Teased fibre study of early nerve lesions in leprosy and in contacts, with electrophysiological correlates.

A teased fibre technique was used to study 19 biopsies of the index finger branch of the radial cutaneous nerve of leprosy patients and contacts. These were compared with four normal nerves. Five nerves were from patients with preclinical nerve lesions, five from leprosy patients with minimal sensory nerve impairment, and five from contacts of lepromatous leprosy. The extent of demyelination in preclinical nerve lesions in leprosy and in contacts of leprosy is recorded. The usefulness of nerve conduction velocity studies in early leprosy patients and in contacts is discussed.     

Respective importance of different nerve conduction velocities in leprosy

Motor and sensory nerve conduction studies were performed in the distal part of the ulnar, median and radial nerves of 12 tuberculoid and 12 lepromatous leprosy patients, compared with 15 normal subjects. Slowing of sensory conduction velocity (SCV) was shown in all nerves with no difference between tuberculoid and lepromatous patients. The radial SCV slowing is correlated (P < 0.001) with the clinical findings. Impairment of motor distal latencies was observed only in tuberculoid patients. It is concluded that the radial SCV is the most reliable conduction test and is proposed as an early diagnostic test for leprosy.     

The pathology of early leprous neuropathy

A qualitative and quantitative study was made of early changes in nerves from 10 patients with tuberculoid or lepromatous type of leprosy. Five nerve biopsies, taken from sites remote from skin lesions, were considered to be unaffected when examined by paraffin histology but showed abnormalities in semi-thin resin sections and by electron microscopy; 5 showed mild to moderate involvement by paraffin histology. Changes in 'unaffected' nerves in both types of leprosy included the presence of subperineurial oedema; occasional evidence of fibre regeneration, sometimes with atypical features; increased numbers of small myelinated fibres, possibly a consequence of axonal atrophy; a few thinly remyelinated fibres, probably due to secondary demyelination, and some loss of unmyelinated axons. In more affected nerves there was variable loss of axons, both myelinated and unmyelinated. Demyelination was not a conspicuous feature; there was evidence of axonal atrophy in some fibres. Similarities in some of the changes observed in tuberculoid and lepromatous types of leprosy suggest a common mechanism of nerve damage, at least in the early stages. The presence of abnormalities in nerves at a distance from skin lesions implies a more diffuse nerve involvement than might have been expected in both types of leprosy.     

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.     

Mechanism of nerve destruction in tuberculoid-borderline leprosy. An electron-microscopic study

The ultrastructural changes in radial cutaneous nerve biopsies from 3 tuberculoid and 14 tuberculoid-borderline patients were studied. In tuberculoid leprosy the nerve parenchyma was almost entirely replaced by tuberculoid granuloma. In nerves from borderline-tuberculoid leprosy many axons showed segmental demyelination and Wallerian degeneration. The nerve tissue was gradually replaced by proliferating collagen fibrils and inflammatory granulomata. M. leprae were rare and when present they were found in phagolysosomes of Schwann cells and macrophages. Schwann cells were surrounded and occasionally infiltrated by lymphocytes and macrophages. It was suggested that “sensitized Schwann cells” were the target of a hypersensitivity reaction resulting in their degeneration or death which in turn produced segmental demyelination or Wallerian degeneration.     

Teased fibre studies in leprous neuropathy

Nerve biopsies were taken from four cases of leprosy, which included borderline tuberculoid, borderline and lepromatous types. They were examined in 1-micron resin sections and in teased preparations. The most common finding in teased fibres from each leprosy type was paranodal demyelination affecting successive internodes. In transverse sections some fibres showed changes associated with axonal atrophy. Together, these findings suggest that demyelination in some cases may be secondary to axonal changes. In addition, there was evidence of focal areas of demyelination affecting whole internodes of many fibres at the same level across the nerve and which was possibly caused by local factors.     

DO NERVE GROWTH FACTOR‐RELATED MECHANISMS CONTRIBUTE TO LOSS OF CUTANEOUS NOCICEPTION IN LEPROSY?

