Intravenous immunoglobulin preparation attenuates neurological signs in rat experimental autoimmune neuritis with the suppression of macrophage inflammatory protein -1α expression

To clarify the mechanism of action of an intravenous immunoglobulin (IVIG) preparation in chronic inflammatory demyelinating polyneuropathy, the effects of IVIG were investigated using an experimental autoimmune neuropathy model in the rat. IVIG significantly suppressed the progression of neurologic signs and sciatic nerve conduction velocity with the inhibition of inflammatory cell infiltration, mainly of macrophages, to the peripheral nerves. A significant suppressive effect on the expression of macrophage inflammatory protein 1-α (MIP-1α) was simultaneously observed in the nerves. These results suggest that IVIG is effective for inflammatory demyelinating polyneuropathy by inhibiting the chemotactic factor of macrophages.     

B-cell neurolymphomatosis confined to the peripheral nervous system

Patients with neurolymphomatosis show lymphoma cells within the peripheral nerves, nerve root/plexus, or cranial nerves. However, most neurolymphomatosis patients show lymphomatous infiltration not only in the peripheral nervous system (PNS), but also in the meninges, Virchow–Robin space, and brain parenchyma. Here, we report a 74-year-old woman with diffuse large B-cell lymphoma presenting with motor–sensory–autonomic polyneuropathy and multiple cranial neuropathies. A diagnosis of neurolymphomatosis was made by sural nerve biopsy. Postmortem examination indicated that lymphoma cell infiltration in the nervous system was confined to the PNS with no involvement of the central nervous system, including the meninges. This was a very rare case of B-cell neurolymphomatosis with lymphomatous infiltration confined to the PNS, suggesting specific affinity of the lymphoma cells for the PNS in this patient.     

Matrix metalloproteinase expression and inhibition after sciatic nerve axotomy

Wallerian degeneration is characterized by breakdown of myelin and axons with subsequent macrophage infiltration and removal of the degenerating nerve components. Proteinases of the matrix metalloproteinase (MMP) family seem to play an important role in demyelinating processes, since some of their members have been shown to cleave myelin basic protein. In the present study we investigated the expression of MMP-2 and MMP-9 (gelatinases A and B) during myelin removal after peripheral nerve trauma. After transection of the sciatic nerve an upregulation of MMP-2 and MMP-9 with a first peak 12 h and a second peak 48 h after axotomy was observed by zymography. These peaks correlate with the breakdown of the blood-nerve barrier, the accumulation of granulocytes, and the invasion of macrophages into the damaged nerves, respectively. Furthermore, MMP-2 was found to be upregulated in the contralateral nontransected nerves. Immunocytochemistry for MMP-9 and in situ zymography identified MMP-reactive cells within the distal nerve stump. Chloracetate esterase staining was used to detect granulocytes, which accumulated at the transection site and were colocalized with the in situ zymography signal. Wallerian degeneration of the transected nerve could be delayed either by intraperitoneal injections of hydroxamate (Ro 31-9790), a nonspecific MMP inhibitor, or by local application of an MMP-9-specific antibody. Following these treatment strategies, a decreased number of invading macrophages was seen in the nerves associated with an increased amount of preserved myelin sheaths. These results suggest that the invasion of macrophages into a transected peripheral nerve is accompanied by an increased expression of MMPs, particularly MMP-9. Thus, MMPs may seem to play an important role in the breakdown of the blood-nerve barrier and subsequent cell recruitment from the systemic circulation into the damaged nerve.     

Pioglitazone promotes peripheral nerve remyelination after crush injury through CD36 upregulation

In our previous study, we found that CD36-deficient mice showed significant delays in peripheral nerve remyelination after sciatic nerve crush injury and suggested that CD36 played an important role in the restoration of injured peripheral nerves. The aim of this study was to investigate whether CD36 upregulation can promote peripheral nerve remyelination. We made crush injury that caused demyelination and mild axonal degeneration to sciatic nerves and investigated the effect of pioglitazone (PIO) on the remyelination post-injury in C57Bl/6 wild-type and CD36-deficient mice. The immunohistochemistry with anti-CD36 antibody showed that CD36 was upregulated in macrophages infiltrating peripheral nerves from the wild-type mice by PIO administration at 1 week post-injury. The lectin histochemistry represented that infiltrating macrophages lessened in the wild-type mice at 3 weeks post-injury by PIO administration. General histopathology and morphometry indicated that thinly myelinated fibers and naked axons diminished in PIO-treated wild-type mice compared with non-treated wild-type mice at 3 weeks post-injury. No significant differences were observed in remyelination and number of infiltrating macrophages between PIO-treated and non-treated CD36-deficient mice. These results indicate that PIO promotes peripheral nerve remyelination possibly through CD36. It may be possible to apply PIO to the remedy against demyelinating neuropathies.     

