Standard nerve conduction studies (NCS) allow the physician to directly measure large fiber motor and sensory nerve function. These fibers are involved in position and vibration sensation, deep tendon reflex function, and muscle strength. Small diameter fibers, which convey pain and temperature sensation and autonomic function, are not routinely studied.
Thus, in diabetes where large fiber nerve function is often impaired, NCS are ideally suited to define the extent and severity of disease. Motor and sensory nerves are tested individually with NCS but the underlying principle for each is similar. A nerve is stimulated at one or more sites along its course and a recording is made at a second site. If a motor nerve is being studied, the recording electrode is placed over a muscle which the nerve supplies. Sensory nerves, unlike motor nerves, have no end organ from which a recording can easily be made; both the recording and stimulating electrodes are placed over the nerve at some distance apart.
Electromyography (EMG) complements NCS in the study of peripheral nerve function. Indeed, NCS and
EMG are often performed in tandem and referred together as “an EMG” – as in “get an EMG.” Specifically, EMG is the study of the electrical activity of muscle, performed by means of a needle electrode inserted directly into the muscle. Together with NCS, EMG can distinguish neuropathy from myopathy, localize neuropathic disorders, and quantify and provide prognostic information for nerve and muscle disorders. Electrophysiologic findings in diabetes are well described. When large diameter nerve fibers are affected in diabetic polyneuropathy, NCS reveal decreased evoked response amplitudes of both motor and sensory nerve fibers with mild conduction velocity slowing. As previously discussed, standard NCS are often normal in purely small fiber neuropathy nature, as these smaller fibers are not measurable by these routine studies.
Computers (CASE IV systems) can evaluate small diameter nerve fiber function and, when warranted, patients may be referred to centers where this is available. In most instances, however, this will not be necessary. As a general rule, electrophysiological deficits, when present, should be symmetrical in the context of a polyneuropathy. If the clinical problem is asymmetrical, the NCS will reflect this as well. For example, NCS in peroneal neuropathy at the fibular head causing unilateral foot drop will show abnormalities limited to the peroneal branch of the sciatic nerve, sparing of the tibial nerve, and slowing of peroneal conduction velocity across the fibular head but not in the distal calf. Similarly, ulnar neuropathy at the elbow or median neuropathy at the wrist (carpal tunnel syndrome) will demonstrate slowing localized to the elbow or wrist, respectively. EMG textbooks should be consulted for details in any specific case.
In the setting of sensory symptoms and normal electrodiagnostic studies, a skin biopsy can be performed to investigate for a small fiber neuropathy. In this study, a 3-mm diameter circular “punch” biopsy is obtained from the surface skin of the lateral ankle and proximal thigh. The specimens are immunostained with antibodies against markers expressed by peripheral nerve fibers (such as protein gene product 9.5) and the density of epidermal nerve fibers is determined. Qualitative information (such as the orientation of the nerve fibers or the presence of inflammatory cells or congophilic material) may also be useful. Serial biopsies from the same region have been used in research studies to monitor for interval changes or treatment response. Corneal confocal microscopy is a promising, noninvasive technique that assesses small nerve pathology in vivo.
The twin goals of treatment are to (1) halt or slow progression of the neuropathy by targeting the underlying pathophysiological mechanisms (Table 23.6) and (2) manage the clinical symptoms (Table 23.7).
Table 23.6 Management aimed at underlying pathogenic mechanisms
Lifestyle intervention (diet, exercise, weight loss) – Found to result in improved pain and cutaneous innervations in patients with pre-diabetic neuropathy Glycemic control – Found to reduce clinical and electrophysiologic evidence of neuropathy (particularly in Type 1 DM) Aldose reductase inhibitors – Found to diminish the reduction in motor nerve conduction velocity. Fidarestat and ranirestat in clinical trials. Epalrestat marketed in Japan. Clinical benefits unclear at this time Alpha-lipoic acid – Possible effect in reducing somatic and autonomic neuropathies.
Dose of 600 mg daily is effective and well tolerated Gamma-linoleic acid (or evening primrose oil) – An important constituent of membrane phospholipids. Under investigation. One study found benefit at 480 mg daily Aminoguanidine – Inhibits formation of advanced glycosylation end products. Human trials discontinued secondary to toxicity Human intravenous immunoglobulin – Anecdotal reports of effectiveness in diabetic neuropathy associated with autoimmunity, e.g., DLRPN Steroids (methylprednisolone) – May help pain, but not disability in DLRPN Neurotrophic therapy – Initial positive effects of recombinant human nerve growth factor in sensory neuropathy not borne out in two large multicenter studies
