Language：English   Publisher：European Journal of Neurology  

Background: This study conducted a comprehensive glycan analysis of serum to determine how glycan biomarkers are associated with the pathophysiology of chronic inflammatory demyelinating polyneuropathy (CIDP) and the effects of its treatment. Methods: We comparatively analyzed N- and O-glycans in the pretreatment serum of 27 treatment-naïve patients with typical CIDP and 20 age- and sex-matched healthy controls (HC) using mass spectrometry. We determined the association between clinical parameters and glycans. The serum glycan and neurofilament light-chain (NfL) levels were assessed at the baseline, and treatment response was defined according to the degree of improvement in the modified Rankin scale 12 weeks after the first dose of intravenous immunoglobulin (IVIg). Results: Compared with the HC, the CIDP group demonstrated significantly lower levels of serum total N-glycans (CIDP, median 973.3 [IQR 836.2–1131.3] pmol/μL; HC, 1125.0 [1005.0–1236.2] pmol/μL; p < 0.05), especially sialylated N-glycans (CIDP, 898.0 [752.2–1037.2] pmol/μL; HC, 1064.4 [942.7–1189.8] pmol/μL; p < 0.01). In contrast, the O-glycan levels did not differ significantly between the two groups. The treatment response was associated with low N-glycan levels, but not with the serum NfL levels. Low levels of sialylated N-glycans were associated with resistance to treatment over 12 weeks, with an area under the curve of 0.822 (p < 0.01). Conclusions: Low levels of sialylated N-glycans could potentially serve as a novel biomarker, reflecting pathophysiology and therapeutic resistance in typical CIDP.

DOI： 10.1111/ene.70023

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Language：English   Publisher：BMC Neurology  

Background: Guillain-Barré syndrome (GBS) is a clinically heterogenous disease and encompasses several distinct clinical variants. Overlap between these variants can pose a diagnostic challenge. We report a case of finger drop variant and acute bulbar palsy overlap as an unusual manifestation of GBS. Case presentation: An 81-year-old man presented with dysarthria, dysphagia, and upper limb weakness. Neurological examination revealed impaired tongue protrusion, the finger drop sign, and diminished brachioradial and triceps muscle reflexes. Nerve conduction studies showed reduced amplitudes and decreased velocities in the median and ulnar nerves. Cerebrospinal fluid analysis revealed albuminocytological dissociation and an anti-ganglioside antibody study revealed positivity for GM1, asialo-GM1, GT1a, GD1b, and GQ1b. As GBS was suspected, we initiated intravenous immunoglobulin treatment, resulting in gradual improvement within the next 3 weeks. Conclusion: To the best of our knowledge, this is the first reported case of an overlap between the finger drop variant and acute bulbar palsy in GBS, highlighting the importance of considering GBS when patients present with a combination of atypical symptoms. Anti-ganglioside antibodies can be helpful and add diagnostic value in these complex cases.

DOI： 10.1186/s12883-024-03899-3

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Language：English   Publisher：BMC Neurology  

Background: Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is a rare disease characterized by a persistent increase in NK cells in peripheral blood and is generally asymptomatic. If present, symptoms may include fatigue, B symptoms (fever, night sweats, and unintentional weight loss), autoimmune-associated diseases, splenomegaly, and infection due to neutropenia. Peripheral neuropathy, however, is uncommon with an incidence of 3%. Neurolymphomatosis is a neurological manifestation of non-Hodgkin lymphoma and leukemia in which neurotropic neoplastic cells infiltrate the nerves. Moreover, neurolymphomatosis caused by CLPD-NK is extremely rare, with even fewer cases of autonomic dysfunction. We report a case of neurolymphomatosis associated with CLPD-NK and developed autonomic dysfunction, including orthostatic hypotension and gastrointestinal symptoms. Case presentation: The patient was a 61-year-old male who was referred to our hospital for leukocytosis. He was diagnosed with CLPD-NK; however, was untreated since he had no hepatosplenomegaly, and other systemic symptoms. He later developed numbness in his lower extremities. Cerebral spinal fluid examination revealed a markedly elevated protein level of 140 mg/dL, and contrast-enhanced magnetic resonance imaging showed bilateral L4 and 5 nerve roots with enlargement and contrast effect. An immune-mediated polyradiculoneuropathy was suspected, and he was treated with intravenous methylprednisolone and immunoglobulin followed by oral prednisolone and cyclosporine. Although his symptoms were relieved by the immunotherapy, significant autonomic dysfunction, including intractable diarrhea, decreased sweating, and orthostatic hypotension, appeared. Additionally, tests for onconeuronal antibodies, ganglionic nicotinic acetylcholine receptor (gAChR) antibody, NF155, CNTN1, Caspr1 antibody, and anti-ganglioside antibodies were all negative. A sural nerve biopsy revealed lymphocytic infiltration, and immunohistochemical staining of lymphocytes confirmed the infiltration of NK and T cells. Therefore, a diagnosis of neurolymphomatosis caused by CLPD-NK was made, and chemotherapy led to partial symptom improvement. Conclusions: We experienced a case of pathologically diagnosed neurolymphomatosis with autonomic dysfunction associated with CLPD-NK. In cases of subacute to chronic autonomic dysfunction, paraneoplastic neuropathy, amyloidosis, and autoimmune autonomic ganglionopathy are considered; however neurolymphomatosis caused by CLPD-NK, an important cause of autonomic dysfunction, is not. In difficult to make diagnosis, aggressive nerve biopsy is required.

