Brain, Vol. 126, No. 2, 376-385,
February 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg029
Inflammatory vasculopathy in multifocal diabetic neuropathy
1 Service de Neurologie and Laboratoire Louis Ranvier, and 2 Laboratoire de Neuropathologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris and Université Paris-sud, France
Correspondence to: Professor Gérard Said, Service de Neurologie, Centre Hospitalier Universitaire de Bicêtre, 94275 Le Kremlin Bicêtre, France E-mail: gerard.said{at}bct.ap-hop-paris.fr
Received July 8, 2002. Revised August 12, 2002. Accepted August 23, 2002.
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Summary |
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Besides the common distal symmetrical sensory–motor polyneuropathy (DSP) that is often associated with autonomic dysfunction, diabetic patients may develop multifocal sensory–motor deficits (MDN) secondary to roots, plexus and nerve trunk involvement. Nerve ischaemia has been suggested as a common mechanism for the different patterns of diabetic neuropathies, yet the important clinical differences that exist between DSP and MDN suggest concurrent factors. In order to learn more on the subject, we prospectively studied 22 consecutive diabetic patients with MDN, for which other causes of neuropathy were excluded by appropriate investigations, including biopsy of a recently affected sensory nerve. Three patients had a relapsing course, and the others an unremitting subacute-progressive course. Painful MDN progressed over 2–12 months. The neurological deficit predominated in distal lower limbs which were involved in all patients, unilaterally in seven, bilaterally in the others, with an asynchronous onset in most cases. In addition, a proximal deficit of the lower limbs was present on one side in seven patients, and on both sides in six. Thoracic radiculoneuropathy was present bilaterally in two patients, and unilaterally in one. The ulnar nerve was involved in one patient, and the radial nerve in two. The CSF 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. Asymmetrical axonal lesions were found in all nerve specimens. The mean density of myelinated axons was reduced to 1340 ± 1070 per mm2 of endoneurial area versus 8370 ± 706 myelinated fibres/mm2 in controls. The mean density of unmyelinated fibres was reduced to 5095 ± 6875 per mm2 (extremes: 0–26 600). On teased fibre preparations, 34 ± 31% of the fibres were at different stages of axonal degeneration (extremes 0–99%); 7 ± 6% of the fibres showed segmental demyelination or remyelination. Necrotizing vasculitis of perineurial and endoneurial blood vessels were found in six patients. Endoneurial seepage of red cells was present in 11 specimens, and endoneurial haemorrhage in five. Ferric iron deposits that characterize previous bleeding were found in seven patients, including two who had no red cells in the endoneurium. Perivascular mononuclear cell infiltrates were present in the nerve specimens of 21 out of 22 patients, prominently in four patients. In comparison, nerve biopsy specimens of 30 patients with severe distal symmetrical diabetic polyneuropathy showed mild epineurial mononuclear cell infiltrate in one patient and endoneurial seepage of red cells in another. We conclude that MDN is related to pre-capillary blood vessel involvement in elderly diabetic patients with a secondary inflammatory response.
Keywords: diabetic neuropathy; nerve biopsy; multifocal diabetic neuropathy; vasculitic neuropathy
Abbreviations: DSP= distal symmetrical polyneuropathy; MDN = multifocal diabetic neuropathy; PDN = proximal diabetic neuropathy
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Introduction |
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A wide range of neuropathic syndromes are observed in diabetic patients, the most common of which is the distal symmetrical predominantly sensory–motor, polyneuropathy (DSP) that progresses following a fibre length-dependent pattern, often associated with autonomic disturbances (Thomas and Tomlinson, 1993
; Said, 1996). Some diabetic patients develop proximal neuropathy of the lower limbs (Raff and Asbury, 1968; Raff et al, 1968; Asbury 1987; Said et al., 1994; Said and Thomas, 1999) characterized by weakness and pain of proximal lower limbs, in which setting inflammatory nerve lesions and vasculitis have been documented (Said et al., 1994; Krendel et al., 1995; Llewelyn et al., 1998; Dyck et al., 1999; Kelkar et al., 2000). Besides these two well characterized patterns of neuropathy, some diabetic patients are disabled by a severe, subacute, multifocal sensory–motor neuropathy (MDN) that massively predominates in distal lower limbs, and variously affects other territories including proximal lower limbs, thoracic nerves and the upper extremities. Although a common ischaemic mechanism has been suggested for the different patterns of diabetic neuropathy, the self-limited, yet protracted course of MDN and its clinical distribution are quite different from those of DSP. In an attempt to understand better the pathophysiology of MDN and the relationship between the different patterns of diabetic neuropathy, we performed a prospective clinicopathological study of 22 consecutive diabetic patients with multifocal neuropathy and subsequently compared the lesions of nerve blood vessels found in nerve biopsy specimens with those of a series of patients with severe distal symmetrical sensory polyneuropathy.
