Diabetic neuropathy

Diabetic neuropathy is a heterogeneous disorder that encompasses a wide range of abnormalities affecting both proximal and distal peripheral sensory and motor nerves, as well as the autonomic nervous system (ANS)

Multiple etiologies of diabetic neuropathy include a metabolic insult to nerve fibers, neurovascular insufficiency, autoimmune damage, and neurohormonal growth factor deficiency. Hyperglycemic activation of the polyol pathway leading to accumulation of sorbitol and potential changes in the NAD:NADH ratio may cause direct neuronal damage and/or decreased nerve blood flow. Activation of protein kinase C induces vasoconstriction and reduces neuronal blood flow. Increased oxidative stress with increased free radical production causes vascular endothelium damage and reduces nitric oxide bioavailability. Excess nitric oxide production may result in formation of peroxynitrite and damage endothelium and neurons, a process referred to as nitrosative stress.

a) Cardiovascular autonomic neuropathy:

Cardiovascular autonomic neuropathy occurs in ~17% of patients with type 1 diabetes and 22% of those with type 2.It is characterised by abnormalities in heart rate control and central and peripheral vascular dynamics.

Clinical features:

1. Orthostatic hypotension, usually due to damage to the efferent sympathetic vasomotor fibers, particularly in the splanchnic vasculature. In addition, there is a decrease in cutaneous, splanchnic and total vascular resistance that occurs in the pathogenesis of this disorder. Patients with orthostatic hypotension typically present with lightheadedness and presyncopal symptoms. Symptoms such as dizziness, weakness, fatigue, visual blurring, and neck pain also may be due to orthostatic hypotension.

2. Exercise intolerance due to impaired sympathetic and parasympathetic responses that normally augment cardiac output and redirect peripheral blood flow to skeletal muscles. Exercise tolerance is also reduced by a reduced ejection fraction, systolic dysfunction, and decreased diastolic filling.

3. Enhanced intraoperative cardiovascular lability,

4. Increased incidence of asymptomatic ischemia, and myocardial infarction. These patients have more chances of silent ischemia. Reduced appreciation for ischemic pain can impair timely recognition of myocardial ischemia or infarction and thereby delay appropriate therapy.The characteristic diurnal variation in the onset of myocardial infarction is altered in diabetic patients, with a lower morning peak and a higher percentage of infarction during evening hours. Mortality rates after a myocardial infarction are also higher for diabetic patients than for nondiabetic patients.

5. Increased heart rate followed by a decrease in heart rate and, ultimately, a fixed heart rate due to progressive dysfunction of the cardiac sympathetic nervous system. Heart rate variability is considered the earliest indicator and most frequent finding in symptomatic cardiovascular autonomic dysfunction. Regional myocardial autonomic denervation and altered vascular responsiveness in diabetic autonomic neuropathy may predispose to malignant arrhythmogenesis and sudden cardiac death.

Tests for diagnosing cardiac autonomic neuropathy:

Ewing et al proposed five simple non-invasive cardiovascular reflex tests -1.Valsalva maneuver

2. Heart rate response to deep breathing,

3. Heart rate response to standing up,

4. Blood pressure response to standing up, and

5. Blood pressure response to sustained handgrip

Today, sensitive and early assessment of cardiovascular autonomic neuropathy is possible by means of noninvasive autonomic function tests, including power spectral analysis of a series of successive R-R intervals (frequency domain analyses).

Treatment :

1. Antioxidant alpha-lipoic acid slows the progression of neuropathy

2. Cardioselective beta blockers restores the parasympathetic sympathetic imbalance by sympathetic inhibition and thus may be helpful in treating orthostatic hypotension.

3. ACE inhibitors like quinapril improves heart rate variability but controversial

4. 9-alpha flurohydrocortisone may be helpful for treating orthostatic hypotension. Treatment is initiated with a 0.1 mg tablet and can be increased to 0.5 mg daily

5. The peripherally acting selective -agonist midodrine is the most widely used of these pressors. Patient sensitivity to this agent varies and the dose should be titrated from 2.5 mg to 10 mg three times a day.

b) Impaired microvascular skin blood flow:

In diabetes, the rhythmic contraction of arterioles and small arteries is disordered.

