Focal limb neuropathies are usually due to entrapment and mononeuropathies must be distinguished from entrapment syndromes (Table B) (17,30) Mononeuropathies often occur in the older population with an acute onset, associated with pain, and a self-limiting course, resolving in 6–8 weeks. These can involve the median (5.8% of all diabetic neuropathies), ulnar (2.1%), radial (0.6%), and common peroneal nerves (31). Cranial neuropathies in diabetic patients are extremely rare (0.05%) and occur in older individuals with a long duration of diabetes (32). Entrapment syndromes start slowly, progress and persist without intervention. Carpal tunnel syndrome occurs 3-times as frequently in diabetics compared with healthy populations (33) and is found in up to one-third of patients with diabetes. Its’ increased prevalence in diabetes may be related to repeated undetected trauma, metabolic changes, or accumulation of fluid or edema within the confined space of the carpal tunnel (30). The diagnosis is confirmed by electrophysiological studies. Treatment consists of resting aided by placement of wrist splint in a neutral position to avoid repetitive trauma. Anti-inflammatory medications and steroid injections are sometimes useful. Surgery should be considered if weakness appears and medical treatment fails(12,17). It consists of sectioning the volar carpal ligament(34)

For many years proximal neuropathy has been considered a component of DN. Its pathogenesis was ill understood (36), and its treatment was neglected with the anticipation that the patient would eventually recover, albeit over a period of some 1-2 years, suffering considerable pain, weakness and disability. The condition has a number of synonyms including diabetic amyotrophy and femoral neuropathy. It can be clinically identified based on the occurrence of these common features: 1) primarily affects the elderly (50 to 60 years) with type 2 diabetes, 2) onset can be gradual or abrupt, 3) presents with severe pain in the thighs, hips and buttocks, followed by significant weakness of the proximal muscles of the lower limbs with inability to rise from the sitting position (positive Gower's maneuver). 5) can start unilaterally and then spread bilaterally, 6) often coexists with distal symmetric polyneuropathy, and 7) spontaneous muscle fasciculation, or provoked by percussion can be detected. Pathogenesis is not yet clearly understood although immune-mediated epineurial microvasculitis has been demonstrated in some cases. Immunosuppressive therapy is recommended using high dose steroids or intravenous immunoglobulin (37). The condition is now recognized as being secondary to a variety of causes unrelated to diabetes, but which have a greater frequency in patients with diabetes than the general population. It includes patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy, circulating GM1 antibodies and inflammatory vasculitis (38) (39) (32;33). In the classic form of diabetic amyotrophy, axonal loss is the predominant process (40). Electrophysiologic evaluation reveals lumbosacral plexopathy (41). In contrast, if demyelination predominates and the motor deficit affects proximal and distal muscle groups, the diagnosis of CIDP, monoclonal gammopathy of unknown significance (MGUS) and vasculitis should be considered (42) (43). The diagnosis of these demyelinating conditions is often overlooked, although recognition is very important, because, unlike DN, they are sometimes treatable. They occurs 11-times more frequently in diabetic than nondiabetic patients (44,45). Biopsy of the obturator nerve reveals deposition of immunoglobulin, demyelination and inflammatory cell infiltrate of the vasa nervorum (46) (38). Cerebrospinal fluid (CSF) protein content is high and there is an increase in the lymphocyte count. Treatment options include: intravenous immunoglobulin for CIDP (47), plasma exchange for MGUS, steroids and azathioprine for vasculitis and withdrawal from drugs or other agents that may have caused vasculitis. It is important to divide proximal syndromes into these two subcategories, because the CIDP variant responds dramatically to intervention (42) (48), whereas amyotrophy runs its own course over months to years. Until more evidence is available, they should be considered as separate syndromes.

Diabetic truncal radiculoneuropathy affects middle-aged to elderly patients and has a predilection for male sex. Pain is the most important symptom and it occurs in a girdle-like distribution over the lower thoracic or abdominal wall. Can be uni- or bilaterally distributed. Motor weakness is rare. Resolution generally occurs within 4-6 months.