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Patients and methods |
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Patient inclusion criteria
Insulin- or non-insulin-dependent (NIDDM) diabetic patients with motor and sensory deficit affecting simultaneously or successively more than one nerve or root territory with asymmetric or asynchronous motor and sensory deficit in a radicular or nerve trunk distribution in distal lower limbs were included in the study. Patients gave informed consent to be included in the study, which was approved by the Bicêtre Hospital Ethics Committee.
Patient exclusion criteria
Any detectable cause of neuropathy other than diabetes was excluded after complete workout, including nerve and muscle biopsy, confirmed by long-term follow-up. Diabetic patients with generalized demyelinating polyneuropathy fulfilling electrophysiological or neuropathological criteria for chronic inflammatory demyelinating polyneuropathy were excluded, as well as those with clinical or biological markers of a polysystemic disorder, abnormal blood cell count, presence of monoclonal gammopathy or abnormal chest radiogram. Patients with isolated sensory manifestations or with isolated proximal neuropathy were also excluded.
Population
Twenty-two diabetic patients, 13 females, nine males; mean age: 65 ± 9 years, range 41–81 years were included in the study from May 1992 to February 2000.
Clinical assessment
Neurological examination was carried out in all patients. Muscle testing was performed giving a five-grade scale motor score according to the Medical Research Council for global motor scores. Light touch, pinprick, temperature sensation at +4°C and at +40°C, vibratory sensation and position sense were tested to explore the functions of different subpopulations of axons.
Laboratory investigations
These included routine blood tests, CSF examination and other appropriate investigations to exclude causes of neuropathy other than diabetes, including familial, toxic, drug abuse, nutritional, metabolic, dysglobulinaemic, amyloid, inflammatory and malignancy. All patients had routine glycaemic control, measurements of glycosylated haemoglobin, assessment of renal function and ophthalmological examination.
Neurophysiological investigations
Electrophysiological tests included evaluation of motor and sensory conduction velocities in all four limbs; nerve and muscle compound action potentials and nerve conduction velocity, and distal motor and F-wave latencies measured by standard methods. Sensory nerve conduction studies were performed on sural, superficial peroneal, median, radial and ulnar nerves. Motor studies included peroneal, posterior tibial, radial, median and ulnar nerves. Both sides were studied. The sensory action potentials (SAPs) were recorded antidromically. When SAPs were not detectable by surface electrodes, the near-nerve needle method was used. EMG examination of muscles in clinically affected territories was performed using a monopolar needle. A summary of relevant results is given in Table 1.
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Morphological studies
After written informed consent, a nerve biopsy was performed in a territory recently affected clinically. The superficial peroneal nerve and the neighbouring peroneus brevis muscle were sampled during the same procedure in 20 patients. The superficial radial nerve was biopsied in one patient (patient 4) and the intermediate cutaneous nerve of the thigh and the adjacent quadriceps muscle in one (patient 22).
The nerve samples were fixed at 4°C in 3.6% glutaraldehyde, buffered at pH 7.4. One nerve fragment was embedded in paraffin, cut at 6 µm thickness and examined after haematoxylin and eosin staining. Serial sections of all paraffin-embedded specimens were examined.
Another fragment was post-fixed in 1% osmium tetroxide in buffer for 3 h at 4°C and embedded in epon. Thionin-stained 1 µm thick transverse sections were used for morphometry and 0.1 µm thick sections stained with uranyl acetate and lead citrate for electron microscopic examination. The density of myelinated fibres was calculated on enlarged photographic montages of 1 µm thick sections and compared with control values of the laboratory.
