Giant Axonal Neuropathy Locus Refinement To A < 590 KB Critical Interval

Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) has been shown to be due to ischemic injury from microvasculitis. The present study tests whether ischemic injury and microvasculitis are the pathologic cause of non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN), and whether the pathologic alterations are different between LSRPN and DLSRPN. We studied distal cutaneous nerve biopsies of 47 patients with LSRPN and compared findings with those of 14 age-matched healthy controls and 33 DLSRPN patients. In both disease conditions, we found evidence of ischemic injury (multifocal fiber degeneration and loss, perineurial degeneration and scarring, characteristic fiber alterations, neovascularization, and injury neuroma) that we attribute to microvasculitis (mural and perivascular mononuclear inflammation of microvessels, inflammatory separation, fragmentation and destruction of mural smooth muscle, and previous microscopic bleeding [hemosiderin]). Teased nerve fibers in LSRPN showed significantly increased frequencies of axonal degeneration, segmental demyelination, and empty nerve strands. The segmental demyelination appeared to be clustered on fibers with axonal dystrophy. The nerves with abnormal frequencies of demyelination were significantly associated with nerves showing multifocal fiber loss. We reached the following conclusions: 1) LSRPN is a serious condition with much morbidity that mirrors DLSRPN. 2) Ischemic injury from microvasculitis appears to be the cause of LSRPN. 3) Axonal degeneration and segmental demyelination appear to be linked and due to ischemia. 4) The pathologic alterations in LSRPN and DLSRPN are indistinguishable, raising the question whether these 2 conditions have a common underlying mechanism, and whether diabetes mellitus contributes to the pathology or is a risk factor in DLSRPN. 5) Both LSRPN and DLSRPN are potentially treatable conditions.     

Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy

OBJECTIVE: To determine whether microscopic vasculitis explains the clinical and pathologic features of diabetic lumbosacral radiculoplexus neuropathy (DLSRPN). BACKGROUND: DLSRPN is usually attributed to metabolic derangement or ischemic injury, but microscopic vasculitis as the sole cause needs consideration. METHODS: We prospectively studied the clinical, laboratory, and EMG features as well as the pathology of distal cutaneous nerve biopsy specimens of patients with DLSRPN. RESULTS: Study of DLSRPN nerve biopsy specimens (n = 33) compared with those from healthy controls (n = 14) and those with diabetic polyneuropathy (n = 21) provided strong evidence for ischemic injury (axonal degeneration, multifocal fiber loss, focal perineurial necrosis and thickening, injury neuroma, neovascularization, and swollen fibers with accumulated organelles), which we attribute to microscopic vasculitis (epineurial vascular and perivascular inflammation, vessel wall necrosis, and evidence of previous bleeding). Segmental demyelination was significantly associated with multifocal fiber loss. CONCLUSIONS: 1) This severe, debilitating neuropathy begins with symptoms unilaterally and focally in the leg, thigh, or buttock and spreads to involve the other regions of the same and then opposite side and is due to multifocal involvement of lumbosacral roots, plexus, and peripheral nerve (i.e., diabetic lumbosacral radiculoplexus neuropathy). 2) Motor, sensory, and autonomic fibers are all involved. 3) Ischemic injury explains the clinical features and pathologic abnormalities of nerve. 4) The proximate cause of the ischemic injury appears to be microscopic vasculitis. 5) The segmental demyelination is probably secondary to ischemic axonal dystrophy, thus providing a unifying hypothesis for both axonal degeneration and segmental demyelination.     

Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) (also called diabetic amyotrophy) is a well-recognized subacute, painful, asymmetric lower-limb neuropathy that is associated with weight loss and type II diabetes mellitus. Nondiabetic lumbosacral radiculoplexus neuropathy (LRPN) has received less attention. Comparison of large cohorts with DLRPN and LRPN demonstrated that age at onset, course, type and distribution of symptoms and impairments, laboratory findings, and outcomes are similar. Both conditions are lumbosacral radiculoplexus neuropathies that are associated with weight loss and begin focally with pain but that evolve into widespread, bilateral paralytic disorders. Although both are monophasic illnesses, patients have prolonged morbidity from pain and weakness, and many patients become wheelchair-dependent. Although motor-predominant, there is unequivocal evidence that autonomic and sensory nerves are also involved. Cutaneous nerves from patients with DLRPN and LRPN show pathological evidence of ischemic injury (multifocal fiber loss, perineurial thickening and degeneration, neovascularization, microfasciculation, and swollen axons with accumulated organelles) and microvasculitis (mural and perivascular inflammation, separation and fragmentation of mural smooth muscle layers of microvessels and hemosiderin-laden macrophages). Controlled trials with immune-modulating therapies in DLRPN are in progress, and preliminary data suggest that such therapy may be beneficial in LRPN. It is likely that DLRPN and LRPN are immune-mediated neuropathies that should be separated from chronic inflammatory demyelinating polyneuropathy and from systemic necrotizing vasculitis.     

METHYLPREDNISOLONE MAY IMPROVE LUMBOSACRAL RADICULOPLEXUS NEUROPATHY

Objective: To report on an open trial of intravenous methylprednisolone (IV MP) in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN). Background. Lumbosacral radiculoplexus neuropathy is a subacute, unilateral or asymmetric syndrome of pain, weakness, and paresthesia of the lower extremity, which is attributed to ischemic injury from microvasculitis in lumbosacral roots, plexus, and nerves. Methods: Eleven nondiabetic patients with worsening LSRPN were treated - ten with infusions of IV MP (1 gm/wk) for 8 to 16 weeks and one with an equivalent dosage of oral prednisone. The main endpoints evaluated were: 1) the Neuropathy Impairment Score (NIS), and 2) the Neuropathy Symptoms and Change (NSC) scores. Results: The median age of our patients was 67 years, range 49 to 86 years. Seven patients were women. All 11 patients reported improvement during treatment—nine reported marked improvement. The median NIS improved from 42 points (range 9 to 106 points) before treatment, to 20 points (range 5 to 57 points) (p = 0.005) after treatment. Pain was completely resolved in four patients and much improved in seven. The change subscore and the severity subscore of the NSC were statistically significantly improved after treatment. Prior to treatment, all patients had significant weakness with six confined to wheelchairs and four using mechanical devices to aid in ambulation. After treatment, the weakness was markedly improved in nine patients; only one still required a wheelchair and six walked independently (p = 0.03). Conclusions: 1) In LSRPN, pain and neurological deficits improved (often dramatically) with IV MP treatment. 2) Although our results should be interpreted with caution since this trial is uncontrolled, IV MP may favorably affect the natural history of LSRPN. 3) The results are sufficiently promising to provide a rationale for prospective, sham controlled, double blind trials.     

Multifocal motor neuropathy: pathologic alterations at the site of conduction block

The pathologic changes of nerves in multifocal motor neuropathy (MMN), a rare neuropathy with selective focal conduction block of motor fibers in mixed nerves, remain essentially unstudied. Fascicular nerve biopsy of 8 forearm or arm nerves in 7 patients with typical MMN was undertaken for diagnostic reasons at the site of the conduction block. Abnormalities were seen in 7 of 8 nerves, including a varying degree of multifocal fiber degeneration and loss, an altered fiber size distribution with fewer large fibers, an increased frequency of remyelinated fiber profiles, and frequent and prominent regenerating fiber clusters. Small epineurial perivascular inflammatory infiltrates were observed in 2 nerves. We did not observe overt segmental demyelination or onion bulb formation. We hypothesize that an antibody-mediated attack directed against components of axolemma at nodes of Ranvier could cause conduction block, transitory paranodal demyelination and remyelination, and axonal degeneration and regeneration. Alternatively, the antibody attack could be directed at components of paranodal myelin. We favor the first hypothesis because in nerves studied by us, axonal pathological alteration predominated over myelin pathology. Irrespective of which mechanism is involved, we conclude that the unequivocal multifocal fiber degeneration and loss and regenerative clusters at sites of conduction block explains the observed clinical muscle weakness and atrophy and alterations of motor unit potentials. The occurrence of conduction block and multifocal fiber degeneration and regeneration at the same sites suggests that the processes of conduction block and fiber degeneration and regeneration are linked. Finding discrete multifocal fiber degeneration may also provide an explanation for why the functional abnormalities remain unchanged over long periods of time at discrete proximal to distal levels of nerve and may emphasize a need for early intervention (assuming that efficacious treatment is available).     

