Erythropoietin reduces nerve demyelination, neuropathic pain behavior and microglial MAPKs activation through erythropoietin receptors on Schwann cells in a rat model of peripheral neuropathy.

Neuroprotective effects of erythropoietin (EPO) on peripheral nerve injury remain uncertain. This study investigated the efficacy of EPO in attenuating median nerve chronic constriction injury (CCI)-induced neuropathy. Animals received an intraneural injection of EPO at doses of 1,000, 3,000, or 5,000 units/kg 15 min before median nerve CCI. Afterwards, the behavioral and electrophysiological tests were conducted. Immunohistochemistry and immunoblotting were used for qualitative and quantitative analysis of microglial and mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, activation. Enzyme-linked immunosorbent assay and microdialysis were applied to measure pro-inflammatory cytokine and glutamate responses, respectively. EPO pre-treatment dose-dependently ameliorated neuropathic pain behavior, decreased microglial and MAPKs activation, and diminished the release of pro-inflammatory cytokines and glutamate in the ipsilateral cuneate nucleus after CCI. Moreover, EPO pre-treatment preserved myelination of the injured median nerve on morphological investigation and suppressed injury-induced discharges. We also observed that EPO receptor (EPOR) expression was up-regulated in the injured nerve after CCI. Double immunofluorescence showed that EPOR was localized to Schwann cells. Furthermore, siRNA-mediated knockdown of EPOR expression eliminated the therapeutic effects of EPO on attenuating the microglial and MAPKs activation, pro-inflammatory cytokine responses, injury discharges, and neuropathic pain behavior in CCI rats. In conclusion, binding of EPO to its receptors on Schwann cells maintains myelin integrity and blocks ectopic discharges in the injured median nerve, that in the end contribute to attenuation of neuropathic pain via reducing glutamate release from primary afferents and inhibiting activation of microglial MAPKs and production of pro-inflammatory cytokines.

Therapy with eculizumab for patients with CD59 p.Cys89Tyr mutation.

OBJECTIVE: The objective of this work was to report on the outcome of eculizumab treatment in pediatric patients with recurrent acute predominantly motor, demyelinating neuropathy with conduction block, and chronic hemolysis attributed to p.Cys89Tyr mutation in the CD59 gene. METHODS: Four patients were recruited from our new registry of patients with homozygosity for the p.Cys89Tyr mutation on CD59. Participants received repeated intravenous eculizumab. In this 24-month open-label phase IIa study, we aimed to determine whether eculizumab reduces chronic hemolysis, and cumulative doses of steroids and intravenous immunoglobulin (IVIG), and ameliorates neurological deficits, compared to pretreatment status. Treatment response was evaluated every 2 to 4 weeks over 104 weeks and included examination with gross motor scoring by American Spinal Injury Association Impairment Scale and Inflammatory Neuropathy Cause and Treatment disability score, laboratory examination, well-being [12-item Short Form Health Survey; SF-12]). Neurological relapses and cumulative dose of IVIGs and/or corticosteroids before and after treatment were documented. Red blood cells (RBCs) and neutrophils were stained to evaluate C5b-9 deposition. ClinicalTrials.gov: NCT01579838. RESULTS: Dramatic and significant neurological amelioration in the upper limbs and trunk with more-modest amelioration in the lower limbs was observed in all patients. Corticosteroid and IVIG treatment was completely stopped. No patient relapsed during treatment despite infections, and there were no hospital admissions. Decreased C3bi and C5b-9 deposition on RBCs and neutrophils was documented (p < 0.0001). The SF-12 health questionnaires indicated significant improvement (p < 0.003). INTERPRETATION: Eculizumab was safely administered to these patients. Marked clinical improvement suggests that eculizumab may be a life-saving treatment for patients with acute predominantly motor, demyelinating neuropathy with conduction block, and secondary axonal damage attributed to primary p.Cys89Tyr mutation in the CD59 gene. Ann Neurol 2016;80:708-717.

[Chronic demyelinating polyradiculoneuropathy revealing a solitary plasmacytoma of the right iliac bone]. / Polyradiculonévrite chronique révélant un plasmocytome solitaire de l'os iliaque droit.

Solitary bone plasmacytoma (pso) is a rare tumor, made of malignant plasma cells observed in a single bone, and without systemic proliferation. We report the case of a 33 year-old man who was admitted with chronic demyelinating sensorimotor polyneuropathy. Immunoelectrophoresis with immunofixation of serum proteins showed a monoclonal peak igg with lambda light chain and the workup was in favour of right hipbone secreting solitary plasmacytoma. The patient was treated with radiotherapy and steroids, and the evolution has been marked by a partial recovery of the motor deficit. An acute demyelinating sensorimotor polyneuropathy has often been described in association with pso. However, subacute and chronic demyelinating polyradiculoneuropathies have rarely been described in such patients with pso.the diagnosis should differentiate pso, poems and multiple myeloma.