Teased fibre study
After post-fixation in osmium tetroxide, another nerve fragment was macerated in 66% glycerin for 48 h before dissection in pure glycerin. One hundred consecutive nerve fibres were isolated over >10 internodes, and classified according to their morphology into normal fibres; fibres showing segmental abnormalities of myelination; and fibres showing Wallerian degeneration as early and late stages of Wallerian degeneration following the size of row of ovoids and balls of myelin debris that decrease in size with time.
Immunopathology
Immunolabelling of cellular infiltrates was performed on frozen and/or paraffin-embedded specimens of patients whose nerve biopsy specimens showed inflammatory infiltrates, namely in specimens of patients 3, 4, 7–11, 14, 16, 17 and 19–22. Monoclonal antibodies to common leukocyte antigens, CD68, CD3, CD4, CD8 and CD20 were thus used (Dako, Denmark).
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Results |
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Diabetic status
Patients 2 and 4 had insulin-dependent diabetes mellitus for >35 years, with glycosylated haemoglobin at 7 and 8.8%, respectively, without renal or retinal complication. Twenty patients had NIDDM, which had been discovered on average 11.7 ± 7.8 years prior to the onset of neuropathic symptoms; extremes: 6 months to 30 years. Seven patients with NIDDM required treatment with insulin. In the NIDDM patients, the glycosylated haemoglobin level was between 6 and 8% in nine (patients 1, 3, 5, 6, 9, 12, 16, 17 and 22); between 8 and 10% in nine (patients 2, 4, 8, 10, 11, 14, 15, 18 and 20); and >10% in four (patients 7, 13, 19 and 21) (N < 6 IU). Blood urea and creatinine levels were normal in all patients; microalbuminuria was above normal values in three patients (patients 4, 12 and 13). Patients 16 and 22 had mild proteinuria. Background retinopathy was present in four patients (patients 1, 8, 10 and 15); proliferative retinopathy was present in patient 12 only. Patients 1, 5 and 15 had symptomatic macroangiopathy, affecting the lower limbs in patients 1 and 5, and the coronary arteries in patient 15.
Neurological data at referral
The onset period before referral extended over 2–12 months (see Table 1). Patients 1, 20 and 19 had two neuropathic episodes within 1, 2 and 3 years, respectively, with spontaneous remission after the first episode. Pain and motor deficit of subacute onset and progression were the most constant complaints. Only one patient (patient 17) did not complain spontaneously of pain. Spontaneous pains, often burning, more disturbing at night, and contact dysaesthesia had been present for several weeks in the others. Pains were graded as mild to moderate in eight patients (patients 2, 4–7, 11, 12 and 19) and severe in the other 13 patients, who all required administration of opiates.
Neuropathic manifestations started in the distal lower limbs in 16 patients (patients 1, 2, 4–10, 12, 14, 16 and 18–21). At referral, all patients had a motor and sensory deficit of the distal lower limbs. The motor deficit was severe in most patients, with distal strength at 0–2 on a scale of 5. In seven patients, the neurological deficit was unilateral and predominated in the peroneal nerve territory (patients 1, 6, 8, 9, 14, 19 and 22). In the other 15 patients, the distal deficit was bilateral, with an asynchronous onset in most cases. Proximal deficit of the lower limbs was the first manifestation in three patients (patients 3, 11 and 22). At referral, the proximal deficit was present in 13 patients, unilaterally in seven patients (patients 4, 6, 8, 15, 19, 21 and 22) and bilaterally in six (patients 2, 7, 11, 13, 14 and 16). Bilateral thoracic radiculoneuropathy with spontaneous burning pains, hypoaesthesia and allodynia in the corresponding territory was the first manifestation in two patients (patients 13 and 15). One additional patient had a unilateral thoracic neuropathy (patient 17). The ulnar nerve was involved in patient 1. The median nerve was affected on both sides, in patient 2, without electrophysiological signs of carpal tunnel entrapment. A motor and sensory deficit in the radial nerve territory was present in two patients (patients 1 and 4).
Symptomatic autonomic disturbances included some degree of impotence in all male patients, and sphincter disturbances in patients 6 and 16. Patients 2 and 16 had asymptomatic light-near dissociation of pupillary reflexes. Postural hypotension and gastrointestinal autonomic neuropathy were not found. The CSF was acellular in all patients; the CSF protein ranged from 0.40 to 3.55 g/l; mean: 0.87 g/l.
