Acute painful neuropathy (42) is a variant of sensory polyneuropathy in which severe burning pain of the extremities is combined with deep aching pain in proximal muscles, jabs of pain radiating from the feet to the legs, and striking hypersensitivity or allodynia of the extremities and trunk to touch, clothing, or bed sheets that is often likened to sunburn. Objective sensory deficit is surprisingly mild in comparison with the painful paresthesia and dysesthesia. Nerve-conduction velocities are frequently normal or minimally abnormal.

Anorexia, weight loss, and depression are often so prominent that the term “diabetic neuropathic cachexia” as coined by Ellenberg (43) to describe this syndrome. This syndrome often correlates poorly with severity of diabetes or presence of other diabetic microangiopathic complications. Prognosis may be good in some patients, with gradual recovery over a period of months (42), particularly if the onset of symptoms follows a metabolic disturbance (44). The condition appears more commonly in males (45). Recurrent episodes may occur infrequently (46).

Sensory neuropathy sometimes appears for the first time coincident with treatment with insulin or oral hypoglycemic agents (47,48) and has been referred to as a treatment-induced neuropathy (49). Although the cause is unknown, it has been suggested that improved glycemic control may initiate regenerating axonal sprouts, which generate ectopic nerve impulses (49). Alternately, it has been proposed that the pain is due to changes in the epineurial vasculature, such as arterial attenuation and tortuosity, arteriovenous shunting, and neovascular proliferation (50). There is usually gradual improvement as treatment continues and glycemic control is maintained.

“Hyperglycemic” neuropathy refers to widespread paresthesias of the extremities and trunk that occasionally occur in patients with newly diagnosed or poorly controlled diabetes and that rapidly improve with control of hyperglycemia. The unique reversibility of this form of neuropathy and the diffuse rather than distal distribution of paresthesias suggest a pathophysiologic basis different from that for later-appearing diabetic sensory neuropathy. In an experimental model of diabetes, acute hyperosmolar hyperglycemia was associated with reduced nerve-conduction velocity and axon shrinkage (51).

Several investigators have drawn attention to the association between chronic inflammatory demyelinating polyneuropathy (CIDP) and diabetes. The typical presentation of patients with superimposed CIDP includes symmetric weakness with demyelination and conduction block on electromyography and demyelination on nerve biopsy. The clinical progression is characteristically more rapid than that of diabetic polyneuropathy, weakness may be more prominent and there is often a satisfactory clinical response to immune modulation (51a,51b,51c,51d).

The differentiation from patients with diabetic polyneuropathy is not easily accomplished owing to several features in common. An elevated cerebrospinal fluid protein is present in both conditions, as are demyelinating changes on nerve conduction studies. The presence of conduction block on nerve conduction studies, however, is more suggestive of CIDP. The prevalence of conduction block appears similar in CIDP patients with and without diabetes mellitus (51b).

The characteristic nerve biopsy in both CIDP and diabetic polyneuropathy shows axonal and demyelinating changes (51a,51e). While a prominent inflammatory infiltrate on nerve biopsy may indicate CIDP, inflammation is only rarely seen in CIDP, and, furthermore, inflammation may also be present on
nerve biopsies of patients with a generalized diabetic peripheral neuropathy (51f,51g).

Cranial neuropathies also belong to the category of mononeuropathies. The majority of diabetic cranial neuropathies affect the third and sixth cranial nerves (52,53), whereas the fourth cranial nerve is rarely affected alone (52). Onset of diplopia is followed by complete ophthalmoplegia within several days. In cases of third-nerve involvement, there may be complete ptosis but the pupil is typically spared. Weakness involves all extraocular muscles except the lateral rectus and superior oblique muscles. The pain, which is characteristically in the frontal and periorbital region, accompanies ophthalmoplegia in about 50% of cases. Unlike painful ophthalmoplegia associated with temporal arteritis (54), eye muscle weakness occurs in a specific nerve distribution rather than from ischemic muscle involvement. The suggestion that pain may be due to involvement of the first and second divisions of the trigeminal nerve in the cavernous sinus is supported by the occasional presence of sensory impairment in the distribution of the trigeminal nerve (52). However, a more likely explanation is that pain originates from ischemia or pain-sensitive terminals in the sheath of the third nerve (55). Differentiation from a neoplastic or vascular lesion in the orbital fissure, cavernous sinus, infarction at the base of the brain, or focal midbrain infarction (56) should be made with brain imaging studies such as magnetic resonance imaging (MRI). Sparing of the pupil may be a consequence of the relatively intact peripherally located pupillomotor fibers supplied by cavernous sinus blood and spared by the centrally placed nerve lesion. However, compressive lesions of the third nerve within the cavernous sinus also may spare the pupil (57) and should be excluded by brain imaging studies. Recovery without residual weakness always occurs and is usually complete within 3 months, supporting the notion that focal demyelination without axonal destruction is the responsible lesion (58).

