Giant axonal neuropathy: report on a case with focal fiber loss

Summary We report on a 5 1/2 year-old boy with chronic progressive polynèuropathy, ataxia, and pyramidal signs. His hair was not curled. Sural nerve biopsy disclosed many axons enlarged by accumulation of 10-nm neurofilaments and a marked variability in the number of myelinated fibers as well as in the amount of axonal enlargements among different fascicles. These findings and the electrophysiological data were consistent with a giant axonal polyneuropathy with a multifocal fiber loss.     

Value of nerve biopsy in the diagnosis and follow-up of leprosy: the role of vascular lesions and usefulness of nerve studies in the detection of persistent bacilli

Nerve biopsy specimens from 53 patients with leprosy and neuropathy were taken from the sural, the dorsal branch of the ulnar, or the superficial radial nerves and processed for light and electron microscopy. There was inflammation in 40 cases (75%), 7 with a granulomatous reaction, various stages of fibrosis in 35 (66%), and endoneurial vascular neoformation in 7. In two cases, small focal infarcts were associated with marked endoneurial inflammation compressing the vessels, in addition to endoneurial lymphocytic vasculitis. Most had an axonal neuropathy of varying degree, some with total fibre loss, others with predominant small myelinated and unmyelinated fibre loss. Signs of demyelination and remyelination were the main findings in 9 cases (17%). Bacilli were present in endothelial, perineurial, Schwann cells and in macrophages. On two occasions, they lost their alcohol acid resistance, were suspected in semithin sections, and confirmed ultrastructurally. The biopsy was decisive for the diagnosis of leprosy in 15 cases (28%), most without skin lesions. We evaluated the effectiveness of the treatment in 20 (37.7%), 12 without and 8 with bacilli, despite negativity in the skin. The diagnosis of leprosy based on skin lesions was confirmed with the nerve biopsy in 9 cases, 6 had an inflammatory neuropathy suggestive of leprosy in the absence of bacilli, and 3 had nonspecific changes in the sural nerve since the neuropathy was in the upper limbs. We conclude that nerve biopsy is indicated for the diagnosis of leprosy in cases without clinically visible skin lesions and to evaluate the effectiveness of the treatment. In these cases the ultrastructural studies are important for recognition of the bacilli. Vascular lesions may play an important role in the progression of the nerve damage, including the occurrence of focal nerve infarcts which, to our knowledge, have not been previously reported in association with leprosy. Received: 8 December 1995 Received in revised form: 8 December 1996 Accepted: 13 January 1997     

瘤型麻风病周围神经损害及病理特征

目的探讨麻风病周围神经损害的临床表现及病理特征。方法分析1例麻风病的临床资料,行神经电生理、神经超声及病理检查,并对相关文献报道进行综述,研究麻风病的流行特征。结果该例患者神经损害主要累及双侧尺神经、腓总神经等。皮肤损害表现为反复的皮损,疤痕,皮肤病理见泡沫细胞组成的肉芽肿。结论麻风病以周围神经及皮肤损害为主,且有地区分布及年龄分布特点,致残率高,传染源仍然存在,因此应加强麻风病的防治工作。     

Giant axonal neuropathy (GAN): an immunohistochemical and ultrastructural study report of a Latin American case

Summary Giant axonal neuropathy (GAN), a progressive childhood disorder of intermediate filaments (IF), is characterized by a peripheral neuropathy and central nervous system involvement. Twenty-eight cases have been reported while several pathogenic hypotheses have been proposed. Sural nerve biopsy of a 10-year-old Argentinian girl showed a reduced number of myelinated fibers as well as several enlarged axons up to 30 m in diameter, thinly myelinated or devoid of myelin sheath, displaying accumulation of neurofilaments (NF), but few microtubules (MT) beneath the axolemmal membrane. There was IF accumulation in Schwann and perineural cells as well as in melanocytes, fibroblasts, pericytes, endothelial and epithelial cells in both nerve and skin biopsy. Our findings strongly support GAN as a generalized IF disorder with MT segregation from NF in giant axons. Abnormal NF phosphorylation is suggested by heavy immunostaining of enlarged axons by a monoclonal antibody to NF phosphorylated determinants (SMI 31-Sternberger's) and lack of reaction with a monoclonal antibody with different phosphoepitopes affinity (SMI 34-Sternberger's).Part of this work has been presented at the meeting of the American Association of Neuropathologists Charleston 1988     