Defective blood flow in the small capillary circulation is found with decreased responsiveness to mental arithmetic, cold pressor, handgrip, and heating. Impaired microvascular skin blood flow causes:

1. Reduction in the amplitude of vasomotion

2. Premature aging

3. Dry skin, loss of sweating, and the development of fissures and cracks that are portals of entry for microorganisms, leading to infectious ulcers and ultimately gangrene.

4. Increased osteoclastic activity resulting in reduced bone density

c) Gastrointestinal autonomic neuropathy:

Esophageal dysfunction due to vagal neuropathy. Symptoms include heartburn and dysphagia for solids. Diabetic autonomic neuropathy can impair both gastric acid secretion and gastrointestinal motility, causing gastroparesis diabeticorum.

Major clinical features of this disorder are early satiety, anorexia, nausea, vomiting, epigastric discomfort, and bloating. Patients with gastroparesis have emesis of undigested food consumed many hours or even days previously. The finding of retained food in the stomach after an 8- to 12-hour fast in the absence of obstruction is diagnostic of gastroparesis. Gastroparesis is also associated with the development of bezoars. Due to gastroparesis there is disruption between glucose absorption and exogenous insulin administration. This can result in wide swings of glucose levels and unexpected episodes of postprandial hypoglycemia and apparent "brittle diabetes."

Diarrhea and other lower gastrointestinal tract symptoms may also occur. Diabetic diarrhea manifests as a profuse, watery, typically nocturnal diarrhea, which can last for hours or days and frequently alternates with constipation.

Fecal incontinence due to anal sphincter incompetence or reduced rectal sensation is another manifestation of diabetic gastrointestinal neuropathy.

Tests to diagnose:

1. Esophageal dysmotility diagnosed by esophageal motility testing and esophageal scintigraphy.

2. Gastroparesis can be diagnosed by visualising gastric emptying of radionuclide labelled food by scintigraphic imaging.

Treatment:

1. Good diabetic control

2. Small frequent meals

3. Prokinetic agents used to treat diabetic gastropathy are metoclopramide, domperidone, erythromycin, and levosulpiride

4. In case of diabetic diarrhea restriction of soluble fiber and regular effort to move the bowels is indicated. In addition, trials of gluten-free diet, restriction of lactose, cholestyramine, clonidine, somatostatin analog, pancreatic enzyme supplements, and antibiotics such as metronidazole may be indicated.

d) Genitourinary autonomic dysfunction:

Charachterised by:

1. Erectile dysfunction

2. Retrograde ejaculation

3. Neurogenic bladder

Treatment:

Treatment includes psychological counseling, medical treatment, or surgery. Medical treatment may include sildenafil taken at a dose of 50 mg. Sildenafil is a guanine monophosphate type-5 phosphodiesterase inhibitor that enhances blood flow to the corpora cavernosae with sexual stimulation. A lower dosage is needed for individuals with renal failure or liver dysfunction. Tadalafil (20 mg) and vardenafil (20 mg) are also effective in more than 60% of diabetic patients with erectile dysfunction.

e) Sudomotor dysfunction:

Manifests as anhidrosis of the extremities, which may be accompanied by hyperhidrosis in the trunk. Initially, patients display a loss of thermoregulatory sweating in a glove and stocking distribution that, with progression of autonomic neuropathy, extends from the lower to the upper extremities and to the anterior abdomen, conforming to the length dependency of diabetic neuropathy.

f) Hypoglycemic autonomic failure:

The spectrum of reduced counterregulatory hormone responses (in particular epinephrine) and decreased symptom perception of hypoglycemia due to decreased ANS activation after recent antecedent hypoglycemia has been termed "hypoglycemia-induced autonomic failure."45Hypoglycemia-induced autonomic failure leads to a vicious cycle of hypoglycemia unawareness that induces a further decrease in counterregulatory hormone responses to hypoglycemia.