While sensory loss in leprosy skin is the consequence of invasion by M. leprae of Schwann cells related to unmyelinated fibres, early loss of cutaneous pain sensation, even in the presence of nerve fibres and inflammation is a hallmark of leprosy, and requires explanation. In normal skin, nerve growth factor (NGF) is produced by basal keratinocytes, and acts via its high affinity receptor (trk A) on nociceptor nerve fibres to increase their sensitivity, particularly in inflammation. We have therefore studied NGF‐ and trk A‐like immunoreactivity in affected skin and mirror‐site clinically‐unaffected skin from patients with leprosy, and compared these with non‐leprosy, control skin, following quantitative sensory testing at each site. Sensory tests were within normal limits in clinically‐unaffected leprosy skin, but markedly abnormal in affected skin. Sub‐epidermal PGP 9.5‐ and trk A‐positive nerve fibres were reduced only in affected leprosy skin, with fewer fibres contacting keratinocytes. However, NGF‐immunoreactivity in basal keratinocytes, and intra‐epidermal PGP 9.5‐positive nerve fibres, were reduced in both sites compared to non‐leprosy controls, as were nerve fibres positive for the sensory neurone specific sodium channel SNS/PN3, which is regulated by NGF, and may mediate inflammation‐induced hypersensitivity. Keratinocyte trk A expression (which mediates an autocrine role for NGF) was increased in clinically affected and unaffected skin, suggesting a compensatory mechanism secondary to reduced NGF secretion at both sites. We conclude that decreased NGF‐ and SNS/PN3‐immunoreactivity, and loss of intra‐epidermal innervation, may be found without sensory loss on quantitative testing in clinically‐unaffected skin in leprosy; this appears to be a sub‐clinical change, and may explain the lack of cutaneous pain with inflammation. Sensory loss occurred with reduced sub‐epidermal nerve fibres in affected skin, but these still showed trk A‐staining, suggesting NGF treatment may restore pain sensation.     

Pathology of the peripheral nerves in leprosy: report of a case

Peripheral nerve trunks were examined from a case of lepromatous leprosy. M. leprae was seen in the nerves in several types of cells. Isolated nerve fibre preparations showed demyelinating lesions due to Schwann cell damage and complete nerve fibre degeneration. The causes of this mixed pattern of damage may involve both a direct effect of the bacilli on nerve fibres and various epiphenomena.     

Electromyographic recording and muscle biopsy in lepromatous leprosy

The aim of this study was to detect early muscular changes in lepromatous leprosy using simultaneously electromyography and muscle biopsy. In 13 subjects a single clinically normal muscle innervated by the popliteal nerve was studied. Three were found to be normal. All the others were electromyographically denervated. Histopathologic findings included only 3 cases of fascicular atrophy. In 8 cases inflammatory nodules were observed in the connective tissue of the muscle and acid-fast bacilli were present in Virchow cells in 5. In only one patient were intact acid-fast bacilli found in muscle cells. It was concluded that electromyography was the better method of detecting early denervation, while muscle biopsy was the better examination to detect “lepromatous myositis”. In practice these techniques are complementary in the study of muscle data in lepromatous leprosy.     

麻风性神经炎的临床与病理特征(附1例报告)

目的探讨麻风性神经炎的临床与病理特点。方法分析1例麻风性神经炎患者的临床资料,对其腓肠神经活检标本进行组织病理和超微病理观察。结果本例患者的临床特点以感觉损害为主,主要表现为肢体远端麻木、疼痛,伴自主神经功能障碍,不对称性尺神经粗大;病理改变主要为神经内外膜大量淋巴细胞浸润,血管内膜增厚,管腔狭窄,管壁及周围大量淋巴及单核吞噬细胞浸润,伴有上皮样细胞形成,抗酸染色可见神经纤维内散在分布的麻风杆菌,有髓纤维几乎完全脱失,纤维组织明显增生;电镜观察发现无髓纤维轴突变性及雪旺细胞里大量麻风杆菌聚集。本例患者经氨苯砜和泼尼松治疗1年,病情好转。结论麻风性神经炎的确诊有赖于神经活检。早期治疗可减轻伤残。     

Rate of recovery in motor and sensory fibres of the radial nerve: clinical and electrophysiological aspects

Electromyography and conduction studies in motor and sensory fibres were performed in 58 patients with different types of radial nerve injury. The site of nerve injury was predicted by clinical and electromyographic findings and correlated with changes in conduction, thereby permitting a more exact classification of the type of nerve injury. In patients with Saturday-night palsy, there was considerable slowing of conduction in both motor and sensory fibres across the presumed site of the lesion with return to normality within six to eight weeks. These observations suggest that local demyelination is the cause of nerve palsy. There were changes in sensory conduction even when there was no sensory deficit clinically, with no difference in susceptibility of motor and sensory fibres to ischaemia. In patients with radial nerve palsy secondary to fracture of the humerus, out-growth in motor and sensory fibres was equal and estimated to be about 1 mm per day. When the radial nerve palsy was attributed to traction or mild blunt injury the site of lesion was based on clinical and electromyographic findings. The rate of conduction in motor and sensory fibres was normal, suggesting that axonal damage was the cause of paresis, with sparing of some of the fastest conducting fibres.     