Giant axonal neuropathy

Summary Giant axonal neuropathy (GAN) is a disease characterized by a slowly progressive neuropathy and signs of central involvement, manifested by visual impairment, corticospinal tract dysfunction, ataxia, and dementia. Pathological hallmarks of the disease include axonal swellings packed with neurofilaments in both peripheral and central nervous systems, and accumulations of intermediate filaments in Schwann cells, fibroblasts, melanocytes, endothelial, and Langerhans cells. Rosenthal fibers, sometimes appearing in masses and mimicking Alexander's disease, emerge as a conspicuous characteristic in longstanding GAN.Supported by a grant from the National Institutes of Health (NS 22786)     

Ultrastructural changes in blood vessels of peripheral nerves in leprosy neuropathy. II. Borderline,borderline-lepromatous and lepromatous leprosy patients

Summary The ultrastructure of blood vessels in endo-, peri- and epineurium was studied in peripheral cutaneous nerve biopsies of 16 borderline (BB), borderline-lepromatous (BL) or lepromatous (LL) leprosy patients some of whom were in reversal reaction. Comparable vessels in nerve biopsies of control cases and vessels in skin lesion biopsises of the leprosy patients were also studied.Vascular changes were found in nerves of all the leprosy patients. The changes were pronounced in endoneurial vessels and affected 1. endothelial continuity and surface structure, 2. basement membranes of endothelium and pericytes, and 3. the vessel lumen. In addition, intra-endothelial (IE)Mycobacterium leprae were a feature in some of the patients.Gaps occurring between endothelial cells and plasma insudation both noticed in vessels of fascicles with early to very early neuropathy suggested extensive leakage which, in all probability, causes early nerve fibre damage. Luminal and abluminal endothelial protrusions, which were frequently observed, may enhance transendothelial transport. Fenestrations and endothelial attenuation, possibly, lead to an increase in vascular permeability. Endothelial phagocytotic activity, particularly in small (epineurial) arteries, appeared to be stimulated, possibly, by circulatingM. leprae.Basement membrane multilayering (a hyaline zone) was found peripherally to pericytes, as is the case in tuberculoid leprosy (Boddingius, 1976). In a number of patients, multilayering occurred also peri-endothelially. Perivascular zones, which are thought to initiate or aggravate neuropathological changes by impairment of diffusion of oxygen and nutrients or metabolites, were very wide in endoneurial vessels of patients in reversal reaction and this suggested an immunological aetiology.Partial or total vessel lumen occlusion, seen in advanced lepromatous neuropathy, most likely contributes to final nerve fibre degeneration and endoneurial fibrosis. M. leprae were found intra-endothelially in endoneurial vessels, though only in fascicles with advanced neuropathy whereas bacilli were not seen in vessel lumina. By contrast, in fascicles with relatively early neuropathy, solid (viable) bacilli were frequently encounteredintra-axomally in myelinated fibres. This suggests that, in many instances, primary infiltration ofM. leprae into nerve fascicles may arise from intra-axonal (IA) bacilli which ascend from dermal nerves and are released within main nerve trunks after demyelination of the host fibre.     

Myelin changes in leprous neuropathy

Summary Myelin changes were observed in fibres of nerves from cases of leprosy. The myelin had a loosened appearance caused by increased and irregular separation of the intraperiod line. Loosening might affect all, or only some, of the lamellae forming a myelin sheath. There was a pathcy distribution of fibres with abnormal myelin, and they were seen only in nerves showing other marked pathological changes including the presence of oedema. The appearances are suggestive of intramyelinic oedema which may be related to the presence of endoneurial oedema.Supported by the Brain Research Trust and the British Council, who funded an exchange arrangement between the Institute of Neurology, London and the Foundation for Medical Research (FMR), Bombay     

Coexpression of glial fibrillary acidic protein and vimentin in the central and peripheral nervous systems of the twitcher mutant

A method to purify glial fibrillary acidic protein (GFAP) from mouse spinal cord is described, which permits the measurement of GFAP in the sciatic nerve of the twitcher mutant and control mouse. Cytoskeletal proteins from sciatic nerves and purified GFAP standards were electrophoresed on gel, transferred to nitrocellulose paper, and immunostained with anti-GFAP antibody. From the immunostained, 51,000-dalton band, we estimated about 200 ng GFAP per 50 μg of cytoskeletal protein in the twitcher sciatic nerve. The control nerve showed no detectable GFAP. Double-labeled fluorescence immunocytochemistry showed that in the brainstem of twitcer mutant, GFAP and vimentin were coexpressed in the majority of astrocytes.     