Electrophysiological data
All patients had severe, multifocal, axonal neuropathy, with unexcitable nerves or a major decrease of nerve action potentials in affected territories in all cases. Sural nerve sensory action potentials were abolished in 18 patients. They were within the normal range in patients 4, 8, 17 and 22. Conduction blocks were not found.
Morphological data
Alteration of nerve fibres observed by nerve cross-section
Asymmetrical axonal lesions, within and between nerve fascicles, were a consistent finding. The mean density of myelinated axons was reduced to 1340 ± 1070 per mm2 of endoneurial area (extremes ranged from 4840 fibres/mm2 in patient 14 to 15 myelinated fibres/mm2 in patient 8), versus 8370 ± 706 myelinated fibres/mm2 in the controls. On electron microscopic examination, the nerve fibre abnormalities included demyelination and remyelination, axonal degeneration and clusters of regenerating myelinated and unmyelinated axons. Major fibre loss was noted in nerve biopsy specimens of patients 4, 8 and 9, with only fibroblasts and Schwann cell processes forming pockets of collagen surviving. The mean density of unmyelinated fibres was reduced to 5095 ± 6875 per mm2 (extremes: 0–26 600), versus an average 32 600 ± 3500 per mm2 in non-diabetic control patients. Clusters of regenerating myelinated and unmyelinated axons were common in nerve specimens of patients 1–3, 5, 15, 16 and 19. Rigid residual basal lamina often persisted around clusters of regenerating axons, single myelinated fibres and bundles of collagen fibres.
Nerve teased fibre preparations
On teased fibre preparations, 34 ± 31% of the fibres were at different stages of axonal degeneration (extremes 0–99%); 7 ± 6% of the fibres showed segmental abnormalities of the myelin sheath including demyelinated and short, thinly remyelinated internodes (extremes: 0–25%). Demyelination/remyelination was noted in 10% or more of the surviving fibres in six patients (patients 1, 3, 7, 12, 17 and 20) (see Fig. 1).
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Nerve blood vessels and endoneurial red cell seepage
Diabetic microangiopathy, characterized by increased capillary wall and basement membrane thickness on 1 µm thick sections and on electron microscopic examination were observed in 20 specimens, although with a variable intensity (Fig. 2). Necrotizing vasculitis of perineurial and endoneurial blood vessels was found in six patients (patients 7, 9, 12, 14, 15 and 21) in association with mononuclear cell infiltrates (Fig. 3). In some sections, however, fibrinoid necrosis affected only part of the vessel, without inflammatory infiltration.
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Red cell seepage in the endoneurium was observed in 11 patients (patients 1, 2, 9–12, 15–18 and 21), with frank haemorrhage in five of them (patients 2, 3, 11, 12 and 18). Ferric iron deposits were identified by Perls staining in seven patients (patients 1, 7, 9, 10, 15, 17 and 21). Thus, a total of 12 patients had signs of previous and/or current endoneurial bleeding. On 1 µm thick preparations and on electron microscopic examination of thin sections, many of the red cells were engulfed by phagocytic cells (Figs 1 and 4). None of the patients was taking anti-platelet aggregants or anticoagulants during the weeks that preceded performance of the biopsy. In one patient (patient 21), a longitudinal paraffin section of the serial sections clearly showed a damaged blood vessel bleeding in the endoneurium (Fig. 4). The end stage of the process is characterized by complete occlusion of the perineurial blood vessel associated with major axon loss, but still with endoneurial red cells (Fig. 6)
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Muscle biopsy findings
Examination of serial sections of muscle biopsy specimens showed neurogenic atrophy in 11 patients; Perls staining was positive in patients 1 and 9; inflammatory infiltrates were present in patients 2, 5 and 10; necrotizing vasculitis in patient 7; and non-necrotizing vasculitis in patient 9.