Le plasmocytome solitaire osseux (pso) est une tumeur rare, faite de plasmocytes malins qu'on observe dans un seul os, sans atteinte plasmocytaire proliférative systémique. Nous rapportons l'observation clinique d'un patient de 33 ans qui a été admis pour une polyradiculonévrite chronique sensitivo-motrice démyélinisante. L'immunoélectrophorèse avec immunofixation des protéines sériques a révélé un pic monoclonal igg à chaîne légère de type lambda et le bilan étiologique a mis en évidence un plasmocytome solitaire sécrétant de l'os iliaque droit. Le patient a été traité par radiothérapie et corticothérapie, et l'évolution a été marquée par une récupération partielle du déficit moteur. C'est la polyneuropathie sensitivo-motrice démyélinisante aiguë qui a été le plus souvent décrite en association avec le pso alors que les polyradiculoneuropathies démyélinisantes subaiguës ou chroniques ont été rarement rapportées. Le diagnostic différentiel, parfois difficile, doit se faire entre un pso, un poems et un myélome multiple.

Progressive polyradiculoneuropathy due to intraneural oxalate deposition in type 1 primary hyperoxaluria.

INTRODUCTION: A 24-year-old man with primary hyperoxaluria type 1 (PH1) presented with a rapidly progressive axonal and demyelinating sensorimotor polyradiculoneuropathy shortly after the onset of end-stage renal disease. His plasma oxalate level was markedly elevated at 107 µmol/L (normal<1.8 µmol/L). METHODS: A sural nerve biopsy was performed. Teased fiber and paraffin and epoxy sections were done and morphometric procedures were performed on this sample and on an archived sample from a 22-year-old man as an age- and gender-matched control. Embedded teased fiber electron microscopy was also performed. RESULTS: The biopsy revealed secondary demyelination and axonal degeneration. Under polarized light, multiple bright hexagonal, rectangular, and starburst inclusions, typical of calcium oxalate monohydrate crystals, were seen. CONCLUSIONS: The proposed mechanisms of nerve damage include disruption of axonal transport due to crystal deposition, toxic effect of oxalate, or nerve ischemia related to vessel occlusion from oxalate crystal deposition.

Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy.

Mutations in myelin protein zero (MPZ) protein result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms. In some patients, neuropathic pain can be a prominent symptom, making the diagnosis challenging mainly in those with other risk factors for neuropathy. We describe a 77-year-old woman with impaired glucose tolerance presenting with rapidly progressive axonal neuropathy leading to excruciating pain and severe weakness of lower limbs within 2 years from the onset. Her son abruptly complained of similar painful symptoms at the age of 47 years. Molecular analysis revealed a novel heterozygous missense mutation (c.106A>G) in MPZ exon 2, causing the substitution of arginine-36 with glycine in the extracellular domain. Our observation suggests that MPZ-related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.

Varicella zoster virus associated-polyradiculoneuritis in an elderly woman: A new subtype of varicella zoster virus neuropathy.

An 82-year-old Japanese woman without underlying disease was admitted to our hospital 3 days after she noticed lower-limb weakness. At presentation, she had lower-leg motor paralysis with mild upper-limb paresis and left Ramsay Hunt syndrome. Cerebrospinal fluid (CSF) findings revealed moderate pleocytosis. A polymerase chain reaction for varicella zoster virus (VZV) DNA in CSF was positive. MRI using 3D Nerve-VIEW (Philips) and contrast T1 images showed high-intensity lesions on the L2-5 and S1-2 spinal roots. A new subtype of VZV-associated polyradiculoneuritis was diagnosed in this patient. We provide the case details and compare three similar reported cases.

Acute lumbosacral polyradiculoneuropathy heralding transformation to systemic lupus erythematosus in a patient with discoid lupus.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease with which a variety of neuropathic disorders have been associated. Among these, the acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain-Barré syndrome has been well established. However, acute axonal lumbosacral polyradiculoneuropathy accompanied by albuminocytological dissociation in the cerebrospinal fluid has been extremely rarely reported in SLE. We report on a 47-year-old woman with discoid lupus presenting with acute onset of flaccid paraplegia. Extensive investigations suggested the diagnoses of axonal lumbosacral polyradiculoneuropathy and SLE. Treatment with intravenous methylprednisolone and cyclophosphamide resulted in clinical recovery. Development of immune-mediated polyneuropathy in a patient with discoid lupus should forewarn the clinician regarding transformation into the systemic form of the disease.