Polyneuropathy attributes: a comparison between patients with anti-MAG and anti-sulfatide antibodies

Thirty-two patients with a peripheral neuropathy and paraproteinemia were tested for IgM antibodies against myelin-associated protein (MAG) and sulfatide by means of enzyme-linked immunosorbent assay. Nine patients (28%) had increased anti-sulfatide IgM antibodies and showed a chronic, slowly progressive, distally pronounced, and symmetric polyneuropathy with sensory to sensory-motor impairment, ataxia, hyporeflexia, and axonal involvement in electrophysiological studies. Ten patients (31%) with increased anti-MAG antibodies had a similar, homogeneous polyneuropathy syndrome but presented with demyelinating features. A weak crossreactivity between anti-MAG and anti-sulfatide antibodies was present in only three patients. In conclusion, although the two neuropathy groups clearly differed in their electrophysiological features, their clinical presentation was rather similar. Received: 19 July 1999 / Received in revised form: 23 December 1999 / Accepted: 2 May 2000     

Study of visual evoked potentials in the assessment of the central optic pathways in leprosy patients

Abstract. We evaluated the possible involvement of central optic pathways (COP) in leprosy patients with visual evoked potentials, an easy, sensitive and reliable noninvasive method for evaluation of COP. In 37 patients with lepromatous leprosy and in 37 age-matched controls, we measured reversal pattern visual evoked potentials (RP-VEP) and nerve conduction parameters. The mean latency value of positive peak P100 in leprosy patients was significantly delayed compared to that of controls (patients, 108.02±9.61 ms in left eye and 108.23±8.51 ms in right eye; controls, 96.22±4.20 ms in left eye and 95.75±4.03 ms in right eye; p<0.05). Abnormally delayed P100 latency was recorded in 5 of 37 leprosy patients (13.5%). The mean amplitude of P100 latency in leprosy patients was smaller than that of controls (patients, 8.7±5.6 µV in left eye and 9.5±4.8 µV in right eye; controls, 10.7±4.6 µV in left eye and 10.5±5.1 µV in right eye), but this difference was not significant. No correlation was observed between abnormalities of RP-VEP and sensorimotor nerve conduction parameters. This study suggests that involvement of COP may develop in patients with lepromatous leprosy. RP-VEP measurement, which can be easily and rapidly performed in an EMG laboratory using standard equipment, can show these alterations.     

Ultrastructural and histophysiological studies on the blood-nerve barrier and perineurial barrier in leprosy neuropathy

Summary Onset and nature of ultrastructural changes in endoneurial vasa nervorum during the pathogenesis of leprosy neuropathy and possibly associated alterations in the blood-nerve barrier were investigated, together with perineurial barrier functioning, in mice infected 20–28 months previously withMycobacterium leprae and in (ageing) non-infected mice. Barriers were tested by i.v. administration of markers (Trypan blue and ferritin) 1–4 days before killing the mice.Twenty-eight months after infection, histopathology of sciatic nerves was comparable to that seen in sensory nerves in clinically early human (borderline-) lepromatous leprosy. Schwann cells and endoneurial macrophages were bacillated, endothelia of endoneurial vessels not, and the perineurium rarely.Many infected mice and all (ageing) controls possessed ultrastructurally and functionally normal endoneurial vessels. Their continuous endothelium with close junctions had prevented marker passage, even when surrounding endoneurial tissue cells were quite heavily bacillated. The perineurium was also normal.By contrast, in infected mice showing hind limb paralysis serious histopathologic involvement and large globi of bacilli intrafascicularly in sciatic nerves, endoneurial blood vessels were abnormal. Open endothelial junctions, extreme attenuation, fenestrations, and luminal protrusions were all features comparable to neural microangiopathy encountered in leprosy patients (Boddingius 1977a, b). The blood-nerve barrier clearly had become defective allowing excessive exudation of Trypan blue and ferritin, via four pathways from the vessel lumen, deep into surrounding endoneurial tissues but halted by a normal perineurial barrier. Markers in such blue nerves were not found in bacillated or non-bacillated Schwann cells, thus denying significant phagocytotic and lysosomal activities of Schwann cells at this stage of neuropathy. Possible implications of barrier performances for anti-leprosy drug treatment of patients are discussed.Supported by the British Medical Research Council (MRC), the British Leprosy Relief Association (LEPRA), the Wellcome Trust, and the Netherlands Leprosy Relief Association (NSL)     

