Dr:Moallemy Painful Diabetic Polyneuropathy

INTRODUCTION In the industrialized world, polyneuropathy induced by diabetes mellitus (DM) is one of the most prevalent forms of neuropathy. Diabetic neuropathy is related to the chronicity of diabetes and to the glycemic control. The incidence of DM will probably continue to escalate because of increased risks for obesity. Inadequate treatment of DM in young people can lead to diabetic polyneuropathy within only a few months.

Polyneuropathy occurs to a lesser degree also with the non- insulin dependent form of DM. Diabetic neuropathy can result from a direct toxic effect of glucose on nerve cells. Additionally, the damage of the nerve structures (central and peripheral) is accompanied by a microvascular dysfunction,which damages the vasa nervorum. neuropathy and neuropathic pain occur more often in patients whose diabetes is chronically poorly controlled and who also have other cardiovascular risk factors such as hypertension and—more importantly—hyperlipidemia and especially dyslipidemia(high triglycerides and low high density lipoprotein cholesterol).

various types of diabetic neuropathy

A distal and symmetric peripheral neuropathy is the most frequent form, which can be subdivided depending on the damaged fibers. These can be small and unmyelinated (C fibers) or thicker fibers that are more or less myelinated. Small fiber damage is thought to result in painful symptoms, leading to painful diabetic polyneuropathy (PDP).

DIAGNOSIS A. HISTORY B. PHYSICAL EXAMINATION C. ADDITIONAL TESTS

HISTORY HISTORY More than 80% of the patients with DM-induced polyneuropathy have a distal, symmetric type of this condition. The symptoms usually present initially in the feet and gradually work their way up. This can be explained by the pathophysiological mechanism that the longest nerves are damaged first. This is also termed lengthdependent diabetic polyneuropathy (LDDP). Sensory defects can usually be observed in the hands when the sensation around the knee is affected.

Although there is an interval of a few years between the appearance of DM and the manifestation of LDDP, these symptoms can be the first symptoms of type 2 DM. diminished sensation; burning feet, which may occur particularly during the night and worsen when touched; and the sensation of tingling in the feet. Attacks of shooting pain also occur.

Medical history and a specific physical examination determine the diagnosis. The neurological examination should include at least the following: (1) examination of all qualities of somatosensory function, which should take symmetry and a distal-proximal gradient into account; (2) reflexes; and (3) muscle strength. One of the signs is diminished sensitivity to a pinprick along with reduced temperature sensitivity (ie, sensory examination of the spinothalamic tract). PHYSICAL EXAMINATION

A decrease in proprioception may be manifested as, for example, abnormal sensation of position of the joints (toes, increased risk of falling), reduced pressure sensation,blunted two-point discrimination, or a reduced sense of vibration. Allodynia and hyperpathia can also occur.

ADDITIONAL TESTS Microscopic examination of nerves with diabetic polyneuropathy showed axonal degeneration and demyelination because of the dysfunction of the Schwann cells. This explains the occurrence of a reduction of the axonal conduction velocity and a conduction delay in the electromyogram (EMG), as a result of demyelination and degeneration of the thicker fibers. A “normal” EMG, however, does not rule out LDDP because this examination mainly measures the larger fibers and should therefore be combined with a proper clinical evaluation.

Motor disturbances because of diabetes are very rare. Laser-evoked potentials could possibly have an additional value. Because abnormal vascularization occurs, a so-called micro- angiopathy might also be detected at a microscopic level. inflammatory processes may also play a role in the development of neurological defects. This is then called multifocal diabetic polyneuropathy. The autonomic manifestations in DM may include orthostasis, rhythm disorders, gastroparesis, gastric function disorders, renal function disorders, and pupillary defects.

Autonomic neuropathy may lead to a severe interaction with the pharmacological therapy of neuropathic pain. Finally, defects in the diameter of the spinal cord in DM could be a contributing factor for the occurrence of generalized neurological Defects.

DIFFERENTIAL DIAGNOSIS The presence of DM makes the diagnosis of polyneuropathy resulting from diabetes likely. Further examination for another possible cause of polyneuropathy is required if there are reports of the following alarm symptoms: acute onset, asymmetry, much pain, a particularly proximal condition, considerable motor symptoms,or rapid progression of motor symptoms.

