Diabetic neuropathy: clinical manifestations and current treatments

Abstract

Diabetic peripheral neuropathy is a prevalent, disabling disorder. The most common manifestation is distal symmetrical polyneuropathy (DSP), but many patterns of nerve injury can occur. Currently, the only effective treatments are glucose control and pain management. While glucose control substantially decreases the development of neuropathy in those with type 1 diabetes, the effect is probably much smaller in those with type 2 diabetes. Evidence supports the use of specific anticonvulsants and antidepressants for pain management in patients with diabetic peripheral neuropathy. However, the lack of disease-modifying therapies for diabetic DSP makes the identification of new modifiable risk factors essential. Growing evidence supports an association between components of the metabolic syndrome, including prediabetes, and neuropathy. Studies are needed to further explore this association, which has implications for the development of new treatments for this common disorder.

Figure 1. Patterns of nerve injury in diabetic neuropathy

Many patterns of nerve injury are observed in patients with diabetes. By far the most common neuropathy subtype is distal symmetric polyneuropathy (DSP), which is the focus of this review. However, clinicians should be aware of all potential patterns as they have implications for the evaluation and treatment of these patients. For example, patients with diabetes can develop a radiculopathy without a disc herniation or degenerative changes in the spine. This knowledge could prevent a patient from spine surgery in the case where imaging results are equivocal. Furthermore, patients with diabetes can have more than one pattern of nerve injury, and the clinician needs to ask patients about specific symptoms such as autonomic involvement, which is often overlooked. The following patterns are shown in the figure: (A) DSP, small fiber predominant neuropathy, treatment induced neuropathy (B) radiculoplexopathy, radiculopathy (C) mononeuropathy, mononeuritis multiplex (D) autonomic neuropathy, treatment induced neuropathy. Note that small fiber predominant neuropathy has the same pattern as DSP but that the neurologic examination and electrodiagnostic studies are quite different, which has the potential to lead the clinician astray. Diabetic radiculoplexopathy may be responsive to immunotherapy and in contrast to most nerve injury in patients with diabetes, usually improves with time^, . Treatment induced neuropathy is an under-recognized phenomenon. Unlike the other peripheral manifestations of diabetes, this condition is caused by overaggressive control of glucose levels.

Figure 2. Small fiber predominant neuropathy on skin biopsy

(A) Skin biopsy evaluating intra-epidermal nerve fiber density (stained with protein gene product 9.5, 50 micrometer sections) from a 41 year old male without neuropathy. Two nerves are seen crossing the dermal-epidermal junction. (B) Skin biopsy evaluating intra-epidermal nerve fiber density from a 50 year old male with diabetic neuropathy. No nerves are seen crossing the dermal-epidermal junction. (C) Sural nerve biopsy from a 44 year old male with diabetic neuropathy (40X magnification). Biopsy reveals axonal loss of small and large diameter nerves.

Figure 2. Small fiber predominant neuropathy on skin biopsy

(A) Skin biopsy evaluating intra-epidermal nerve fiber density (stained with protein gene product 9.5, 50 micrometer sections) from a 41 year old male without neuropathy. Two nerves are seen crossing the dermal-epidermal junction. (B) Skin biopsy evaluating intra-epidermal nerve fiber density from a 50 year old male with diabetic neuropathy. No nerves are seen crossing the dermal-epidermal junction. (C) Sural nerve biopsy from a 44 year old male with diabetic neuropathy (40X magnification). Biopsy reveals axonal loss of small and large diameter nerves.

Figure 2. Small fiber predominant neuropathy on skin biopsy

(A) Skin biopsy evaluating intra-epidermal nerve fiber density (stained with protein gene product 9.5, 50 micrometer sections) from a 41 year old male without neuropathy. Two nerves are seen crossing the dermal-epidermal junction. (B) Skin biopsy evaluating intra-epidermal nerve fiber density from a 50 year old male with diabetic neuropathy. No nerves are seen crossing the dermal-epidermal junction. (C) Sural nerve biopsy from a 44 year old male with diabetic neuropathy (40X magnification). Biopsy reveals axonal loss of small and large diameter nerves.

Figure 3. Mechanisms of diabetic neuropathy

Factors linked to type 1 diabetes (yellow), type 2 diabetes (blue) and both (green) cause DNA damage, ER stress, mitochondrial dysfunction, apoptosis and loss of neurotrophic signaling. This cell damage can occur in neurons, glial cells and vascular endothelial cells, as well as triggering macrophage activation, all of which can lead to nerve dysfunction and neuropathy. The relative importance of the pathways in this network will vary with cell type, disease profile and time. Abbreviations: AGE, advanced glycation end-products; LDL, low-density lipoprotein; HDL, high-density lipoprotein; FFA, free fatty acids; ROS, reactive oxygen species (red star); ER, endoplasmic reticulum; PI3K, phosphatidylinositol 3-kinase.

Figure 4. Algorithm for the treatment of diabetic painful neuropathy

First and seconds line treatments for diabetic painful neuropathy.