Anticeramide antibody and butyrylcholinesterase in peripheral neuropathies

Ceramide is a glycosphingolipid, a component of nerve and non neuronal cell membrane and plays a role in maintaining the integrity of neuronal tissue. Butyrylcholinesterase (BChE) is a multifunctional enzyme, its involvement in neurodegenerative diseases has been well established. Anticeramide antibody (Ab-Cer) and enzyme BChE have been implicated in peripheral neuropathies. The present study investigates whether there is an association between Ab-Cer and BChE activities and peripheral neuropathies. Patients included: human immunodeficiency virus associated peripheral neuropathy (HIV-PN, n = 39), paucibacillary leprosy (PB-L, n = 36), multibacillary leprosy (MB-L, n = 52), diabetic neuropathy (DN, n = 22), demyelinating sensory motor polyneuropathy (DSMN, n = 13) and chronic inflammatory demyelinating polyneuropathy (CIDP, n = 10). Plasma Ab-Cer was measured by indirect enzyme linked immune assay (ELISA) and BChE activity in plasma was measured by colorimetric method. Ab-Cer levels were significantly elevated in MB-L and DN as compared to healthy subjects (HS). BChE levels were significantly higher in MB-L and DN as well as in HIV and HIV-PN. There is no significant difference in either Ab-Cer or BChE levels in DSMN and CIDP. Elevated plasma Ab-Cer and BChE levels may be considered significant in the pathogenesis of neuropathies. The variation in concurrent involvement of both the molecules in the neuropathies of the study, suggest their unique involvement in neurodegenerative pathways.     

急性砷化物中毒的周围神经病变

目的 探讨急性砷化物中毒性周围神经病的临床表现和总结治疗体会。方法 回顾性分析34例饮用砷超标水引起急性砷化物中毒中25例并发周围神经病患者临床资料及随访恢复情况。结果 经综合治疗，23例肌力、肌张力、感觉及腱反射均恢复正常，19例神经传导速度完全恢复正常，14例失神经电位的患者肌电图正常；追踪观察6个月，病情无反复。结论 急性砷化物中毒可致明显的周围神经病变，及时驱砷和神经营养等综合治疗效果较好。     

Demonstration ofMycobacterium leprae antigen in nerves of tuberculoid leprosy

Summary Twenty nerve biopsies of tuberculoid leprosy patients who showed no acid-fast bacilli in their skin smears or in tissue biopsies, were stained for mycobacterial antigens using anti-bacille Calmette-Gúerin (BCG) by the peroxidase-antiperoxidase method. Adjacent parts of some of these nerves were examined for the presence of osmiophilic bacilli under the transmission electron microscope. Eight of the 20 nerves were both clinically and histologically uninvolved. All the 20 involved nerves showed presence of antigen located, mainly intracellularly, in the cytoplasm of epithelioid cells and to a lesser degree in Schwann, endothelial and plasma cells. A few nerves with caseated nerve abscesses showed clusters of antigen deposits in both the caseous mass as well as the wall of the abscess. In six of the nine nerves processed for electron microscopy, electron-dense bacilli were noted within the cytoplasm of Schwann cells but not within the infiltrating cells. The uninvolved nerves showed neither antigen deposits nor osmiophilic bacilli despite fine ultrastructural changes. Our observations indicate that (a) the specificity of the immune response in paucibacillary nerve lesions is probably against bacterial components. (b) There is a differing antigen handling by Schwann cell and the inflammatory epithelioid cell. (c) Plasma cells may play a role in presenting antigen. (d)Mycobacterium leprae may be acting as an adjuvant in causing damage to uninvolved nerves at distal sites.     

