Focal And Multifocal Limb Neuropathy

Isolated involvement of peripheral nerve of the limbs including radial, median, and ulnar nerves in the upper limbs and of the peroneal nerve for the lower limbs, occurs in patient with diabetes. It is sometimes, difficult to know whether it is a manifestation of increased liability of nerves to pressure palsy in common sites of entrapment in patients with diabetes, or a specific diabetic neuropathy. In other cases development of a senso-rimotor deficit in the territory of one or several nerve trunks occur without evidence of a superimposed cause for neuropathy. Such cases are extremely rare considering the frequency of distal symmetrical diabetic neuropathy and should always be investigated as in patients without diabetes. In particular, it is necessary to perform electrophysiological testings to enable a more accurate localization of the lesions, and when clinical and electrophysiological data point to spinal root lesions, magnetic resonance imaging of the spine has to be performed, or any other investigation needed to exclude another cause of neuropathy. When nerve trunks are clearly affected clinically and electrophysiologically, a nerve and muscle biopsy in an affected territory should be considered to exclude such causes as necrotizing arthritis, sarcoidosis, or leprosy. In some cases however, no other cause than diabetes is found and the diagnosis of diabetic neuritis is likely. In the lower limbs, the most common pattern of focal neuropathy is that of proximal sensory and motor manifestations. It is worth noting that markers of systemic inflammation are normal in diabetic multifocal neuropathy, but dramatic weight loss is common.

PDN of the Lower Limbs

Patients with diabetes, usually more than 50 years of age, might also present with proximal neuropathy of the lower limbs characterized by a variable degree of pain and sensory loss associated with uni- or bilateral proximal muscle weakness and atrophy. This syndrome, which was originally described by Bruns in 1890 (20) has been subsequently reported under the terms of diabetic myelopathy (21), diabetic amyotrophy (22), femoral neuropathy (23,24), PDN (25,26), femoral-sciatic neuropathy (27), and the Bruns-Garland syndrome (28,29). The neurological picture is limited to the lower limbs and is usually asymmetrical (30). Clinically, the different patterns and the course of PDN strikingly differ from those of DSSP, suggesting different pathophysiological features. In a recent study with 27 patients (31), 24 with type 2 diabetes and 3 with type 1 diabetes had a mean age at diagnosis of 62 years (range 46-71) and the male: female ratio was 16:11.

The onset of the neuropathy is acute or subacute. The patient complains of numbness or pain of the anterior aspect of the thigh, often of the burning type and worse at night. Difficulty in walking and climbing stairs occurs because of weakness of the quadriceps and iliopsoas muscles. Muscle wasting is also an early and common phenomenon, which is often easier to palpate than to observe in fatter patients. The patellar reflex is decreased or more often abolished. The syndrome progresses during weeks or months in most cases, then stabilizes and spontaneous pains decrease, sometimes rapidly. In many instances, as in those originally reported, there is no any marked or sensory loss, as emphasized by Garland (22) who found inconstant extensor plantar response and increased cerebrospinal fluid (CSF) protein content, felt that they resulted from a metabolic myelopathy in patients who were treated for diabetes, but not under full diabetic control. In approximately, one-third of the patients there is a definite sensory loss on the anterior aspect of the thigh, and in the others a painful contact dysesthesia in the distribution of the cutaneous branches of the femoral nerve, without definite sensory loss.

Bruns (20) who had described this condition, found in 1890 that the disorder was reversible only by dietetic restriction. Garland (22) also noticed that in four of his five patients there had been a striking recovery of power, with less obvious improvement of muscle wasting. Most of the features identified by Garland were subsequently confirmed, including the usual good long-term prognosis, independently of the quality of diabetic control.

In most cases, the patient's condition improves after months, but sequelae including disabling weakness and amyotrophy, sensory loss, and patellar areflexia are common (31,32). In a recent survey of long-term follow-up of upto 14 years, recovery began after a median interval of 3 months (range 1-12 months) (31). Pain was the first symptom to improve, resolution being comparatively rapid, beginning within a few weeks and being almost completed by 12 months. Residual discomfort in the patients of Coppack and Watkins took up to 3 years to subside. Motor recovery was satisfactory and none of their 27 cases showed disabling residual deficits, but seven complained of some persisting weakness and significant wasting of the thigh was evident in half of the cases (31). Denervation atrophy found in the muscle samples fits well with the long-term, or permanent weakness and amyotrophy that often affected distal muscles. Relapses on the other side are common, sometimes in spite of good diabetic control. In one-fifth of the patients that were investigated for this syndrome relapses occurred on the other side within a few months, the same proportion as in (31). Thus, the clinical features of PDN with frequent motor involvement, asymmetry of the deficit, gradual yet often incomplete spontaneous recovery, markedly differ from those of DSSP in which the length dependent symmetrical sensory deficit is associated with motor signs only in extreme cases and which virtually never improves spontaneously. In the syndrome described by Garland as "diabetic amyotrophy" motor manifestations are more prominent and both sides are affected, but the syndrome is a variant of PDN, as lesions of the sensory branch of the femoral nerve are also present in patients who have no sensory signs or symptoms (32).

