The noradrenergic innervation of the vasa nervorum in old rats: a fluorescence histochemical study

The effect of ageing on the density and pattern of noradrenergic nerves in the perivascular nerve plexus supplying the vasa nervorum of the rat sciatic nerve was studied using combined catecholamine histofluorescence and quantitative image analysis techniques. The density of noradrenergic fibres around arteries and arterioles of the rat sciatic nerve vasa nervorum increased in the old animals. In contrast, no changes in perivascular nerve fibres supplying the veins and venules were found in the vasa nervorum of old rats. The increase in old age of noradrenergic innervation of arteries and arterioles of the vasa nervorum may be related to the pathogenesis of some peripheral nerve diseases.     

Microangiopathy of vasa nervorum in dysglobulinemic neuropathy

Thickening of vessel walls resulting from endothelial proliferation was observed in the vasa nervorum of eleven patients with peripheral neuropathy associated with dysglobulinemia. Electron microscopy showed endothelial proliferation accompanied by abnormal accumulation of masses of intracytoplasmic filaments in each case. Of the eleven patients with dysglobulinemia, nine had monoclonal gammopathy and two were found to have polyclonal elevation of gamma globulin levels. Symptoms of neuropathy characteristically preceded detection of serum protein abnormalities by months to years. Nerve fiber lesions involved primarily the axon in four cases; segmental demyelination was the principal abnormality in the other seven. Both abnormalities were present to some degree in all eleven patients. Biphasic myelinopathy with uniform separation of myelin lamellae attributable to globulin deposition was observed in four cases. The microvascular changes included endothelial cytoplasmic enlargement, virtually obliterating the vessel lumen in many instances, with thickening of pericytes, in which intracytoplasmic filaments were prominent and pinocytotic vesicles numerous. No extracellular filaments were noted, and amyloid stains were negative. Possible effects of these microvascular changes include ischemia resulting from severe vascular luminal narrowing, and altered vascular permeability. Severe loss of axons in this group of neuropathies may be the result of ischemia, whereas altered vascular permeability may admit globulin into the endoneurium, where it may directly affect the myelin sheath and precipitate demyelination.     

Peripheral and central nervous system involvement in essential mixed cryoglobulinemia: a case report

We describe a man with essential mixed cryoglobulinemia who developed peripheral neuropathy and multiinfarctual encephalopathy. Vasculitis was observed in the vasa nervorum and in the small vessels of the brain. The possible pathogenetic role of the cryoglobulins in the nervous system lesions is discussed.     

Occlusive microangiopathy by immunoglobulin (IgM-kappa) precipitation: pathogenetic relevance in paraneoplastic cryoglobulinemic neuropathy

Summary Histological, immunohistochemical and ultrastructural sural nerve and skin biopsy findings in a case of cryoglobulinemia secondary to an IgM-kappa-producing non-Hodgkin lymphoma are described. The main finding was an occlusive microangiopathy present in both the sural nerve and the skin. Widespread cryoglobulin deposits of the proliferated vasa nervorum were associated with pronounced changes probably evoked by ischemia. Moderate perivascular inflammation, but no florid vasculitis was additionally present. Our observations indicate that occlusive microangiopathy by precipitated cryoglobulins may be a relevant pathogenetic factor in cryoglobulinemic peripheral neuropathy.     

Behçet's disease associated with peripheral neuropathy

INTRODUCTION: The involvement of the peripheral nervous system in Beh?et's disease is very rare. CASE REPORT: We report a case of a 47-year-old man with a six-year history of Beh?et's disease and a two-year history of peripheral nervous system involvement. This patient presented with paraesthesia and weakness of the upper and lower limbs, diarrhea and erectile dysfunction. The electromyogram showed evidence of an axonal sensorimotor neuropathy and the nerve biopsy showed an axonal neuropathy. Routine blood tests were normal, there was no increase of serum creatine kinase, aspartate aminotransfease or lactate dehydrogenase and no signs of hyperthyroidism. Fibroscopy and colonoscopy showed no signs of entero-Beh?et. The patient was treated with prednisone, cyclophosphamide and carbamazepine with an improvement of paraesthesia. CONCLUSION: The mechanism of the peripheral neuropathy in Beh?et's disease is still unknown, it might be due to vasculitis of the vasa nervorum or to the side effects of colchicine. Our report is particular by the association of sensorimotor and autonomic involvement of peripheral neuropathy in a patient with Beh?et's disease.     