Peripheral neuropathy in patients with benign monoclonal gammopathy — A pilot study

Summary It is well known that peripheral neuropathy ocurs in patients with myeloma or macroglobulinaemia, but its pathogenesis is still obscure. In recent years, neuropathy has also been reported in association with benign monoclonal or oligoclonal gammopathy. Modern histo-immunological methods have revealed evidence of antibody production to peripheral nerve tissue, probably the myelin sheath.The present study included 21 unselected, consecutive patients with benign monoclonal gammopathy observed in the Division of Haematology. Clinical and laboratory investigations included electrophysiological examination and analyses of the M components. Of the 21 patients 11 had noticed slight neuropathic symptoms in their extremities; in 5 both clinical and electrophysiological findings were compatible with neuropathy; 6 showed positive clinical signs of neuropathy; 4 had either positive electromyographic or electroneurographic findings. In summary, 15 of 21 patients had some signs of peripheral neuropathy. In spite of the screening design of the study, this strikingly high frequency is comparable with other recent reports. Haematological studies did not reveal any significant differences between the patient groups with positive or negative neurological findings. The findings indicate that even benign gammopathies may be associated with peripheral neuropathy.

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Zusammenfassung Das Vorkommen peripherer Neuropathien bei Myelomen und Makroglobulinämien ist wohl bekannt. Die Pathogenese allerdings ist noch unklar. In den letzten Jahren wurde über einen möglichen kausalen Zusammenhang zwischen Polyneuropathien und den gutartigen Formen von monoklonalen oder oligoklonalen Gammopathien berichtet. Moderne immunologische Methoden ergaben Anhaltspunkte für eine Antikörperproduktion gegen peripheres Nervengewebe, wahrscheinlich gegen Myelinstrukturen.Der vorliegende Bericht bezieht sich auf 21 nicht selektionierte Patienten mit gutartiger monoklonaler Gammopathie, die wir in der hämatologischen Abteilung beobachten konnten. Die Patienten wurden klinisch und labormäßig untersucht, wobei auch elektrophysiologische Untersuchungen und eine Analyse der M-Komponenten durchgeführt wurde. Von den 21 Patienten hatten fünf leichte polyneuropathische Symptome ihrer Extremitäten bemerkt. Bei fünf waren sowohl die klinischen wie elektrophysiologischen Befunde mit einer Neuropathie vereinbar; sechs hatten lediglich positive klinische Zeichen einer Neuropathie, und vier weitere hatten entweder ein positives Elektromyogramm oder eine positive Elektroneurographie. Zusammenfassend hatten also 15 von 21 Patienten mindestens einen Hinweis auf eine periphere Neuropathie. Trotz der begrenzten Zahl von Patienten ist diese erstaunlich große Häufigkeit neuropathischer Syndrome durchaus vergleichbar mit anderen kürzlichen Untersuchungen. Hämatologische Untersuchungen ergaben keine signifikanten Unterschiede zwischen der Patientengruppe mit und jener ohne neurologische Befunde.Unsere Untersuchungsergebnisse sprechen dafür, daß auch gutartige Gammopathien mit einer peripheren Neuropathie einhergehen können.

     

