Definition

Although there are several different types of DPN, this article focuses on the most common type, namely, distal symmetric polyneuropathy (DSPN). The definition of DPN for clinical practice is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.” This definition highlights the important distinction that up to 10% of neuropathies in diabetics can be caused by other things than DPN. There are various risk factors that have been linked with DPN including height, weight, gender, age, disease duration, glycemic control, high blood pressure, tobacco use, alcohol use, and lipids. One of the most interesting of these risk factors is height, specifically tallness. The odds ratio for DPN increases 1.2 for every 10 cm of height, reflecting the length-dependent nature of DPN.

Symptoms

Many of the symptoms of DPN contribute to the cascade that leads to limb loss. Symptoms include pain, weakness, unsteadiness, ataxia, and falls. Some of the most prominent changes occur to sensation. Pain is the most frequently experienced symptom. Pain can be experienced as burning, electrical, deep aching, or stabbing. Often the pain is worse at night. The symptoms are experienced mainly in the feet and lower limbs. When the symptoms get above the ankles or even to the knees, the hands can become involved. Neuropathic sensory changes include the loss of proprioception, pain, and temperature. These changes can increase the risk of trauma, infection, and foot ulceration. Loss of vibration perception places patients at 15 times greater risk of falling.

Unsteadiness was not previously recognized as a feature of DPN. Of late, it has been acknowledged as a legitimate symptom in the literature. Unsteadiness occurs because of changes in lower limb proprioception. Abnormal muscle sensory function also contributes to unsteadiness. This state leads to repetitive trauma and falls that can add to the limb loss cascade. Another cause of falls is “intrinsic minus” muscle wasting in the hands and feet. These changes in the foot lead to unopposed strength in the long toe extensors, resulting in hammertoe deformities. Deformities in the feet increase the risk of ulceration. In addition, poor blood flow from vascular changes compromises wound healing further, increasing the risk of amputation.

Many of the symptoms of DPN can be divided into large fiber versus small fiber. Large fiber changes include weakness, deformities, loss of proprioception, and wasting of small muscles. Small fiber changes include decreased sweating, loss of pain and temperature sensation, dryness of skin, and decreased cutaneous blood flow. All these changes lead to ataxia, falls, fractures, repetitive trauma, deformed joints, ulcerations, and amputations.

As pain is the most common symptom, it is worth further exploration. Many words have been used to describe the variety of sensations experienced by patients with DPN. In contrast, some patients have difficulty putting words to their pain and paresthesias. It is important for clinicians to record patients’ own words regarding their experience. There are several screening questionnaires that can help capture and define the pain experience of patients with DPN, such as the Michigan Neuropathy Screening Instrument, the visual analog scale, and the NeuroQoL (Neuro Quality of Life).

Sensory symptoms can be divided into positive and negative sensory symptoms. Positive symptoms occur in response to some stimulus or spontaneously, whereas negative symptoms are a decreased response to stimuli. Positive symptoms can be further divided into painful and nonpainful. Examples of nonpainful positive sensory symptoms are descriptors such as stiff, thick, or asleep. A descriptor such as prickling appears in both the painful and nonpainful lists. Painful words include squeezing, throbbing, and freezing. Negative symptoms have been described as numbness or a “dead” feeling. Negative symptoms are easy to measure with Quantitative Sensory Testing (QST); this is not the case with positive symptoms.

For this reason, the natural history of negative symptoms has been studied more. A significant question is whether patients’ symptoms will improve over time. There have been anecdotal reports of patients’ pain symptoms improving or remitting. This remission clinically occurs with worsening sensory changes. One of the limitations of studies looking at this specific issue is that acute and chronic pain syndromes are not always treated separately. Measuring negative symptoms with QST allows researchers to quantify sensory symptoms. In particular, researchers can measure the degree of hypoesthesia with QST. One study showed that type 2 diabetics with hypoesthesia progressed little in the early course of DPN. In patients further in their disease course and experiencing more sensory loss, progression of hypoesthesia was increased.