Convincing evidence that other cranial nerve palsies occur with increased frequency in diabetes is lacking. In one uncontrolled study, impaired olfaction was reported in 35 of 58 patients with diabetes who showed no evidence of abnormalities of the nasal mucosa (59).

Optic disc edema indistinguishable in appearance from papilledema with associated hemorrhages of the nerve fiber layer and cotton-wool spots has been described in juvenile-onset diabetes (60,61). This usually is associated with only mild impairment in visual acuity and a favorable prognosis. This condition is of obscure etiology but is believed to be due to vasculopathy of the most superficial capillary layer of the disc and adjacent retina (60,61). Anterior ischemic optic neuropathy may occur in diabetes but is more closely associated with hypertension. This is an ischemic infarction of the anterior optic nerve that produces acute edema of the optic disc, profound visual loss, and subsequent development of optic atrophy. Optic atrophy and nerve deafness are associated with diabetes in Wolfram syndrome.

Facial paralysis due to seventh nerve palsy may occur with increased frequency in patients with diabetes (62), and the prognosis for recovery may be worse than in patients without diabetes (63). In view of the high frequency of this neuropathy in the general population, its designation as a diabetic mono-neuropathy remains uncertain.

Diabetic amyotrophy was originally described by Bruns (64) in 1890 and again by Garland and Taverner (65) in 1953 as diabetic myelopathy. Because clinical and pathologic evidence for spinal cord involvement was not forthcoming, this syndrome was subsequently designated diabetic amyotrophy (66), a deliberately noncommittal term with regard to localization of the disease process. An array of terms have subsequently been used for this syndrome, including femoral neuropathy (67,68), asymmetric motor neuropathy (69), subacute proximal diabetic neuropathy (70,71), proximal mononeuropathy multiplex (72), diabetic poly radiculopathy (73), and diabetic lumbosacral radiculoplexus neuropathy (74). Asbury (75) has recommended that the term diabetic amyotrophy be dropped because of its ambiguity and that the term proximal motor neuropathy be used instead.

This neuropathy typically occurs with a peak incidence in the fifth or sixth decade in patients with type 2 diabetes. Many patients have mild or unrecognized diabetes at the time of diagnosis. In a recent series, diabetic amyotrophy was the presenting manifestation of diabetes in one third of the subjects (76). Some authors have emphasized an association with poor glycemic control (66,77,78).

The clinical picture is one of acute or subacute pain, weakness, and atrophy of the pelvic girdle and thigh musculature. The iliopsoas and quadriceps are usually involved, producing weakness of hip flexion and knee stabilization within several weeks of onset of pain. As a result, buckling of the knee and difficulty climbing stairs are typical symptoms. In some cases, coexistent weakness of the glutei, hamstrings, thigh adductors, and, less commonly, the peroneal and tibial muscles is present, indicative of the more widespread distribution of the disorder. Symptoms may have a monophasic or stepwise progression (77,79,80,81,82,83). Symptoms begin unilaterally but extend to the opposite extremity within weeks or months (74). Most patients have weight loss, and some appear cachectic. The extent of the weight loss highlights the systemic nature of the disorder. The weight loss may be compounded by anorexia caused by reactive depression or the use of narcotic analgesics.

Despite its designation as a motor neuropathy, subtle sensory symptoms and signs are commonly present in the form of paresthesias and sensory disturbance in the anterior thigh and anteromedial aspects of the lower leg typically in the anterior femoral cutaneous and saphenous nerve distribution. The knee jerk is nearly always reduced or absent on the affected side, whereas ankle jerks may be preserved unless compromised by a coexistent distal polyneuropathy.

Deep, aching pain is prominent and is localized to the hip, buttock, and anterior thigh. Pain is unrelieved by rest, is typically worse at night than during the day, and is not increased with straight leg raising or other mechanical maneuvers. The process is typically unilateral in onset, but subsequent involvement of the opposite leg often occurs within 3 to 4 months.