Methylprednisolone may improve lumbosacral radiculoplexus neuropathy

OBJECTIVE: To report on an open trial of intravenous methylprednisolone (IV MP) in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN). BACKGROUND: Lumbosacral radiculoplexus neuropathy is a subacute, unilateral or asymmetric syndrome of pain, weakness, and paresthesia of the lower extremity, which is attributed to ischemic injury from microvasculitis in lumbosacral roots, plexus, and nerves. METHODS: Eleven nondiabetic patients with worsening LSRPN were treated - ten with infusions of IV MP (1 gm/wk) for 8 to 16 weeks and one with an equivalent dosage of oral prednisone. The main endpoints evaluated were: 1) the Neuropathy Impairment Score (NIS), and 2) the Neuropathy Symptoms and Change (NSC) scores. RESULTS: The median age of our patients was 67 years, range 49 to 86 years. Seven patients were women. All 11 patients reported improvement during treatment--nine reported marked improvement. The median NIS improved from 42 points (range 9 to 106 points) before treatment, to 20 points (range 5 to 57 points) (p = 0.005) after treatment. Pain was completely resolved in four patients and much improved in seven. The change subscore and the severity subscore of the NSC were statistically significantly improved after treatment. Prior to treatment, all patients had significant weakness with six confined to wheelchairs and four using mechanical devices to aid in ambulation. After treatment, the weakness was markedly improved in nine patients; only one still required a wheelchair and six walked independently (p = 0.03). CONCLUSIONS: 1) In LSRPN, pain and neurological deficits improved (often dramatically) with IV MP treatment. 2) Although our results should be interpreted with caution since this trial is uncontrolled, IV MP may favorably affect the natural history of LSRPN. 3) The results are sufficiently promising to provide a rationale for prospective, sham controlled, double blind trials.     

Schwann cell changes and demyelination in chronic galactose neuropathy

Dystrophic changes of Schwann cells and demyelination occurred in rats with chronic nerve edema induced by feeding a galactose-rich diet for two years. The mechanism for edema is the sorbitol pathway which generates osmotically active polyols from galactose or glucose. The blood-nerve barrier impedes diffusion of macromolecules from peripheral nerves, and endoneurial fluid pressure (EFP) becomes elevated. After 24-26 months of feeding with 40% galactose diet, myelinated nerve fibers showed segmental demyelination with bubbly disintegration of myelin sheaths, axonal degeneration, and remyelination. These pathologic changes were significantly more common than similar abnormalities in age-matched controls. Massive glycogen accumulation in Schwann cells, a unique morphologic finding, appeared only in experimental rats. Since edema and increased EFP are the earliest pathologic changes and are present for months before demonstrable nerve fiber injury, we suggest that they are responsible for the changes of myelinated fibers in chronic galactose neuropathy.     

Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy

Nerve microvasculitis and ischemic injury appear to be the primary and important pathogenic alterations in lumbosacral radiculoplexus neuropathy of patients with (DLRPN) and without (LRPN) diabetes mellitus (DM). Here, we examine the involvement of inflammatory mediators in DLRPN and LRPN. Paraffin sections of sural nerves from 19 patients with DLRPN, 13 patients with LRPN, and 20 disease control patients were immunostained for intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor κB (NF-κB). The findings were correlated with histopathology. The pathologic and immunohistochemical alterations of DLRPN and LRPN nerves were indistinguishable. The nerves of both types of LRPN had a significantly greater number of ICAM-1 positive vessels than did the controls (P < 0.01). TNF-α expression was seen in Schwann cells and some macrophages of DLRPN and LRPN nerves, whereas IL-6 expression was minimal. There was greater NF-κB immunoreactivity in vessels and endoneurial cells of DLRPN and LRPN nerves than of the controls (P < 0.001). NF-κB expression correlated with the number of empty nerve strands (P < 0.01) and the frequency of axonal degeneration (P < 0.05), whereas TNF-α expression correlated inversely with the number of empty nerve strands of teased fibers (P < 0.05). Our findings suggest that up-regulation of inflammatory mediators target different cells at different disease stages and that these mediators may be sequentially involved in an immune-mediated inflammatory process that is shared by both DLRPN and LRPN. Up-regulated inflammatory mediators may be immunotherapeutic targets in these two conditions. Nobutoshi Kawamura was a Research Fellow in Phillip A. Low’s Peripheral Neuropathy Research Laboratory. Supported in part by grants obtained from the National Institute of Neurological Disease and Stroke (NS 36797) (NS 32352) (NS 22352) (NS 43364).     

