Diabetic Neuropathy--A Review

Clinical Aspects of Diabetic Neuropathy

Length-dependent Diabetic Polyneuropathy

More than 80% of patients with clinical diabetic neuropathy have a distal symmetrical form of the disorder.^[6,7] In this neuropathic pattern, signs and symptoms start—and remain more pronounced—in the feet, and go on to affect more-proximal parts of the lower limbs and eventually the distal parts of the upper limbs, indicating that the longest nerve fibers are affected first. Shorter sensory axons subsequently become involved, accounting for neuropathic manifestations in more-proximal parts of the limbs and eventually the anterior trunk. This is often referred to as a length-dependent pattern. Progression of polyneuropathy is not specific to diabetes, also occurring in alcoholic and amyloid polyneuropathies.^[8] LDDP usually becomes symptomatic several years after the onset of type 1 diabetes, but can often also reveal diabetes of mature onset. Inaugural symptoms of LDDP include numbness, burning feet, pins-and-needles sensations and lightning pains. The symptoms are often most pronounced at night, and the burning pains can be exacerbated by contact. The sensory neuropathy can be totally silent and detected only by systematic neurological examination of the feet, or can be revealed by painless trauma or burns, or by trophic changes that include plantar ulcers or neuropathic osteoarthropathies (Charcot's joints).

The distal symmetrical sensory loss can be restricted to the toes, extend over the feet, or spread over the lower legs or higher above the knee level, depending on the intensity of peripheral nerve lesions. When sensory loss extends above knee level, it develops over the fingers and spreads up over the hands and the forearms while progressing proximally in the lower limbs. Later on, the anterior aspect of the trunk can become affected owing to involvement of the distal territory of the sensory nerve fibers of the intercostal nerves. In the most severe cases the summit of the scalp can be affected as a consequence of the involvement of the longest fibers of the trigeminal nerve, and in exceptional cases the loss of sensation can spread over almost the whole body.^[9] Eventually, all modalities of sensations are lost in the distal parts of the lower limbs, whereas superficial sensations—especially temperature and pain sensations—are predominantly affected in the proximal regions. Thermal sensibility can be reduced in isolation or in combination with loss of vibration sense, but selective loss of vibration sense is rare.^[10] The maximum dissociation between functions of small and large fibers (i.e. small-fiber functions are heavily affected, whereas large-fiber functions are spared) occurs in the so-called 'pseudosyringomyelic type' of diabetic neuropathy, originally reported by Vergely.^[11] Small-fiber sensory neuropathy presenting with reduced intraepithelial-nerve-fiber densities and correlated elevation of warm thresholds is also a major manifestation of type 2 diabetes.^[11] In small-fiber LDDP, the length-related sensory loss mainly affects pain and temperature sensations, and leads to the occurrence of painless burns, persistent foot ulcers and neuropathic osteoarthropathy.^[9,12] In these cases, prominent autonomic disturbances are also present, suggesting simultaneous alterations of the autonomic unmyelinated fibers.

Loss of large myelinated fibers and other proprioceptive afferent fibers leads to disturbance of light touch sensation, sensibility to pressure and vibration, and joint position sense. Disturbance of joint position sense can result in increased instability of posture with, in the most severe cases, a positive Romberg's sign and ataxia. Although this 'pseudo-tabetic' pattern of diabetic neuropathy was recognized more than a century ago at a time when there was no treatment for diabetes,^[13] it seems to be rare nowadays, at least in industrialized countries. Distal weakness is a late event in the natural history of LDDP.^[14] Distal weakness and wasting can be observed in association with severe sensory loss in this setting, but predominantly motor neuropathy is not a feature of distal neuropathy in patients with diabetes.^[12,14,15]

Established LDDP is irreversible despite improvements in metabolic markers. At best, the sensory deficit can remain stable or worsen slowly over time. Strict glycemic control is associated with a lower risk of deterioration of the neurological condition,^[3,4] but serious complications commonly occur in the course of LDDP.