Acute sensory (painful) neuropathy is considered by some authors a distinctive variant of the distal symmetrical polyneuropathy. The syndrome is characterized by severe pain, cachexia, weight loss, depression and, in males, erectile dysfunction. It occurs predominantly in male patients and may appear at any time in the course of both type 1 and type 2 diabetes. It is self-limiting and invariably responds to simple symptomatic treatment. Conditions such as Fabry's disease, amyloidosis, HIV infection, heavy metal poisoning (such as arsenic) and excess alcohol consumption should be excluded. (14).

Patients report unremitting burning, deep pain and hyperesthesia especially in the feet. Other symptoms include sharp, stabbing, lancinating pain, “electric shock” like sensations in the lower limbs that appear more frequently during the night, paresthesia, tingling, coldness and numbness (50). Signs are usually absent with a relatively normal clinical examination, except for allodynia (exaggerated response to non-noxious stimuli) during sensory testing and, occasionally, absent or reduced ankle reflexes.

Acute sensory neuropathy is usually associated with poor glycemic control but may also appear after sudden improvement of glycemia and has been associated with the onset of insulin therapy, being termed "insulin neuritis" on ocations (51). Although the pathologic basis has not been determined, one hypothesis suggests that changes in blood glucose flux produces alterations in epineurial blood flow, leading to ischemia. A study, using in vivo epineurial vessel photography and fluorescein angiography, demonstrated abnormalities of epineurial vessels in patients with acute sensory neuropathy, with arteriovenous shunting and proliferating new vessels (52). Other authors relate this syndrome to diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and propose an immune mediated mechanism (27).

The key in the management of this syndrome is achieving blood glucose stability (51). Most patients also require medication for neuropathic pain. The natural history of this disease is resolution of symptoms within one year (53)

Clinical Presentation:

DPN is probably the most common form of the diabetic neuropathies (12,27). It is seen in both type 1 and type 2 DM with similar frequency and it may be already present at the time of diagnosis of type 2 DM (22). A population survey reported that 30% of type 1 and 36 to 40% of type 2 diabetic patients experienced neuropathic symptoms (54). Several studies have also suggested that impaired glucose tolerance (IGT) may lead to polyneuropathy, reporting rates of IGT in patients with chronic idiopathic polyneuropathies between 30 and 50% (55-58). Studies using skin and nerve biopsies have shown progressive reduction in peripheral nerve fibers from the time of the diagnosis of diabetes or even in earlier pre-diabetic stages (IGT and metabolic syndrome) (26,59).

Sensory symptoms are more prominent than motor and usually involve the lower limbs. These include pain, paresthesiae, hyperesthesiae, deep aching, burning and sharp stabbing sensations; similar but less severe to those described in acute sensory neuropathy. In addition, patients may experience negative symptoms such as numbness in feet and legs leading in time to painless foot ulcers and subsequent amputations if the neuropathy is not promptly recognized and treated. Unsteadiness is also frequently seen due to abnormal propioception and muscle sensory function (60,61). Some patients may be completely asymptomatic and signs may be only discovered by a detailed neurological examination.

On physical examination a symmetrical stocking like distribution of sensory abnormalities in both lower limbs is usually seen. In more severe cases hands may be involved. All sensory modalities can be affected, particularly loss of vibration, touch and position perceptions (large Aα/β fiber damage); and pain with abnormal heat and cold temperature perception (small thinly myelinated Aδ and unmyelinated C fiber damage, see figure 2). Deep tendon reflexes may be absent or reduced specially on the lower extremities. Mild muscle wasting may be seen but severe weakness is rare and should raise the question of a possible non-diabetic etiology of the neuropathy (6,12,27). DPN is frequently accompanied by autonomic neuropathy, which will be described in more detail below. It is important to remember that all patients with DPN are at increased risk of neuropathic complications such as foot ulceration and Charcot´s neuroarthropathy.

Clinical manifestations of small fiber neuropathies (Figure 3):

Clinical manifestations of large fiber neuropathies

Most patients with DPN, however, have a "mixed" variety of neuropathy with both large and small nerve fiber damages.