Introduction
Indications of diabetic neuropathy vary and depend on the nervous system involved, thus specifying a complex picture of signs and symptoms depending on the organ involved. However, peripheral neuropathy is the most common and could affect almost 50% of individuals with diabetes mellitus during their lifetime. Peripheral neuropathy is one of the main microvascular complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM), more frequent than nephropathy and retinopathy, and is the leading cause of lower limb amputation in Western countries. However, there is a difference in the lifetime prevalence of peripheral neuropathy between T1DM and T2DM. As indicated by some trials, diabetic peripheral neuropathy frequently is not present at the moment of diagnosis, while it could appear at least 10 years of disease duration and could affect 34% of subjects after 25 years. In contrast, diabetic peripheral neuropathy may also be present at the time of diagnosis in individuals with T2DM. The precise prevalence of pre-diabetic neuropathy is not known, but it appears to be intermediate between individuals with normoglycemia and those with overt diabetes. The estimated global prevalence of diabetes is almost 10% in 20-79-year-old subjects and this prevalence will grow up to 11-12% in 2045.
Based on the nervous system involved, autonomic or peripheral there are different indications of diabetic neuropathy and consequently related to the type of nerve and organ involved. Diabetic peripheral neuropathy can arise as symmetric sensory-motor axonal neuropathy, proximal asymmetric painful motor neuropathy, autonomic neuropathy, and mononeuropathy. Among the different forms of Diabetic neuropathy, symmetric sensory-motor axonal diabetic peripheral neuropathy is the one with the highest prevalence. The pathophysiology is characterized by metabolic/inflammatory damage that impacts the peripheral nerves responsible for conducting the motor and sensory impulses. This microvascular complication is known as “length-dependent” neuropathy as it affects the longest nerve fibres more frequently. Diabetic peripheral neuropathy is the main risk factor for the development of lower limb ulcers and subsequent disabling. To prevent these terrible difficulties and to decrease the cost of the healthcare system, adequate prevention and therefore an early proper diagnostic screening appears necessary.
Pathophysiology of Peripheral Neuropathy in Diabetes
There are many pathophysiological mechanisms through which diabetes causes neuropathic damage and involves various metabolic and intracellular signaling processes. Axonal degeneration, with both primary and secondary demyelination, has been documented in nerve biopsies from both animal models and individuals with diabetic polyneuropathy. In particular myelin sheath and Schwann cells impairment have been shown. Accordingly, axonal impulse conduction and signaling are disrupted, with a reduction of neurotrophic factors, therefore resulting in centripetal degeneration and distal axonal loss that progresses length-dependently. This demonstrates that the longest nerve fibers are at the greatest risk of being involved. Among the postulated mechanisms, an inflammatory process appears to cause nerve damage through cellular and metabolic pathways. Moreover, other metabolic risk factors related to diabetes appear to be associated.
Figure 1.Main pathophysiological mechanisms of Diabetic Peripheral Neuropathy. Adapted from source
The Nerve Barrier Disruption
The microvessels of peripheral nerves are lined by a blood-nerve barrier (BNB) within the presence of the peripheral neural parenchyma (endoneurium). The elements of this barrier are the endothelial cells bound by tight junction proteins, pericytes, and basal lamina. This barrier constitutes a significant structure of energy supply by expressing transporters for nutrients and constitutes a defence for the nerve.
The altered BNP function appears to be the first marker of damage responsible for the development and progression of diabetic neuropathy. The increased permeability of the damaged barrier facilitates the passage of high-molecular-weight proteins, like albumin and immunoglobulin G (IgG) into the endoneurium. Also, as evidenced in sural nerve biopsies, the endothelial cells of the small endoneurium vessels undergo swelling and together with the thickening of the basal lamina results in a reduction of the vascular lumen.
Role of Inflammation
The systemic inflammatory status detected in people with Diabetes Mellitus seems to underlie the development of diabetic neuropathy. Cytokines, inflammatory cells, and growth factors have been suggested as mediators of the development of this complication in both human and animal models. In particular, hyperglycaemia seems to be associated with the stimulation of the cyclooxygenase-2 (COX-2) pathway in micro-vessels. The continuation of diabetes for 6 months in a diabetic mouse model with an active COX-2 gene resulted in increased oxidative and inflammatory stress, reduction of nerve conduction, and intraepidermal fibre density.