Painful Symmetrical Polyneuropathy. Neuropathic pain is a major burden in diabetic patients, and is a common complication of LDDP. The occurrence of different types of spontaneous pain in hyperalgesic diabetic polyneuropathy had been recognized by the end of the nineteenth century.^[16] In spite of several attempts, however, it has not been possible to ascribe the occurrence of pain to specific morphological findings.^[9,17,18] Recent studies of intraepidermal nerve fibers (IENFs) showed that more-severe loss of these fibers was associated with the presence of neuropathic pain only in patients with little or no objective sign of neuropathy. Consequently, loss of IENFs cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy.^[19] From a physiological point of view, however, microneurographic recordings from unmyelinated fibers of diabetic patients with painful and nonpainful neuropathies revealed an abnormal ratio of mechanoresponsive to mechano-insensitive nociceptors in patients with diabetes, suggesting that mechanoresponsive nociceptors had lost their responsiveness to mechanical stimuli and heat.^[20] Small-fiber neuropathy in diabetes, therefore, seems to affect the receptive properties of nociceptors, leading specifically to impairment of mechanoresponsive nociceptors.^[20]

Recent developments in our understanding of pain perception have shown that transmission of painful stimuli depends on activation of sodium channels that are expressed at high levels in cell membranes of nociceptive neurons of dorsal root ganglia.^[21] The identification of mutations in the gene coding for a sodium channel in patients with familial insensitivity to pain indicates that the response to painful stimuli is to some extent genetically determined.

Acute painful neuropathy with allodynia is sometimes associated with cachexia and depression, especially in young adults with type 1 diabetes.^[22,23] Acute painful neuropathy rarely precipitates once tight glycemic control has been established.

Trophic changes in distal symmetrical sensory polyneuropathy. Trophic changes predominantly affecting the distal parts of the lower limbs are a major complication of LDDP. The earliest change is frequently a callus (often in the region of the metatarsal heads), which might recur despite regular foot care. In other cases, the first manifestation is a painless phlyctenular lesion. Both of these conditions are painless, and are associated with loss of pain sensation over the feet. Chronic ulcers can subsequently develop. Idiopathic bullae (bullosis diabeticorum), which can precede the onset of plantar ulcers, can occur in territories with sensory loss on the hands. Neuropathic osteoarthropathy is a complication of long-standing diabetic neuropathy. Painless foot deformity, sometimes of acute onset, is the main sign of this condition. On X-ray, the feet can show the following features: increased radiotransparency; painless fractures especially affecting the metatarsal bone, with disruption of articular surfaces; and disorganization of joints, especially the metatarsophalangeal joints. Penetration of bacteria through neuropathic ulcers can lead to chronic osteomyelitis. Foot ulceration and neuropathic osteoarthropathy are not specific to the 'diabetic foot'—similar complications of loss of pain sensation occur in a number of conditions, including leprosy, hereditary sensory neuropathies, alcoholic sensory polyneuropathy,^[24] and hereditary indifference to pain with normal nerve biopsy findings.^[25] Loss of pain sensation with preservation of normal muscle strength or with subnormal strength can lead to painless trauma and development of plantar ulcers and osteoarthropathy. Vasculopathy seems to be an additional risk factor for trophic changes in patients with diabetes.^[26,27]

Autonomic Neuropathy

Autonomic dysfunction is one of the characteristic manifestations of diabetic neuropathy, and can be life-threatening.^[28,29] Clinical cardiovascular disturbances usually start with resting tachycardia; the heart rate might return to its normal value later on, but does not exhibit normal variations in response to changing physiological situations. Postural hypotension (a fall in systolic blood pressure of more than 30 mmHg on changing from a lying to a standing position, without an increase in heart rate) can be an extremely disabling symptom of autonomic neuropathy with postural syncopes. Postural hypotension can be aggravated by tricyclic antidepressants—which are often used for treatment of chronic pain in diabetic neuropathy—and by episodes of diarrhea. Cardiac autonomic neuropathy seems to be strongly associated with increased risks of silent myocardial ischemia and mortality.

Gastroparesis, which is a common manifestation of disturbances of alimentary tract function, is often asymptomatic, but is at times revealed by a sensation of fullness, or less commonly by vomiting. Gastroparesis might result in poor glycemic control, with hypoglycemia occurring because of stagnation of aliments in the stomach. Diabetic diarrhea occurs at night or after meals and is watery. The diarrhea can be accompanied by fecal incontinence. Bladder atony leads to the presence of large residual volume after micturition, sometimes complicated by infection. Retrograde ejaculation is frequent in patients with atonic bladder. Impotence, which can be evaluated by continuous nocturnal monitoring of penile tumescence and rigidity, is a common complication in male patients with diabetes. Vascular and psychogenic factors, as well as aging, might also contribute to impotence. If left untreated, hypoglycemia could complicate autonomic neuropathy, owing to failure of catecholamine release. Abnormal pupillary responses, the most striking signs of which are miosis and reduced light reflexes, are common in patients with diabetes.