Inflammatory infiltrates
Inflammatory infiltrates were present in the nerve specimens of 21 out of 22 patients, prominently in patients 3, 12, 13 and 18 (Fig. 2). They were made of mononuclear cells infiltrating the perineurium and epineurial blood vessels in all, and endoneurial capillaries in eight of them (patients 2, 3, 4, 6, 13, 14, 15 and 18). Perivascular infiltrates were composed of a mixture of CD4/CD8 T cells and macrophages. Endoneurial macrophages labelled with anti-CD68 monoclonal antibodies were closely associated with myelin debris that resulted from axonal degeneration of myelinated fibres. Polymorphonuclear cells were seldom seen in the perivascular infiltrates.
After these findings, we re-examined cross and longitudinal plastic and paraffin sections of nerve biopsy specimens of 30 patients with different patterns of severe distal symmetrical diabetic polyneuropathy, including some patients reported in previous series (Said et al., 1983, 1992, 1998). Although severe diabetic microangiopathy was observed in all those with longstanding diabetes, only one of these nerve specimens showed mild epineurial mononuclear cell infiltrate and one had minimal endoneurial seepage of red cells.
Follow-up evaluation
Eighteen patients were followed-up in our service for 2–10 years. Hyperglycaemia was well controlled in all patients. Pain subsided spontaneously within a few weeks in four patients (patients 1, 5, 11 and 19). Of the four patients who received high doses of immunoglobulins, pain subsided in one (patient 3). Prednisone 0.75 mg/kg/day was prescribed in 10 patients. After 3–4 weeks, prednisone was tapered gradually to zero over the following 6 months on average. Treatment of diabetes required adjustment with insulin in all the patients who received corticosteroids. Pain subsided within a few days in all patients treated with corticosteroids (patients 4, 6, 7, 9, 13–15, 21 and 22). In patient 22, pain recurred in the radial nerve territory after withdrawal of corticosteroids, and then decreased spontaneously over 1 year. Gradual improvement of motor deficit took several months. Minor to moderate residual deficit persisted in half of the patients.
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Discussion |
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All patients included in this series manifested a multifocal motor and sensory neuropathy that markedly predominated in distal lower limbs. Unilateral or asymmetrical distal motor and sensory deficit was associated with involvement of proximal lower limbs in half of the patients, with thoracic neuropathy in three, and with upper limbs sensory–motor deficit in six patients. In all patients, pain and sensory–motor deficit were prominent, with few or no symptoms of autonomic disturbances.
Multifocal neuropathy and the other patterns of neuropathy in diabetic patients
Multifocal diabetic neuropathy differs markedly from the common distal symmetrical, predominantly sensory, polyneuropathy that progresses following a fibre length-dependent pattern. In the latter, autonomic disturbances are prominent and sometimes life threatening, and motor deficit is very uncommon. Although reported in early descriptions of severe diabetic polyneuropathy, at a time when no treatment of diabetes was available (Charcot, 1890), symptomatic motor deficit is seldom observed in patients with DSP in industrialized countries. Motor deficit is a late event in the natural history of DSP. When observed in this setting, motor deficit is always bilateral, distal and roughly symmetrical. Its onset is also more gradual and indolent, with an unrelenting course. In contrast, in patients with MDN, the onset of the neurological deficit is acute or subacute, sometimes with spontaneous remissions and relapses, as in three patients in this series. In this respect, MDN can be paralleled by proximal diabetic neuropathy (PDN) in which patients with documented inflammatory nerve lesions also have a spontaneously favourable outcome (Said et al., 1997).
Patients of this series differ from the usual pattern of PDN, in which condition proximal involvement is a constant feature and distal neurological deficit is only occasional. However, it is our opinion that PDN, as well as the cases of ischaemic mononeuropathy multiplex (Raff and Asbury, 1968; Raff et al., 1968) and the recently termed diabetic lumbosacral radiculoplexus neuropathies (Dyck et al, 1999) are variants of MDN. Some patients with the so-called lumbosacral radiculoplexus neuropathies also had upper limb involvement. We think thus that the term multifocal neuropathy is more appropriate to this clinical pattern.
The occurrence of lumbosacral radiculoplexus neuropathy in non-diabetic patients has been underlined recently (Bradley et al., 1990; Dyck et al., 2000). In this respect, it is important to remember that none of the neuropathic patterns observed in diabetic patients is specific to this population. For example, proximal neuropathy was observed in diabetic patients in only 14 out of the 19 cases reported by Calverley and Mulder (1960). As a rule, when a diabetic patient manifests a peripheral neuropathy, causes other than diabetes must be excluded before concluding that the neuropathy is of diabetic origin (Mulder et al., 1961; Lozeron et al., 2002). The conjunction of a neuropathic pattern common in diabetic patients with the absence of another detectable cause of neuropathy is necessary to incriminate diabetes as the sole cause of the neuropathy.