Chronic inflammatory demyelinating polyradiculoneuropathy with diffuse and massive peripheral nerve hypertrophy: Distinctive clinical and magnetic resonance imaging features

We present 3 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with extensive and diffuse hypertrophy of the nerve roots and peripheral nerves. They exhibited slowly progressive sensory impairment and distally predominant limb weakness and muscular atrophy, and markedly enlarged palpable nerve trunks. They responded beneficially to corticosteroid. Magnetic resonance imaging demonstrated diffuse and extensive hypertrophy of the peripheral nerves in the four limbs and the spinal nerve roots, with gadolinium enhancement in the nerve roots but not in the peripheral nerves. These patients were considered to have a hypertrophic variant of CIDP. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:805–808, 1998.     

Physiologic-pathologic correlation in Guillain-Barré syndrome in children

OBJECTIVE: To correlate electrophysiologic patterns with sural nerve pathology in children with Guillain-Barré syndrome (GBS). BACKGROUND: Based on electrophysiologic and pathologic observations, GBS has been divided into demyelinating and axonal subtypes. The acute motor axonal neuropathy (AMAN) involves predominantly motor nerve fibers with a physiologic pattern suggesting axonal damage, whereas the acute inflammatory demyelinating polyneuropathy (AIDP) involves both motor and sensory nerve fibers with a physiologic pattern suggesting demyelination. In this study, we sought to confirm these observations by correlating sural nerve pathology with electrophysiologic findings in GBS patients. METHODS: Biopsies of sural nerve from 29 of 50 prospectively studied GBS patients were obtained. Nerves were examined by light and electron microscopy, and with immunocytochemistry for macrophages, lymphocytes, and complement activation products. RESULTS: Sural nerves from AMAN patients were normal or had only a few (0.1% to 0.7%) degenerating fibers without lymphocytic infiltration or complement activation. One patient with reduced sural sensory nerve action potential classified as acute motor sensory axonal neuropathy (AMSAN) had many degenerating fibers (2.3%) in the sural nerve. All three AIDP patients displayed active demyelination, and in two patients, lymphocytic infiltration and complement activation products were observed on the abaxonal Schwann cell surface. CONCLUSION: Classification of Guillain-Barré syndrome subtypes based on motor conduction studies correlates closely with pathologic changes seen in sural nerve. In acute motor axonal neuropathy cases, the sural nerve is almost completely spared pathologically. In acute inflammatory demyelinating polyneuropathy cases, macrophage-mediated demyelination and lymphocytic infiltration are common in the biopsies of sural nerves.     

T cells from patients with Guillain-Barré syndrome produce interferon-gamma in response to stimulation with the ganglioside GM1

Guillain-Barré syndrome (GBS) is an acquired demyelinating neuropathy, characterized by infiltration of peripheral nerves with macrophages and T cells. There have been reports of antibodies to glycolipids in GBS. We have previously found T cell reactivity to glycolipids in patients with the demyelinating form of GBS. This study was performed to characterize the cytokines produced by these T cells. Peripheral blood lymphocytes from patients with GBS, chronic inflammatory demyelinating polyradiculoneuropathy, healthy control patients and other neuropathies were incubated with the ganglioside GM1 and transferred to enzyme-linked immunospot plates. The average number per well of spot-forming cells (SFC) in the absence of antigen was counted. The average spontaneous SFC number was subtracted from the average SFC number in the presence of GM1, to produce a corrected SFC. There was significantly increased production of interferon-gamma but not interleukin-5 in response to stimulation with the ganglioside GM1. This could indicate that SFC have a role in pathogenesis of disease.     