[Herpes zoster duplex associated with Ramsay Hunt syndrome and cervical zoster paresis. A case report].

A 63-year-old Japanese female in an immunocompetent state developed right Ramsay Hunt syndrome and left shoulder pain, and left upper limb motor paresis with herpes zoster (HZ) duplex in the right auricle and left shoulder regions. With her Ramsay Hunt syndrome, neural deafness, tinnitus and vestibular symptoms were observed, and she lacked facial nerve palsy. Cerebrospinal fluid (CSF) findings revealed an increase in lymphocytes (21 cells/µl) and protein content (29 mg/dl), and polymerase chain reaction for varicella-zoster virus DNA in CSF was negative. Cervical root MRI using 3D Nerve VIEW (Philips) imaging showed high-intensity lesions on the C5-C8 spinal roots with contrast enhancements. No abnormalities were observed in the median or ulnar motor sensory nerve conduction velocity conduction studies including the F wave. PubMed search revealed no report of a patient with this profile, and to the best of our knowledge HZ duplex with concomitant neurological impairments has not been reported. We compare our present case with several similar cases from the literature.

Steroid-responsive myeloneuropathy associated with antithyroid antibodies.

BACKGROUND/OBJECTIVE: To present information about 2 steroid-responsive, antithyroid antibody-positive patients with myeloneuropathy and myelopathy. METHODS: Case reports. RESULTS: A 48-year-old woman and a 42-year-old man presented with acute onset tetraparesis and magnetic resonance imaging studies showing cervical spinal lesions. Nerve conduction and biopsy studies of the woman were suggestive of a demyelinating polyradiculoneuropathy. Detailed diagnostic workup turned out to be negative for both patients, except for highly elevated antithyroid antibodies with normal thyroid functions and imaging. Both patients responded remarkably well to high-dose steroid treatment, and their symptoms disappeared in a few months. Both patients' antithyroid antibody levels were reduced shortly after steroid treatment and in parallel with the amelioration of symptoms. CONCLUSIONS: Antithyroid antibodies might be associated with acute demyelinating myeloneuropathy or myelopathy pathogenesis and might indicate a good response to steroid treatment in these syndromes.

[Case of chronic progressive encephalo-myelo-radiculo-neuropathy].

A 65-year-old man developed urinary impairment and gait disturbance over a period of four months. On admission, neurological examinations revealed paraplegia, decreased deep tendon reflexes in the extremities, bilateral positive Babinski and Chaddock signs, superficial and deep sensory disturbances and neurogenic bladder. Cerebrospinal fluid examination disclosed a total cell count of 70/mm3, and protein of 76 mg/dl. Nerve conduction studies and somatosensory evoked potential suggested demyelinating neuropathy and myelopathy. Brain MRI revealed irregular-shaped white matter lesions distributed over the bilateral cerebral hemispheres and the brain stem. In addition spinal MRI disclosed long spinal cord lesions disseminated from the higher cervical to the lower thoracic spine. A 1 microm-thick epon-embedded section and teased fiber preparations of a biopsied sural nerve showed segmental demyelination and remyelination. Treatments using intravenous methylprednisolone and IVIg were both effective. The positive responses to immunological treatment, along with the findings, strongly suggested that the demyelinating lesions occurred in both the central and peripheral nervous systems. We regarded this case as one of chronic progression of Encephalo-myelo-radiculo-neuropathy.

Sensory-motor polyradiculoneuropathy as the first manifestation of sternum bone plasmacytoma only revealed by bone scintigraphy.

Bone plasmacytoma is a rare plasma cell neoplasm that can present with a polyradiculoneuropathy. A 57-year-old man presented with 2-month history of progressive weakness and numbness of both legs. Neurological examination showed symmetric distal weakness, reduced vibration senses in limbs and areflexia. CSF had high protein content. Electrophysiological evaluation revealed a demyelinating sensory-motor polyneuropathy. IgG-lambda paraprotein was present in serum. Full skeletal survey, spinal MRI and body CT-scan were normal. 99mTc-methylene-dyphosphonate scintigraphy (99mTc-MDP) revealed a solitary accumulation in the sternum. Biopsy of the lesion demonstrated a plasmacytoma. We emphasize that 99mTc-MDP scintigraphy can be a useful screening procedure for patients with polyradiculoneuropathy and occult bone plasmacytoma.

Long-lasting remission after rituximab treatment in a case of anti-Hu-associated sensory neuronopathy and gastric pseudoobstruction.

