POLÍTICAS EDUCATIVAS:

The basic neurotrophic factor concept is defined by the hypothesis that trophic proteins are synthesized in target tissues and delivered to the neuronal soma via retrograde transport, where they exert a trophic and survival effect¹³⁰. The abnormalities in the synthesis and availability of these neurotrophic factors have been implicated in the pathogenesis of DSPN. These factors include neurotrophins such as nerve growth factor (NGF), brain – derived neurotrophic factor, neurotrophin 3, and neurotrophin 4/5 IGFS and cytokine – like growth factor^130,131.

44 2.9.9 CHANNELOPATHIES:

There is experimental evidence for changes in sodium channel expression that are associated with pain in diabetic peripheral neuropathy. Allodynia and mechanical hyperalgesia develop within weeks following the onset of hyperglycemia in streptozotocin (STZ) – induced diabetes mellitus. This is associated with a significant upgrading of mRNA and protein for Nav1.3,Nav1.6, and Nav1.9 sodium channels, with a down regulation of Nav1.8 mRNA and protein¹³². Craner and colleagues¹³², demonstrated evidence indicating that dysregulated sodium channel gene transcription contributes to hyper excitability of dorsal root ganglion (DRG) neurons which may produce neuropathic pain after axonal transection. Specifically genes for the following sodium channels were dysregulated: Nav1.3, Nav1.6, Nav1.8, and Nav1.9 . The consequence is that the net result of the upgrading and down grading will contribute to hyper excitability in these cells¹³². Hong and colleagues¹³³, also working in strptozotocin induced diabetes in rats were able to demonstrate that diabetic rats showed a significant reduction in threshold for escape from innocuous mechanical pressure(allodynia), and a reduction in the latency to withdraw from a noxious thermal stimuli.

2: 10 RISK FACTORS FOR DIABETIC PERIPHERAL NEUROPATHY

Since diabetic symmetrical polyneuropathy increases the risk of other complications of diabetes including foot ulcers and amputation⁹³, the identification of risk factors for diabetes peripheral neuropathy may provide a means of identifying

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patients at high risk of lower limb complication, as well as lead to interventions and treatment.

Studies that have attempted to define the risk factors for diabetic peripheral polyneuropathy are inevitably difficult to compare owing to lack of standardized definitions. In a study defining DSPN as presence of pain, and poor nerve conduction, poor glycemic control but not age was identified as a risk factor¹³⁴. Another study, using information on self-reported symptoms of neuropathy (e.g. numbness, tingling sensation), found independent associations between symptoms and longer duration of diabetes mellitus, hypertension, and hyperglycaemia¹³⁵.

The development of DSPN in type 2 diabetes mellitus has been associated strongly with age, duration of disease and poor glycemic control¹³⁶. It has also been associated with potentially modifiable risk factors, such as hypertension, hyperlipidemia, obesity and cigarette smoking¹³⁶.

A Colorado study of neuropathy prevalence defined by the presence of 2 of 3 criteria (pain symptoms, decreased Achilles reflexes, and decreased thermal sense), showed that age, glycohemoglobin levels, insulin use, male sex, and duration of diabetes mellitus, independently increased the risk of developing neuropathy¹³⁷.

Recently other studies have implicated cardiovascular risk factors such as obesity¹³⁸, and triglycerides^139,140, with the development of DSPN. In a cohort of mild to moderate diabetic neuropathy, Wiggine et al¹⁴¹, found that elevated triglycerides

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correlated with myelinated fiber loss independent of disease duration, age, diabetes control, or other variables.

The diabetes control and complications trial. (DCCT) study group working exclusively on type 1 diabetes patients, and defining neuropathy as the presence of three findings (neuropathic symptoms, sensory deficits, or impaired reflexes) in the lower limb in the absence of other known causes of neuropathy, showed an inverse relationship between intensity of treatment and risk of neuropathy¹⁴². Height has been associated with slowed nerve conduction, decreased vibration sense, and abnormal biothesiometry¹⁴³.

2. 11: ASSESSMENT OF DIABETIC PERIPHERAL NEUROPATHY

Though diabetic peripheral neuropathy has long been recognized, no universally accepted standard exists for the diagnosis. Thus the process of diagnosis has undergone quite some evolution from the traditional methods of symptomatology, and the use of hand held instrument, to direct morphological evaluation of whole nerve biopsies¹⁴⁴.

Traditional approaches to the detection of diabetic neuropathy involve clinical assessment of “signs” of sensory deterioration. Unfortunately, this aspect of neurologic examination requires extensive experience, and depends greatly on the expertise of the individual examiner. Although the method yields valid ‘index’ of DSPN quickly, it has two major limitations namely: the rating scales are nominal or at best ordinary , and intra – and inter – rater variability, limits reproducibility and reliability of test results¹⁴⁴.

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Standard electrophysiologic methods have also been used extensively to diagnose and follow the progression of diabetic peripheral neuropathy¹⁴⁵. Furthermore, the whole nerve electrophysiology measures function in the large diameter neurons, and the spectrum of nerve fibers involved in the diabetic peripheral neuropathy include both large heavily myelinated axons and small – diameter, thinly myelinated and unmyelinated fibers that convey information about pain and temperature¹⁴¹. Nerve fiber types may not be uniformly affected in diabetic peripheral neuropathy¹⁴⁶, thus electrophysiology; particularly conduction velocity may provide a poor measure of early dysfunction in some patients¹⁴⁷.