Signs

Signs of DPN show a symmetric sensory loss to all modalities in a distal to proximal distribution. A study by Perkins and colleagues demonstrated this high degree of symmetry in all the nerves commonly tested in nerve conduction studies except the median nerve. As mentioned before, the sensory loss typically starts to include the hands as the length-dependent neuropathy ascends proximally up the lower limb. Ankle deep tendon reflexes are usually absent or diminished. Sometimes in more severe cases the knee reflexes are also absent. Motor weakness is a less prominent symptom compared with the sensory changes. Intrinsic muscle atrophy occurs commonly in the feet and, in more severe cases, in the hands. More prominent motor signs bring the diagnosis of DPN into question, especially if the motor changes are asymmetric. Physical examination signs of this weakness are often seen on dorsiflexion and plantarflexion weakness. The unsteadiness suffered by DPN patients can manifest as a poor performance on the Rhomberg test, tandem gait, or one-foot stand. Autonomic neuropathy manifests in a distal distribution. Examination may reveal warm, dry skin (without evidence of peripheral vascular disease) or a plantar callus in a pressured area. All these physical examination signs contribute to the diagnosis of DPN.

While tests for DPN are discussed in more depth later, it is worth mentioning the nonpowered, handheld devices that are often used in clinical practice to enhance the neurologic examination. These screening devices are often less sensitive than QST, but are inexpensive, simple, and portable. These devices include the Semmes-Weinstein monofilament test, the tuning fork, and the Neurotip.

The best example is the Semmes-Weinstein monofilament test, which consists of a nylon filament that applies a calibrated degree of pressure on the skin when the monofilament buckles. The main monofilament used is called 5.07 and exerts 10 g of force. The 5.07 is usually assessed at multiple points on the foot. Care must be taken about the type of monofilament used because some studies have identified products that are not correctly calibrated to 10 g of force.

The common tuning fork is 128 Hz. This fork is tested at the apex of the big toe and normally distinguishes vibration. The graduated Rydel-Seiffer tuning fork actually visualizes the vibration intensity using an 8-point scale. This tuning fork correlates accurately with QST. Another device called the Neuropen that has a pin on one side and a 10-g monofilament on the other has also been shown to be sensitive for checking nerve function. These three tools assist in discerning the signs of DPN on physical examination.

Staging

DPN can be further characterized by a 4-staging (0–3) system proposed by Dyck. The staging is based on four tests: Neurology Symptoms Score (NSS), Neurologic Disability Score (NDS), Quantitative Autonomic Function Testing (QAFT), and QST. The NSS allows patients to describe symptoms including sensory, motor, and autonomic changes with an abnormal score being greater than 1. The NDS is based on the neurologic examination. A normal score is greater than 6 and based on sensory, motor, and reflex changes. Autonomic function results are based on heart rate change with deep breathing and are described as normal, borderline, or abnormal. QST uses temperature and vibration sensation tested at the big toe. All these measures synthesize into Stage 0, which is no neuropathy; Stage 1 meaning asymptomatic neuropathy; Stage 2 meaning symptomatic neuropathy; and Stage 3 meaning disabling neuropathy. In Stage 3, there are at least 2 abnormalities on the previously described tests, and evidence of disability on the NDS and NSS.

A complementary staging system adds clinical characteristics to each stage of Dyck’s system. Clinical neuropathy corresponds with Stage 1. In addition, this system divides Stage 1 into 2 categories: chronic painful and acute painful. Chronic painful is characterized by burning, shooting, and stabbing pains that are increased at night, with reduced or absent reflexes, and absent sensation to multiple modalities. Acute painful has the same symptoms as chronic painful but has few signs on examination and is initiated by changes in insulin therapy. Stage 2 corresponds to painless with complete/partial sensory loss. This stage is defined more by what is not present in symptomatology. There is numbness of the feet or no symptoms, no pain with injury, reduced to absent sensation, absent reflexes, and decreased temperature sensation. Finally, Stage 3 corresponds to late complications that include foot ulceration, joint deformity, and limb loss. Boulton and colleagues suggest that this system adds appropriate clinical modifications to Dyck’s staging system ( Table 1 ).