Overlapping and association between the different patterns of diabetic neuropathy is common. Silent or symptomatic DSP, the most frequent type of diabetic neuropathy, is often associated with PDN (Bastron and Thomas, 1981). In a previous report, all 10 patients with PDN had signs of DSP, which was symptomatic in one patient only (Said et al., 1994). The same proportion of patients had MDN and signs of DSP in this series.
Acute or subacute, asymmetrical sensory–motor deficit can also be symptomatic of an acquired demyelinating polyneuropathy in a diabetic patient. Subacute or chronic inflammatory demyelinating polyneuropathy (CIDP) seems more common in diabetic patients than in the general population (Cornblath et al., 1987; Stewart et al., 1996). However, the higher frequency of CIDP in diabetic than in non-diabetic patients should be confirmed by epidemiological studies to determine whether or not diabetes is a risk factor for CIDP. The diagnosis of CIDP must be considered when a diabetic patient manifests a subacute neurological deficit with prominent loss of function of large myelinated fibres, namely motor deficit and loss of proprioception, which is not common in diabetic DSP. The results of electrophysiological testing point to a demyelinating process in diabetic CIDP, while it has an axonal pattern in MDN. In some cases, however, only the nerve biopsy permits identification of CIDP in this setting, due to the association with severe axonal loss related to pre-existing diabetic neuropathy.
Pathological findings
On a pathological basis, asymmetrical axonal loss within and between nerve fascicles and axonal degeneration were common in this series, which fits well with an ischaemic process (Said et al., 1988; Fujimura et al., 1991). The incidence of fibres showing segmental abnormalities, including recently demyelinated and segmentally remyelinated fibres, was relatively high in a few patients, which suggests that several mechanisms including demyelination secondary to axonal injury, a metabolic process due to hyperglycaemia and the consequences of endoneurial inflammatory infiltrates could play a role. Mononuclear cell infiltrates, consisting of CD8+, CD4+ and macrophages, were present in nearly all patients. In some of them, however, fibrinoid necrosis of the vessel wall was not associated with inflammatory infiltrates, which suggests that damage of the vessel wall was the first pathological event. Inflammatory infiltrates predominated around epineurial, perineurial and, less often, endoneurial blood vessels. In addition to the perivascular infiltrates, many endoneurial CD68-positive macrophages had been attracted by axonal and myelin debris during massive axonal degeneration.
Lesions of nerve blood vessels and endoneurial haemorrhage
Occlusion of epineurial and perineurial blood vessels was present in most cases. Extension of fibrinoid necrosis to endoneurial capillaries was also observed in some cases. Endoneurial haemorrhage and iron deposits were present in half of the nerve biopsy specimens. The presence of iron deposits in nerve biopsies from patients with lumbosacral radiculoplexus neuropathy was also emphasized recently by Dyck et al. (1999), but the presence of endoneurial bleeding had not been documented in this setting. Fresh blood in a nerve biopsy specimen suggests surgical trauma, in which case red blood cells are usually free in the epineurium and less often in the endoneurium. In the nerve specimens studied, phagocytosis of debris of red cells by endoneurial macrophages and the presence of iron deposits in nerve specimens cannot result from the surgical procedure, since both phenomena require time to develop. Endoneurial bleeding thus is definitely related to the pathological process.
Conclusion
Endoneurial bleeding is common in necrotizing vasculitis, and red cell seepage is observed in different patterns of inflammatory-infectious polyneuropathies. Demonstration of ongoing endoneurial bleeding with numerous Perls-positive iron deposits points to a sustained haemorrhagic process. Both inflammation, which makes the blood–nerve barrier more permeable to cells, and focal destruction of the vessel wall by fibrinoid necrosis can lead to endoneurial bleeding. However, haemorrhage of the type observed in some patients of this series occurs only in patients with necrotizing vasculitis of the polyarteritis nodosa type. Besides loss of weight, our patients had no general manifestation, organ involvement or biological markers of a general inflammatory illness. When present, necrotizing vasculitis affected epineurial, perineurial and often endoneurial blood vessels, but leukocytoclasia and polymorphonuclear cell infiltrates, which are classical features of polyarteritis nodosa, were uncommon in diabetic patients.