Role of Advanced Glycation End Products (AGE)
A relevant role in the development of neuronal damage appears to be specified by the increased amount of AGEs, which are highly expressed in people with hyperglycaemic status. AGEs are induced through the nonenzymatic aggregation of glucose, or other saccharides, to proteins, lipids, and nucleotides.
Role of Lipids
Some studies have focused on the association between metabolic syndrome, frequently present in subjects with T2DM, and the development of diabetic neuropathy. Recently some authors have examined the presence of potential biomarkers of diabetic peripheral neuropathy and have evaluated whether there are any metabolic-syndrome-derived metabolites associated with diabetic peripheral neuropathy. The result indicates that in individuals with diabetic peripheral neuropathy some biomarkers (e.g. perfluorooctanoate, N-acetyl-3-methylhistidine, tartrate, and citrate) are associated with alterations in plasma lipid metabolites.
Diagnosis
The diagnosis of diabetic peripheral neuropathy is primarily clinical, and a screening visit should be conducted at least once a year. The history of the patient together with screening scores and neurological physical assessment of the lower limbs for the evaluation of signs and symptoms could exclude other types or causes (e.g., vasculitic, alcoholic, tarsal tunnel) of peripheral neuropathies and identify the typical characteristics of diabetic peripheral neuropathy. As per the literature, the presence of symptoms or signs of neuropathy defines the picture of possible diabetic peripheral neuropathy.
Screening Scores
Presently, different validated scores are used for the evaluation of symptoms and signs of diabetic peripheral neuropathy. Dolor neuropatique 4 (DN4) is one of the most widely used validated scores to evaluate the main symptoms and signs of neuropathic pain and painful diabetic neuropathy. As per some authors, it allows the identification of neuropathic pain with a sensitivity of 80% and a specificity of 91%. For these reasons and based on the results and experience gained by clinicians over the years, DN4 is still indicated as beneficial by the guidelines, especially for the screening of neuropathic pain, even in subjects without diabetes mellitus.
The Michigan Neuropathy Screening Instrument (MNSI) is a simple and non-invasive test that allows one to conduct a neurological examination. This score aims to highlight the specific signs of diabetic peripheral neuropathy. The Toronto Clinical Neuropathy Score and the modified Toronto Clinical Neuropathy Score (mTCNS) are simple and non-invasive and have been utilized in some trials. These are still indicated and validated for screening diabetic neuropathy and other clinical indications of neuropathic pain.
Quantitative Sensory Testing and Neurological Tools
Quantitative sensory testing (QST) is a beneficial tool in clinical practice, complementary to physical examination and scores, and it is capable of determining signs of altered sensitivity in individuals with suspected neuropathy. In particular, QST can be performed to evaluate the functional impairment of sensory nerve fibers. QST is a non-invasive method that can be utilized to evaluate the characteristics of neuropathic pain and to evaluate both loss and gain of sensory function.
Nerve Conduction Studies (NCS)
Nerve conduction studies (NCS) are the gold standard exam for diagnosing diabetic peripheral neuropathy. NCS allows an evaluation of the large fibres, while with this tool it is not possible to specify the function of the small fibres.
Conclusion
Diabetic peripheral neuropathy is one of the main microvascular complications of diabetes mellitus. The pathophysiology underlying the development of this complication implicates different cells and tissues in a mix of pathways that together appear to its development. Despite substantial improvement in discovering these pathways, further studies appear essential to better explain the development of this complication, particularly regarding the role of endothelial dysfunction and the inflammatory cascade. Regarding the diagnosis of diabetic neuropathy, in most cases, thanks to clinical evaluation, scores, and the use of some non-invasive tools (e.g., QST), it appears possible to achieve a diagnosis of diabetic peripheral neuropathy, both for the involvement of large and small fibers.