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b. Isolated peripheral neuropathy - Involvement of the distribution of only one nerve ("mononeuropathy") or of several nerves ("mononeuropathy multiplex") is characterized by sudden onset with subsequent recovery of all or most of the function. This neuropathology has been attributed to vascular ischemia or traumatic damage. Cranial and femoral nerves are commonly involved, and motor abnormalities predominate. The patient with cranial nerve involvement usually has diplopia and single third, fourth, or sixth nerve weakness on examination but the pupil is spared. A full recovery of function occurs in 6-12 weeks.

Diabetic amyotrophy presents with onset of severe pain in the front of the thigh. Within a few days or weeks of the onset of pain, weakness and wasting of the quadriceps develops. As the weakness appears, the pain tends to improve. Management includes analgesia and improved diabetes controls. The symptoms improve over 6-18 months.

c. Painful diabetic neuropathy - Hypersensitivity to light touch and occasionally severe "burning" pain, particularly at night, can become physically and emotionally disabling. Amitriptyline, 25-75 mg at bedtime, has been recommended for pain associated with diabetic neuropathy. Dramatic relief has often resulted within 48-72 hours. This rapid response is in contrast to the 2 or 3 weeks required for an antidepressive effect. Patients often attribute the benefit to having a full night's sleep.

Mild to moderate morning drowsiness is a side effect that generally improves with time or can be lessened by giving the medication several hours before bedtime. This drug should not be continued if improvement has not occurred after 5 days of therapy. If amitriptyline's anticholinergic effects are too troublesome, then nortriptyline can be used. Desipramine in doses of 25-150 mg/d seems to have the same efficacy as amitriptyline. Tricyclic antidepressants in combination with the phenothiazine, fluphenazine have been shown in two studies to be efficacious in painful neuropathy, with benefits unrelated to relief of depression. Gabapentin (900-1800 mg/d in three divided doses) has also been shown to be effective in the treatment of painful neuropathy and should be tried if the tricyclic drugs prove ineffective. Pregabalin, a congener of gabapentin, has been shown in an 8-week study to be more effective than placebo in treating painful diabetic peripheral neuropathy.

However, this drug was not compared with an active control. Also because of its abuse potential, it has been categorized as a schedule V controlled substance. Duloxetine a serotonin and norepinephrine reuptake inhibitor, has been approved for the treatment of painful diabetic neuropathy. In clinical trials, this drug reduced the pain sensitivity score by 40-50%. Capsaicin, a topical irritant, has been found to be effective in reducing local nerve pain; it is dispensed as a cream (Zostrix 0.025%, Zostrix-HP 0.075%) to be rubbed into the skin over the painful region two to four times daily. Gloves should be used for application since hand contamination could result in discomfort if the cream comes in contact with eyes or sensitive areas such as the genitalia.

Diabetic neuropathic cachexia is a syndrome characterized by a symmetric peripheral neuropathy associated with profound weight loss (up to 60% of total body weight) and painful dysesthesias affecting the proximal lower limbs, the hands, or the lower trunk. Treatment is usually with insulin and analgesics. The prognosis is generally good, and patients typically recover their baseline weight with resolution of the painful sensory symptoms within 1 year.

2. Autonomic neuropathy - With autonomic neuropathy, there is evidence of postural hypotension, decreased cardiovascular response to Valsalva's maneuver, gastroparesis, alternating bouts of diarrhea (particularly nocturnal) and constipation, inability to empty the bladder, and impotence. Gastroparesis should be considered in type 1 diabetic patients in whom unexpected fluctuations and variability in their blood glucose levels develops after meals. Impotence due to neuropathy differs from psychogenic impotence in that the latter may be intermittent (erections occur under special circumstances), whereas diabetic impotence is usually persistent; aortoiliac occlusive disease may contribute to this problem.

a. Management of autonomic neuropathy - There is no consistently effective treatment for diabetic autonomic neuropathy. Metoclopramide has been of some help in treating diabetic gastroparesis over the short term, but its effectiveness seems to diminish over time. It is a dopamine antagonist that has central antiemetic effects as well as a cholinergic action to facilitate gastric emptying. It can be given intravenously (10 mg three or four times a day, 30 minutes before meals and at bedtime) or orally (20 mg of liquid metoclopramide) before breakfast and dinner.