Anti-Hu paraneoplastic syndromes are usually associated with an underlying neoplasia, although a few patients who are anti-Hu-positive never develop cancer after long-term follow-up. Tumour therapy remains the mainstay of therapeutic options, and early immune therapy in parallel is advisable. When no tumour is found, immunologically-based therapies are nowadays the only options. Recent studies have shown rituximab associated with the tumour therapy to be effective for some patients with anti-Hu paraneoplastic syndrome. We report a case of a patient with anti-Hu antibodies-associated sensory neuronopathy and gastric pseudo-obstruction without an underlying neoplasia four years after the first manifestation who has achieved sustained improvement for two years after treatment with rituximab. This case report supports the effectiveness of rituximab in these syndromes, even for cases where no underlying neoplasia is demonstrated. Further studies are warranted in order to confirm these preliminary data.

A clustering of immune-mediated polyradiculoneuropathy among swine abattoir workers exposed to aerosolized porcine brains, Indiana, United States.

In November 2007 a novel neuropathy, immune-mediated polyradiculoneuropathy (IP), was identified among workers at a Minnesota swine abattoir where a unique compressed air technique was used to remove porcine brains. An epidemiologic investigation at another abattoir in Indiana that also uses this process was launched to evaluate workers self-reporting neurologic illness compatible with IP. A nested case-control study was performed to identify cases and risk factors. Six confirmed, one probable, and three possible IP cases were detected. IP cases were 28-52 years old, of Latino origin, and 62.5% female. Onset dates ranged from April 2005-December 2007; 60% were hospitalized. IP cases at this plant were similar in clinical presentation and exposure risks to those detected in Minnesota. Swine abattoirs using similar brain extraction methods should discontinue this process.

[Acute polyneuritis and polyradiculoneuritis: uncommon causes and their pathomechanisms]. / Akute Polyneuritiden und Polyradikuloneuritiden: Ungewöhnliche Ursachen und deren Pathomechanismen.

Although the total incidence rate of acute inflammatory polyneuropathies is low, it is the most frequent cause of acute progressive, generalized paresis in developed countries (> 50 %). The most common form of the disease is the Guillain-Barré syndrome (GBS). Even though the clinical and pathologic spectrum of GBS has substantially grown over the last decade, about 15 % of cases of acute polyneuritis or polyradiculoneuritis do not fulfil the revised and extended diagnostic criteria and classification for GBS and its variants. The underlying pathogenesis still remains unclear. It is assumed that these "untypical" acute inflammatory polyneuropathies and cases fulfilling the GBS criteria are variants of the same underlying immune disorder, but that pathogenetic mechanisms produce different acute neurological syndromes. Thus, immunotherapy (which is not GBS-specific) is also effective for treating acute inflammatory polyneuropathies that do not fulfil the diagnostic criteria for GBS, and early diagnosis and treatment of these cases is essential. Since no reliable serological and electrodiagnostic markers of autoimmune neuropathies are currently available, the diagnosis is based on its clinical presentation. However, clinical symptoms are variable, and a rational diagnostic decision can be challenging. Thus, it is important to know that acute inflammatory polyneuropathies not fulfilling the diagnostic criteria of GBS are less often preceded by an infective condition but frequently associated with uncommon causes and triggers. This report presents our experiences with uncommon variants of inflammatory polyneuropathies and polyradiculoneuritides that do not fulfil the international diagnostic criteria for GBS. We provide a detailed review of the pertinent literature discussing possible pathomechanisms, its clinical associations and possible dispositions.

Polyradiculoneuropathy in dourine-affected horses.

Dourine is an equine protozoan disease caused by Trypanosoma equiperdum. Dourine-afflicted animals die after developing neurological clinical signs, such as unilateral paresis. The disease has been a problem for many years; however, the pathogenesis regarding the neurological clinical signs of dourine has been unclear. In the present study, we conducted a histopathological examination in order to investigate the mechanisms by which dourine-afflicted horses develop the accompanying neurological clinical signs. Four dourine-afflicted horses in Mongolia were evaluated. An apparently healthy horse exhibited multifocal neuritis without axonal or myelin degeneration. The other horses, which had obvious neurological clinical signs, also exhibited multifocal neuritis. In particular, the nerves that innervated areas associated with neurological clinical signs exhibited neuritis with demyelination in the latter horses. Inflamed, non-demyelinating nerves were infiltrated with B lymphocytes and T lymphocytes; while inflamed, demyelinating nerves were infiltrated with mononuclear phagocytes. Our observations revealed lesion progression in the nerves, such that polyradiculoneuropathy could explain the accompanying neurological clinical signs of dourine. To our knowledge, this is the first report to describe a pathogenic mechanism for the development of the neurological clinical signs found in dourine-afflicted horses.