In spite of these differences, the focal and multifocal neuropathy observed in middle-aged diabetic patients fits well with our current knowledge of ischaemic neuropathy complicating occlusion of small and middle sized nerve arteries. In addition to the much higher frequency of endoneurial bleeding and of inflammatory infiltrates than in diabetic symmetrical sensory polyneuropathy, occlusion or necrosis of the small and middle sized epineurial and perineurial nerve arteries sharply differentiates the multifocal pattern from the distal symmetrical pattern of diabetic neuropathy. These findings suggest the presence of an inflammatory vasculopathy, which is different from diabetic microangiopathy, and probably results from damage of pre-capillary and small nerve artery walls by diabetes in elderly patients, at an age when atherosclerotic lesions are common.
Association of inflammation with atherosclerosis is increasingly recognized (Libby et al., 2002). It has been shown that after initiation of an atherogenic diet, patches of arterial endothelial cells begin to express on their surface selective adhesion molecules that bind to various classes of leukocytes. In particular, the role of vascular cell adhesion molecule-1 that binds the type of cells found in early human and experimental atheroma, the monocyte and T lymphocytes, has been shown recently in genetically engineered mice (Cybulsky et al., 2001). Hyperglycaemia associated with diabetes can also lead to modification of macromolecules by forming advanced glycation end products and can augment the production of proinflammatory cytokines (Libby et al., 2002). Inflammatory responses have also been observed in atherosclerotic lesions of the carotid artery (Carr et al., 1997; Jander et al., 1998). These findings may account for the presence of inflammatory arterial lesions in elderly diabetic patients. A superimposed immune mechanism triggered by altered vessel wall may also be considered.
The good response of these patients with refractory pain to short courses of corticosteroids is probably related to the control of the inflammatory reaction. The overall favourable course of neuropathic manifestations in patients with MDN contrasts with the gradual worsening, or at best an apparent steady state, of diabetic patients with a length-dependent polyneuropathy. In MDN, improvement is comparable with that observed in long-term follow-up of patients with necrotizing arteritis and ischaemic neuropathy. The discrepancy in the outcome of the two patterns of neuropathy strongly suggests that metabolic control plays a greater role in DSP than in MDN, and that nerve ischaemia secondary to lesions of pre-capillary blood vessels is far more important in MDN than in DSP.
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Acknowledgements |
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We wish to thank the following investigators for their collaboration: E. Kaloustian, F. Desmoulin, B. Bussel, O. Thurninger, A. Barré-Coignet, M.-G. Bousser; T. Albert, F. Elgrably, M. Letanoux, G. Slama, Martine Gayraud, Béatrice Flageul, P. Chanson, J. P. Usdin, Michel Hautecouverture, Isabelle Cerf-Payrastre, Corinne Delmer and Nicolas Miret.
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References |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Asbury AK. Focal and multifocal neuropathies of diabetes. In: Dyck PJ, Thomas PK, Asbury AK, Winegrad AI, Porte D, editors. Diabetic neuropathy. Philadelphia: W.B. Saunders; 1987. p. 45–55
Bastron JA, Thomas JE. Diabetic polyradiculopathy. Clinical and electromyographic findings in 105 patients. Mayo Clin Proc 1981; 56: 725–32.[Web of Science][Medline]
Bradley J, Thomas PK, King RH, Llewelyn JG, Muddle JR, Watkins PJ. Morphometry of endoneurial capillaries in diabetic sensory and autonomic neuropathy. Diabetologia 1990; 33: 611–8.[CrossRef][Web of Science][Medline]
Calverley JR, Mulder DW. Femoral neuropathy. Neurology 1960; 10: 963–7.
Carr SC, Farb A, Pearce WH, Virmani R, Yao JS. Activated inflammatory cells are associated with plaque rupture in carotid artery stenosis. Surgery 1997; 122: 757–64.[CrossRef][Web of Science][Medline]
Charcot JM. Sur un cas de paraplégie diabétique. Arch Neurol (Paris) 1890; 19: 305–30.