DOI： 10.1186/s12883-024-03879-7

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Language：English   Publisher：Journal of Neuroimmunology  

Contactin-associated protein 1 (Caspr1) is widespread in both the peripheral and central nervous systems (CNS). However, anti-Caspr1 antibody-positive nodopathy associated with CNS symptoms has not previously been reported. In this case, a 69-year-old man presented with polyneuropathy and memory loss. The patient had negative myoclonus, positive myoclonus, and pseudoathetosis in the upper limbs, and we detected anti-Caspr1 antibodies in the serum and cerebrospinal fluid. Therefore, anti-Caspr1 nodopathy was diagnosed. After rituximab treatment, all symptoms of polyneuropathy, involuntary movements, and memory impairment improved. In conclusion, anti-Caspr1 antibodies might also affect the CNS; therefore, CNS symptoms of anti-Caspr1 nodopathy require attention.

DOI： 10.1016/j.jneuroim.2024.578420

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Language：English   Publisher：Neurology Neuroimmunology and Neuroinflammation  

Background and Objectives This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. Methods Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. Results Screening of 78 CIDP patient sera by WB revealed a positive band around 60–70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies’ reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. Discussion Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.

DOI： 10.1212/NXI.0000000000200199

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Language：English   Publisher：European Journal of Neurology  

Background: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. Methods: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. Results: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. Conclusions: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.

DOI： 10.1111/ene.16091

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Publisher：Neurology and Therapy  

Introduction: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. Methods: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. Results: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10^–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10^–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10^–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10^–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10^–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. Conclusion: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment. Trial Registration Number: ClinicalTrials.gov: NCT03759379.

DOI： 10.1007/s40120-023-00522-4

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>We herein report a 77-year-old man with a 4-month history of progressive gait and sensory disturbances of the extremities. A nerve conduction study indicated demyelinating polyneuropathy. Serum IgG4 levels and anti-contactin 1 IgG4 antibodies were markedly increased. The sural nerve biopsy specimen showed IgG4-positive plasma cell infiltration in the epineurium. Treatment with steroids resulted in an amelioration of functional status, improvement of nerve conduction parameters, decreased serum IgG4 levels, and negative conversion of anti-contactin 1 antibody. Further studies are needed to clarify the significance of IgG4-positive plasma cell infiltration in anti-contactin 1 antibody-positive neuropathies. </p>

DOI： 10.2169/internalmedicine.9286-21

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Language：English   Publisher：Advances in Therapy  

In Table 1, the clinical trial number attributed to the mepolizumab study (in column 2) was incorrectly attributed with the benralizumab MANDARA study (NCT04157348). The clinical trial number for the mepolizumab study should be NCT03298061. The original article has been updated.

DOI： 10.1007/s12325-022-02363-3

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Language：English   Publisher：Expert Review of Neurotherapeutics  

Introduction: Vasculitic neuropathy can present associated with both primary and secondary systemic vasculitis as a result from underlying diseases such as rheumatic diseases and infections, Moreover, confined vasculitis in the peripheral nervous system may be present. Thus, the diagnosis and management of vasculitic neuropathy require multidisciplinary approaches. Areas covered: Current views as well as relevant clinical research on the diagnosis, assessment, and management of vasculitic neuropathy are reviewed to suggest appropriate treatment strategies. We searched PubMed and Google Scholar for reports published between July 2017 and July 2022. Expert opinion: For the treatment of vasculitic neuropathy, determining the causative primary disease is important and often requires diagnosis by tissue biopsy. Due to the scarce research on the treatment of vasculitic neuropathy, treatment is empirically based on findings from studies of systemic vasculitides involving other organs, particularly antineutrophil cytoplasmic antibody-associated vasculitis. In addition to conventional glucocorticoids and immunosuppressive agents, complement-targeted therapy, anti-B-cell therapy, and disease-specific molecular targeted therapies have recently gained relevance. Future research is needed to develop new patient-specific therapeutic options.

DOI： 10.1080/14737175.2022.2166831

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Language：English   Publisher：Advances in Therapy  

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg–Strauss syndrome, is a systemic disorder characterized by asthma, eosinophilia, and vasculitis primarily affecting small vessels. Although this disease is classified as an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis along with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), observations suggest that eosinophils play a vital role in the pathophysiology of EGPA. Therefore, biopsy specimens derived from patients with EGPA demonstrated an increase in eosinophils within the vascular lumen and extravascular interstitium, especially in patients negative for ANCA. In addition, active secretion of eosinophil intracellular components by cytolysis and piecemeal degranulation occurs in the extravascular interstitium and bloodstream. Although the treatment for EGPA is described in the context of ANCA-associated vasculitis along with MPA and GPA, a therapeutic approach to suppress eosinophils is also considered. Monoclonal antibodies directed against interleukin-5 (IL-5) or its receptors are good therapeutic agents because IL-5 plays an important role in eosinophil growth, activation, and survival. Currently, mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra) have been studied for use in patients with EGPA. These monoclonal antibodies were initially approved for use in patients with severe eosinophilic asthma. Mepolizumab is now approved for treating EGPA following the success of phase 3 randomized controlled trial. Therefore, further studies are needed to clarify long-term safety and efficacy of anti-IL-5 agents and establish indications of individual therapeutic agents tailored to individual conditions of patients with EGPA.