多发性硬化周围神经损害的肌电图及病理研究

目的：探讨多发性硬化（MS）产生周围神经损害的肌电图，病理特点和影响MS累及周围神经的相关因素。方法：33例MS患者，均满足Poser的确定诊断标准，排除其他神经系统疾病，30名正常自愿受试者作为对照，排除周围神经损害的相关因素，两组分别进行运动，感觉神经传导检测，F波潜伏期及出现率，H反射潜伏期检测，腓肠神经活检，光镜及电镜观察周围神经病理变化。结果：（1）33例MS患者中，9例有根性疼痛，3例有手袜套样感觉障碍，6例不对称性肌萎缩，2例有明显的自主神经症状；（2）肌电图显示复合肌肉动作电位波幅降低，正中神经，尺神经感觉运作电位波幅增高，F波及H反射的潜伏期延长，F波出现率降低。MS周围神经损害的程度与神经功能缺损、病程及病变部位有关，神经功能缺损越重，病程越长，胫神经和腓总神经运动传导波幅降低越明显，正中神经、尺神经感觉动作电位波幅增高越明显；脊髓型MS周围神经受损明显高于脑型；（3）6例患者腓肠神经活检，光镜下可见有髓纤维呈不同程度的髓鞘脱失。电镜下以轴索变性为主，髓鞘板层解离及髓球形成。结论：MS是一种以CNS受损为主的脱髓鞘疾病，在部分患者可对同时累及周围神经系统，脱髓鞘改变主要发生在脊神经根，远端轴突可继发轴索损害，肌电图是比较理想的可全面评价MS周围神经损害的临床检测手段，对判断预后有一定的实用价值。     

Lymphoma and peripheral neuropathy: a clinical review

Lymphoma occasionally affects the peripheral nervous system. When it does, the diagnosis can be elusive since many patients present without known lymphoma. Most peripheral nerve complications are due to non-Hodgkin's lymphoma (NHL), which infiltrates nerves causing axonal damage. This disorder can affect nerve roots and cranial nerves, often associated with lymphomatous meningitis. NHL may also infiltrate peripheral nerves and cause plexopathy, mononeuropathy, or generalized neuropathy. These neuropathies may resemble an asymmetric mononeuropathy multiplex or a generalized disorder such as chronic inflammatory demyelinating polyradiculoneuropathy. When NHL infiltrates diffusely, the term neurolymphomatosis is used. Hodgkin's lymphoma (HL), by contrast, rarely infiltrates nerves. More often, HL causes immunological disorders of the peripheral nervous system such as inflammatory plexopathy or Guillain-Barré syndrome. Other rare lymphomas such as intravascular lymphoma and Waldenstrom's macroglobulinemia can also affect peripheral nerves in specific ways. In addition, other malignant and nonmalignant lymphoproliferative disorders enter into the differential diagnosis of lymphomatous neuropathy. This review discusses the multiple peripheral nerve presentations of lymphoma from the clinician's point of view and provides a guide to the evaluation and diagnosis of these uncommon, challenging disorders.     

Non-Hodgkin's malignant lymphoma of the peripheral nervous system: clinicopathological correlations in ten patients

INTRODUCTION: Identifying tumor infiltration or compression in patients with non-Hodgkin's malignant lymphoma presenting peripheral neuropathy can be a difficult task. METHODS: We collected a series of patients with peripheral neuropathy with demonstrated lymphomatous infiltration or compression managed between October 1977 and October 2001 to search for clinico-pathological correlations. RESULTS: Ten cases were reviewed. Neurological manifestations were the inaugural symptom of the disease in 7 patients. Clinical presentations included 5 focal (3 cranial nerve palsies, 2 brachial radiculopathies) and 5 diffuse neuropathies (3 polyradiculoneuropathies, 1 polyneuropathy and 1 mononeuritis multiplex). The mechanisms of peripheral nerve involvement were classified into lymphomatous meningoradiculitis (5 cases), involvement of cranial nerves or spinal roots in their extraneuraxial course (3 cases) and infiltration of distal peripheral nerves (2 cases). Four long lasting survivals after treatment were observed. CONCLUSIONS: Prognosis depends much more on the haematological disease than on the neurological symptoms or tumor location.     

Ultrasound differentiation of axonal and demyelinating neuropathies

Introduction: Ultrasound can be used to visualize peripheral nerve abnormality. Our objective in this study was to prove whether nerve ultrasound can differentiate between axonal and demyelinating polyneuropathies (PNPs). Methods: Systematic ultrasound measurements of peripheral nerves were performed in 53 patients (25 with demyelinating, 20 with axonal, 8 with mixed neuropathy) and 8 healthy controls. Nerve conduction studies of corresponding nerves were undertaken. Results: Analysis of variance revealed significant differences between the groups with regard to motor conduction velocity, compound muscle action potential amplitude, and cross‐sectional area (CSA) of different nerves at different locations. Receiver operating characteristic curve analysis revealed CSA measurements to be well suited for detection of demyelinating neuropathies, and boundary values of peripheral nerve CSA could be defined. Conclusions: Systematic ultrasound CSA measurement in different nerves helped detect demyelination, which is an additional cue in the etiological diagnosis of PNP, along with nerve conduction studies and nerve biopsy. Muscle Nerve 50: 976–983, 2014     

Expression of glial cell line-derived neurotrophic factor and GDNFR-α mRNAs in human peripheral neuropathies

