**2.2 Clinical manifestations**

Diabetes can damage different parts of the peripheral nervous system with distal symmetric polyneuropathy (DSP) being the most common presentation. The symptoms are symmetric and with predominant sensory symptoms over motor involvement. Sensory symptoms such as numbness, tingling, and pain are common in DSP patients. These characteristics begin in the feet and spread proximally in a length-dependent pattern known as stocking-and-glove distribution [24]. Other patterns of injury include small-fiber predominant neuropathy, radiculo-plexopathy and autonomic neuropathy, among others.

DSP has an effect on the physical and emotional well-being of patients. Sensory loss caused by DSP often causes trouble walking, which can lead to falls. DSP is one of major risk factors for falls in diabetic patients along with retinopathy and vestibular dysfunction. Diabetic DSP patients are 2–3 times more likely than diabetics without neuropathy to fall. Diabetes is the leading cause of lower extremity amputations, with a 15-fold increase in the likelihood of this life-changing complication. Moreover, 80,000 lower extremity amputations are performed each year in patients with diabetes [25–27].

Neurogenic pain, numbness, a lack of control of voluntary movements, and a susceptibility to foot ulceration that contributes to infections and toe or foot amputations are all signs of diabetic neuropathy. Diabetic patients have a 15-fold higher risk of toe or foot amputations than nondiabetic patients [28].

According to Toronto Consensus Panel on Diabetic Neuropathy, DPN is defined as a symmetrical, length-dependent sensorimotor polyneuropathy that develops in the background of long-standing hyperglycemia, associated de-arrangements, and cardiovascular risk factors [29]. Different studies reported that some patients with prediabetes develop neuropathic complications, whereas others reported little evidence of neuropathy even after long-standing diabetes. This observation confirms the involvement of genetic etiological factors associated with the development of DPN [30].

Neuropathic pain is one of the major disabling symptoms of patients with DSP. It is estimated that diabetic neuropathic pain (DNP) develops in 10–20% of the diabetic population overall and can be found in 40–60% with documented neuropathy. Like other types of neuropathic pain, DNP is characterized by burning, electric, and stabbing sensations with or without numbness [31–33]. It is characteristically more severe at night often resulting in sleep disturbance. Together with painful symptoms during the day, this often leads to a reduction in quality of life. In one study, the burden of painful DPN was reported to be significant, resulting in persistent discomfort following polypharmacy and high resource usage, as well as limitations in everyday activities and dissatisfaction with treatments that were frequently deemed ineffective. DPN that is chronic, persistently painful, and highly distressing is linked to severe depression, anxiety, and sleep loss [34, 35]. Other types of diabetic neuropathies includes small-fiber polyneuropathy, mononeuropathy, mononeuropathy multiplex, radiculopathy, plexopathy (diabetic amyotrophy), autonomic neuropathy, and treatment-induced neuropathy.
