Peripheral neuropathy in essential mixed cryoglobulinemia

Sixteen patients with essential mixed cryoglobulinemia were studied and followed up clinically and electrophysiologically for 4.2 years. Peripheral neuropathy was diagnosed in seven cases. Five of these patients had distal symmetrical sensorimotor polyneuropathy. Nerve conduction velocities were normal and therefore indicative of pure axonal neuropathy. Sural nerve biopsy showed moderate loss of myelinated axons in two patients and severe loss in one. This patient also had necrotizing arteritis. The remaining two had both clinical and electrophysiologic signs of overlapping mononeuritis multiplex with severe denervation in the territory of the involved nerves, but normal conduction velocities. Sural nerve biopsy in one of these two patients showed marked loss of myelinated fibers and signs of vasculitis. Two types of neuropathy were noted: (1) a mild distal neuropathy with relatively minor neurologic deficit, probably due to vasa nervorum microcirculation occlusion caused by intravascular deposits of cryoglobulins and (2) a severe distal symmetrical sensorimotor neuropathy or overlapping mononeuritis multiplex, associated with necrotizing vasculitis.     

Rheumatoid neuropathy: a histological and electrophysiological study

Peripheral nerves in five patients with rheumatoid neuropathy were examined electrophysiologically and by sural nerve biopsy. There was close correlation between the clinical severity of the disease and the degree of nerve damage found histologically and by EMG. Group 1 patients with a mild distal sensory neuropathy showed varying degrees of axonal degeneration in the large myelinated fibres and some segmental demyelination. Group 2 patients with a severe, rapidly progressive sensori-motor neuropathy had extensive loss of myelinated fibres. In one case all the large fibres had degenerated. The second case had lost both large and small myelinated fibres together with many of the non-myelinated axons. The major nerve damage in both groups appeared to be axonal degeneration but some segmental demyelination was detected. Occlusive vascular disease in the vasa nervorum was considered to be the major cause of the nerve damage.     

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.     

Thin axons relative to myelin spiral length in hereditary motor and sensory neuropathy, type I

The relationship of axonal to myelin area in semithin transverse sections of myelinated fibers obtained from sural nerves at the ankle level was morphometrically assessed using computer imaging. Ten patients with hereditary motor and sensory neuropathy, type I and 41 control subjects were examined. In large- and intermediate-diameter myelinated fibers of diseased nerves, axons were significantly attenuated relative to the amount of myelin. Using electron micrographs, a similar finding was obtained when axon area was regressed on myelin spiral length. The altered relationship was found to be greater with more severe fiber loss. These data, plus other evidence, indicate that in this disorder there is a progressive atrophy of axons, usually most severe in distal aspects of lumbosacral neurons and associated with secondary segmental demyelination and remyelination and hypertrophic neuropathy, preceding distal axonal loss. Because the process may begin in utero or in infancy, not only atrophy but also maldevelopment of axons may be involved.     

Polyneuropathy with lipid deposits in Schwann cells and axonal degeneration in cerebrotendinous xanthomatosis

The present paper is a histological, histochemical and electron microscopic study of biopsied specimens from both right and left Achilles tendon, sural nerve and gastrocnemius muscle in a case of peripheral neuropathy with decreased sensory conduction velocity within a cerebrotendinous xanthomatosis confirmed biochemically in a 29-year-old woman. The tendon specimens contained large deposits of complex, non-homogeneous lipids, distributed intra- and extracellularly. The right sural nerve specimen showed a very severe neuropathy with massive diffuse myelinated fiber loss, presence of foamy macrophages and lipid droplets in Schwann cells. Segmental de- and remyelination was noted in 17% of the teased myelinated fibers. No onion bulbs were observed. Two years later, the left sural nerve specimen revealed a mild diffuse myelinated fiber loss, a more active segmental de- and remyelination (23%) without onion bulbs, and an active regeneration. Lipid storage aspects were absent. The gastrocnemius muscle specimens exhibited slight alterations of neurogenic origin. The pathogenesis of this neuropathy is discussed.     

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.     

Ganglioside treatment of neuropathy in diabetic mice

Diabetic neuropathy in 180-day-old C57BL/Ks inbred mice is characterized by a marked reduction of nerve conduction velocity (NCV) and by axonal atrophy, as suggested by the decreased number of large diameter myelinated fibers. No demyelination or remyelination was observed. Ganglioside treatment from 150 to 180 days of age significantly improved the NCV and returned the fiber size distribution to control values.     