Focal and Multifocal Neuropathy

Focal and multifocal neuropathies are much less common than LDDP in patients with diabetes. These forms of neuropathy are usually seen after 50 years of age, and mainly in patients with type 2 diabetes. Focal neuropathies include cranial nerve involvement, limb and truncal neuropathies, and proximal diabetic neuropathy (PDN) of the lower limbs. Development of sensorimotor deficits in the territories of one or several nerve trunks, roots or plexuses, is rare in patients with diabetes and warrants exclusion of other causes of neuropathy, by nerve biopsy if necessary.

Cranial Neuropathy. Cranial neuropathy in patients with diabetes is restricted largely to unilateral oculomotor nerve palsies. Third and sixth cranial nerve palsies seem to be equal in prevalence. Heralded by transient frontal pain in around 50% of cases, the onset of cranial neuropathy is usually abrupt, with progression of the deficit occurring over 1 or 2 days. In third nerve palsy the oculomotor dysfunction is usually nearly or fully complete (with the exception of the pupillary reflex, which is usually spared). Fourth nerve palsy is supposedly rare in this setting, although it can be seen in association with third nerve palsy. No sensory deficits have been observed in the territory of the trigeminal nerve. In patients with third nerve palsy it is advisable to perform a brain MRI scan and a magnetic resonance angiogram to exclude other causes of oculomotor nerve palsy. Patients with diabetic oculomotor nerve palsy recover spontaneously within 2-3 months, although relapses on the opposite side of the body can occur. Multiple cranial nerve palsies are extremely rare.

Two serial section studies performed in patients with third cranial nerve palsy demonstrated a centrofascicular lesion of the nerve in its intracavernous portion.^[30,31] The fibers at the periphery of the nerve trunk were relatively spared, which accounted for the sparing of the pupillary reflex. In both reports the authors suggested that the observed centrofascicular lesions of the third nerve were likely to be ischemic in origin.

Truncal Neuropathies. Truncal neuropathy is usually predominantly or completely unilateral.^[32,33] The onset is abrupt or rapid, with pains or dysesthesias as the main features. The pain often has a radicular distribution and is almost always worse on contact and at night. Weakness of abdominal muscles also occurs. Isolated involvement of peripheral nerves of the limbs is extremely rare, with the exception of median nerve entrapment in carpal tunnel syndrome.

Proximal Diabetic Neuropathy of the Lower Limbs. Patients with diabetes can present with proximal neuropathy of the lower limbs, characterized by a variable degree of pain and sensory loss, associated with unilateral or bilateral proximal muscle weakness and atrophy. This syndrome, which was originally described by Bruns in 1890,^[34] has subsequently been reported using different terminology.^[35] The onset is acute or subacute, and the patient complains of numbness or pain of the anterior aspect of the thigh, often of the burning type and most pronounced at night. The patient experiences difficulty in walking and climbing stairs, owing to weakness of the quadriceps and iliopsoas muscles. Wasting of the quadriceps muscle and loss of the patellar reflex occur at an early stage in the disease. The syndrome progresses over several weeks or months in most cases, then it stabilizes and spontaneous pains decrease, sometimes rapidly. In approximately one-third of patients with PDN of the lower limbs there is a definite sensory loss over the anterior aspect of the thigh, and in the others there is a painful contact dysesthesia in the distribution of the cutaneous branches of the femoral nerve, without definite sensory loss. The long-term prognosis is good, regardless of the quality of glycemic control.^[36] In a fifth of the patients that we investigated for this syndrome relapses occurred on the other side of the body within a few months.^[37] The clinical features of PDN, with its frequent motor involvement, asymmetry of the deficit, and gradual yet often incomplete spontaneous recovery, differ markedly from those of LDDP, in which motor signs are seen only in extreme cases, and in which the condition never improves.

Multifocal Diabetic Neuropathy. In a small proportion of patients with diabetes a multifocal diabetic neuropathy (MDN) is observed, with successive involvement over several weeks or months of roots and nerves of the lower limbs, trunk and upper extremities, sometimes with a relapsing course.^[38] The distal parts of the lower limbs are invariably involved unilaterally or bilaterally, and there are also proximal deficits in most patients. Truncal and upper limb nerves are less commonly affected. The cerebrospinal fluid protein level is increased in most patients. Electrophysiological testing demonstrates an axonal pattern. Multifocal neuropathy is by no means specific to diabetic patients, underlining the need to exclude a superimposed cause of neuropathy in this setting.

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