[How to Perform Autoantibody Testing for Autoimmune and Inflammatory Diseases of Peripheral Nerves and Muscles].

Measurement of autoantibodies is essential for the management of several peripheral nerve and muscle diseases. The clinical significance of autoantibody testing differs for each antibody. In addition, clinicians must understand several issues including the accuracy of the test, isotype and subclass distribution, and its relationship to disease activity. Moreover, many autoantibody tests are not covered by health insurance. With limited medical resources, clinicians are required to be up-to-date with the latest information to utilize test results in daily practice without misunderstanding.

The Diversity of Neurological Complications Associated with Herpes Zoster: A Retrospective Case Series of 26 Patients.

Objects This study clarified a variety of neurological phenotypes associated with varicella-zoster virus (VZV) reactivation. Methods This retrospective single-center study included consecutive patients with herpes zoster accompanied by neurological disturbances from April 2016 to September 2022. A comparative analysis was performed to examine whether or not the neurological phenotype and severity were associated with the distribution of herpes zoster, clinical and laboratory findings, and treatments. Results Twenty-six patients with a median age of 74 years old were enrolled. None of the patients had been vaccinated against herpes zoster. Of the 26 patients, 14 (54%) developed monoparesis, 5 (19%) developed meningitis, 5 (19%) developed encephalitis, 1 (4%) developed paraplegia, and 1 (4%) developed bladder and rectal problems. Monoparesis of the upper limb is associated with herpes zoster involving the cervical and thoracic dermatomes, whereas meningitis and encephalitis often occur in patients with herpes zoster in the trigeminal and thoracic dermatomes. Neurological disability was generally severe [modified Rankin Scale (mRS) score ≥3] on admission [17 of 26 (65%) patients]. Good recovery after admission was associated with a lower mRS value before the onset of neurological disability, clinical meningitis, and elevated cell counts and protein levels in the cerebrospinal fluid. Good recoveries were observed in patients with herpes zoster in the trigeminal or thoracic dermatomes more frequently than in other dermatomes. Conclusion This study revealed that VZV-related neurological complications are heterogeneous, commonly leading to severe disability and poor outcomes, and that neurological phenotypes and outcomes are related to the distribution of herpes zoster.

Lead Encephalopathy in a 73-year-old Man Manifesting as Acute Disturbance of Consciousness with a Unique Magnetic Resonance Imaging Appearance.

A 73-year-old man was admitted with Cheyne-Stokes respiration and progressive disturbance of consciousness over the course of a month. Cranial magnetic resonance imaging revealed signs suggestive of angioedema in the posterior limb of the internal capsule, external capsule, and subcortical white matter. Acute lead encephalopathy was diagnosed based on abnormally high plasma lead levels. After methylprednisolone pulse therapy followed by chelation therapy, the patient fully recovered. In this case, the angioedema with a distinctive magnetic resonance imaging appearance was attributed to the cytotoxic effects of lead on the nervous system, which responded well to methylprednisolone pulse therapy.

Antineutrophil cytoplasmic antibody-associated vasculitis with predominant truncal muscle weakness: a retrospective case series.

Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) frequently leads to mononeuritis multiplex, which are characterized by distal weakness associated with sensory disturbances. Although AAV has also been reported to be associated with myopathy, the pathogenesis and characteristics remain unclear. We aimed to show the clinical and laboratory findings in AAV-associated myopathy. Methods: This retrospective single-center study included patients with the diagnosis of AAV who had been admitted to the neurology department and had biopsy specimens of muscle and/or nerve tissue. Results: We identified four patients with a distinct clinical presentation of muscle weakness in the trunk and proximal limbs. The weakness resembled that of inflammatory muscle disease. These patients denied symptoms associated with neuropathy, and had normal serum creatine kinase (CK) levels. Needle electromyography (needle EMG) showed spontaneous electrical activity at rest, and results of magnetic resonance imaging (MRI) suggested inflammatory myopathy. Muscle biopsy specimens from all four patients revealed vasculitis and inflammation in proximity to the affected vessels, without any discernible characteristics of other myopathies. The patients also complained of symptoms affecting other organs, such as the ears and kidneys, which is typical of AAV cases. Remission induction therapy, such as cyclophosphamide pulse therapy in addition to oral prednisolone, were effective for all four patients. However, relapses occurred in two patients during maintenance therapy and two patients died of aspiration pneumonia. Discussion: The clinical course of our patients might represent a subtype of AAV that is characterized by muscle weakness of the trunk and proximal extremities and arises from vasculitis within the muscles. The clinical manifestations of our patients were similar to those of patients with inflammatory myopathy with regard to the distribution of muscle weakness, MRI and needle EMG findings. However, there are notable differences between AAV associated myopathy vs. inflammatory myositis like dermatomyositis; (1) the absence of elevated CK levels, (2) the presence of complications in other organs, (3) distinct pathological findings, and (4) severe outcomes. Awareness that AAV patients with muscle involvement could have a subtype of AAV that seriously affects various organs is critical for an accurate diagnosis and effective therapeutic management.