Despite early reports to the contrary (66), signs of myelopathy are absent and plantar responses are usually flexor. Pain, sensory abnormalities, and weakness in thoracic root distribution occasionally occur concomitantly (25), but isolated shoulder-girdle involvement is distinctly uncommon (73) and, when present, usually occurs in patients with marked leg weakness (70,78,79).

Differentiation from compressive lumbar nerve-root disease and neoplastic infiltration of lumbosacral plexus may be difficult, and laminectomies and laparotomies have occasionally been carried out in such patients in search of a structural cause. As originally pointed out by Root and Rogers (84), and more recently discussed by Hirsh (85), the absence of mechanical signs and symptoms, lack of back pain, prominent nocturnal pain with failure to respond to bed rest, and muscular atrophy and weakness involving more than one lumbar root usually distinguishes proximal motor neuropathy from nerve-root compression.

The prognosis is usually good, with most patients showing resolution of pain followed later by gradual return of strength over a period of 6 to 18 months (73,77,78). Patients with unilateral and relatively focal pain and weakness seem to improve more rapidly and completely than patients with more widespread involvement. Because of the severe pain and disability associated with this syndrome, the ability to reassure affected patients of a favorable prognosis provides them great psychological relief.

There has been considerable debate concerning the etiology and proper classification of proximal motor neuropathy (75). Subramony and Wilbourn (86) have emphasized the heterogenicity of the syndrome, in that some patients with proximal motor neuropathy have clinical and electromyographic evidence of distal polyneuropathy whereas others appear to have a more localized process. The finding of slow nerve-conduction velocities in femoral and distal nerves (81,86,87,88,89) and of features of demyelination in nerve biopsy specimens in these patients indicates that “diabetic amyotrophy” is a form of diabetic neuropathy with a predilection for proximal nerves rather than a primary disorder of anterior horn cells of muscle. On the basis of extensive clinical electrophysiologic experiences, Bastron and Thomas (73) at the Mayo Clinic concluded that the disorder is a polyradiculopathy. Electromyography of patients with diabetic amyotrophy characteristically displays abundant fibrillations in the affected limb muscles and the paraspinal muscles. Nerve-conduction studies are unable to differentiate patients with diabetic amyotrophy from those with a generalized polyneuropathy.

Recent studies have emphasized the likelihood that this disorder has a vascular basis (90,91). A vascular etiology was first proposed for the more acute case of diabetic amyotrophy by Raff and Asbury (72,75), who documented occlusion of intrafascicular artery of the obturator nerve and numerous small-vessel infarcts in the lumbosacral plexus and proximal nerve trunks of the patient who exhibited the rapid appearance of painful proximal asymmetric leg weakness.

The possibility that this disorder has an inflammatory etiology has led to the use of immune-modulating therapies. Intravenous immunoglobulins, plasmapheresis, and corticosteroids have all been used in open-label, uncontrolled studies (71,90,92). While preliminary results suggest some clinical benefit, the need for blinded, placebo-controlled trials is highlighted by the patient of Said et al. (91), who had a spontaneous remission shortly after biopsy and prior to the initiation of corticosteroid therapy (92a).

This entity, also known as thoracoabdominal neuropathy, did not gain attention in the English-language literature until the late 1970s (23,24). Similar to painful proximal motor neuropathies of the legs, this disorder usually occurs in middle-aged patients and often in those who have relatively mild diabetes. In many cases, patients with this syndrome have had previous or concomitant painful lumbar root syndromes in the lower extremities.