Criteria

The American Academy of Neurology (AAN) has designated five criteria for the diagnosis of DPN. DPN is asymptomatic in many patients and requires multiple tools to diagnose this disease with such prominent complications. The five criteria are symptoms, neurologic examination, electrodiagnostic studies, QST, and autonomic function testing. The AAN recommended that one parameter from each category be tested in the diagnosis of DPN. In clinical practice, two of the five criteria are needed to confirm a diagnosis. Research protocols are more stringent, requiring five out of five categories. The importance of these criteria for the diagnosis of DPN cannot be overemphasized. One study showed that mild DPN was underdiagnosed 62% of the time whereas severe DPN was missed 39% of the time.

Diagnostic Studies

Diagnostic studies including direct biopsy, skin punch biopsy, and QST are reviewed in this section. Studies of more minor importance are discussed together, including magnetic resonance imaging (MRI), confocal corneal microscopy, autonomic testing, and composite measures. The strengths and weaknesses of each test are briefly discussed. Electrodiagnostic studies are discussed in the Section Electrodiagnosis.

Direct biopsy of the nerve has been used to follow the progression of DPN. Direct biopsy is not used routinely for several reasons: it is invasive, can cause sensory deficits, and requires considerable expertise for the analysis. Typically, the sural nerve posterior to the lateral malleolus is sampled. Complications include persistent sensory deficits in the sural distribution and cold intolerance. These complications occur more commonly in diabetics. Direct biopsy of the nerve has mostly been replaced with the skin punch biopsy.

The skin punch biopsy is less invasive, easy, and sensitive. Biopsy technology improved with the discovery of protein gene product 9.5. This gene product is a pan-axonal marker and improves peripheral nerve immunohistologic visualization. The typical skin biopsy only requires a 3- to 4-mm diameter sample, sterile technique, and local anesthesia. This technique can look at small nerve fibers, which are difficult to assess in electrodiagnostic studies. Another advantage with punch biopsies is that because there is little trauma, multiple different biopsies can be done, allowing for the examination, if necessary, of different populations of axons especially along a distal to proximal gradient. Punch biopsy is also a good way to monitor progression of DPN. Even with punch biopsies, expertise is still a limitation because only a few centers have the required experience to analyze the biopsy results.

QST pairs well with electrodiagnostic studies. QST can provide information on small fiber changes that are not reflected on nerve conduction studies. QST tests vibration, thermal, and pain thresholds. QST is particularly good at assessing subclinical neuropathy and marking DPN progression. Sima and colleagues suggest that QST, especially vibration and thermal testing combined, should be the primary screening test for DPN. A reduced vibration threshold has been shown to predict for foot ulceration. Thermal testing shows similar predictions. There are several QST devices that are inexpensive, noninvasive, and specific. One recent study showed that vibratory perception testing (VPT) performed on two different instruments yielded equivalent results. Testing with the device takes about 10 minutes for a session. Trained nonmedical personnel can perform this test. The stimulus can be well controlled and can measure a broad range of intensities. QST can be tested at multiple anatomic sites and can track the distal to proximal gradient of DPN. Finally, there is a plethora of data available on normals.

There are a few disadvantages to QST. One limitation is that QST is only semiobjective: it is affected by a patient’s motivation, attention, age, sex, and use of tobacco or alcohol. This limitation makes QST unsuitable for assessing patients suspected of malingering or those involved in legal proceedings. QST also is not specific to peripheral nerves. Similar to evoked potentials, it assesses the entire neuroaxis. Abnormal results on QST can be due to spinal cord or cortical lesions. In the 2005 review of the literature by England and colleagues, QST was not found to be reproducible enough to be recommended as the primary criterion for diagnosis of DPN.

Additional Studies

There are several other methods of looking at DPN, one of which is peripheral nerve imaging. MRI of the nerve is noninvasive, targets specific areas, and is easily repeatable. The limits include cost and poorly defined sensitivity. Studies of the sural nerve in diabetics with known DPN and even subacute DPN shows increased water content. This finding indicates endoneurial edema, which reflects early changes that will eventually yield electrodiagnostic changes.

Another suggested method is confocal corneal microscopy, consisting in scanning the cornea for the Bowman layer, which is abundant with a nerve plexus. With microscopy it is easy to examine nerve fiber density, length, and branch density. These nerve characteristics can correlate with progression and severity of DPN. Like MRI, confocal corneal microscopy is noninvasive and might serve a more prominent role in the future.