Degeneration and regeneration in teased nerve fibres

Summary The pattern of myelin degeneration and regeneration was studied in 40 nerve biopsy or necropsy specimens, using the teased fibre method, including 35 specimens of leprous neuritis, and 5 control specimens, 3 from humans and 2 from monkeys.The specimens of leprous nerves were derived from 10 lepromatous, borderline, or tuberculoid cases in an advanced polyneuritic stage. Nearly two-thirds showed Wallerian degeneration, which was very frequent in all types of leprosy. Segmental demyelination was observed in about one-fourth of the specimens and was more frequent in lepromatous cases.Regeneration was frequently encountered in nerve specimens from cases of all types of leprous neuritis. There was more often regeneration after Wallerian degeneration in the form of thin fibres with short uniform internodes, than an irregular remyelination after segmental demyelination. The two were further distinguished from one another by measuring the internodal lengths and fibre diameters.Extensive Schwann sheath proliferation was observed in almost all specimens of leprosy; the non-specificity of this is stressed.The significance of studying degenerative and regenerative changes at different levels of the same nerve from leprous neuritis, is discussed. The findings have shown that the myelin of the distal-most parts of the nerves sustains more severe damage, confirming earlier similar observations on paraffin sections.The control specimens, 3 of which were fixed in formalin for prolonged periods, did not show any significant abnormalities in the myelin.     

A morphological study of nerve biopsies from cases of multibacillary leprosy given multidrug therapy

Summary Nerve biopsies were examined from 17 cases of lepromatous leprosy given WHO-recommended multidrug therapy (MDT) for 2 years. The pathological changes were assessed qualitatively and quantitatively to judge the effectiveness of MTD> The nerves varied very considerably in the severity of their lesions. Some regenerating fibres were seen in most of the nerves. In a few cases, the nerves were almost entirely populated by regenerated fibres, confirming that MTD was effective in halting the disease process within the nerve. Mycobacterium leprae showed morphological features of degenerate bacilli. Some pathological features of the lepromatous lesion are described.Supported by LEPRA     

The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia

Characterization and quantitation of the spatial distribution of pathological abnormalities along the length of nerves may be helpful in understanding the underlying mechanisms of diabetic polyneuropathy. To this end, by examining transverse sections of nerve roots and proximal-to-distal levels of lower limb nerves in 9 controls and 15 diabetic patients with polyneuropathy, we have determined the myelinated fiber (MF) number, size distribution, median diameter, and variability of density (MFs/mm²) among frames and among fascicles. Even in cases with mild polyneuropathy, fiber loss, a decrrease in the median diameter, and an increase in the variability of density among frames and among fascicles began in proximal nerve and extended to distal levels. Multifocal fiber loss along the length of nerves and sprouting provide the best explanation for these findings. The pattern is dissimilar from that observed in diffuse metabolic disease of Schwann cells, neuronal degeneration, and dying-back neuropathy, but like that found in experimental ischemic neuropathy induced by embolization of nerve capillaries.     

Sensory action potentials and biopsy of the sural nerve in neuropathy.

In 167 consecutive patients with various types of neuropathy, the amplitude of the sensory potential and the maximum conduction velocity along the sural nerve were compared with conduction in other sensory nerves, and were related to structural changes revealed by nerve biopsy. Electrophysiological findings in the sural nerve were similar to those in the superficial peroneal and the median nerve, though the distal segment of the median nerve was normal in 20 per cent of the patients when it was abnormal in the sural nerve. Quantitation of histological findings was a more sensitive method than the electrophysiological study in that two-thirds of 33 patients with normal electrophysiology in the sural nerve showed mild loss of fibres or signs of remyelination in teased fibres. The amplitude of the sensory potential was grossly related to the number of large myelinated fibres (more than 7 micrometer in diameter). Considering the 95 nerves from which teased fibres were obtained, maximum conduction velocity was abnormal in half. In 18 of these nerves, slowing in conduction was due to axonal degeneration: the velocity was as to be expected from the diameter of the largest fibres in the biopsy ("proportionate slowing"). In 9 nerves slowing was severe and more marked than to be expected from loss of the largest fibres ("disproportionate slowing"); these nerves showed paranodal or segmental demyelination in more than 30 per cent of the fibres. In 16 nerves from patients with neuropathy of different aetiology neither loss of fibres nor demyelination could explain the moderate slowing. The cause of slowing in these nerves is unknown; other conditions are referred to in which slowing in conduction cannot be attributed to morphological changes. Finally, electrophysiological and histological findings are reported in some patients with neuropathy associated with malignant neoplasm, with rheumatoid arthritis, with polyarteritis nodosa, with acute intermittent porphyria and with cirrhosis of the liver.     