Onset of pain is usually acute, and the pain may be located in the back, chest, or abdomen. The character of the pain resembles that of herpes zoster and is usually deep and aching with some elements of superficial sharp or burning pain. Changes in pain with alterations of position or physical activity are variable. Paresthesia and cutaneous hypersensitivity are usually present but may be mild or absent, sometimes resulting in failure to recognize the neuropathic basis for pain. The pain is usually unilateral but is sometimes bilateral, may be distributed over more than one dermatomal segment, and often does not have a classic girdling radicular distribution. There may be an accompanying area of sensory loss or dysesthesia in the distribution of one or more adjacent intercostal nerves, the dorsal or ventral rami, or their branches (93). Impairment in light touch and hypersensitivity to pin stimulation, however, are often absent. In severe cases, weakness and laxity of segmental para spinal and abdominal muscles are present and abdominal hernia may even occur (94,95). Electromyography of paraspinal, intercostal, and abdominal muscles is diagnostically helpful and usually shows changes of acute denervation (24,25,96,97). As with proximal lower-extremity motor neuropathy, weight loss may be prominent, and because of the frequent absence of definite neuropathic symptoms and signs, exhaustive, unfruitful searches for an intrathoracic or intraabdominal neoplasm often are undertaken. The finding of electromyographic abnormalities usually leads to the correct diagnosis. Cases in which the distribution of symptoms and signs conforms to a single thoracic root should be evaluated with x-ray and MRI studies of the thoracic spine to exclude a compressive radiculopathy. The prognosis is usually better for the lower extremity radiculopathies, with a gradual recovery within a matter of months to a year (23).

Similar to other diabetic mononeuropathies and radiculopathies, the etiology of thoracic radiculopathy is obscure, although the acute onset and spontaneous recovery suggest a focal ischemic process. The observation that thoracic radiculopathy, proximal asymmetric motor neuropathy, and cranial mononeuropathy occur among middle-aged patients with type 2 diabetes, often appear in the same patient, improve spontaneously, and have a tendency to recur suggests a common physiologic mechanism. Although no pathologic studies of patients with thoracic radiculopathy have been published, postmortem studies of patients with diabetic polyneuropathy do show axonal and demyelinative lesions of nerve roots (81,98). Skin biopsies of patients with thoracic radiculopathy have shown a marked reduction in dermal and epidermal nerve fibers in the affected dermatome (98a).

Mononeuropathy is particularly common in persons with diabetes and may occur on the basis of focal ischemia, entrapment, compression, or trauma to superficially placed nerves (99). Any of the major peripheral nerves may be affected. Symptoms may present suddenly or gradually. When several nerves are involved simultaneously, the disorder is referred to as mononeuropathy multiplex. Many patients with diabetic polyneuropathy have electrophysiologic or clinical evidence of superimposed focal mononeuropathy at various common sites of entrapment or nerve injury, such as the median nerve at the wrist, ulnar nerve at the elbow, peroneal nerve at the fibular head, radial nerve above the elbow, and lateral cutaneous nerve of the thigh (99). This may be because nerves affected by segmental demyelination are known to be particularly sensitive to the effects of compression and anoxia. Differential diagnosis of mononeuropathy or mononeuropathy multiplex include vasculitis, paraproteinemic neuropathy, amyloidosis, acromegaly, hypothyroidism, sarcoidosis, Lyme disease, and bleeding into peripheral nerves caused by coagulation defects.

Carpal tunnel syndrome caused by median-nerve entrapment in the wrist is particularly common among persons with diabetes. A recent study report neurophysiologic evidence consistent with a carpal tunnel syndrome in 23% of patients with mild diabetic neuropathy. The carpal tunnel syndrome usually produces symptoms and signs similar to those in persons without diabetes. Occasionally, however, distal median-nerve mononeuropathy may occur in the absence of the usual pain and sensory symptoms of carpal tunnel syndrome. Although
entrapment is still possible in such cases, coexistent distal ulnar neuropathy and bilateral involvement may suggest distal polyneuropathy rather than nerve entrapment (100). Nerve-conduction studies showing prolonged distal latencies in multiple nerves rather than limited to the median nerve will serve to distinguish distal polyneuropathy from entrapment.

Peroneal mononeuropathy typically produces sudden painless foot drop and, in addition to vascular factors, may be due to trauma because of the superficial location of the nerve at the fibular head. Ulnar mononeuropathy is probably also related to the vulnerable position of the nerve at the elbow. In this case, symptoms usually appear insidiously and may be due to chronic trauma rather than to acute injury or entrapment. Phrenic neuropathy, resulting in diaphragmatic paralysis, may occur rarely in patients with diabetes (101).

The pathophysiologic basis of diabetic distal polyneuropathy remains uncertain. The two major prevailing theories relate the metabolic effects of chronic hyperglycemia and the effects of ischemia on peripheral nerves to the pathogenesis of this disorder (102,103). Alterations in neurotrophic factors and immunologic mechanisms also may play a pathogenetic role. It is likely that multiple interacting factors play a role in the pathogenesis of this disorder.