Ischaemic monomelic neuropathy: A rare cause of unilateral foot drop

Ischaemic neuropathy is a rare phenomenon given the rich arterial collateral supply afforded to peripheral nerves by the vasa nervorum. We report an unusual case of unilateral foot drop secondary to long-segment popliteal artery occlusion. Without expedient vessel imaging and revascularisation of the occluded artery, this reversible cause of neurological deficit would likely have resulted in a poor functional outcome for our patient.     

Tangier disease. A case with sensorimotor distal polyneuropathy and lipid accumulation in striated muscle and vasa nervorum

Summary A 65-year-old man with Tangier disease (analphalipoproteinemia) had had a progressive sensorimotor distal neuropathy with sensory ataxia for 1 year. Muscle biopsy demonstrated excess lipid vacuoles on histochemical and electron-microscopic techniques. Sural nerve biopsy showed a marked loss of large fibers and an increase in small myelinated fibers, with presence of remyelinating fibers and clusters of regeneration; a few aspects of active demyelination and some onion-like formations were also present. Lipid accumulation chiefly affected the Schwann cells of unmyelinated fibers and, to a lesser degree, of myelinated fibers, endoneurial fibroblast, and vasa nervorum. Teased fibers showed prevalent aspects of de-/remyelination and, often in association, marked myelin wrinkling suggesting axonal atrophy.This Tangier patient differs from known cases for the presence of a distal symmetrical sensorimotor polyneuropathy (not previously reported in Tangier disease) and because of the morphological findings of de-/remyelination coexisting with aspects of axonal atrophy and previous degeneration, and of lipid accumulation within striated muscle and vasa nervorum. This latter finding contrasts with the assumption that in Tangier disease vessel walls are not a site of lipid storage: probably the vasa nervorum are different, in this respect, from other vessels, because of the intense lipid metabolism of the nervous tissue. Thus we suggest that involvement of vasa nervorum in Tangier disease may be more important than previously suspected, possibly playing a role in the causation of neuropathy.     

Axonopathy and microangiopathy in chronic alloxan diabetes

Summary A significant reduction in the myelinated nerve fiber population was observed during quantitative electron-microscopic examination of peripheral nerves in chronic alloxan diabetic rats. Dystrophic axonal abnormalities and regenerating fibers were more numerous in diabetics than age-matched controls. Schwann cells showed reactive changes including prominent pi granules of Reich and intracytoplasmic filament accumulation. Enumeration of these alterations, however, revealed no singificant difference from controls. Endoneurial macrophages in diabetic rats were also filled with lamellar intracytoplasmic inclusions characteristic of a chronic neuropathy. Quantitation of pathologic lesions in teased nerve fibers confirmed the preponderance of axonal over demyelinative disease and showed demyelination to be segmental.Microangiopathy was noted throughout the vasa nervorum of diabetic rats, and quantitative electron microscopy showed endothelial proliferation with doubling of the number of endothelial cells and proportional capillary mural thickening. Swollen, reactive endothelial cells appeared to effece the vascular lumen and may impair capillary perfusion. These microcirculatory changes, in the presence of biochemical and rheologic disturbances may contribute to tissue hypoxia and underly the loss of axons in experimental diabetic neuropathy.Supported in part by NS-14162 and NS-09053 from the National Institute for Neurological and Communicative Disorders and Stroke and the Veterans Administration Research Service     

Reduced nerve blood flow in hexachlorophene neuropathy: relationship to elevated endoneurial fluid pressure

To test the hypothesis that increased endoneurial fluid pressure (EFP) causes a reduction in nerve blood flow (NBF) in the vasa nervorum, we adapted a noninvasive method for measurement of nerve blood flow which was originally developed for measurement of local cerebral blood flow. This technique measures tissue distribution to the radioisotope, 14C-iodoantipyrine, and was used to compare NBF in sciatic nerves of rats with increased EFP induced by feeding them hexachlorophene (HCP), a neurotoxin which causes edema exclusively to the nervous system and confined to the myelin sheath. Elevation of interstitial fluid pressure in peripheral nerves from control values of 2.0 +/- 1.0 cm H2O to over approximately 6 cm H2O was associated with a statistically significant reduction in nerve blood flow from 14.8 +/- 5.9 to 7.8 +/- 2.5 ml/100 g of tissue/minute (min). These results support the hypothesis that increased endoneurial fluid pressure exacerbates the neuropathy by diminishing local blood flow.     