DOI： 10.1007/s12325-022-02307-x

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Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<p>Objective : This prospective, observational study aimed to investigate the infusion time and patient satisfaction with intravenous immunoglobulin (IVIg) maintenance therapy in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).</p><p>Methods : A total of 23 patients aged 20 years or older who received regular maintenance therapy with 5% IVIg (n＝10) or 10% IVIg (n＝13) were included. The infusion preparation and administration times were measured for both groups. Quality of life (QOL), treatment satisfaction, and work productivity impairment were also investigated.</p><p>Results : The total infusion time was approximately half for the 10% IVIg group compared to the 5% IVIg group (204 min vs. 437 min, p＝0.0026). The 10% IVIg group had a higher mean index value on EuroQol 5 Dimensions 5–level (EQ–5D–5L) than the 5% IVIg group (0.74 vs. 0.57) with better scores in all 5 dimensions. The treatment satisfaction scores and work productivity impairment were similar in both the groups.</p><p>Conclusion : Although the therapeutic effect of 10% IVIg was comparable to that of 5% IVIg, the shorter infusion time of 10% IVIg was considered to improve the QOL.</p>

DOI： 10.15082/jsnt.40.2_104

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Language：English   Publisher：Neuropathology  

This study aims to describe electron microscopic findings of vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) and complement. Sural nerve biopsy specimens were obtained from 10 patients with microscopic polyangiitis (MPA), a representative ANCA-associated vasculitis, and six patients with nonsystemic vasculitic neuropathy (NSVN), who were negative for ANCA but positive for complement deposition. In patients with MPA, attachment of neutrophils to epineurial vascular endothelial cells, migration of neutrophils to the extravascular space via the penetration of the endothelial layer, and release of neutrophil components to the extracellular space were observed. Such neutrophil-associated lesions were not observed in patients with NSVN. Nonetheless, morphological changes in epineurial vascular endothelial cells, such as increases in cytoplasmic organelles and cytoplasmic protrusions into the vascular lumen, were observed in patients with NSVN. Since these findings were observed where light microscopy-based findings suggestive of vasculitis (e.g., the disruption of vascular structures and fibrinoid necrosis) were absent, they were considered early lesions that preceded the formation of the so-called necrotizing vasculitis. In conclusion, this study enabled the visualization of distinctive early ultrastructural lesions associated with ANCA and complement. Further studies are needed to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of vasculitis.

DOI： 10.1111/neup.12821

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Language：English   Publisher：Muscle and Nerve  

Introduction/Aims: The mechanism of complement-mediated neurological injury in vasculitic neuropathy associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is unknown. The current study aimed to investigate the local activation of the complement system in vasculitic neuropathy associated with SLE and RA. Methods: We analyzed sural nerve biopsy specimens collected from patients with SLE (n = 12) and RA (n = 12). The deposition of complement components comprising the classical and lectin pathways was assessed via immunohistochemistry. Results: The disease duration was longer in the RA group than in the SLE group (median [interquartile range]: 11.5 [5.5–31.0] and 4 [2–10] y, respectively). Complement components were found in the epineurial blood vessel walls in patients with SLE and RA, but not in controls. Deposition of the classical pathway component C1q in the blood vessel wall was more commonly observed in the SLE group (71.3% [25.6–85.8]) than in the RA group (20.1% [10.5–35.6]). As for the lectin pathway component, the incidence of ficolin-3 deposition in the blood vessel wall was higher in the SLE group (42.3% [25.7–51.3]) than in the RA group (17.2% [10.3–26.8]). On the contrary, the mannose-binding lectin level was higher in the RA group (37.5% [21.7–51.4]) than in the SLE group (17.8% [11.4–31.0]). Discussion: The classical and lectin pathways of the complement system may be involved in vasculitic neuropathy associated with SLE and RA.

DOI： 10.1002/mus.27636

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Language：English   Publisher：Neuromuscular Disorders  

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot–Marie–Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ± 0.66 vs. 1.57 ± 0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ± 0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.

DOI： 10.1016/j.nmd.2022.04.002

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Language：English   Publisher：Neurology and Therapy  

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic disorder that frequently affects the peripheral nervous system and consists of three distinct conditions: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously Wegener’s granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, previously Churg-Strauss syndrome). The neuropathic features associated with this condition usually include mononeuritis multiplex, which reflects the locality of lesions. Findings suggestive of vasculitis are usually found in the epineurium and occur diffusely throughout the nerve trunk. Nerve fiber degeneration resulting from ischemia is sometimes focal or asymmetric and tends to become conspicuous at the middle portion of the nerve trunk. The attachment of neutrophils to endothelial cells in the epineurial vessels is frequently observed in patients with ANCA-associated vasculitis; neutrophils play an important role in vascular inflammation by binding of ANCA. The positivity rate of ANCA in EGPA is lower than that in MPA and GPA, and intravascular and tissue eosinophils appear to participate in neuropathy. Immunotherapy for ANCA-associated vasculitis involves the induction and maintenance of remission to prevent the relapse of the disease. A combination of glucocorticoids along with cyclophosphamide, rituximab, methotrexate, or mycophenolate mofetil is considered depending on the severity of the condition of the organ to induce remission. A combination of low-dose glucocorticoids and azathioprine, rituximab, methotrexate, or mycophenolate mofetil is recommended to maintain remission. The efficacy of anti-interleukin-5 therapy (i.e., mepolizumab) was demonstrated in the case of refractory or relapsing EGPA. Several other new agents, including avacopan, vilobelimab, and abatacept, are under development for the treatment of ANCA-associated vasculitis. Multidisciplinary approaches are required for the diagnosis and management of the disorder because of its systemic nature. Furthermore, active participation of neurologists is required because the associated neuropathic symptoms can significantly disrupt the day-to-day functioning and quality of life of patients with ANCA-associated vasculitis.