Peripheral axotomy induces neurofilament decrease, atrophy, demyelination and degeneration of root and fasciculus gracilis fibers

We have recently shown that peripheral axotomy by hindlimb amputation in adult cats sequentially results in neurofilament and microtubule decrease and axonal atrophy, myelin wrinkling, myelin remodeling (de- and remyelination), more atrophy and axonal degeneration in proximal sciatic and L7 segmental nerve fibers. The neuropathologic, morphometric and teased fiber alterations in the myelinated fibers (MF) of roots and sampled levels of fasciculus gracilis in groups of adult cats 24 months after hindlimb amputation have now been studied. We found: a severe decrease of neurofilaments, axonal atrophy, myelin wrinkling, de- and remyelination and axonal loss in posterior root axons; that these morphologic abnormalities extended up the fasciculus gracilis in the appropriate territories established from degenerative studies; that the retrograde effect was less severe in ventral root fibers, although atrophy and sprouting were demonstrated here, and that the cellular sequence of retrograde atrophic degeneration of ascending axons was similar to that observed in proximal stump axons. These findings confirm that primary afferent neurons are more vulnerable to axotomy than lower motor neurons and may provide an additional explanation for the poorer functional restoration of sensory than of motor deficit after root compression and in delayed nerve reconnection. Our observations also have important implications for interpretation of neuropathologic alterations in roots and fasciculus gracilis, since the observed features may be secondary to axotomy of peripheral nerve fibers induced by disease and not evidence of a primary derangement.     

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     

Hypertension-induced peripheral neuropathy and the combined effects of hypertension and diabetes on nerve structure and function in rats

Diabetic neuropathy includes damage to neurons, Schwann cells and blood vessels. Rodent models of diabetes do not adequately replicate all pathological features of diabetic neuropathy, particularly Schwann cell damage. We, therefore, tested the hypothesis that combining hypertension, a risk factor for neuropathy in diabetic patients, with insulin-deficient diabetes produces a more pertinent model of peripheral neuropathy. Behavioral, physiological and structural indices of neuropathy were measured for up to 6 months in spontaneously hypertensive and age-matched normotensive rats with or without concurrent streptozotocin-induced diabetes. Hypertensive rats developed nerve ischemia, thermal hyperalgesia, nerve conduction slowing and axonal atrophy. Thinly myelinated fibers with supernumerary Schwann cells indicative of cycles of demyelination and remyelination were also identified along with reduced nerve levels of myelin basic protein. Similar disorders were noted in streptozotocin-diabetic rats, except that thinly myelinated fibers were not observed and expression of myelin basic protein was normal. Superimposing diabetes on hypertension compounded disorders of nerve blood flow, conduction slowing and axonal atrophy and increased the incidence of thinly myelinated fibers. Rats with combined insulinopenia, hyperglycemia and hypertension provide a model for diabetic neuropathy that offers an opportunity to study mechanisms of Schwann cell pathology and suggests that hypertension may contribute to the etiology of diabetic neuropathy.     

Inherited polyneuropathy in Leonberger dogs: A mixed or intermediate form of Charcot‐Marie‐Tooth disease?

A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high-steppage pelvic-limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size-frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X-linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants.     

Permanent axotomy,a model of axonal atrophy and secondary segmental demyelination and remyelination

Permanent axotomy in cats produced by hind limb ablation results in sequential pathological alterations of myelinated fibers of the proximal nerve stump. The changes are like those previously described for human uremic neuropathy and such system atrophies as Friedreich's ataxia; axonal atrophy → myelin wrinkling → nodal lengthening and internodal demyelination → remyelination.     

Axonal attenuation and secondary segmental demyelination in myeloma neuropathies

The sural nerves of 5 patients with osteosclerotic myeloma and polyneuropathy, of 3 patients with multiple myeloma and polyneuropathy, and of 6 healthy subjects were studied by neuropathological, morphometric, and teased-fiber approaches to assess cellular (Schwann cell or axon) vulnerability and to explore the mechanism of segmental demyelination. As compared with controls, the nerves of both types of myeloma neuropathy demonstrated a statistically significant and marked loss of myelinated fibers and increased frequencies of axonal degeneration among teased fibers at statistically significant levels. The peaks of diameter histograms of myelinated fibers of osteosclerotic myeloma/polyneuropathy nerves were displaced to smaller diameter categories, suggesting fiber atrophy. Segmental demyelination and remyelination was clustered, as found in secondary demyelination. Large- and intermediate-diameter myelinated fibers of osteosclerotic myeloma/polyneuropathy nerves had significantly smaller axon calibers relative to myelin spiral length seen in electron micrographs. The loss of myelinated fiber axons, the shift of the peaks of diameter histograms to smaller sizes, the lack of noticeable increased numbers of demyelinated axons, the clustered distribution of segmental demyelination, and the axonal attenuation suggest a special axonal or neuronal vulnerability and appear to provide an explanation for the observed segmental demyelination. Whether axonal attenuation has a perikaryeal or proximal axonal genesis now needs to be determined.     