Direct morphologic evaluation of nerves via whole nerve biopsy has been used for diagnosis and evaluation of progression of diabetic neuropathy¹⁴⁸. Considerable progress has been made in the automation and standardization of measurements of fiber density, which may be valuable in multi – center studies¹⁴⁹. However, traditional nerve biopsy is not recommended for routine use in the evaluation of patients with diabetic peripheral neuropathy¹⁵⁰, moreover, it is invasive, requiring considerable expertise, and full fascicular biopsy is associated with long term sensory deficits and other adverse effects, and is therefore not routinely recommended.^150,151.

Skin punch biopsy and immuno – histochemical staining for peripheral nerves offers a sensitive, and less invasive alternative to whole nerve biopsy for morphologic evaluation of peripheral nerve damage in the patients with diabetes mellitus^150,152. Advances in immuno – histochemical techniques, specifically, the development of antibodies to human protein gene product 9.5 (PGP9.5) an antigen present in peripheral

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nerve fiber of all calibers), permit staining of skin – punch biopsies, and evaluation of effects of disease on multiple classes of peripheral nerve axons. Several immuno-histochemical markers are specific for small myelinated and unmyelinated axons, including substance P (SP) and calcitonin gene – related peptide (CGRP). Levels of both SP and CGRP are reduced in skin biopsies from diabetic patients before clinical or neurological evidence of neuropathy¹⁵². Currently few centers have expertise for this procedure and consequently the data base is limited.

2. 11. 1: QUANTITATIVE SENSORY TESTING

Quantitative sensory testing (QST) procedures facilitate early diagnosis and accurate assessment of diabetic neuropathy¹⁵³. Standardized sensory testing instruments, such as the neurothesiometer are used to control and deliver specific stimuli at designated intensities to test sensory thresholds,( defined as the minimum stimulus energy detectable 50% of the time)¹⁵³. QST is noninvasive, and requires about 10min./session, and can be conducted with non-professionals after adequate briefing.

QST is based on precise definition of the stimulus properties ( modality, intensity, spatial and temporal characteristics), analysis of the quality of evoked sensation and quantification of its intensity. In addition to the assessment of sensory thresholds, QST, includes the assessment of sensations evoked by suprathreshold stimuli¹⁵⁴. It provides a parametric measure of sensory function that can target axons of specific fiber diameters. Abnormalities in QST can reflect axonal pathology, or alterations in sensory transduction, and this is of particular interest because recent results show that abnormalities in distal peptide neurotransmitter levels may occur in peripheral nerve

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fiber of diabetic patients before axon loss is detetable¹⁵⁵. Another important and developing strength of QST is that investigators are beginning to document the relations between results obtained with these techniques and other aspects of diabetic neuropathy associated pathology. It has been shown that reduced vibratory threshold is a significant and independent predictor of the development of foot ulcers in diabetic patients, a similar relation has been demonstrated for thermal threshold¹⁵⁵. QST results have their own drawbacks: it is semi objective and results can be influenced by both attention and motivation of the patient. These factors can induce considerable variation during investigational testing. Abnormalities detected by QST are not specific for peripheral neuropathy. Abnormal results from QST can result from spinal cord pathology (e.g. tumors) as well as cortical lesions, thus though sensitive, it is not specific¹⁵³.

2. 11. 2 ELECTRO PHYSIOLOGIC TESTING

Electro physiologic nerve conduction studies are frequently used to assess the frequency and severity of peripheral nerve involvement in patients with diabetes¹⁵⁶. Electrodiagnostic assessments are sensitive, specific, and reproducible measures of the presence and severity of peripheral nerve involvement with diabetes^157, nevertheless, important assumptions and issues must be considered if data are to be meaningfully interpreted and compared with other studies¹⁵⁷. No electrodiagnostic results are specific for diabetic polyneuropathy, however, electrodiagnostic evidence of axonal degeneration, and substantial conduction slowing in the proper clinical setting is suggestive of diabetic polyneuropathy¹⁵⁷. A reduced conduction velocity has a high

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sensitivity but low specificity for diabetic polyneuropathy¹⁵⁸. Studies are typically performed on the upper and lower limbs on motor and sensory nerves. Testing permits evaluation of neural activity in multiple nerves, as well as in both sensory and motor fibers. It also supports the assessment of distal conduction velocity, response amplitudes, long loop latencies, and in select nerves, a determination of a distal to proximal gradient¹⁵⁹. These measurements are highly reliable and strongly correlated with clinical end points in patients with diabetes mellitus¹⁵⁹. David Cornblath in his review of diagnostic methods used for diabetic neuropathy stated that, electropyhysiologic test results do not always correlate well with symptoms and signs¹⁵⁶. There are several reasons for this. First, some electrodiagnostic abnormalities reflect metabolic changes that are not associated with symptoms; second some symptoms and signs are not clearly associated with electro diagnostic changes¹⁵⁶ .

Maximum conduction velocity reflects the speed of statutory neural propagation for the largest myelinated nerve fibers, whereas the response amplitude can be related to the density of large myelinated axons and the synchrony of their activation. Although velocity is markedly affected by the integrity of myelin, it provides little information about axonal membrane characteristics, it is also relatively insensitive to distal axonopathy¹⁶⁰. The most sensitive electrophysiologic indicator of active axonal degeneration may be evidence from needle electromyography showing changes in fibrillation action potentials and positive sharp waves. The amplitude and area of compound action potentials and sural nerve action potential is indicative of the number of active nerve fibers as indicated from the summated fiber action potential¹⁵⁶. Sural

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nerve action potentials are useful in identifying the more distal nerve involvement, given that lesions proximal to dorsal root ganglia have no effect on the distal sensory nerve. Conduction velocities may reflect specific metabolic abnormalities or segmental demyelination and remyelination but they are a poor indicator of axonal degeneration¹⁵⁶.