Quantitative autonomic function testing (QAFT) has been around for a long time. The common tests used for diabetes are based on blood pressure and heart rate response to different maneuvers. Specific tests can assess other affected systems including the urinary, gastrointestinal, and sudomotor. QAFT is included as one of five criteria for the diagnosis of DPN. An in-depth discussion of QAFT is beyond the scope of this article.

Composite measures have been developed to integrate all the different tests discussed into the difficult task of diagnosing DPN. There are several different composite measures, the most prominent of which is the Neuropathy Impairment Score in Lower Limbs (NIS-LL). Like the other systems, it provides a single score based on the results of multiple tests. The single score is a percentage of the abnormality. One limitation with relying solely on a composite scoring system is it can mask problems noted on individual tests; another is that composite systems are time consuming in a clinical setting.

Criteria

The American Academy of Neurology (AAN) has designated five criteria for the diagnosis of DPN. DPN is asymptomatic in many patients and requires multiple tools to diagnose this disease with such prominent complications. The five criteria are symptoms, neurologic examination, electrodiagnostic studies, QST, and autonomic function testing. The AAN recommended that one parameter from each category be tested in the diagnosis of DPN. In clinical practice, two of the five criteria are needed to confirm a diagnosis. Research protocols are more stringent, requiring five out of five categories. The importance of these criteria for the diagnosis of DPN cannot be overemphasized. One study showed that mild DPN was underdiagnosed 62% of the time whereas severe DPN was missed 39% of the time.

Diagnostic Studies

Diagnostic studies including direct biopsy, skin punch biopsy, and QST are reviewed in this section. Studies of more minor importance are discussed together, including magnetic resonance imaging (MRI), confocal corneal microscopy, autonomic testing, and composite measures. The strengths and weaknesses of each test are briefly discussed. Electrodiagnostic studies are discussed in the Section Electrodiagnosis.

Direct biopsy of the nerve has been used to follow the progression of DPN. Direct biopsy is not used routinely for several reasons: it is invasive, can cause sensory deficits, and requires considerable expertise for the analysis. Typically, the sural nerve posterior to the lateral malleolus is sampled. Complications include persistent sensory deficits in the sural distribution and cold intolerance. These complications occur more commonly in diabetics. Direct biopsy of the nerve has mostly been replaced with the skin punch biopsy.

The skin punch biopsy is less invasive, easy, and sensitive. Biopsy technology improved with the discovery of protein gene product 9.5. This gene product is a pan-axonal marker and improves peripheral nerve immunohistologic visualization. The typical skin biopsy only requires a 3- to 4-mm diameter sample, sterile technique, and local anesthesia. This technique can look at small nerve fibers, which are difficult to assess in electrodiagnostic studies. Another advantage with punch biopsies is that because there is little trauma, multiple different biopsies can be done, allowing for the examination, if necessary, of different populations of axons especially along a distal to proximal gradient. Punch biopsy is also a good way to monitor progression of DPN. Even with punch biopsies, expertise is still a limitation because only a few centers have the required experience to analyze the biopsy results.

QST pairs well with electrodiagnostic studies. QST can provide information on small fiber changes that are not reflected on nerve conduction studies. QST tests vibration, thermal, and pain thresholds. QST is particularly good at assessing subclinical neuropathy and marking DPN progression. Sima and colleagues suggest that QST, especially vibration and thermal testing combined, should be the primary screening test for DPN. A reduced vibration threshold has been shown to predict for foot ulceration. Thermal testing shows similar predictions. There are several QST devices that are inexpensive, noninvasive, and specific. One recent study showed that vibratory perception testing (VPT) performed on two different instruments yielded equivalent results. Testing with the device takes about 10 minutes for a session. Trained nonmedical personnel can perform this test. The stimulus can be well controlled and can measure a broad range of intensities. QST can be tested at multiple anatomic sites and can track the distal to proximal gradient of DPN. Finally, there is a plethora of data available on normals.

There are a few disadvantages to QST. One limitation is that QST is only semiobjective: it is affected by a patient’s motivation, attention, age, sex, and use of tobacco or alcohol. This limitation makes QST unsuitable for assessing patients suspected of malingering or those involved in legal proceedings. QST also is not specific to peripheral nerves. Similar to evoked potentials, it assesses the entire neuroaxis. Abnormal results on QST can be due to spinal cord or cortical lesions. In the 2005 review of the literature by England and colleagues, QST was not found to be reproducible enough to be recommended as the primary criterion for diagnosis of DPN.