Disseminated vasculomyelinopathy in the peripheral nervous system mediated by immune complexes (ICs). Immunohistochemical studies of sciatic nerves in chronic serum sickness (CHSS) in rabbits

Histological examination of 20 sciatic nerves from rabbits with experimental chronic serum sickness (CHSS) revealed patchy vasculitis of the vasa nervorum of various intensity. The vessel lesions ranged from endothelial proliferation to vessel wall necrosis with fibrinoid degeneration and infiltration by lymphocytes, plasma cells, macrophages and, sporadically, by neutrophils. Perivascularly, there were oedema, chronic infiltrates or small haemorrhages. The myelinated fibres in close relation to the vascular system were focally depleted and features of perivascular demyelination were found. Teased fibres showed paranodal and segmental demyelination, axonal degeneration and, sporadically, remyelination. In all cases, immunofluorescent deposits of bovine serum albumin (BSA), IgG and C3 complement were found in and around some vasa nervorum. Other indirect evidence for immune complex (IC) deposition was provided by ultrastructural examination where vascular and endoneurial osmophilic deposits were found; in 4 cases with paracrystalline organization resembling cryoglobulin component. IC-mediated vasculitis led to blood-nerve barrier impairment and leakage of serum proteins into the endoneurial space. The morphological and immunohistochemical changes in this model which develop after a latency period of 2 or more weeks, strongly resemble those observed in human acquired inflammatory demyelinating polyradiculoneuropathies or in connective tissue diseases.     

Chronic neuropathy associated with immune complexes of hepatitis B virus

In 7 patients, including one autopsied case, with neuropathy associated with hepatitis B virus infection, histologic examination of sural nerve biopsies revealed small vessel vasculitis in the vasa nervorum. In all cases, immunofluorescent deposits of hepatitis B surface antigen, immunoglobulin and C3 complement were detected in the vasa nervorum. That these deposits could represent immune complexes composed of hepatitis B virus was supported by the serologic demonstration of high serum-level of immune complexes and by the ultrastructural demonstration of electron-dense deposits around the endoneural capillary and in the endoneurium. The densities of large myelinated fibers were significantly lower than controls (P less than 0.01) in 6 of 7 cases. These results suggest that immune complexes composed of hepatitis B virus might play a significant role in the pathogenesis of endoneural and epineural vascular lesions, through which neuropathy may be induced in patients with hepatitis B virus infection.     

Innervation of the vasa nervorum: changes in human diabetics.

Transperineurial and epineurial vessels are innervated by plexuses of unmyelinated axons. Human sural nerve biopsies were examined ultrastructurally and immunocytochemically with an antibody which recognizes a neuronal and neuroendocrine protein, PGP 9.5, to characterize perivascular axons of these plexuses. Diabetics exhibited a greater degree of abnormal innervation of the vasa nervorum than nondiabetics with and without neuropathy. Abnormal innervation included: a reduction in the percentage of vessels exhibiting perivascular axons and a concomitant increase in the percentage of vessels having denervated Schwann cell units, particularly around vessels confined to perineurial compartments, and remaining axons in nerves from diabetics exhibited fewer varicosities. Denervated arterioles of diabetics also displayed structural changes indicating injury. The arteriolar structural defects and loss of neurogenic control of neural blood flow may lead to or aggravate endoneurial ischemia or hypoxia. The patchy, focal endoneurial fiber loss that is prominent in proximal nerves and associated with the distal myelinated fiber loss of some diabetic patients may be due in part to perivascular denervation of the vasa nervorum.     