Drowsiness, restlessness, fatigue, and lassitude are common adverse effects. Tardive dyskinesia and extrapyramidal effects also occur. Because cisapride has caused life-threatening cardiac arrhythmias, including 80 deaths, it has been withdrawn from the market in the United States. Erythromycin appears to bind to motilin receptors in the stomach and has been found to improve gastric emptying in doses of 250 mg three times daily. Gastric electrical stimulation has been reported to improve symptoms and quality of life indices in patients with gastroparesis refractory to pharmacologic therapy. Diarrhea associated with autonomic neuropathy has occasionally responded to broad-spectrum antibiotic therapy, although it often undergoes spontaneous remission.

Refractory diabetic diarrhea is often associated with impaired sphincter control and fecal incontinence. Therapy with loperamide, 4-8 mg daily, or diphenoxylate with atropine, two tablets up to four times a day, may provide relief. In more severe cases, tincture of paregoric or codeine (60-mg tablets) may be required to reduce the frequency of diarrhea and improve the consistency of the stools. Clonidine has been reported to lessen diabetic diarrhea; however, its usefulness is limited by its tendency to lower blood pressure in these patients who already have autonomic neuropathy, resulting in orthostatic hypotension.

Constipation usually responds to stimulant laxatives such as senna. Bethanechol in doses of 10-50 mg three times a day has occasionally improved emptying of the atonic urinary bladder. Catheter decompression of the distended bladder has been reported to improve its function, and considerable benefit has been reported after surgical severing of the internal vesicle sphincter. Mineralocorticoid therapy with fludrocortisone, 0.2-0.3 mg/d, and elastic stockings or pressure suits have reportedly been of some help in patients with orthostatic hypotension occurring as a result of loss of postural reflexes.

b. Management of erectile dysfunction - There are medical, mechanical, and surgical treatments available for treatment of erectile dysfunction. Penile erection depends on relaxation of the smooth muscle in the arteries of the corpus cavernosum, and this is mediated by nitric oxide-induced cyclic 3´,5´-guanosine monophosphate (cGMP) formation. cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors impair the breakdown of cGMP and improve the ability to attain and maintain an erection. Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) have been shown in placebo-controlled clinical trials to improve erections in response to sexual stimulation.

The recommended dose of sildenafil for most patients is one 50-mg tablet taken approximately 1 hour before sexual activity. The peak effect is at 1.5-2 hours, with some effect persisting for 4 hours. Patients with diabetes mellitus using sildenafil reported 50-60% improvement in erectile function. The maximum recommended dose is 100 mg. The recommended doses of both vardenafil and tadalafil is 10 mg. The doses may be increased to 20 mg or decreased to 5 mg based on efficacy and side effects.

Tadalafil has been shown to improve erectile function for up to 36 hours after dosing. In clinical trials, only a few adverse effects have been reported - transient mild headache, flushing, dyspepsia, and some altered color vision. Priapism can occur with these drugs and patients should be advised to seek immediate medical attention if an erection persists for longer than 4 hours. The PDE5 inhibitors potentiate the hypotensive effects of nitrates and their use is contraindicated in patients who are concurrently using organic nitrates in any form. Caution is advised for men who have suffered a heart attack, stroke, or life-threatening arrhythmia within the previous 6 months; men who have resting hypotension or hypertension; and men who have a history of cardiac failure or have unstable angina. Rarely, a decrease in vision or permanent visual loss has been reported after PDE5 inhibitor use.

Intracorporeal injection of vasoactive drugs causes penile engorgement and erection. Drugs most commonly used include papaverine alone, papaverine with phentolamine, and alprostadil (prostaglandin E₁). Alprostadil injections are relatively painless, but careful instruction is essential to prevent local trauma, priapism, and fibrosis. Intraurethral pellets of alprostadil avoid the problem of injection of the drug.

External vacuum therapy (Erec-Aid System) is a nonsurgical treatment consisting of a suction chamber operated by a hand pump that creates a vacuum around the penis. This draws blood into the penis to produce an erection which is maintained by a specially designed tension ring inserted around the base of the penis and which can be kept in place for up to 20-30 minutes. While this method is generally effective, its cumbersome nature limits its appeal.

In view of the recent development of nonsurgical approaches to therapy of erectile dysfunction, resort to surgical implants of penile prostheses is becoming less common.