Additional Studies

There are several other methods of looking at DPN, one of which is peripheral nerve imaging. MRI of the nerve is noninvasive, targets specific areas, and is easily repeatable. The limits include cost and poorly defined sensitivity. Studies of the sural nerve in diabetics with known DPN and even subacute DPN shows increased water content. This finding indicates endoneurial edema, which reflects early changes that will eventually yield electrodiagnostic changes.

Another suggested method is confocal corneal microscopy, consisting in scanning the cornea for the Bowman layer, which is abundant with a nerve plexus. With microscopy it is easy to examine nerve fiber density, length, and branch density. These nerve characteristics can correlate with progression and severity of DPN. Like MRI, confocal corneal microscopy is noninvasive and might serve a more prominent role in the future.

Quantitative autonomic function testing (QAFT) has been around for a long time. The common tests used for diabetes are based on blood pressure and heart rate response to different maneuvers. Specific tests can assess other affected systems including the urinary, gastrointestinal, and sudomotor. QAFT is included as one of five criteria for the diagnosis of DPN. An in-depth discussion of QAFT is beyond the scope of this article.

Composite measures have been developed to integrate all the different tests discussed into the difficult task of diagnosing DPN. There are several different composite measures, the most prominent of which is the Neuropathy Impairment Score in Lower Limbs (NIS-LL). Like the other systems, it provides a single score based on the results of multiple tests. The single score is a percentage of the abnormality. One limitation with relying solely on a composite scoring system is it can mask problems noted on individual tests; another is that composite systems are time consuming in a clinical setting.

Purpose

Electrodiagnostic studies have four main purposes: they assess the onset and progression of DPN; evaluate the distribution of a polyneuropathy; rule out other disorders; and serve as an end point in clinical studies to test treatments and pathophysiology.

The importance of establishing the diagnosis and assessing the progression of DPN cannot be overstated. DPN is a disease that often has a long subacute phase and is associated with more than half of all limb amputations. DPN is not a reversible condition except through glycemic control. DPN is a disease that shows a disconnection between the development of symptoms and the severity of the pathology. Nerve conduction studies (NCS) are objective, noninvasive, and reliable measures; they are also sensitive and specific to polyneuropathy. For these reasons, electrophysiologic testing is important for establishing the diagnosis and monitoring the progression of DPN.

Electrophysiologic studies can pinpoint distribution and narrow the differential diagnosis. Electromyography (EMG) and NCS help determine distribution; they differentiate focal from multifocal problems, define symmetry, identify proximal from distal, and demonstrate motor and sensory involvement. NCS can specify the segment of the nerve involved. The tests can also distinguish acute from chronic changes and whether a neuropathy is length dependent. All these factors can help rule out conditions not related to diabetes and define the type of neuropathy involved.

One of the most important roles of electrodiagnosis is to rule out nondiabetic causes of a symmetric polyneuropathy. DPN is a difficult diagnosis to make by itself. There is the added complication that up to 10% of patients diagnosed with DPN have neuropathies from other causes. Electrodiagnostic testing can show whether a patient has chronic inflammatory demyelinating polyneuropathy (CIDP), inflammatory myopathy, motor neuron disease, or other conditions. If DPN shows features of a small fiber polyneuropathy, amyloidosis and lepromatous leprosy should be considered in the differential diagnosis. Amyloidosis is associated with autonomic symptoms, but not leprosy. A nerve biopsy showing nerve thickening can differentiate these two conditions. Vitamin B12 deficiency, paraneoplastic syndrome, and Sjögren’s syndrome can present as a pure sensory neuropathy with large fiber involvement. More motor involvement may indicate CIDP or paraproteinemic neuropathy. A nerve biopsy shows inflammation. It is important to identify these conditions because many of them are more treatable than DPN.