DOI： 10.1007/s40120-021-00315-7

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Language：English   Publisher：Japanese Society of Allergology  

<p><i>Background:</i> Although eosinophilic granulomatosis with polyangiitis (EGPA) has been considered as a single disease entity belonging to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, several studies have suggested that in addition to the mechanisms associated with ANCA, those associated with eosinophils play a vital role in tissue damage. Nevertheless, the morphological bases underlying eosinophil-associated lesions have not been completely elucidated.</p><p><i>Methods:</i> We investigated the electron microscopic findings of sural nerve biopsy specimens obtained from 18 patients with EGPA by focusing on the behavior of eosinophils, particularly the mode of secretion.</p><p><i>Results:</i> Eosinophils tended to be located at sites close to endothelial cells within the lumina of epineurial small vessels. Attachment of eosinophils to endothelial cells was observed, particularly at the junction between neighboring endothelial cells, and some of these eosinophils appeared to escape from the vascular lumen to migrate into the extravascular interstitium. Furthermore, we observed eosinophil degranulation via piecemeal degranulation and cytolysis. Degranulating eosinophils were identified in both intravascular and extravascular compartments. Some of the small vessels appeared to be occluded by numerous eosinophils, and eosinophils attached by platelets were also observed, suggesting that coagulopathy occurs in EGPA.</p><p><i>Conclusions:</i> Both extravascular and intravascular eosinophils can induce tissue damage unrelated to classical necrotizing vasculitis associated with ANCA in patients with EGPA. Further research is necessary to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of eosinophil-related diseases.</p>

DOI： 10.1016/j.alit.2022.02.009

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Language：English   Publisher：Journal of Neurology  

Objectives: To clarify whether serum neurofilament light chains (NfLs) serve as a biomarker of axonal damage in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), especially in patients with anti-neurofascin 155 (NF155) antibodies. Methods: The Simoa system was used to examine serum NfL levels from 58 patients with CIDP, including 13 anti-NF155 antibody-positive patients, and from 14 age- and sex-matched healthy individuals. Serum NfL levels were evaluated before and after treatment in eight patients with anti-NF155 antibodies. Clinical features, electrophysiological findings, and cerebrospinal fluid (CSF) protein levels, were evaluated. The pathological features of sural nerves from 40 patients were also examined. Results: Serum NfL levels were significantly higher in patients with CIDP than in healthy individuals (median 29.63 vs. 7.71 pg/mL, p < 0.001) and were correlated with both modified Rankin Scale scores (r = 0.584, p < 0.001) and CSF protein levels (r = 0.432, p = 0.001). The NfL levels of anti-NF155 antibody-positive patients were higher than those of antibody-negative patients (p = 0.005). Serum NfL levels were negatively correlated with compound muscle action potential amplitudes of the tibial nerves (r = − 0.404, p = 0.004) and positively correlated with the degree of active axonal degeneration in the pathological findings (r = 0.485, p = 0.001). In the antibody-positive group, NfL levels and antibody titers decreased after treatment in all examined patients. Conclusion: Serum NfL correlated with pathological indices of axonal degeneration, and may serve as a biomarker that reflects active axonal damage of CIDP.

DOI： 10.1007/s00415-021-10537-2

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Language：English   Publisher：Journal of the Neurological Sciences  

Introduction: Although polyneuropathy in patients with immunoglobulin light chain (AL) amyloidosis has been considered to be attributable to axonal degeneration resulting from amyloid deposition, patients with nerve conduction parameters indicating demyelination that mimics chronic inflammatory demyelinating polyneuropathy (CIDP) have also been reported anecdotally. Methods: We evaluated the electrophysiological and pathological features of 8 consecutive patients with AL amyloidosis who were referred for sural nerve biopsy. Results: Although findings of axonal neuropathy predominantly in the lower limbs were the cardinal feature, all patients showed one or more abnormalities of nerve conduction velocities or distal motor latencies. In particular, 2 of these patients fulfilled the definite electrophysiological for CIDP defined by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). On electron microscopic examination of sural nerve biopsy specimens, Schwann cells apposed to amyloid fibrils became atrophic in all patients, suggesting that amyloid deposits directly affect neighboring tissues. Additionally, detachment of the neurilemma from the outermost compacted myelin lamella was seen where amyloid fibrils were absent in 4 patients. Electrophysiological findings suggestive of demyelination were more conspicuous in these patients compared with the other patients. The detachment of the neurilemma from the outermost compacted myelin lamella was particularly conspicuous in patients who fulfilled the definite EFNS/PNS electrophysiological criteria for CIDP. Conclusion: Abnormalities of myelinated fibers unrelated to amyloid deposition may frequently occur in AL amyloidosis. Disjunction between myelin and the neurilemma may induce nerve conduction abnormalities suggestive of demyelination.