Cornblath DR, Drachman DB, Griffin JW. Demyelinating motor neuropathy in patients with diabetic polyneuropathy [abstract]. Ann Neurol 1987; 22: 126.
Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 2001; 107: 1255–62.[Web of Science][Medline]
Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999; 53: 2113–21.
Dyck PJ, Engelstad JN, Norell J, Dyck PJ. Microvasculitis in non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN): similarity to the diabetic variety (DLSRPN). J Neuropathol Exp Neurol 2000; 59: 525–38.[Web of Science][Medline]
Fujimura H, Lacroix C, Said G. Vulnerability of nerve fibres to ischaemia: a quantitative study and electron microscope study. Brain 1991; 114: 1929–42.
Jander S, Sitzer M, Schumann R, Schroeter M, Siebler M, Steinmetz H, et al. Inflammation in high-grade carotid stenosis. Stroke 1998; 29: 1625–30.
Kelkar P, Masood M, Parry GJ. Distinctive pathologic findings in proximal diabetic neuropathy (diabetic amyotrophy). Neurology 2000; 55: 83–8.
Krendel DA. Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 1995; 52: 1053–61.
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. [Review]. Circulation 2002; 105: 1135–43.
Llewelyn JG, Thomas PK, King RH. Epineurial microvasculitis in proximal diabetic neuropathy. J Neurol 1998; 245: 159–65.[CrossRef][Web of Science][Medline]
Lozeron P, Nahum L, Lacroix C, Ropert A, Guglielmi J-M, Said G. Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients. J Neurol 2002; 249: 569–75.[CrossRef][Web of Science][Medline]
Mulder DW, Lambert EH, Bastron JA, Sprague RG. The neuropathies associated with diabetes mellitus: a clinical and electromyographic study of 103 unselected diabetic patients. Neurology 1961; 11: 275–84.
Raff MC, Asbury AK. Ischemic mononeuropathy and mononeuropathy multiplex in diabetes mellitus. N Engl J Med 1968; 279: 17–21.[Web of Science][Medline]
Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol 1968; 18: 487–99.
Said G. Diabetic neuropathy: an update. J Neurol 1996; 243: 431–4.[CrossRef][Web of Science][Medline]
Said G, Thomas PK. Proximal diabetic neuropathy. In: Dyck PJ Thomas PK, editors. Diabetic neuropathy. 2nd edn. Philadelphia: W.B. Saunders; 1999. p. 474–80.
Said G, Slama G, Selva J. Progressive centripetal degeneration of axons in small fibre diabetic polyneuropathy. Brain 1983; 106: 791–807.
Said G, Lacroix-Ciaudo C, Fujimura H, Blas C, Faux N. The peripheral neuropathy of necrotizing arteritis: a clinicopathological study. Ann Neurol 1988; 23: 461–5.[CrossRef][Web of Science][Medline]
Said G, Goulon-Goeau C, Slama G, Tchobroutsky G. Severe early-onset polyneuropathy in insulin-dependent diabetes mellitus. A clinical and pathological study. N Engl J Med 1992; 326: 1257–63.[Abstract]
Said G, Goulon-Goeau C, Lacroix C, Moulonguet A. Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol 1994; 35: 559–69.[CrossRef][Web of Science][Medline]
Said G, Elgrably F, Lacroix C, Planté V, Talamon C, Adams D, et al. Painful proximal diabetic neuropathy: inflammatory nerve lesions and spontaneous favorable outcome. Ann Neurol 1997; 41: 762–70.[CrossRef][Web of Science][Medline]
Said G, Bigo A, Améri A, Gayno J-P, Elgrably F, Chanson P, et al. Uncommon early-onset neuropathy in diabetic patients. J Neurol 1998; 245: 61–8.[CrossRef][Web of Science][Medline]
Stewart JD, McKelvey R, Durcan L, Carpenter S, Karpati G. Chronic inflammatory demyelinating polyneuropathy (CIDP) in diabetics. J Neurol Sci 1996; 142: 59–64.[CrossRef][Web of Science][Medline]
Thomas PK, Tomlinson DR. Diabetic and hypoglycaemic neuropathy. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral neuropathy. 3rd edn. Philadelphia: W.B. Saunders; 1993. p. 1219–50.
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