Pathophysiology of diabetic painful neuropathy


<< Common causes of neuropathic pain include Management of Diabetic Painful Neuropathy >>


Diabetes affects approximately 250 million people world-wide. It is estimated that about 20-25% of these patients have diabetic neuropathy.

There are several types of diabetic neuropathy which include autonomic neuropathy, distal symmetrical neuropathy (painful neuropathy being a component of this), focal neuropathy such as cranial neuropathy; truncal neuropathy and multifocal diabetic neuropathy. Emphasis will be on painful diabetic neuropathy.

The prevalence of diabetic neuropathy increases with time and poor glycemic control. It can, however, rapidly progress in Type 1 diabetes mellitus.

Over 80% of patients with diabetic neuropathy have length dependent diabetic polyneuropathy; symptoms starting distally and progressing proximally. Common symptoms include burning feet, numbness, pins-and-needles and lightning pain. Sensory symptoms may be salient and only be detected by meticulous clinical evaluation and quantitative sensory testing methods.

Neuropathic pain is a common manifestation of length dependent diabetic polyneuropathy.

Studies of histological quantification of intra epidermal nerve fiber (IENF) density have been done. Information from IENF density studies gives a quantitative analysis of un-myelinated epidermal C-fibers that may be a better indicator of state of degeneration of small C-fibers

Genetic factors such as polymorphism of AKRIBI gene (AKRIBI gene codes for aldose reductase.)

 are strongly associated with thermal perception in Type 1 diabetes mellitus. Accumulation of polyols    in nerves have been implicated but not proven since use of aldose reductase inhibitors have been tried in management of painful diabetic neuropathy with minimal success.

Nerve ischemia has also been implicated in pathophysiology of diabetic neuropathy. Circulatory factors noted include micro-angiopathy as exemplified by thickening of basal lamina of endoneural capillaries.

Mitochondrial cytopathy with damage to DNA and cell membrane in sensory nerves in dorsal horn ganglia is a mechanism recently implicated in pathophysiology of diabetic neuropathy. Nerve damage by advanced glycation end products from hyperglycemia and oxidative stress are mechanisms being considered as well.

There are several risk factors for developing diabetic neuropathy.  Two of the main contributing factors are glucose control and duration of diabetes.  Those who have had diabetes for at least 25 years and/or those who have had poor glucose control are at greatest risk of developing symptoms.

Modifiable risk factors include: Glycemic control, obesity, hyperlipidaemia, drugs, toxins, mechanical injury to nerves, lifestyle factors, smoking and diet.

Non-modifiable risk factors include: Duration of Diabetes, age, male gender, family history of neuropathic disease, autoimmune factors, Aldolase reductase gene hyperactivity and ACE genotype.

Mechanical injury can lead to compression of the nerves and cause disorders such as carpal tunnel syndrome and other compression neuropathies.  Autoimmune dysfunction can cause inflammation of the nerves which can aggravate neuropathy.  Inherited traits can increase susceptibility to nerve disease.  Finally, lifestyle factors such as smoking and alcohol abuse can cause blood vessel damage leading to nerve damage.

Clinical assessment of diabetic neuropathy include: High index of suspicion, Pain assessment questionnaires, test sensation, pinprick sensation, Tuning fork (vibration perception), 10 gm monofilament (pressure sensation); note that this is not a very sensitive test and ankle reflexes amongst others. Note that testing for vibration perception and ankle reflexes are more sensitive bedside clinical tests which should be used more frequently.

Consequences of undiagnosed and untreated of diabetic neuropathy include: Half of all limb, amputations are caused by diabetes, 85% of all amputations begin with an ulcer, the risk is 40 times increased in diabetes, and 70% of people die five years following an amputation, 49-85% of amputations can be prevented.


<< Common causes of neuropathic pain include Management of Diabetic Painful Neuropathy >>




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