DOI： 10.1016/j.jns.2020.117305

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Language：English   Publisher：Neurology  

DOI： 10.1212/WNL.0000000000011142

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Language：English   Publisher：Muscle and Nerve  

DOI： 10.1002/mus.27079

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Language：English   Publisher：Journal of Neurology Neurosurgery and Psychiatry  

Objective To describe the pathological features of Guillain-Barré syndrome focusing on macrophage-associated myelin lesions. Methods Longitudinal sections of sural nerve biopsy specimens from 11 patients with acute inflammatory demyelinating polyneuropathy (AIDP) exhibiting macrophage-associated demyelinating lesions were examined using electron microscopy. A total of 1205 nodes of Ranvier were examined to determine the relationship of the macrophage-associated demyelinating lesions with the nodal regions. Additionally, immunohistochemical and immunofluorescent studies were performed to elucidate the sites of complement deposition. Results Overall, 252 macrophage-associated myelin lesions were identified in longitudinal sections. Of these, 40 lesions exhibited complete demyelination with no association with the lamellar structures of myelin. In 183 lesions, macrophage cytoplasm was located at internodes without association with the nodes of Ranvier or paranodes. In particular, these internodal lesions were more frequent in one patient (152 lesions). In the remaining 29 lesions, the involvement of nodal regions was obvious. Lesions involving nodal regions were more frequently observed than those involving internodes in four patients. Invasion of the macrophage cytoplasmic processes into the space between the paranodal myelin terminal loops and the axolemma from the nodes of Ranvier was observed in three of these patients. Immunostaining suggested complement deposition corresponding to putative initial macrophage-associated demyelinating lesions. Conclusions The initial macrophage-associated demyelinating lesions appeared to be located at internodes and at nodal regions. The sites at which the macrophages initiated phagocytosis of myelin might be associated with the location of complement deposition in certain patients with AIDP.

DOI： 10.1136/jnnp-2019-322479

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Language：English   Publisher：Neurology  

Objective: To investigate the clinicopathologic features of eosinophilic granulomatosis with polyangiitis (EGPA)-associated neuropathy with a focus on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCAs). Methods: We examined the clinical features and pathologic findings of sural nerve biopsy specimens from 82 patients with EGPA-associated neuropathy. Of these patients, 32.9% were myeloperoxidase (MPO)-ANCA positive, and 67.1% were MPO-ANCA negative. PR3-ANCA was negative in all of 78 examined patients. Results: Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs 14.6%, p &lt; 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p &lt; 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (i.e., destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p &lt; 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels (p &lt; 0.01) and epineurial vessels occluded by intraluminal eosinophils (p &lt; 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group (p &lt; 0.01). Conclusions: This study suggests that the pathogenesis of EGPA comprises at least 2 distinct mechanisms: ANCA-associated vasculitis resulting in ischemic effects and inflammation, which is prominent in MPO-ANCA-positive patients, and eosinophil-associated vascular occlusion leading to ischemia and eosinophil-associated tissue damage, which is conspicuous in MPO-ANCA-negative patients.

DOI： 10.1212/WNL.0000000000009309

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Language：English   Publisher：Jmir Research Protocols  

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated peripheral neuropathy that is currently classified into several clinical subtypes, which are presumed to have different pathogenic mechanisms. Recently, studies identified a subgroup of patients with CIDP who were positive for IgG4 autoantibodies against paranodal proteins, such as neurofascin-155 and contactin-1, who respond poorly to first-line therapies for typical CIDP, including intravenous immunoglobulin therapy. Objective: This study aims to evaluate the efficacy and safety of intravenous rituximab according to IgG4 autoantibody status in patients with refractory CIDP. Methods: The Evaluation of the Efficacy and Safety of Rituximab in Refractory CIDP Patients with IgG4 Autoantibodies in the Exploratory Clinical (RECIPE) trial consists of 2 cohorts: a multicenter, placebo-controlled, randomized study cohort of 15 patients with IgG4 autoantibody-positive CIDP (rituximab:placebo = 2:1) and an open-label trial cohort of 10 patients with antibody-negative CIDP. The primary endpoint is improvement in functional outcome assessed using the adjusted Inflammatory Neuropathy Cause and Treatment Disability Scale score at 26, 38, or 52 weeks after the start of treatment with rituximab in patients with CIDP and anti-paranodal protein antibodies. Secondary outcome measures include grip strength, manual muscle testing sum scores, results of nerve conduction studies, and other functional scales. Results: We plan to enroll 25 cases for the full analysis set. Recruitment is ongoing, with 14 patients enrolled as of January 2020. Enrollment will close in September 2020, and the study is planned to end in December 2021. Conclusions: This randomized controlled trial will determine if rituximab is safe and effective in patients with anti-paranodal antibodies. An open-label study will provide additional data on the effects of rituximab in patients with antibody-negative CIDP. The results of the RECIPE trial are expected to provide evidence for the positioning of rituximab as a pathogenesis-based therapeutic for refractory CIDP.