Finally, electrodiagnostic studies have helped elucidate pathophysiology and vet treatments. The pathogenesis of DPN is controversial. The major proposed ideas include immunologic changes, metabolic disturbances, or ischemic damage. What is agreed on is the pattern of structural and neural deficits. DPN is characterized as an axonopathy. The cell body remains intact whereas the distal peripheral axon changes. One change in DPN is the alteration of the transmembrane ion gradient. This change disturbs the transduction of neural activity, causing hyperexcitable firing of the nerve that can lead to positive symptoms such as pain and paresthesias. Demyelination occurs in the later stages of DPN. Wallerian degeneration and other changes add to negative symptoms, such as, numbness and weakness. Results of glycemic control can be reflected in the nerve conduction velocity, a component of NCS. Nerve conduction velocity can change with efficacious therapies such as transplantation. All this information adds value to electrophysiologic tests in the assessment of DPN.

Limitations

There are several limitations to the electrodiagnostic testing that are worth highlighting. A weakness of NCS is that the recordings are only taken at the surface, meaning that only a small fraction of the neural activity is measured. Nerve conduction velocity measures mainly large-diameter, heavily myelinated axons, does not show axonopathy well, and reflects the speed of only the largest myelinated fibers. These tests do not reflect changes in the small fibers either. Perkins argues that this is not such a big weakness. He notes that DPN causes a progressive loss of all nerve fibers. Finally, the decreased availability and discomfort of electrodiagnostic studies limits their utility as a screening test.

Evaluation

The goals of an electrodiagnosis evaluation are simple. First, it is important to identify sensory and motor involvement. A full evaluation localizes changes to the motor neuron, nerve root, axon, neuromuscular junction, or muscle fiber. Second, it is necessary to separate axonal degeneration from demyelination. Axonal lesions show reduced amplitudes, little or no changes in nerve conduction velocity, and neurogenic changes on EMG. Conduction slowing mostly reflects demyelination. Standard NCS includes examination of the motor function of peroneal, tibial, median, and ulnar nerves. The sensory function is measured mainly in the sural, median, ulnar, and radial nerves.

Donofrio and Albers lay out a polyneuropathy protocol in the American Academy of Electromyographers minimonograph. These investigators discuss a standard examination including multiple nerves in the upper and lower extremities, both sides, and distal and proximal places. Severity of the disease helps shape the examination. Patients with mild symptoms need the most sensitive or susceptible nerves to be checked. One study found the plantar and sural sensory nerves showed the first indication of early DPN. Sensory and motor nerve amplitudes decline in a nonlinear, distal to proximal fashion as DPN progresses. It is important to take an individual approach to each electrodiagnostic study in assessing DPN.

Components

The components of electrodiagnostic studies include nerve conduction velocity, sensory and motor amplitudes, EMG, F waves, H reflexes, and somatosensory evoked potentials. NCS can give clues about the underlying pathology. Wallerian degeneration demonstrates small changes in amplitude with no changes in nerve conduction velocity. Axonopathy reflects only mild changes in nerve conduction velocity. Demyelination shows changes in the conduction velocity or latency. Conduction block from focal compression shows a sudden drop in amplitude. Nerve conduction parameters such as nerve conduction velocity have revealed much about the natural history of DPN. Nerve conduction velocity decreases very gradually over time. In the early stages of DPN, the maximal conduction velocity changes 0.5 to 0.7 m/s per year, reflecting the lack of demyelination in the early stages of DPN. The sural nerve changes slightly more than the peroneal nerve. Nerve conduction velocity can detect subclinical deficits in DPN in asymptomatic patients.

Progression of DPN can be followed via slight changes in the amplitude and conduction velocity. Symmetry of the nerve abnormalities has been shown to be very important. A study by Perkins and colleagues suggests that if side-to-side differences are more than 10% in DPN, another disease should be considered. The study also suggests unilateral NCS are adequate for following progression of DPN. Amplitudes can correspond to fiber density, but variability in amplitude measures makes it difficult to use amplitude as an early measure of DPN.

EMG can reveal some clues about the timing of the neural changes. Fibrillation potentials can indicate a more acute process. Absence of fibrillation potentials can be seen in a milder, more chronic neuropathy. Somatosensory evoked potentials, F-wave latencies, and H reflexes can show changes proximally. F waves, especially, are sensitive to accumulated changes along the entire length of the nerve. Changes solely in the distal segment might not be well represented with F-wave latencies.