The steady-state mRNA levels of glial cell line-derived neurotrophic factor (GDNF), GDNFR-α and RET were examined in various human peripheral neuropathies to determine the relationship with myelinated fiber pathology, and T cell and macrophage invasions in the diseased nerves. GDNF and GDNFR-α mRNA levels were elevated to variable extent in the diseased nerves, although they were not specific to the type of diseases. The increase of GDNFR-α mRNA levels was correlated with the extent of the nerves with axonal pathology, and was proportional to the extent of invasion of the nerves by T cells and macrophages. The GDNF mRNA levels were not related to axonal, demyelinating pathology, or inflammatory cell invasions. RET mRNA expression was not detected in normal nor diseased nerves. The GDNF and GDNFR-α expression in the diseased human nerves is regulated by an underlying pathology-related process, and could play a role in peripheral nerve repair.     

Attenuated demyelination in the absence of the macrophage-restricted adhesion molecule sialoadhesin (Siglec-1) in mice heterozygously deficient in P0

Mouse mutants heterozygously deficient for the myelin component P0 mimic some forms of inherited neuropathies in humans. We have previously shown that both T lymphocytes and macrophages contribute to the demyelinating neuropathy. Both cell types appear to influence each other mutually, i.e., impaired T lymphocyte development in RAG-1-deficient P0 mutants leads to decreased macrophage numbers and retarded macrophage activation causes reduced T lymphocyte numbers in the peripheral nerves of P0(+/-) mice. In the present study, we investigated the possible role of the macrophage-restricted sialic acid-binding Ig-like lectin sialoadhesin (Sn, Siglec-1) in the pathogenesis of inherited demyelination in P0(+/-) mice. We found that most peripheral nerve macrophages express Sn in the mutants. Myelin mutants devoid of Sn show reduced numbers of CD8+ T lymphocytes and macrophages in peripheral nerves and less severe demyelination, resulting in improved nerve conduction properties. Our findings are potentially important in the development of future treatment strategies for inherited demyelinating neuropathies.     

Follow-up evaluation with ultrasonography of peripheral nerve injuries after an earthquake

Published data on earthquake-associated peripheral nerve injury is very limited. Ultrasonography has been proven to be efficient in the clinic to diagnose peripheral nerve injury. The aim of this study was to assess the role of ultrasound in the evaluation of persistent peripheral nerve injuries 1 year after the Wenchuan earthquake. Thirty-four patients with persistent clinical symptoms and neurologic signs of impaired nerve function were evaluated with sonography prior to surgi- cal repair. Among 34 patients, ultrasonography showed that 48 peripheral nerves were entrapped, and 11 peripheral nerves were disrupted. There was one case of misdiagnosis on ultrasonogra- phy. The concordance rate of ultrasonographic findings with those of surgical findings was 98%. A total of 48 involved nerves underwent neurolysis and the symptoms resolved. Only five nerves had scar tissue entrapment. Preoperative and postoperative clinical and ultrasonographic results were concordant, which verified that ultrasonography is useful for preoperative diagnosis and postoperative evaluation of injured peripheral nerves.     

Hypertrophic neuritis due to chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): A postmortem pathological study

A postmortem pathological study of a 65-year-old woman with hypertrophic neuritis associated with hand tremor and limb ataxia is described. There were many onion bulbs and loss of myelinated nerve fibers in the peripheral nerves, including the facial and subserosal visceral nerves. The hypertrophic neuritis was caused by chronic inflammatory demyelinating neuropathy (CIDP), in which interstitial amorphous substances in the endoneurium and onion bulb formation might contribute to nerve swelling. We speculate that visceral autonomic nerves as well as somatic peripheral nerves are involved in patients with a long clinical CIDP course and that peripheral nerve pathology in this disorder shows more heterogeneous changes than previously recognized. © 1996 John Wiley & Sons, Inc.     

A case of asymmetric demyelinating neuropathy in a patient with chronic graft-versus-host disease]

A 47-year-old man, who suffered from acute lymphocytic leukemia at 45 years old and was treated with hematopoietic stem cell transplantation at 46 years old after the induction of complete remission by the standard chemotherapy, developed the symptoms of chronic graft-versus-host disease (cGVHD) such as dry eyes, dry mouth, skin thickening, skin scaling, skin pigmentation and impaired liver function. He was admitted to our hospital because of the acute development of diplopia and weakness of his left upper extremity accompanying with the exacerbation of other symptoms of cGVHD. Neurological examinations revealed the right abducens nerve palsy and asymmetric muscular weakness of the extremities; the proximal part of the left upper extremity and the distal part of the right upper extremity were markedly involved. Neurophysiological studies including magnetic motor root stimulation revealed demyelinating neuropathy specifically involving the motor nerves. On the basis of these findings, a diagnosis of peripheral neuropathy associated with cGVHD was made. Nighteen reports are available on peripheral neuropathy in cGVHD patients, but to date little is known about the pathophysiology of this condition. Most of those patients have been diagnosed as having symmetric demyelinating polyneuropathy, such as Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. In this study, contrary to previous reports, the asymmetric involvement of motor nerves is noteworthy. Accumulation and further analyses of the cases like the present case are necessary to elucidate the pathogenesis of peripheral neuropathy in cGVHD.     