DOI： 10.2196/17117

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>We herein report the case of a 67-year-old man who presented with the acute onset of limb weakness. Brain magnetic resonance imaging revealed multiple abnormal-signal-intensity lesions. Steroids were administered, and the patient initially responded. Nerve conduction testing findings were consistent with demyelinating polyneuropathy. A sural nerve biopsy specimen revealed fascicles with extensive onion-bulb formation. Although skin and sural nerve biopsies showed no atypical cellular infiltration, the histopathological diagnosis of intravascular large B-cell lymphoma was obtained by a brain biopsy. The neuropathy in this patient may be attributed to a demyelinating process independent of ischemic damage by lymphoma. </p>

DOI： 10.2169/internalmedicine.3228-19

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CiNii Research

Language：English   Publisher：Journal of the Neurological Sciences  

DOI： 10.1016/j.jns.2019.116509

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Publisher：Neurology and Clinical Neuroscience  

Hereditary transthyretin (ATTRv) amyloidosis, also known as familial amyloid polyneuropathy, is a disease caused by the systemic deposition of variant transthyretin (TTR). Although this disease was primarily indigenous to endemic foci in Portugal, Japan, and Sweden, its prevalence has increased throughout the world. The clinical phenotypes of ATTRv amyloidosis are diverse, including neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation type and age of onset. Val30Met, one of the most common TTR mutations, exhibits varying characteristic features in the early-onset patients from conventional endemic foci and the late-onset patients from non-endemic areas. Autonomic dysfunctions and dissociated sensory loss are the characteristic features of the former, whereas motor dysfunctions and loss of all sensory modalities are conspicuous in the latter. Distortion and atrophy of the Schwann cells due to the formation of amyloid fibrils seem to cause predominant small-fiber loss in the early-onset patients, while other mechanisms, such as microangiopathy and the toxicity of TTR oligomers, may contribute to nerve fiber loss in the late-onset patients. In addition to liver transplantation, novel and less invasive disease-modifying therapies, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotide, have been shown to be effective in ATTRv amyloidosis patients. Given their ability to ameliorate ATTRv amyloidosis, early diagnosis and treatment are required. Physicians should be aware of the diversity in ATTRv amyloidosis because this disease can be misdiagnosed with other diseases such as chronic inflammatory demyelinating polyneuropathy and immunoglobulin light-chain amyloidosis.

DOI： 10.1111/ncn3.12306

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Language：English   Publisher：Muscle and Nerve  

DOI： 10.1002/mus.26458

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>Tumor emboli due to a sarcoma are usually confirmed by an autopsy or operative findings. A sarcoma embolus in an acute stroke patient is rare. We herein report a 37-year-old man with acute stroke caused by internal carotid artery occlusion who underwent embolectomy. A histopathological analysis of an embolus obtained with a mechanical retriever device was diagnosed as undifferentiated sarcoma. This is the first case of extracardiac sarcoma extraction via mechanical retrieval performed during intervention for acute ischemic stroke. A histopathologic evaluation with embolectomy is important for diagnosing tumor emboli. </p>

DOI： 10.2169/internalmedicine.1223-18

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CiNii Research

Language：English   Publisher：BMC Neurology  

Background: Guillain-Barré syndrome (GBS), Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE) are a group of autoimmune neurological disorders (GBS spectrum disorder) that rarely recur. Recently, anti-ganglioside complex antibodies (GSC-Abs) were identified in patients with GBS spectrum disorder. However, there has been no case report describing GSC-Abs profiles in a recurrent case showing different phenotypes. Case presentation: We report the case of a 33-year-old male patient with GQ1b-seronegative BBE-GBS after two prior episodes of MFS-GBS. Our patient showed ophthalmoplegia, ataxia, areflexia and a weakness of the extremities (MFS and GBS symptoms) in all episodes. In the episode reported here, our patient showed disturbed consciousness and an extensor response to cutaneous plantar stimulation was observed (BBE symptoms), with severe disability and requirement for artificial respiration management. GSC-Abs detected in previous episodes were also detected in the subsequent episodes, while new GSC-Abs emerged in each episode. Interestingly, whereas antibodies to GA1/GQ1b and GA1/GT1a, which are commonly identified in patients with GBS, MFS or BBE, appeared in all episodes, antibodies to GD1a/GD1b and GD1b/GT1b, which are predominantly associated with severe disability and the requirement for artificial respiration management in GBS, emerged for the first time in this episode. Conclusion: This study reports novel phenomena about the GSC-Abs profiles and its relationship with clinical features in a case with recurrent GBS spectrum disorder, showing different phenotypes in different episodes. Further studies are required to reveal the significance of the GSC-Abs profiles in recurrent GBS spectrum disorder.

DOI： 10.1186/s12883-018-1077-5

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Language：English   Publisher：Muscle and Nerve  

Introduction: In this study we propose electrodiagnostic criteria for early reversible conduction failure (ERCF) in axonal Guillain–Barré syndrome (GBS) and apply them to a cohort of GBS patients. Methods: Serial nerve conduction studies (NCS) were retrospectively analyzed in 82 GBS patients from 3 centers. The criteria for the presence of ERCF in a nerve were: (i) a 50% increase in amplitude of distal compound muscle action potentials or sensory nerve action potentials; or (ii) resolution of proximal motor conduction block with an accompanying decrease in distal latencies or compound muscle action potential duration or increase in conduction velocities. Results: Of 82 patients from 3 centers, 37 (45%) had ERCF, 21 (26%) had a contrasting evolution pattern, and 8 (10%) had both. Sixteen patients did not show an amplitude increase of at least 50%. Conclusion: Our proposed criteria identified a group of patients with a characteristic evolution of NCS abnormality that is consistent with ERCF. Muscle Nerve 56: 919–924, 2017.

