Diagnostic evaluation for suspected diabetes and impaired glucose tolerance. In the case of a patient not known to be diabetic but presenting with a neuropathy, fasting blood sugar and glycosylated hemoglobin levels are often sufficient to make the diagnosis of diabetic neuropathy. If these are negative, an oral glucose tolerance test should be done to evaluate for impaired glucose tolerance (Polydefkis et al 2003). Intraepidermal nerve fiber density assessed by skin punch biopsy (Pittenger et al 2004) or by skin blister (Panoutsopoulou et al 2009) is an emerging technique that is gaining popularity in the diagnosis of small fiber neuropathy and should be included as an endpoint in neuropathy trials. A high index of suspicion is required to diagnose diabetic autonomic neuropathy, and a validated self-reported clinical questionnaire (the Survey of Autonomic Symptoms) improves diagnostic sensitivity (Zilliox et al 2011).
Diagnostic evaluation of diabetic neuropathies. Standard motor and sensory nerve conduction studies and needle electromyographic examination of muscles are the basic techniques used for evaluating the various types of diabetic neuropathies (Perkins and Bril 2003). Because nerve conduction studies and electromyography evaluate the large diameter myelinated fibers only, they can be misleadingly normal in patients with polyneuropathy in whom the involvement is mainly of the small diameter nerve fibers (small fiber neuropathy). Techniques for evaluating that population of peripheral nerve fibers are discussed below.
Sensorimotor and autonomic polyneuropathy. Several diagnostic modalities are available to study nerves in diabetic neuropathy.
Electrodiagnosis. The electrodiagnostic features of diabetic sensorimotor peripheral polyneuropathy are characteristic of a primarily axon loss polyneuropathy. The lower limbs are affected first, so the priority should be for nerve conduction studies to be done there. Because it is usually a symmetrical process, 1 limb can be studied. The tibial and the peroneal motor nerve conduction studies are performed, recalling that the peroneal motor response recording extensor digitorum brevis is prone to focal muscle damage. The sural nerve is preferred over the superficial peroneal sensory nerve for the same reason. Tibial H-reflexes and F waves are useful adjunctive studies. To evaluate if the neuropathy is severe enough to involve the upper limbs, median, ulnar, or radial nerves can be studied. The radial sensory nerve conduction study is preferred because of the propensity for the other nerves to suffer focal nerve entrapment at the elbow or wrist.
Early changes are typically restricted to the lower extremities and consist of 1 or more of these NCS abnormalities: absent H-reflexes, low amplitude or absent sural and superficial peroneal sensory responses, low amplitude tibial and peroneal motor responses, and mild slowing of peroneal and tibial motor distal latencies and conduction velocities. With more advanced disease, the upper extremities become involved. This is often manifested by reduction of the median, ulnar, and radial sensory amplitudes with mild slowing and low or borderline median and ulnar motor amplitudes with mild sensory and motor conduction slowing. In severe diabetic polyneuropathy, there is often complete absence of all routine sensory and motor conduction studies in the legs and absent sensory responses in the hands with very low amplitude median and ulnar motor responses in the upper limbs. The needle electromyography often shows long-duration, high-amplitude, and rapidly recruited motor unit action potentials with or without fibrillation potentials. This is usually symmetrical and worse in the leg muscles distally with a clear distal to proximal gradient.
Quantitative sensory testing. Techniques for detecting small nerve fiber involvement include quantitative sensory testing (Stewart and Freeman 2002). In quantitative sensory testing, graded degrees of warm, cool, or vibration sensations can be applied to the patient's extremities; the thresholds for sensory perception are established and compared with normal values. Temperature sensation is mediated via small diameter nerve fibers, so quantitative sensory testing is a useful complimentary test to nerve conduction studies. Vibration is mediated through large diameter sensory fibers, so testing this modality overlaps with sensory nerve conduction studies. The use of quantitative sensory testing in diabetic neuropathy is specifically reviewed by Chong and Cros (Chong and Cros 2004). Abnormal thresholds for cool and warm sensations may be detected when the nerve conduction studies are normal, confirming the presence of a small fiber or a predominantly small fiber neuropathy. Questions have been raised as to the reproducibility (test-retest reliability) of thermal threshold tests that might limit their use in following the course of neuropathy as in a drug trial study (Valk et al 2000). This does not, however, detract from its use as a diagnostic tool in the patient with neuropathic symptoms and normal nerve conduction studies.
Autonomic testing. Specialized sudomotor evaluation techniques include heart rate variability, quantitative sudomotor axon reflex testing, thermoregulatory sweat testing, and sweat droplet testing (Low 1997). Non-invasive cardiovascular procedures, such as heart rate variability with deep breathing or Valsalva maneuver, are relatively sensitive methods for detecting early cardiovagal denervation. A resting tachycardia and a fixed heart rate on deep breathing and on going from lying to standing can be demonstrated by EKG recordings. Noninvasive recording of beat-beat blood pressure can be done in specialized laboratories (Low 1997; Low 2003). Sudomotor function tests, including thermoregulatory sweat testing and quantitative sudomotor axon reflex test (QSART), may reveal abnormalities. Hemodynamic tilt tests often are valuable when orthostatic hypotension is present.