Polymyositis associated with peripheral nerve lesion: clinico-pathological investigation of 8 cases

Polymyositis with peripheral nerve lesion are rare. The study of eight cases of polymyositis with some peripheral lesion, pathologic investigation of muscle biopsy of all patients and biopsy of sural nerve in six cases were reported. Age: 19-52 (average 34) yrs. Course: 4mo-10 (average 4) yrs. They showed symmetric weakness and tenderness of the proximal muscles, peripheral hypoesthesia and hypo even areflexia. Electrophysiological parameters showed myogenic lesion in 8 cases and neurogenic in 3 cases. Pathological (light and electron-microscopic) findings coincide with acute and chronic myositis, consisting of focal necrosis of muscle fiber, monocyte infiltration, myofibril regeneration, hyperplasia of interstitial vessels and fibrous tissue in muscle biopsy of 8 cases; mild to moderate loss of density of myelinated fibers, mostly thin myelin sheath and demyelinating changes, axonal degeneration also, mainly loss of unmyelinated fiber, perivascular monocyte and macrophages in sural nerve biopsy of six cases. The aforementioned clinical and pathological findings suggest that involving both muscle and nerve be able to primary. No primary course involving nerve has been found, except in only one case with coexisting SLE, another case six months later carcinomatous myositis was diagnosed, but there are no evidence of vasculitis and ischemic neuropathy.     

CHRONOLOGICAL STUDY OF ULTRASTRUCTURAL CHANGES IN THE PERIPHERAL NERVES IN MAREK'S DISEASE

Chronological study of ultrastructural changes in the peripheral nerves in Marek's disease
A chronological study was made of the ultrastructural changes in peripheral nerves following inoculation of 1-day-old chicks with a neurogenic strain of Marek Disease virus. No virus particles were found in nerves. Cellular infiltration of nerves was detected as early as 5 days after inoculation and by 3 weeks some nerves contained proliferative lesions which possessed many of the ultrastructural features characteristic of normal, reactive lymphoid tissue. About 4 weeks after inoculation, coinciding with the onset of neurological signs, areas of widespread demyelination appeared within these lesions; lymphocytes and macrophages penetrated and destroyed the myelin sheath, but spared Schwann cells and most axons. Later oedematous, sparsely infiltrated B type lesions were observed, some of which contained demyelin-ated nerve fibres undergoing repair; these were therefore a stage in the regression of the proliferative lesions. Our observations do not favour the hypothesis that cellular infiltration of nerves in Marek's disease is the direct result of auto-sensiti-zation to normal myelin. They are consistent with the hypothesis that demyelination is a secondary feature and that the primary lesions are preferential sites for immune demyelination.     

Behavioral, electrophysiological, and histopathological characterization of a severe murine chronic demyelinating polyneuritis model

The objective of this study was to define the behavioral, electrophysiological, and morphological characteristics of spontaneous autoimmune peripheral polyneuropathy (SAPP) in female B7-2 deficient non-obese diabetic (NOD) mice. A cohort of 77 female B7-2 deficient and 31 wild-type control NOD mice were studied from 18 to 40 weeks of age. At pre-defined time points, the dorsal caudal tail and sciatic motor nerve conduction studies (MNCS) were performed. Sciatic nerves were harvested for morphological evaluation. SAPP mice showed slowly progressive severe weakness in hind and forelimbs without significant recovery after 30 weeks of age. MNCS showed progressive reduction in mean compound motor action potential amplitudes and conduction velocities, and increase in mean total waveform duration from 24 to 27 weeks of age, peaking between 32 and 35 weeks of age. Toluidine blue-stained, semi-thin plastic-embedded sections demonstrated focal demyelination associated with mononuclear cell infiltration early in the disease course, with progressively diffuse demyelination and axonal loss associated with more intense mononuclear infiltration at peak severity. Immunohistochemistry confirmed macrophage-predominant inflammation. This study verifies SAPP as a progressive, unremitting chronic inflammatory demyelinating polyneuropathy with axonal loss.