Peripheral nerve disorders in Lyme-Borreliosis

Summary Clinical, cerebrospinal fluid and nerve biopsy findings from eight patients with peripheral nervous system complications of Lyme-Borreliosis are reported. Five cases showed the typical features of the Garin-Bujadoux-Bannwarth syndrome (meningoradiculoneuritis), one patient had a multiple mononeuritis associated with acrodermatitis chronica atrophicans Herxheimer. Two cases could not be classified under these diagnostic categories. In all patients we observed a prompt relief of signs and symptoms after antibiotic treatment. Nerve biopsy studies showed gross infiltrations of epineurial vasa nervorum and small infiltrations around endoneurial capillaries. The infiltrations consisted of lymphocytes, histiocytes and plasma cells. We did not find necrotizing changes of the vessel walls, but thrombosis and recanalization was observed in some epineurial vessels. Seven biopsies showed a significant loss of myelinated axons due to axonal degeneration. Only in one biopsy did we observe segmental demyclination next to axonal degeneration. We conclude that the PNS complications of Lyme-Borreliosis in early and late stages of the disease are angiopathic due to vasculitis of the vasa nervorum and primarily caused by axonal degeneration.Supported in part by the Swiss National Fund (No. 3.913-0.86) and the Wander Foundation     

Quantitative assessment of the innervation of epineurial arteries in the peripheral nerve by immunofluorescence: differences between controls and patients with peripheral arterial disease

The peripheral nerve is supplied by the vasa nervorum. The epi- and perineurial vessels are innervated by an autonomic plexus, which plays a role in regulation of the endoneurial blood flow. This innervation is decreased in diabetes and alcohol polyneuropathy and seems to precede the development of diabetic polyneuropathy. A decreased innervation may therefore play a role in the development of polyneuropathy. In peripheral arterial disease (PAD) clinical and morphological features are present, related to severity of ischemia. To investigate the innervation of the vasa nervorum in severe ischemia, we performed immunofluorescence staining with the general neural marker protein gene product (PGP) 9.5 in whole mount preparations of epineurial vessels of nine sural nerves taken from patients with legs amputated because of severe PAD (59+/-15 years, mean +/- SD) and ten age-matched controls (61+/-24 years). In patients with PAD the nerve density of the perivascular plexus was decreased in comparison with controls (mean intercept density/mm +/- SD) 26.0+/-6.9 in PAD and 39.9+/-10.7 in controls, area% 6.0+/-1.6 in PAD and 9.9+/-2.6 in controls, both P<0.01, t-test). A decreased perivascular plexus may result in a diminished regulation of the endoneurial blood flow in patients with severe PAD.     

Correction of nerve conduction and endoneurial blood flow deficits by the aldose reductase inhibitor, tolrestat, in diabetic rats

Increased activation of the first half of the polyol pathway, the conversion of glucose to sorbitol by aldose reductase, has been implicated in aldose reductase inhibitor-preventable neurochemical changes that may contribute to the aetiology of diabetic neuropathy. Tolrestat has been used as a standard aldose reductase inhibitor to dissect out polyol pathway-dependent mechanisms in many experimental studies; however, doubt has been cast upon its ability to prevent nerve conduction velocity deficits in diabetic rats. Nerve dysfunction has also been linked to abnormal endoneurial blood flow and oxygenation via increased vasa nervorum polyol pathway flux. The aim of this study was to test whether tolrestat could correct sciatic conduction velocity and perfusion defects in diabetic rats. Sciatic motor conduction velocity, 21% reduced by 1 month of streptozotocin-induced diabetes, was corrected by 23% and 84% with 1 month of tolrestat treatment at doses of 7 and 35 mg/kg/day respectively. Endoneurial blood flow, 44-52% reduced by untreated diabetes, was within the nondiabetic range with high-dose tolrestat treatment and the flow deficit was 39% corrected by the low dose. Sciatic sorbitol and fructose concentrations were approximately 13-fold and approximately 4-fold elevated by untreated diabetes. This was 32-50% attenuated by low-dose tolrestat and sorbitol and fructose content was suppressed below the nondiabetic level by high dose treatment. A 58% nerve myo-inositol deficit was partially (32%) corrected by high-dose tolrestat treatment. We conclude that tolrestat restores defective conduction and blood flow in diabetic rats and is a good pharmacological tool for studies on polyol pathway effects in peripheral nerve.     