Electrophysiological Studies

Needle electromyography reveals signs of denervation in affected muscles with spontaneous fibrillation, usually bilaterally even in cases with weakness restricted to one side. In more severe cases there may be evidence of widespread denervation affecting distal leg muscles as well and also those innervated by the lower thoracic spinal roots. In cases of long duration, motor unit potentials are of increased amplitude, reflecting reinnervation by collateral sprouting from surviving motor axons. The motor action potentials might be polyphasic and of low amplitude leading to the suspicion of myopathy (33). Nerve conduction studies indicate axonal loss rather than demyelination (26) and the compound muscle action potential in the quadriceps muscles on femoral nerve stimulation is reduced in amplitude. The F wave latencies to distal muscles (34,35) are difficult to interpret in view of the frequent coexistence of a distal polyneuropathy (26,36,37).

Diabetic Cranial Neuropathy

Fig. 1. One micron thick cross section of a biopsy specimen of the intermediate cutaneous nerve of the thigh from a patient with NIDDM who presented with proximal, purely motor, neuropathy of the lower limbs. There was no sensory loss upon examination. Note the striking reduction in the density of nerve fibers with several regenerating axons forming clusters (arrows). Thionin blue staining. Magnification: x1000.

Fig. 1. One micron thick cross section of a biopsy specimen of the intermediate cutaneous nerve of the thigh from a patient with NIDDM who presented with proximal, purely motor, neuropathy of the lower limbs. There was no sensory loss upon examination. Note the striking reduction in the density of nerve fibers with several regenerating axons forming clusters (arrows). Thionin blue staining. Magnification: x1000.

Pathological Aspects of PDN

In a recent pathological study of biopsy specimens of the intermediate cutaneous nerve of the thigh, a sensory branch of the femoral nerve, which conveys sensation from the anterior aspect of the thigh, a territory commonly involved in PDN it is found that the pathology of proximal nerves varied with the clinical aspects of the neuropathy (32). Patients with the most severe sensory and motor deficit examination of the biopsy specimen revealed lesions characteristic of severe nerve ischemia, including total axon loss in two patients with the most severe deficit, and centrofascicular degeneration of fibers associated with a large number of regenerating fibers in one (Fig. 1), following a pattern of axonal loss observed in clinical and experimental nerve ischemia (38,39). Lesions of nerve fibers coexisted with occlusion of a perineurial blood vessel in one of the patients, in keeping with the only detailed postmortem study of PDN available (40) in which the authors found a small infiltration with mononuclear cells associated with the occlusion of an interfascicular artery of the obturator nerve in a patient with proximal and distal deficit of the left lower limb. In a patient who developed a rapid, asymmetrical, distal, sensorimotor deficit shortly after the onset of the proximal deficit, recent occlusion of a perineurial blood vessel and perivascular, perineurial, and subperineurial inflammatory infiltration with mononuclear cells were demonstrated, along with axonal degeneration of the majority of nerve fibers of the superficial peroneal nerve. In the other patients, lesions of nerve fibers and of endoneurial capillaries were similar to those observed in the sural nerve in diabetic patients with symptomatic DSSP. Mixed, axonal, and demyelinative nerve lesions were associated with increased

Segmental Demyelination

Fig. 2. Consecutive segments of groups of teased nerve fibers to illustrate the mixture of axonal degeneration (fiber 3) and segmental demyelination (fiber 2) and remyelination (fiber 1) observed in the intermediate cutaneous nerve of the thigh from a patient with clinically purely motor proximal diabetic neuropathy.

Fig. 2. Consecutive segments of groups of teased nerve fibers to illustrate the mixture of axonal degeneration (fiber 3) and segmental demyelination (fiber 2) and remyelination (fiber 1) observed in the intermediate cutaneous nerve of the thigh from a patient with clinically purely motor proximal diabetic neuropathy.

endoneurial cellularity made of mononuclear cells that suggested the presence of a low grade endoneurial inflammatory process in four of them (Fig. 2). In a recent study of patients with extremely painful PDN, similar inflammatory lesions with B and T lymphocytes mixed with macrophages were found (41). The patients who were already treated with insulin for weeks or months, became painless within days after performance of the biopsy, without additional treatment (Fig. 3). These observations show that the presence of inflammatory infiltrates does not preclude spontaneous recovery (41).

The relationship between the occurrence of inflammatory infiltrates, vasculitis, and diabetes is not clear. Small inflammatory infiltrates have been occasionally encountered in sural nerve biopsy specimens of patients with diabetes with neurological deficit (42) and in autonomic nerve bundles and ganglia (43). Lesions of nerve fibers and of blood vessels because of diabetes might trigger an inflammatory reaction and reactive vas-culitis in some patients; alternatively diabetes might make the nerves more susceptible to intercurrent inflammatory or immune processes. In both cases, lesions of epi- or per-ineurial blood vessels can induce ischemic nerve lesions responsible for severe proximal sensory and motor deficits. Conversely, in milder forms the lesions are more reminiscent of those observed in distal symmetrical polyneuropathy.