TREATMENT OPTIONS A. CONSERVATIVE MANAGEMENT B. INTERVENTIONAL MANAGEMENT

CONSERVATIVE MANAGEMENT Proper treatment of the underlying DM is essential to prevent the onset of painful symptoms. Spontaneous recovery is rare once the painful symptoms have developed. treatment of PDP is based on the drugs that are commonly used for neuropathic pain,such as anticonvulsants, antidepressants, and opioids. The objectives of the treatment of PDP are to (1) reduce peripheral sensitization,(2) reduce ectopic activity, (3)reduce central sensitization,(4) reduce central facilitation, and (5) increase central inhibition.

Comparison of several pharmacological treatments for PDP indicates that TCAs are the most effective drugs.Their use in a sufficiently high dosage,however, is often limited because of a high frequency of adverse effects. Also, specific contraindications often prevent their use. On the basis of published results, it seems that the selective serotonin and noradrenaline reuptake inhibitors (SNRIs) duloxetine and venlafaxine have a favorable effect on the pain complaints caused by PDP. The SNRIs, however, also have many adverse effects, which frequently cause patients to discontinue the medication prematurely.

Several anticonvulsants were studied in PDP. Duloxetine, pregabalin, and gabapentin seem to have a similar effect on pain in PDP. Carbamazepine is less effective than pregabalin. A limited number of studies have tested the application of local anesthetics in painful diabetic neuropathy The efficacy of 5%lidocaine-medicated plaster treatment was compared with pregabalin in patients with diabetic peripheral neuropathy (DPN) in a two-stage, adaptive,randomized, controlled, open-label, multicenter trial. After 4 weeks, 5% lidocainemedicated plaster treatment was associated with similar levels of analgesia in PDP patients but substantially fewer adverse events than with pregabalin.

The effectiveness of intravenous lidocaine in patients with intractable painful diabetic neuropathy was studied in a small double-blind, placebo-controlled crossover trial of two doses of intravenous lidocaine (5 and 7.5 mg/kg) vs. saline. Infusions were administered in random order over 4 hours at four weekly intervals in 15 patients with painful DPN. This study shows that intravenous lidocaine ameliorates pain in some diabetic participants with intractable neuropathic pain, who have failed to respond to,or are intolerant of, available conventional therapy. A favorable effect of opioid agonists on PDP was demonstrated in three studies. Opioids are frequently used as supplementary therapy together with another pharmacological approach.

Based on a recently published National Institute for Health and Clinical Excellence guidelines, duloxetine is the first-line agent of choice. If duloxetine is contraindicated,treatment should be initiated with amitriptyline. If first-line therapy does not result in sufficient pain relief, treatment should be continued with amitriptyline, pregabalin,or a combination of both. Third-line treatment options include tramadol and topical lidocaine. In refractory cases, intravenous lidocaine infusion may be considered as part of an investigational trial.

INTERVENTIONAL MANAGEMENT Neurostimulation can be considered if an adequate pharmacological treatment does not lead to sufficient pain reduction or it is accompanied by serious adverse effects. there are four studies that specifically investigate the treatment of diabetic polyneuropathy by means of spinal cord stimulation. These studies show that spinal cord stimulation can potentially provide pain alleviation for a longer term in patients with PDP.

COMPLICATIONS OF INTERVENTIONAL MANAGEMENT Complications associated with the device of spinal cord stimulation include lead migration (14%), lead breakage (7%), implanted pulse generator migration (1%),and loss of therapeutic effect/paresthesias. Medical adverse events of spinal cord stimulation include infection or wound breakdown (10%), pain at pulse generator implantation site (12%), and fluid collection at pulse generator implantation site (5%). Infection can be treated with antibiotics and removal of the implant.

Summary of the Evidence for Interventional Management Technique Evaluation Spinal cord stimulation 2 C+

Practice algorithm for the treatment of diabetic polyneuropathy Practice algorithm for the treatment of diabetic polyneuropathy Diabetic polyneuropathy Exclude other causes of neuropathy Conventional medical management of diabetes Optimal pharmacological management with (combination of) anti-neuropathic pain drugs Consider spinal cord stimulation in treatment resistant cases