Uncommon early-onset neuropathy in diabetic patients

An acute neuropathy rarely occurs early in the course of diabetes mellitus. Five cases are described of adult patients who developed a peripheral neuropathy at the time or shortly after the onset or discovery of diabetes mellitus. Patient 1, an 80-year-old woman who developed a subacute tetraparesis with proximal and distal muscle weakness with normal cranial nerves, proved to have insulin-requiring diabetes mellitus. In the other patients, all men aged 23–34 years, symptomatic neuropathy occurred simultaneously (patient 2) or 1–6 months after the onset of insulin-dependent diabetes mellitus (IDDM) (patients 3–5). Patients 2 and 3 developed a symptomatic multifocal neuropathy; patients 4 and 5, a painful distal symmetrical sensory polyneuropathy (DSSP) shortly after beginning treatment with insulin. Nerve biopsy showed active axonal lesions in patients 2 and 5 and mixed axonal and demyelinating lesions in the others, with severe axon loss in patients 4 and 5. Vasculitic lesions were found in patient 2, who improved without additional treatment. Neurological examination remained unchanged after 2 years in patients 3–5. Although a coincidence cannot be excluded for patients 1–3, whose neuropathy was not of the pattern commonly found in diabetes, it is suggested that acute disequilibrium in the diabetic status may facilitate the occurrence of a variety of neuropathies. Alternatively, the autoimmune process which led to IDDM may also trigger an autoimmune neuropathy with vasculitis (patient 2) or demyelinative nerve lesions. Only the distal symmetrical sensory polyneuropathy with severe axonal lesions observed in patients 4 and 5 seems directly related to diabetes mellitus. In spite of their occurrence shortly after beginning insulin therapy, the role of treatment with insulin in the onset is uncertain. Received: 29 November 1996 Received in revised form: 4 September 1997 Accepted: 10 Oktober 1997     

Peripheral nerve conductions in relapsing remitting multiple sclerosis (RRMS) patients

PurposeThe purpose of this study was to investigate with Elektromioneurografija (EMNG) whether there is any affection on peripheral nerves in (RRMS) patients.Material and MethodMotor and sensory nerve conductions were studied in the control group including 33 RRMS patients and 25 healthy individuals. Expanded Disability Status Scale (EDSS) scores, mean annual attack frequency, duration of disease and treatments of RRMS patients were recorded.ResultsThere was a statistically significant (p < 0.05) elongation in motor distal latency of the right peroneal nerve, slowing in the left peroneal nerve conduction velocity, and an elongation in the F-wave response in the RRMS group compared to the control group. It was observed that motor nerve conduction velocities were slower, albeit not statistically significant, and F wave latencies were longer than control group.ConclusionThere are studies in the literature related to the association between MS and peripheral neuropathy. In this study, we found demyelinating type changes, differing significantly from the control group, in motor nerve conductions in RRMS patients. There may be demyelinating type affection in peripheral nervous system with common autoimmune mechanism in MS, a demyelinating disease of the central nervous system.     

Vasomotor reflexes in the fingertip skin of patients with type 1 diabetes mellitus and leprosy

Fingertip skin blood flow was measured by laser Doppler flowmetry (as LDflux) under environmental conditions promoting vasodilatation in Scottish patients with diabetes mellitus and Indian patients with leprosy. The reflex control of fingertip blood flow was assessed by measuring the reduction in LDflux induced by deep inspiratory gasp (IG) and cold challenge (CC) of immersing the contralateral hand in cold water.The uncomplicated diabetic patients showed normal vasomotor reflexes and an increased, though non significant, LDflux level (p < 0.06). The patients with diabetic neuropathy had resting LDflux levels significantly less than the uncomplicated group and also had substantial impairment of both IG and CC reflexes. Those with retinopathy (but no clinically apparent neuropathy) had LDflux within the normal range, but they showed minor evidence of impairment of the vasomotor reflexes.The uncomplicated newly registered leprosy patients had reduced LDflux and substantial impairment of CC reflexes. These changes were more marked in newly registered leprosy patients with clinical evidence of neuropathy. Leprosy patients with long-standing neuropathy requiring orthopaedic treatment had LDfluxes so greatly reduced that measurement of vasomotor reflexes was not practicable. The CC reflex was more severely affected than the IG reflex and more frequently absent in leprosy patients, possibly because of associated sensory neuropathy affecting the afferent limb of this response.Thus laser Doppler flowmetry can detect impairment of reflex control of fingertip blood flow in both diabetes mellitus and leprosy, but there are functional differences in the pattern of autonomic impairment between the diseases, suggesting differences in the pathogenesis of nerve damage.     

Sensory neuropathy and anti-Hu antibodies in a patient with seminoma

A man with subacute sensory ncuronopathy (SSN) had a stage 1 seminoma. His serum and cerebrospinal fluid (CSF) contained anti-Hu antibodies (type 1 anti-neuronal nuclear antibodies, ANNA-1). Following orchidectomy, radiotherapy, prednisolone, plasma exchange and intravenous immunoglobulin the antineuronal antibody titre fell and the neuropathy improved.