DOI： 10.1002/mus.25577

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DOI： 10.1016/j.jns.2017.08.2361

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DOI： 10.1016/j.jns.2017.08.926

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Language：English   Publisher：Current Alzheimer Research  

Background: Gangliosides are enriched in the neuronal membranes. Gangliosides are shown to interact with amyloid-β proteins, leading to formation of amyloid fibrils in Alzheimer’s disease (AD) brains. Several earlier studies indicated that the alterations of ganglioside metabolism could contribute the pathogenesis of AD. Methods: Gangliosides were isolated from the frontal lobes in five patients with AD and three control subjects. Gangliosides were assessed by high performance thin-layer chromatography (HPTLC) with resorcinol staining and immunostaining using mouse monoclonal antibodies against cholinergic neuronspecific (Chol-1α) gangliosides. Results: In all AD brains, not only the total sialic acid content but also a-series gangliosides, GM1 and GD1a, were dramatically reduced as compared with those in control subjects. These results are a hallmark of the pathogenesis in AD. In contrast, Chol-1α gangliosides, GT1aα and GQ1bα, which are specific markers of cholinergic neurons, were significantly increased in AD brains. Conclusion: The expression of Chol-1α gangliosides may be caused by a compensation to preserve the function of the cholinergic neuron and play an important role in cholinergic synaptic transmission.

DOI： 10.2174/1567205014666170117094038

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Language：English   Publisher：Developmental Medicine and Child Neurology  

Aim: Central nervous system (CNS) autoantibodies have been reported in a range of neuroimmune diseases, but there has not been a systematic evaluation of autoantibodies in paediatric patients with brainstem encephalitis. Method: Serum samples from 57 children (40 male, 17 female, median age 12y, range 0.6–18y) with a diagnosis of brainstem encephalitis were tested retrospectively for antibodies to GQ1b, aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), N-methyl-D-aspartate receptor, LGI1, CASPR2, glycine receptor (GlyR), DPPX, and the voltage gated potassium channel (VGKC)-complex. Results: Disease localized to the brainstem was seen in 19 patients: Bickerstaff's brainstem encephalitis (n=14) and clinically isolated syndrome (n=5). Polyfocal presentation was seen in 38 children, with predominantly white matter disease in 18 patients and grey matter in 20 patients. CNS surface antibodies were found in 22/57 patients (two patients with double positivity): GQIb (n=6), NMDAR (n=7), GlyR (n=5), MOG (n=5), and one AQP4. Three patients were positive for VGKC-complex antibodies. All patients were negative for antibodies to DPPX and the VGKC-complex antigens LGI1, CASPR2, and contactin-2. Although there were some partial differences in the presentations, the clinical features and outcomes did not relate clearly to the presence or absence of specific antibodies. Interpretation: As determined retrospectively, 39% of patients had cell surface antibodies. The results did not suggest any relationship with treatment or outcomes obtained but it is possible that specific antibody detection could be a helpful guide to more intensive immunotherapies in some cases.

DOI： 10.1111/dmcn.13090

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Language：English   Publisher：Neurology  

Objective: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. Methods: In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested. Results: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155-negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes. Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments.

DOI： 10.1212/WNL.0000000000002418

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PubMed

Language：English   Publisher：Journal of Neurology Neurosurgery and Psychiatry  

Objective: Sialylation in Fc portion of IgG plays a crucial role in the pathogenesis of autoimmune diseases and the working mechanism of intravenous immunoglobulin (IVIG). We aim to test whether IgG-Fc sialylation is a biomarker of disease activity for chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: By using specific lectins for sialylation, galactosylation and agalactosylation, lectin-enzyme assay and lectin blotting with pretreatment of IgG degradating enzyme of Streptococcus pyogenes were performed to compare the glycosylation levels of serum IgG-Fc (1) between patients of untreated CIDP (n=107) and normal control subjects (n=27), (2) among patients with untreated CIDP of different clinical severities and (3) before and after IVIG treatment of patients with CIDP (n=12). Results: Sialylation and galactosylation of IgG-Fc were significantly reduced in patients with CIDP than normal control subjects (p=0.003 and 0.033, respectively), whereas agalactosylation was increased in CIDP (p=0.21). Ratios of sialylated/agalactosylated IgG-Fc levels were significantly reduced in CIDP (p<0.001) and inversely related to disease severity (p=0.044). After IVIG treatment, levels of sialylated IgG-Fc significantly increased (p=0.003). Conclusions: Sialylation of IgG-Fc is reduced in CIDP. Its level correlated with clinical severity and increased after IVIG treatment. Sialylated as well as ratio of sialylated/agalactosylated IgG-Fc could be new measures to monitor the disease severity and treatment status in CIDP.

DOI： 10.1136/jnnp-2014-309964

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PubMed

Language：English   Publisher：European Journal of Neurology  

Background and purpose: Anti-GQ1b antibodies have been found in patients with Miller Fisher syndrome as well as its related conditions. Our aim was to identify the mechanism by which autoantibodies produce various clinical presentations in 'anti-GQ1b antibody syndrome'. Methods: Immunoglobulin G antibodies to ganglioside complex (GSC) of GQ1b or GT1a with GM1, GD1a, GD1b or GT1b were tested in sera from patients with anti-GQ1b (n = 708) or anti-GT1a (n = 696) IgG antibodies. Optical densities of the single anti-GQ1b or anti-GT1a antibodies were used as reference (100%), and those of anti-GSC antibodies were expressed in percentages to reference. The relationships between anti-GSC antibody reactivity and the corresponding clinical features were assessed by multivariate logistic regression analysis. Results: Ophthalmoplegia and hypersomnolence were significantly associated with complex-attenuated anti-GQ1b and anti-GT1a antibodies. Ataxia was associated with GD1b- and GT1b-enhanced anti-GQ1b antibodies or GM1-enhanced anti-GT1a antibodies. Bulbar palsy was associated with GT1b-enhanced anti-GQ1b antibodies. Neck weakness was associated with GD1a-enhanced anti-GQ1b antibodies. Arm weakness was associated with GD1b-enhanced anti-GQ1b and GD1a-enhanced anti-GT1a antibodies. Leg weakness was associated with GD1a-enhanced anti-GQ1b and anti-GT1a antibodies. Conclusions: Differences in fine specificity of anti-GQ1b antibodies are associated with clinical features, possibly due to the different expression of gangliosides in different parts of the nervous system.