Table 23.7 Treatment options for painful diabetic neuropathy
Agent,Daily dosag, Side effects/remarks
Amitriptyline 25–150 mg
Nortriptyline 25–150 mg
Dry mouth, urinary retention, sedation,
somnolence, postural hypotension
Duloxetine 60–120 mg
Nausea, vomiting; studied in small series; less
effective than TCAs
1. Gabapentin 300–3600 mg (divided in 3–4 doses) NB: renally metabolized; must make adjustment
2. Pregabalin 300–600 mg (divided in 2–3 doses) Dizziness, somnolence, peripheral edema
4. Carbamazepine 200–600 mg
5. Oxcarbazepine 1200–1800 mg (600–900 mg bid) Light-headedness, nausea
6. Topiramate Titrate from 25 mg up to 400 mg.
Typical dose ∼100 mg
Diarrhea, weight loss, somnolence
7. Lamotrigine 200–400 mg Rash, headache; must titrate slowly. Inconsistent
Tramadol (weak opioid) <400 mg Inhibits uptake of monoamines; has low-affinity
binding to mu-opioid receptors
Controlled release oxycodone 10–100 mg (average 40 mg/day) Constipation, cognitive dysfunction
Mexiletine 75–225 mg tid, slow titration Gastrointestinal distress;
Class 1B – antiarrhythmic agent; cardiology
1. Capsaicin cream Capsaicin 0.075% applied qid Inhibits substance P uptake at sensory endings
SSRI = selective serotonin reuptake inhibitors
SSNRI = selective serotonin norepinephrine reuptake inhibitors
Management of Underlying Pathogenic Mechanisms
Intensive glycemic control has been shown to slow the progression of DPN in patients with type 1 DM; however, the results in patients with type 2 DM have been variable with intensive therapy resulting in either having partial or no effect. The DCCT showed a 50% reduction in the prevalence rates for clinical or electrophysiologic evidence of neuropathy in patients treated with intensive insulin therapy.1 Pancreatic transplantation resulting in euglycemia has been associated with a gradual improvement of diabetic polyneuropathy. Lifestyle modification with changes in diet, exercise, and weight resulted in cutaneous reinnervation (as determined by serial skin biopsies) and improved pain in one study of 32 patients with pre-diabetic neuropathy.
Alpha-lipoic acid has been shown to diminish oxidative stress, and has been studied in intravenous (600 mg/day for 5 weeks) and oral form (600–2400 mg daily). Recently, a dose of 600 mg daily has been determined to be beneficial and without the side effects noted at higher doses. There is a lack of agreement about the benefits of other treatments that target underlying pathogenic mechanisms. Despite disappointing results to date, there is ongoing interest in the use of aldose reductase inhibitors to prevent excessive sorbitol flux in the nerve. Fidarestat and ranirestat are under investigation, and epalrestat is available in Japan. Ruboxistaurin mesylate has been used as a PKC beta inhibitor in phase II studies with some benefit noted in a subset of patients with less severe DPN.63 Gamma-linolenic acid may have some benefit at a dose of 480 mg/day. As discussed, intravenous methylprednisolone may improve pain symptoms, but not disability in DLRPN, and there are only anecdotal reports of benefit with intravenous immunoglobulin.
Management of Neuropathy Symptoms
Current medical management of neuropathic pain includes antidepressants, anticonvulsant medications, opioids, and topical agents. Currently, only duloxetine and pregabalin have FDA approval for management of diabetic neuropathy pain. Careful consideration of comorbidities or risk factors should be given when selecting a therapeutic agent. The treatments are summarized in Table 23.7.
Tricyclic antidepressants (TCAs) are effective in selected populations, but are less well tolerated and not appropriate for patients with cardiac morbidities. Selective serotonin reuptake inhibitors (SSRIs), such as citalopram and paroxetine, have limited effectiveness, while selective serotonin norepinephrine reuptake inhibitors (SSNRIs), such as duloxetine, have been shown to be helpful. Gabapentin is at least equally effective as TCAs and is often a first-line treatment given its safer side effect profile. Pregabalin is a more specific alpha-2-gamma ligand with a higher binding affinity and simpler dose titration schedule when compared with gabapentin.
There is limited data on the role of carbamazepine for diabetic neuropathy pain and its derivative oxcarbazepine has shown only marginal and inconsistent results. Lamotrigine and topiramate have also produced mixed results, and are not considered first-line therapy. Opioids have a limited role in diabetic neuropathy pain management. One study found benefit with controlledrelease oxycodone versus placebo in a 6-week trial. A role for combination therapy with morphine and gabapentin has also been suggested. Non-pharmacologic approaches, such as transcutaneous electrical nerve stimulation (TENS) and highfrequency muscle stimulation (HFMS) have been investigated mostly in uncontrolled studies. Frequencymodulated electromagnetic nerve stimulation (FREMS) resulted in pain reduction when compared to placebo stimulation.
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