Human diabetic endoneurial sorbitol,fructose, and myo-inositol related to sural nerve morphometry

Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.     

Segmental demyelination in the peripheral nerves of mice affected by a hereditary neuropathy (dystonia musculorum)

Summary A teased fibre and electron-microscopical study was carried out on the sciatic nerves of mice affected with the peripheral neuropathy in dystonia musculorum. Widespread segmental demyelination was present in all the nerves. Focal axon swellings were also seen, but were relatively scarce and similar in appearance to post-traumatic reactive swellings. The variability of dystonic internodal lengths was indicative of segmental demyelination rather than axonal degeneration. The largely motor fibres of the phrenic nerve were seen to undergo a similar degenerative process, but with a later onset and more gradual progression. Segmental demyelination was found to be present before axon swellings and other degenerative changes became visible in developing phrenic nerve. Demyelination is thus an important pathological process in dystonia musculorum, and the present observations are consistent with a primary segmental demyelinating disorder in dystonic peripheral nerve.     

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     

Acute endothelial swelling is induced in endoneurial microvessels by ischemia

Structural alterations of endoneurial microvessels occur in diabetic neuropathy and are statistically associated with severity of nerve fiber loss and teased fiber abnormality. It is therefore hypothesized that the microvessel alterations may cause or contribute to pathologic alterations of nerve fibers in diabetic neuropathy, possibly through hypoxic injury. The mechanism of the microvessel change in diabetic neuropathy is unknown. The role of microvessels and details of microvessel structure in other possible ischemic neuropathies has not been studied completely. Already there is evidence that hypoxia induces endothelial swelling but this has not been characterized or quantitated in nerve. To determine the acute morphologic effect of ischemia on ultrastructural features of transverse profiles of endoneurial microvessels major pelvic arteries were ligated in rats. At 36 h mean lumen and mural areas were greater in ischemic than in control nerves. All components (endothelium, pericytes and basement membrane) were on average greater in ischemic than controls. The greatest increase was in endothelial cells. In these cells swollen mitochondria were abundant. This study demonstrates that acute ischemia induces swelling of the cells and organelles of endoneurial microvessels.     

Morphometric analysis of the peripheral neuropathy of AIDS

A morphometric study of the peripheral nervous system at autopsy was undertaken in 11 AIDS patients and 10 controls. The left L4, L5, and S1 dorsal root ganglia (DRG) and samples of the sciatic nerve at the buttock, tibial nerve at the knee, and sural nerve at the ankle were collected. Indices of neuronal/axonal degeneration and of segmental demyelination/remyelination were measured at each level. The small number of cases and evidence of neuropathy in a number of the control cases resulted in statistical significance for only a limited number of comparisons. Nodules of Nageotte in the DRG were increased fivefold in AIDS cases compared with controls, and axonal degeneration in single-teased nerve fibers was increased 9-fold in the sciatic nerve, 28-fold in the tibial nerve, and 12-fold in the sural nerve. The ratios of AIDS to controls for the density of remaining DRG neurons and large myelinated axons were reduced to 0.71 in the DRG, 0.84 in the sciatic nerve, 0.84 in the tibial nerve, and 0.66 in the sural nerve. Axonal regeneration in single-teased nerve fibers was increased threefold at the sciatic nerve level in AIDS, but was markedly reduced at distal levels. Acute segmental demyelination in single-teased nerve fibers was present to a greater extent than in controls at all levels of the peripheral nerves in the AIDS cases. Remyelinating fibers were increased compared with controls only in the proximal sciatic nerve. No case showed the changes of cytomegalovirus infection. In a parallel immunohistochemical study of these AIDS peripheral nerves, T-cell and macrophage infiltration, with cytokine expression, was demonstrated. The pathological process in the neuropathy of terminal AIDS appears to be a multifocal immunologically mediated inflammatory disease, with increased density of macrophages and T cells at all levels of the peripheral nervous system, producing segmental demyelination and axonal degeneration. Reparative processes (axonal regeneration and remyelination) occurred only at the most proximal levels of the nerves. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1188–1195, 1998.     