Multifocal Diabetic Neuropathy

In a small proportion of patients with diabetes a multifocal neuropathy is observed, with successive or simultaneous involvement during weeks or months of roots and nerves of the lower limbs, the trunk, and upper extremities. Prospectively, 22 consecutive patients with diabetes were studied with MDN for which other causes of neuropathy were excluded by appropriate investigations, including biopsy of a recently affected sensory nerve (44). Three patients had a relapsing course, the others an unremitting subacute-progressive course. Painful multifocal sensory-motor deficit progressed during 2-12 months. Distal lower limbs were involved in all patients, unilaterally in seven, bilaterally in the others, with an asynchronous onset in most cases. In addition, proximal deficit of the lower limbs was present on one side in seven patients, on both sides in six. Thoracic radiculoneuropathy was present bilaterally in two patients, unilaterally in one. The ulnar nerve was involved in one patient, the radial nerve in two. The cerebrospinal fluid protein ranged from 0.40 to 3.55 g/L; mean: 0.87 g/L. Electrophysiological testing showed severe, multifocal, axonal nerve lesions in all cases. MDN is comparable with

Nerve Tease Biopsy Sections

Fig. 3. Paraffin section of the a nerve specimen from a patient with painful proximal diabetic neuropathy who recovered spontaneously after performance of the biopsy of the intermediate cutaneous nerve of the thigh. Note the conspicuous inflammatory infiltration of the epineurium and perineurium (arrow). Immunolabeling showed a mixture of B and T lymphocytes with a few macrophages. H&E staining. Magnification: x250.

Fig. 3. Paraffin section of the a nerve specimen from a patient with painful proximal diabetic neuropathy who recovered spontaneously after performance of the biopsy of the intermediate cutaneous nerve of the thigh. Note the conspicuous inflammatory infiltration of the epineurium and perineurium (arrow). Immunolabeling showed a mixture of B and T lymphocytes with a few macrophages. H&E staining. Magnification: x250.

the lumbosacral radiculoplexus neuropathy (45). However, because this subacute neuropathy can also affect territories beyond the lumbosacral area, multifocal neuropathy seems more appropriate. It is also obvious that multifocal neuropathy or lumbosacral radiculoplexopathy is not specific to patients with diabetes, as further shown (46), which underlines the need to exclude other causes of neuropathy in this setting, including a superimposed cause in patients with diabetes, such as necrotizing arthritis or chronic inflammatory demyelinating polyneuropathy that require specific treatment (47).

Pathological Aspects of PDN

Asymmetrical axonal lesions were present in all nerve specimens of patients with MDN. The mean density of myelinated and of umyelinated axons was reduced to 1340 per mm2 of endoneurial area and to 5095 per mm2 (extremes: 0-26,600), respectively. On teased fiber preparations one-third of the fibres were at different stages of axonal degeneration, whereas 7% showed segmental demyelination or remyelination. Necrotizing vasculitis of perineurial and endoneurial blood vessels were found in six patients. Evidence of present or past endoneurial bleeding that included seepage of red cells, haemorrhage, and/or ferric iron deposits were found in the majority of the specimens. Perivascular mononuclear cell infiltrates were present in the nerve specimens of 21/22 patients, prominently in 4 patients. In comparison, nerve biopsy specimens of 30 patients with severe DSSP showed mild epineurial mononuclear cell infiltrate in one patient and endoneurial seepage of red cells in one. Thus, it is believed that MDN is related to precapillary blood vessel involvement in older patients with diabetes with a secondary inflammatory response.

Besides the high frequency both of endoneurial bleeding and of inflammatory infiltrates, occlusion of small- and middle-sized epineurial and perineurial arteries differentiate MDN from DSP. The intensity and distribution of the lesions seemed more severe in MDN than in PDN, but both patterns can be included in multifocal diabetic neuropathies. The outcome is better in MDN than in DSP. Improvement occurs in all patients after a few months, but sequelae are common.

Focal Neuropathy of the Upper Limbs

Focal nerve lesions of the upper limbs are very uncommon in diabetes, and another cause must always be looked for in this setting. They occurred in the setting of MDN in 3/22 patients of our series. Besides these patients only two patients were seen with painful ulnar nerve involvement, two patients with a radial nerve palsy, and one patient who developed brachial neuritis after a proximal neuropathy of the lower limbs, which could be attributed to diabetes. Proximal weakness of the upper limbs, as it appears in the lower limbs, is very uncommon, and seems to affect predominantly muscles supplied by the C5-C6 spinal roots (48).

Truncal Neuropathy

Trunk or thoracoabdominal neuropathy affects almost only older subjects with diabetes (49). It is unilateral or predominantly so. The onset is abrupt or rapid, with pains or dysesthesiae as the main feature. The pain might have a radicular distribution and is made worse by contact and at night. Weakness of abdominal muscles occurs (50). Thoracic or truncal neuropathy should not be confused with sensory loss that affects the anterior aspect of the trunk in severe forms of length dependent neuropathy, which is virtually never painful on the trunk (51).

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