Etude ultrastructurale du nerf périphérique chez 16 diabétiques sans neuropathie clinique. Comparaisons avec 16 neuropathies diabétiques et 16 neuropathies non diabétiques

Summary The present communication described changes on nerve biopsies from 16 diabetics without neuropathy, except the fact that the ankle jerks were often decreased bilaterally, as it is often encountered in diabetes mellitus. 16 non-diabetic patients with various peripheral neuropathies were also studied; the glucose tolerance tests were always normal in this group and none had any vascular or collagen disease. The three series included patients between 45 to 75 years old. Obervations made on nerve biopsies from these three groups have been compared. The basement membranes of endoneurial capillaries were measured. These measurements have been made on the thinnest part of the basement membranes and pericyte processes were not included. At least 5 capillaries per 1 patient have been studied. Averaging with a computer has permitted demonstration of significant thickenings of basement membranes in diabetic patients without neuropathy; such an observation was not made in non-diabetic patients with various peripheral neuropathies, while the thickenings were the most important in patients with diabetic neuropathy. It must be said that individual variations were encountered in each group. Nerve parenchyma has been carefully studied. In diabetic patients without neuropathy, 14 cases displayed a typical but usually moderate proliferation of Schwann cells. Axon lesions were mild and unfrequent. The exact relationships between thickening of basement membranes of vasa nervorum and lesions of nerve parenchyma need some further informations.

     

Multifocal neuropathy with vasculitis in hypereosinophilic syndrome

Summary A 56-year-old male with a 2-year history of bronchial asthma, together with pulmonary infiltration and marked eosinophilia, developed a subacute multifocal sensorimotor neuropathy. Electrodiagnostic studies demonstrated both multifocal and generalized nerve involvement. Sural nerve and muscle biopsies revealed axonal degeneration with almost complete loss of myelinated fibres, lymphomononuclear vasculitis of interstitial vasa nervorum without eosinophils, and neurogenic atrophy of muscle without angiitis. Although eosinophilia decreased drastically with corticosteroid treatment, neuropathy rapidly progressed to total disability. The patient died from pulmonary embolism 4 months after the onset of neurological signs. Autopsy disclosed vasculitis of epineurial vessels of peripheral nerves and severe axonal neuropathy, particularly of the lower limbs, without vasculitis or other inflammatory lesions in any other organ system, including the lungs. Retrospective analysis revealed that the onset of pulmonary infiltration and eosinophilia coincided with the administration of cromolyn sodium (Intal), which is known to produce PIE syndrome (pulmonary infiltration and eosinophilia), vasculitis and allergic granulomatosis, while multifocal neuropathy with vasculitis appears not to have been reported in connection with this substance.     

MONONEURITIS MULTIPLEX ASSOCIATED WITH POSITIVITY FOR LUPUS ANTICOAGULANT (LA)

Peripheral neuropathy is a common complication of systemic necrotizing vasculitis. Vasculitis may also selectively affect the peripheral nervous system (non-systemic vasculitic neuropathy). We describe two patients affected with overlapping mononeuritis multiplex (MM) associated with LA—positivity in absence of sural nerve biopsy proven involvement of vasa nervorum. Both had livedo reticularis in distal upper and lower limbs. There were no signs of pulmonary, renal, gastrointestinal, ear, nose or throat involvement. Skin biopsy showed a thrombotic microangiopathy. Serological abnormalities were limited to an elevated ESR in one patient and LA—positivity in both. One patient was affected by recurrent brain focal ischemia one year before the onset of MM leading to death. MM associated with LA—positivity has previously been described only in four patients and deserves further investigation to highlight the pathogenetic significance of this association.     

Cryoglobulinemic neuropathy: A pathological study

A 53-year-old woman developed symmetrical polyneuropathy of the lower limbs a few months after she was found to have myeloma with cryoglobulinemia. In musculocutaneous nerve biopsy material, electron microscopy showed both axonal degeneration and demyelination. The most striking finding was the presence, in the endoneurial space, of numerous masses of closely packed tubular structures. These masses also were found in the walls of all the vasa nervorum and within the lumen of some vessels. The morphological features and dimensions of the deposits within nerve were identical to those of cryoprecipitates extracted from serum and examined with the electron microscope. An example of myeloma neuropathy with cryoglobulin deposits within the endoneurial space has not been reported previously.