Diabetic peripheral nerves are susceptible to multifocal ischemic damage from endothelin.

Experimental diabetes is associated with susceptibility to ischemic fiber damage. In a model of ischemia previously studied in our laboratory and induced by topical endothelin-1 (ET-1), diabetic nerves had selective conduction block that progressed to motor fiber inexcitability, associated with prolonged vasoconstrictive ischemia. In this work, we report our analysis of histological consequences of ET-1 ischemia. Our hypothesis was that intense epineurial vasoconstriction would be associated with centrofascicular fiber loss, confined to diabetic nerves. By quantitating the sectorial and fascicular distribution of fibers undergoing axonal degeneration we determined the degree and geographical distribution of axonal damage induced by topical ET-1 in the sciatic nerve trunk two weeks after ischemia. Axonal damage induced by ET-1 in diabetics exceeded that of non-diabetics by a factor greater than 5. The pattern of axonal degeneration was multifocal but not centrofascicular and did not vary with fascicular area. Some small fascicles had rates of axonal degeneration that far exceeded those of large adjacent fascicles. In other instances, sectors with intense axonal degeneration were subperineurial crescentic areas, similar to those originally described by Nukada following microsphere embolization. We conclude that diabetic nerves are highly susceptible to ischemic injury, but that multifocal and not centrofascicular fiber degeneration may be encountered.     

A micro-electrode study of peripheral neuropathy in man. Part 2. Responses to conditioning stimuli.

Surface, needle and micro-electrode recordings were obtained from sensory nerves of patients with various types of peripheral neuropathy. Changes in amplitude and conduction velocity of nerve action potentials were measured after a single conditioning stimulus and after tetanic stimulation for 2 min. In patients with hereditary forms of axonal degeneration (AD), recovery processes of nerve fibres of all conduction velocities were normal; in acquired forms of AD fibres with conduction velocity less than 30 m/sec had greater and more prolonged post-tetanic depression than control nerves of similar conduction velocity. Where neuropathy was associated with segmental demyelination (SD), fibres of all conduction velocities had prolonged recovery processes after both single and tetanic stimulation. The changes were especially marked at higher skin temperature, and were greater than the changes seen in nerves with acquired forms of AD. Finally, 2 sural nerves were studied during the process of Wallerian degeneration after a biopsy had been obtained proximally, and recovery processes did not change during the period of degeneration. Perceptual abnormalities were similar in AD and SD. It is suggested that changes in recovery processes of nerve fibres with segmental demyelination or regeneration after injury contribute to the perceptual abnormalities which occur in clinically encountered peripheral neuropathies.     

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.     

Peripheral nerve pathological findings in familial amyloid polyneuropathy: a correlative study of proximal sciatic nerve and sural nerve lesions

To analyze the peripheral nerve pathological abnormalities in familial amyloid polyneuropathy, a correlative pathological study was carried out on the spinal nerve roots, proximal sciatic nerves, sural nerves, and brachial plexuses from 3 patients with the disease in Japan. The spinal nerve roots appeared to be unaffected except for amyloid deposition on the epineurium. In sciatic nerves and brachial plexuses the nerve lesions had a multifocal distribution, showing prominent interstitial edema in the endoneurium frequently adjacent to deposits of amyloid; in these regions the nerve fibers were severely depleted. A teased-fiber study revealed that segmental demyelination was the predominant type of nerve fiber abnormality. However, these findings were not seen in the sural nerves; instead a diffuse fiber loss with axonal degeneration was observed. It is suggested that multifocal lesions in the proximal portions of the long extremity nerves could summate distally to produce a symmetrical polyneuropathy in the disease. In addition to a space-occupying effect of amyloid deposits in the endoneurium, severe endoneurial edema associated with amyloid deposition in blood vessels and the endoneurial interstitium may induce ischemia in nerve fibers, thus causing the progressive polyneuropathy in this disorder.     