Nerve growth factor receptor immunostaining in the spinal cord and peripheral nerves in amyotrophic lateral sclerosis

Summary In animal experiments, nerve transection is followed by expression of nerve growth factor receptors (NGFR) on Schwann cells of both motor and sensory nerve fibres distally to the site of the lesion. To determine whether denervated Schwann cells in amyotrophic lateral sclerosis (ALS) similarly express NGFR, a study was made of post-mortem material of peripheral nerves and ventral roots from ALS cases and age-matched controls, using immunolabelling methods. Dorsal roots and spinal cords were also examined for the presence of NGFR. In all the ALS cases and controls, NGFR immunostaining was seen in the outer layer of vessel walls, perineurial sheaths, connective tissue surrounding fascicles in nerve roots and in the substantia gelatinosa of the spinal cord. In ALS, NGFR staining was also present in the Schwann cells of degenerated nerve fibres in mixed peripheral nerves, in ventral roots and, to a lesser extent, in dorsal roots. NGFR immunoreactivity was also seen in elongated cells extending from the perifascicular connective tissue into the nerve fascicles. It is concluded that denervated Schwann cells in ALS express NGFR and that NGFR immunostaining on Schwann cells may be used as an indicator of axonal degeneration. The NGFR labelling in the dorsal roots supports the notion that ALS is not a pure motor syndrome.Supported by a grant from the Foundation for Research of ALS and Spinal Muscular Atrophy     

High‐resolution sonography of the superficial radial nerve with two case reports

The purpose of this study was to find out whether high‐resolution sonography can be used to examine the superficial radial nerve. The sonographic appearance of the superficial radial nerve was assessed in 20 control subjects and the cross‐sectional area could be measured in all subjects. The mean cross‐sectional area of the superficial radial nerve in the control subjects was 2 mm² (SD 0.5 mm², range 1–3 mm²). Moreover, two patients with a superficial radial neuropathy and abnormal high‐resolution sonography are reported. One patient had an enlarged nerve after trauma, which was probably a neuroma. The other patient had a histologically proven Schwannoma of the superficial radial nerve. The superficial radial nerve, although small in size, can be visualized by high‐resolution sonography using specific landmarks. High‐resolution sonography can be useful to assess the underlying cause of superficial radial nerve pathology. Muscle Nerve 39: 392–395, 2009     

Imbalance between sympathetic and sensory innervation in peritoneal endometriosis

To investigate possible mechanisms of pain pathophysiology in patients with peritoneal endometriosis, a clinical study on sensory and sympathetic nerve fibre sprouting in endometriosis was performed.Peritoneal lesions (n = 40) and healthy peritoneum (n = 12) were immunostained and analysed with anti-protein gene product 9.5 (PGP 9.5), anti-substance P (SP) and anti-tyrosine hydroxylase (TH), specific markers for intact nerve fibres, sensory nerve fibres and sympathetic nerve fibres, respectively, to identify the ratio of sympathetic and sensory nerve fibres. In addition, immune cell infiltrates in peritoneal endometriotic lesions were analysed and the nerve growth factor (NGF) and interleukin (IL)-1β expression was correlate with the nerve fibre density.Peritoneal fluids from patients with endometriosis (n = 40) and without endometriosis (n = 20) were used for the in vitro neuronal growth assay. Cultured chicken dorsal root ganglia (DRG) and sympathetic ganglia were stained with anti-growth associated protein 43 (anti-GAP 43), anti-SP and anti-TH.We could detect an increased sensory and decreased sympathetic nerve fibres density in peritoneal lesions compared to healthy peritoneum. Peritoneal fluids of patients with endometriosis compared to patients without endometriosis induced an increased sprouting of sensory neurites from DRG and decreased neurite outgrowth from sympathetic ganglia.In conclusion, this study demonstrates an imbalance between sympathetic and sensory nerve fibres in peritoneal endometriosis, as well as an altered modulation of peritoneal fluids from patients with endometriosis on sympathetic and sensory innervation which might directly be involved in the maintenance of inflammation and pain.     

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.     

"Chronic sensory demyelinating neuropathy": chronic inflammatory demyelinating polyneuropathy presenting as a pure sensory neuropathy.

The clinical electrophysiological and histological features of 10 cases of "chronic sensory demyelinating neuropathy" (CSDN) are reported. This entity is characterised by: 1) subacute or chronic progression; 2) pure sensory neuropathy; 3) high spinal fluid protein in the majority of cases; 4) electrophysiological evidence of demyelination affecting motor as well as sensory nerve fibres; 5) demyelination on sural nerve biopsy and 6) good response to immunotherapy in progressive phase. It is believed that this entity represents chronic inflammatory demyelinating polyneuropathy (CIDP) presenting as pure sensory neuropathy.