peripheral nerve demyelination in addition to the more typical axonal loss seen in distal symmetrical polyneuropathy. Generalized demyelinating changes on nerve conduction studies should prompt further evaluation for CIDP. Focal slowing of conduction velocity at common sites of entrapment may indicate one of the mononeuropathy syndromes discussed above.
In patients with diabetes, nerve conduction study abnormalities may be found even in the absence of clinical symptoms of polyneuropathy. In a prospective study by Walter-Höliner et al of 38 children and adolescents with type 1 diabetes, clinical neurologic examination revealed diabetic peripheral neuropathy in 13.2% of the group, compared with 31.6% of patients when diagnosis was made using nerve conduction velocity testing. Thus, the latter test demonstrated the widespread existence of subclinical diabetic peripheral neuropathy in the study’s patients. [72]
Electromyographic sampling of distal lower extremity muscles may reveal acute and ongoing denervation in the form of positive sharp waves and fibrillation potentials (spontaneous discharges). Reinnervation changes such as large-amplitude, long-duration, and polyphasic motor unit potentials reflect chronicity. Abnormalities in paraspinal muscles (eg, spontaneous discharges) usually reflect disease in spinal nerve roots.
Some studies have proposed that the severity of electrophysiologic abnormalities not only correlates with symptoms but also predicts the level of morbidity related to DM. Most authors suggest the NCV results to be stable or worsening over time; however, in 1998, Tkac found that the NCV levels could improve with glycemic control. [73]
Electrophysiologic Studies
Electrophysiologic studies are the most sensitive, reliable, and reproducible measures of nerve function. [74] Electrophysiologic findings usually correlate with morphologic changes on nerve biopsy. Common early findings are abnormal nerve conduction studies or reduced variability of heart rate with deep breathing or Valsalva maneuver. Although electrodiagnostic studies can characterize and quantitate nerve dysfunction, they cannot distinguish diabetic neuropathy from neuropathy of other causes.
Composite scores, combining clinical, quantitative sensory, [43] and electrophysiologic measures, are often used in natural history and efficacy studies. Examples include the Neuropathy Impairment Score in the Lower Limbs + 7 and the Michigan Diabetic Neuropathy score. [54, 75]
MRI and CT
Plexus MRI may be helpful to exclude other problems (eg, tumor) in patients with radiculoplexus neuropathy syndromes. For patients who cannot have MRI, CT myelography is an alternative to exclude compressive lesions and other pathology in the spinal canal. In cranial nerve palsies, brain imaging, usually with MRI, is helpful to exclude intracranial aneurysms, compressive lesions, and infarcts.
Nuclear Imaging
Scintigraphic techniques are used to detect and quantify cardiac autonomic neuropathy (for research purposes). Techniques include radiolabeled analogs of norepinephrine, 123I-metaiodobenzylguanidine (MIBG), and 11C-hydroxyephedrine. Adrenergic nerve terminals of the heart actively take up these compounds. Combining this technique with single-photon emission computed tomography (SPECT) scanning allows detection of decreased innervation of the heart.
Doppler Imaging
Laser Doppler can be used to measure skin perfusion. In this test, skin blood flow is measured by continuous laser Doppler assessment in response to several stimuli.
Microdialysis
Microdialysis has been used to study nitric oxide release, which participates in vasodilation of the microvasculature. In this test, probes are inserted into the dermis (with an ISO-NO Mark II oxide meter, a microsensor that measures nitric oxide release from single cells).
Electrocardiography
Electrocardiography may reveal prolongation of the QT interval. This is secondary to imbalance between right and left heart sympathetic innervation. This abnormality is thought to increase risk of arrhythmias. A screening ECG is advisable for patients with longstanding DM.
Nerve and Skin Biopsy
A nerve biopsy can be obtained, typically of the sural nerve, to confirm and help diagnose the neuropathic stage (ie, mild, moderate, severe). However, this is an invasive procedure and carries the risk of producing chronic pain, numbness, and cold insensitivity in the distribution of the sural nerve. Thus, with NCV/EMG and QST available, the sural nerve biopsy is rarely needed for diagnostic purposes any longer.
A skin biopsy can be obtained for research purposes only. Immunohistochemistry is used to quantify the cutaneous nerves to provide a morphologic assessment of diabetic neuropathies. This tool is new for clinical research, and it is used as an endpoint in diabetic neuropathy. The procedure requires only a 3-cm skin biopsy and enables a direct study of small nerve fibers (ie, C-fibers) that produce pain and temperature sensation.
Biopsy rarely is recommended for clinical purposes. Reasons for this move away from biopsies in clinical trials include the invasive nature of the procedure with its attendant risks, discomfort to the patient, cost, problems with reproducibility due to sampling error, and availability of other methods to obtain similar information. This study is performed primarily when the etiology of the neuropathy is in question or in research settings. Several studies have looked at biopsies, mainly of the sural nerve in humans. These studies were performed in advanced neuropathy; vessels were found to be thickened, and nerves were found to have undergone severe damage. Indications of nerve regrowth were small and weak.
Future Approaches
The following additional diagnostic approaches for diabetic neuropathy are currently in use or under intense study. Details of these techniques are beyond the scope of this review.
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Skin punch biopsy/intraepidermal nerve fiber density testing [76] and immunohistochemical staining of peripheral nerves
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Quantitative sensory testing
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Imaging using MRI and ultrasonography
Tables
Fiber Type |
Size |
Modality |
Myelination |
A-alpha (I) |
13-20 micrometers |
Limb proprioception |
Yes |
A-beta (II) |
6-12 micrometers |
Limb proprioception, vibration, pressure |
Yes |
A-delta (III) |
1-5 micrometers |
Mechanical sharp pain |
Yes |
C (IV) |
0.2-1.5 micrometers |
Thermal pain, mechanical burning pain |
No |
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- Glycemic Control
- Diabetic Neuropathic Pain Management
- Pain Control in Pregnancy
- Diabetic Gastroparesis
- Dietary Supplements
- Experimental Therapies
- Treatment of Autonomic Dysfunction
- Surgical Treatment
- Pancreatic Transplantation
- Rehabilitation
- Complications of Disease
- Consultations
- Long-Term Monitoring
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- Medication
- Medication Summary
- Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
- Analgesics, Topical
- Anticonvulsant
- Antidepressant, Tricyclic
- Antidepressant, Selective Serotonin/norepinephrine Reuptake Inhibitor (SSNRI)
- Antidepressant, Serotonin Reuptake Inhibitor
- Antiarrhythmic Agent, Class I-b
- Prokinetic Agents
- Antidepressant, Tetracyclic
- Synthetic Adrenocortical Steroids
- Cholinergic Agent
- Laxative, Bowel Evacuant
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- Questions & Answers
- Tables
- References