A Japanese family with early-onset ataxia with motor and sensory neuropathy

We report the case of a Japanese family with hereditary ataxia with peripheral neuropathy. Three affected siblings from this family exhibited very similar clinical features: teenage-onset, slowly progressive ataxia, followed by distal weakness, which developed after the age of 30 years. Magnetic resonance imaging studies showed marked atrophy in the cerebellar hemisphere and vermis, and a sural nerve biopsy revealed a marked reduction in the number of both myelinated and unmyelinated fibers. All patients exhibited hyperglutamatemia, but serum levels of albumin and lipid were normal. The clinicopathological and biochemical features of these cases suggest that they form a distinct entity of autosomal recessive hereditary ataxia with peripheral neuropathy.     

Generalized peripheral neuropathy in a dental technician exposed to methyl methacrylate monomer.

A 58-year-old dental prosthetic technician developed generalized sensorimotor peripheral neuropathy. Neurophysiologic studies showed a generalized sensorimotor neuropathy of axonal degeneration type. Examination of a sural nerve biopsy showed a moderately severe axonal neuropathy with loss of large myelinated fibers and unmyelinated axons. There was evidence of slow ongoing degeneration and considerable fiber regeneration. Electron microscopy showed increased numbers of filaments in a few fibers. These findings show resemblances to the nerve changes caused by another acrylic resin, acrylamide. We suggest that the neuropathy may have been caused by 30 years of occupational cutaneous and inhalational exposure to methyl methacrylate monomer since we excluded other recognized causes of neuropathy.     

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     

Hereditary motor and sensory neuropathy with optic atrophy. Ultrastructural and morphometric observations on nerve fibers, mitochondria, and dense-cored vesicles

Nerve biopsy specimens from three cases of hereditary motor and sensory neuropathy with optic atrophy were studied by light and electron microscopy and by morphometry. All cases had a chronic neuropathy of the neuronal/axonal type with little, presumably secondary, demyelination. There was predominant reduction of the large-caliber population of myelinated and unmyelinated nerve fibers. The number of dense-cored vesicles in unmyelinated and small myelinated fibers was increased. Abnormal mitochondria in Schwann cells with paracrystalline inclusions, prominent cristae including paracrystalline material (cases 1 and 2), and axonal mitochondria with presumable hydroxyapatite crystals (case 3) were found. The morphologic results suggest that hereditary motor and sensory neuropathy with optic atrophy should be regarded as a separate entity within the hereditary motor and sensory neuropathy group.     

Peripheral nerve involvement in familial chorea-acanthocytosis

Myelinated fibers and neuronal cell bodies of the ventral spinal outflow and primary sensory neurons were histopathologically examined in a patient with familial chorea-acanthocytosis and age-matched controls. The patient exhibited a marked loss of large myelinated axons and their neuronal cell bodies in the ventral spinal outflow, while there was frequent occurrence of axonal sprouts. Large myelinated fibers in sensory afferents were also decreased in number. Segmental de- and remyelination was markedly increased in teased fiber preparations of both motor and sensory peripheral nerves.     

Xeroderma pigmentosum: neurological, neurophysiological and morphological studies

In 3 cases of xeroderma pigmentosum showing signs of peripheral neuropathy, electrophysiological studies were made. In one of them, a sural nerve biopsy was performed. MCV obtained from the lower limbs were moderately reduced in all cases, and SCV could be obtained in only 1 case from the median nerve. Auditory brain stem responses were not obtainable in all cases. Sural nerve biopsy revealed a marked decrease of myelinated fibers and also suggested severe damage in both myelinated and unmyelinated fibers. Teased fiber study showed myelin ovoids and indicated axonal degeneration. Sensory nerves including the acoustic nerve may suffer damage earlier than the motor nerve. In all cases CT scans revealed brain atrophy and thickening of the skull.     

Relation between myelin area and axon diameter in the aortic depressor nerve of spontaneously hypertensive rats

The hypothesis that the aortic depressor nerve (ADN) from spontaneously hypertensive rats (SHR) does not show the expected correlation between myelin sheath area and the axonal diameter of myelinated fibers detected in normotensive rat myelinated fibers was tested by means of regression analysis. Proximal and distal segments of ADN from 13 normotensive Wistar-Kyoto rats (WKY) and nine SHR were prepared for light microscopy study. With an image analysis system, the area of the myelin sheath and the axonal diameter of all myelinated fibers in each nerve were automatically measured. Regression lines were calculated for all nerve segments from each group. Differences between the regression lines were tested for slope and intercept and differences between the correlation coefficients were also tested. Regression lines for WKY data showed no differences between the proximal and distal segments either for slope or intercept. Proximal and distal SHR regression lines were not coincident between segments or when compared to WKY data. These results agree with previous observations that there are morphological differences between WKY and SHR myelinated fibers of the ADN suggesting that the SHR depressor nerve fibers present characteristics of axonal atrophy and/or remyelination.