Pathological changes in the vagus nerves in chronic alcoholism

A systematic morphometric examination of the vagus nerves at different levels obtained at autopsy in 4 control subjects and 6 alcoholic patients. Morphometric studies on myelinated fibres were performed on the nerve at the mid-cervical, lung hilum and diaphragmatic levels. In the patients with alcoholic neuropathy there was a significant reduction in density of myelinated fibers in the distal part of the vagus nerves when compared with controls. The more severe distal degeneration in the nerves and the pathological changes of axonal degeneration distally are consistent with the dying back neuropathy. The relation between the secondary segmental demyelination and degeneration of the involved nerves were discussed.     

Physiological approach to peripheral neuropathy. Conventional nerve conduction studies and magnetic motor root stimulation]

In this communication, I first show some points we should mind in the conventional peripheral nerve conduction studies and later present clinical usefulness of motor root stimulation for peripheral neuropathy. CONVENTIONAL NERVE CONDUCTION STUDIES (NCS): The most important point revealed by the conventional NCSs is whether neuropathy is due to axonal degeneration or demyelinating process. Precise clinical examination with this neurophysiological information leads us to a diagnosis and treatment. Poor clinical examination makes these findings useless. Long standing axonal degeneration sometimes induces secondary demyelination at the most distal part of involved nerves. On the other hand, severe segmental demyelination often provokes secondary axonal degeneration at distal parts to the site of demyelination. These secondary changes show the same abnormal neurophysiological findings as those of the primary involvement. We should be careful of this possibility when interpreting the results of NCS. NCS of sensory nerves is not good at revealing demyelinating process. Mild temporal dispersion of potentials often reduces an amplitude of SNAP or loss of responses, which usually suggests axonal degeneration, because of short duration of sensory nerve potentials. MOTOR ROOT STIMULATION IN PERIPHERAL NEUROPATHY: Magnetic stimulation with a coil placed over the spine activates motor roots and evokes EMG responses from upper and lower limb muscles. The site of activation with this method was determined to be where the motor roots exit from the spinal canal (intervertebral foramina) (J Neurol Neurosurg Psychiatry 52 (9): 1025-1032, 1989) because induced currents are very dense at such a foramen made by electric resistant bones. In several kinds of peripheral neuropathy, this method has been used to detect a lesion at a proximal part of the peripheral nerves which can not be detected by the conventional NCSs. I present a few cases in whom motor root stimulation had a clinical merit. In a patient with neuralgic amyotrophy, motor root stimulation disclosed a conduction block between the cervical intervertebral foramen and brachial plexus which was not detected by conventional NCSs. Motor root stimulation clearly revealed demyelination in a patient with CIDP in whom sural nerve biopsy findings suggested axonal degeneration, that must be secondary to demyelination. In a patient with tomacular neuropathy, magnetic stimulation revealed conduction delay in the spinal nerve within the spinal canal (Clin Neurol (Jap), 28: 447-452, 1988). Based on the above results, combination of NCSs and magnetic motor root stimulation must brush up the neurophysiological approach to peripheral neuropathy.     

Sensorimotor neuropathy in a patient with Marinesco-Sj?gren syndrome

A case of Marinesco-Sj?gren syndrome, displaying the characteristic signs (ataxia, congenital cataract and mental retardation) is presented. Electrophysiological examination pointed to the presence of a sensorimotor peripheral neuropathy with an underlying mixed process of segmental demyelination and axonal degeneration (probably secondary). The sural nerve and gastrocnemius biopsy confirmed these data, showing that in this case the segmental demyelination process was accompanied by axonal degeneration.