Several autonomic tests have recently been recommended (Level B) by the American Academy of Neurology for evaluation of patients with distal symmetric polyneuropathy, including patients with diabetic neuropathy (England et al 2009). These include:
Gastrointestinal autonomic dysfunction and atony is assessed with various radiographic techniques, but the easiest is simply to demonstrate the abnormally slow passage of barium through the gut (Malcolm and Camilleri 1999). To accurately define the nature of neurogenic urinary bladder and sphincter dysfunction, a battery of specialized tests is required. Urinary bladder dysfunction can be investigated by quantitating the post-voiding residual urine, which typically is increased in diabetic cystopathy; cystoscopy and urodynamic studies are required to document and quantitate the degree of bladder dysfunction. Male sexual dysfunction, including erectile impotence, can be differentiated from psychogenic impotence with various tests, including penial tumescence studies during REM sleep.
The nerve fibers that mediate sweating undergo distal damage in polyneuropathies. One electrophysiological technique for evaluating these nerve fibers is to test for sympathetic skin responses. This can be done with most standard EMG machines (Shahani et al 1984; Niakan and Harati 1988). The utility of this technique for the diagnosis of diabetic neuropathy and diabetic autonomic neuropathy has been questioned (Bril et al 2000).
Skin biopsy. This is a technique of distal leg skin punch biopsy with quantification of the epidermal nerve fiber density (Herrmann et al 1999; Griffin et al 2001; Kennedy and Wendelschafer-Crabb 2003). This is particularly useful in confirming small fiber neuropathy, diabetic or otherwise (Lauria et al 2010). Intraepidermal nerve fiber density assessing skin blister is likely equivalent to skin punch biopsy (Panoutsopoulou et al 2009).
Cutaneous nerve biopsy. This is rarely indicated in patients with sensorimotor or other diabetic neuropathies. It may be of value in the unusual circumstance when the differential diagnoses of amyloidosis or vasculitis are being considered.
Focal limb neuropathies. Carpal tunnel syndrome, ulnar neuropathies at the elbow, and other focal neuropathies are common in diabetics, often superimposed on the sensorimotor polyneuropathy (Wilbourn 1999). Nerve conduction studies and needle electromyographic examination can be used to evaluate the presence and severity of such focal neuropathies. Useful strategies to distinguish such focal neuropathies from diabetic polyneuropathy include using internal comparison studies in the hand such as the median-ulnar palmar mixed studies, median-ulnar sensory studies recording ring finger, median-radial sensory studies recording thumb, and median-ulnar comparative motor studies recording 2nd lumbrical-interossei (Wilbourn 1999; Ubogu and Benatar 2006). Among these studies, the median-ulnar comparative motor studies recording 2nd lumbrical-interossei is the most useful in patients with moderate or severe diabetic polyneuropathy where the sensory studies are either very low or absent (Ubogu and Benatar 2006).
Proximal diabetic neuropathy. In patients with this type of neuropathy, nerve conduction studies usually show the presence of distal sensorimotor polyneuropathy. No nerve conduction tests are specifically useful for the diagnosis of proximal diabetic neuropathy. More helpful is needle electromyographic examination, which usually shows asymmetric neurogenic abnormalities in proximal muscles most often affecting the quadriceps muscles. These needle electromyographic examination abnormalities may extend as far proximally as the paraspinal muscles. It is important to perform imaging studies of the lumbar spine, the retroperitoneal area, and sometimes the sacrum and pelvis; caution must be used in the diagnosis of compressive radiculopathy in this setting. Cerebrospinal fluid analysis is indicated if there is a suspicion of carcinomatous meningitis producing polyradiculopathy.
Truncal neuropathy. Needle electromyographic examination studies can show neurogenic abnormalities in paraspinal and abdominal muscles at the segmental level of the sensory abnormalities determined clinically. Imaging of the thoracic spine should be considered when the area of sensory symptoms is small, or if there is a lot of pain in the spine itself.
Coexisting chronic inflammatory demyelinating polyneuropathy. Nerve conduction studies and even nerve biopsy unfortunately sometimes fail to distinguish diabetic symmetrical polyneuropathy from chronic inflammatory demyelinating polyneuropathy (Stewart et al 1996). Cerebrospinal fluid analysis for elevated protein levels is not helpful in this situation either, as an elevated protein may be found in diabetics without neuropathy (Stewart et al 1996). Thus, it is the tempo of the symptoms and the positive response to immunotherapy that provide the evidence for chronic inflammatory demyelinating polyneuropathy.