DOI： 10.1111/ene.12769

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Language：English   Publisher：Developmental Biology  

Myasthenia gravis (MG), the most common autoimmune disease of neuromuscular junction (NMJ), is heterogeneous in terms of pathophysiology, which is determined by the pathogenic antigen of autoantibodies targeting to synaptic proteins at the NMJs. Currently, patients suspected with MG are routinely screened for the presence of autoantibodies against acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) using a cell-based assay (CBA) that involves the expression of target synaptic membrane protein in heterologous cell lines. However, some autoantibodies may only show reactivity for binding to densely clustered AChR in the physiological conformation, while AChR clustering is known to involve signaling events orchestrated by over a dozen of postsynaptic proteins. To improve the existing serological diagnosis of MG, this study explored the possibility of using the well-established Xenopus primary culture system as a novel CBA for MG. Here, by examining the pathogenic effects of four MG human plasma samples, we found that the samples from both seropositive and seronegative MG patients effectively induced the disassembly of aneural AChR clusters in cultured Xenopus muscle cells, as well as the nerve-induced AChR clusters in the nerve-muscle co-cultures. Importantly, the disassembly of AChR clusters was spatio-temporally correlated to the disappearance of actin depolymerizing factor (ADF)/cofilin, an actin regulator involved in AChR trafficking and clustering. Taken together, this study develops a reliable CBA using Xenopus primary cultures for screening the pathogenicity of human MG plasma samples, and providing a platform for investigating the pathogenic mechanisms underlying the endocytic trafficking and degradation of AChRs at NMJs in MG patients.

DOI： 10.1016/j.ydbio.2015.02.017

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Language：English   Publisher：Brain  

A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option.

DOI： 10.1093/brain/awv054

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Language：English   Publisher：Journal of the Peripheral Nervous System  

DOI： 10.1111/jns.12113

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Language：English   Publisher：Journal of Neurology  

Monospecific IgG antibodies to GD1b ganglioside (GD1b-specific antibodies) have been found in patients with acute ataxic neuropathy and Guillain-Barré syndrome, but the association of the GD1b-specific antibodies with specific neurological conditions has yet to be established. We tested sera from more than 10,000 patients with various neurological disorders, and found six sera, which contained IgG antibodies to GD1b, but not to LM1, GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, GT1b and GQ1b. All six patients who carried GD1b-specific antibodies presented with acute onset of ataxia and monophasic course of the illness, of whom five demonstrated cerebellar-like ataxia. Four patients had antecedent symptoms of upper respiratory tract infection. The six patients demonstrated areflexia, and four complained of distal numbness. All the six patients who had the GD1b-specific antibodies carried IgG antibodies to complex of GQ1b/GM1 and GT1a/GM1. GD1b-specific antibodies were significantly absorbed by GQ1b/GM1 and GT1a/GM1 and anti-GQ1b/GM1 and -GT1a/GM1 antibodies were absorbed by GD1b. In conclusion, the GD1b-specific antibodies, which recognizes GQ1b/GM1 or GT1a/GM1 complex, are associated with acute ataxia. © 2014 Springer-Verlag Berlin Heidelberg.

DOI： 10.1007/s00415-014-7388-6

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Language：English   Publisher：Stroke  

Background and Purpose - Albuminuria, a marker of chronic kidney disease, is associated with an increased risk of incident stroke and unfavorable long-term outcomes. However, the association of albuminuria with short-term outcomes and change in infarct volume in patients with acute small subcortical infarction remains unknown. Methods - We retrospectively reviewed 85 consecutive patients with acute small subcortical infarcts in the lenticulostriate artery territory who were admitted to our stroke center within 24 hours of symptom onset and underwent serial diffusionweighted imaging (DWI). Albuminuria was determined based on the urinary albumin-to-creatinine ratio obtained from a first morning spot urine after admission. Infarct volume was measured on axial sections of the initial and follow-up DWI. Early neurological deterioration (END) was defined as an increase of ≥2 points in the National Institutes of Health Stroke Scale score during the first 5 days after admission. Results - Albuminuria (UACR ≥30 mg/g creatinine) was observed in 14 of 18 patients with END (77.8%) and in 25 of 67 patients without END (37.3%), P=0.002. Multivariate logistic regression analysis revealed that albuminuria was associated with END after adjustment for age, low estimated glomerular filtration rate (<60 mL/min per 1.73 m2), and infarct volume on initial DWI (odds ratio, 6.64; 95% confidence interval, 1.62-27.21; P=0.009). In addition, albuminuria was an independent predictor of increase in infarct volume using multivariate linear regression analysis (β coefficient=0.217; P=0.038). Conclusions - Our findings suggest that albuminuria is associated with END and infarct volume expansion in patients with small subcortical infarcts in the lenticulostriate artery territory. © 2013 American Heart Association, Inc.

DOI： 10.1161/STROKEAHA.113.003164

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