[Guillain-Barré Syndrome: The Benefits of Autoantibodies in Daily Practice].

A huge number of autoantibodies are detected during the clinical encounter of Guillain-Barré syndrome (GBS) and its variants. The autoantibodies sensitivity and specificity are not always sufficient, especially in demyelinating GBS, where they have not yet been identified in most cases. Autoantibody results may mislead the diagnosis if the limitations of the test are not understood. Therefore, if there is any doubt about the interpretation of the results, clinicians should be careful in accurately understanding them by making inquiries to specialists.

Jo-1 Antibodies From Myositis Induce Complement-Dependent Cytotoxicity and TREM-1 Upregulation in Muscle Endothelial Cells.

BACKGROUND AND OBJECTIVES: Muscle microangiopathy due to dysfunction of endothelial cells because of inflammation is a critical hallmark of dermatomyositis (DM); however, its pathomechanism remains unclear. The aim of this study was to evaluate the effect of immunogloblin G (IgG) from patients with idiopathic inflammatory myopathies (IIM) on muscle endothelial cells in vitro. METHODS: Using a high-content imaging system, we analyzed whether IgG purified from sera from patients with IIM (n = 15), disease controls (DCs: n = 7), and healthy controls (HCs: n = 7) can bind to muscle endothelial cells and induce complement-dependent cellular cytotoxicity. RESULTS: IgGs from Jo-1 antibody myositis could bind to muscle endothelial cells and caused complement-dependent cell cytotoxicity. RNA-seq demonstrated the upregulation of genes associated with tumor necrosis factor (TNF)-α, triggering receptor expressed on myeloid cells-1 (TREM-1), CD25, and mitochondria pathways after exposure to IgG from the Jo-1, signal recognition particle (SRP), and polymyositis (PM) groups. The high-content imaging system showed that TREM-1 expression in the Jo-1, SRP, and PM groups was increased in comparison with DCs and HCs and that the TNF-α expression in the Jo-1 group was higher in comparison with the SRP, PM, DC, and HC groups. The expression of TREM-1 was observed in biopsied capillaries and the muscle membrane from patients with Jo-1 and in biopsied muscle fiber and capillaries from patients with DM and SRP. The depletion of Jo-1 antibodies by IgG of patients with Jo-1 antibody myositis reduced the Jo-1 antibody-induced complement-dependent cellular cytotoxicity in muscle endothelial cells. DISCUSSION: Jo-1 antibodies from Jo-1 antibody myositis show complement-dependent cellular cytotoxicity in muscle endothelial cells. IgGs from patients with Jo-1, SRP, and DM increase the TREM-1 expression in endothelial cells and muscles.

[Clinical features of 8 patients with multifocal motor neuropathy in the long-term follow-up].

OBJECTIVE: To clarify the clinical and long-term characteristics of multifocal motor neuropathy (MMN). METHODS: We retrospectively evaluated data from 8 consecutive MMN patients in Yamaguchi University Hospital from 2005 to 2020. Clinical information including dominant hand, occupations, hobbies, nerve conduction data, protein level in cerebrospinal fluid (CSF), responsiveness to intravenous immunoglobulin (IVIg) therapy as initial therapy as well as maintenance therapy were collected. RESULTS: Unilateral upper limb was initially affected in all patients and a dominant upper extremity was affected in six of them. Seven patients had occupations or hobbies which were associated with overuse of their dominant upper extremity. CSF protein level was normal or slightly elevated. Nerve conduction studies showed conduction blocks in 4 cases. Effectiveness of IVIg treatment as initial therapy was observed in all patients. Maintenance therapy was not needed in 2 patients because of mild symptoms with stable clinical course. Long-term maintenance therapy with immunoglobulin was effective in 5 patients during the follow-up period. CONCLUSION: Dominant upper extremity was frequently affected and most patients had job or habit associated with its overuse, suggesting that physical overload induces inflammation or demyelination in MMN. IVIg was commonly effective as both introduction and long-term maintenance therapies. Complete remission was achieved after several IVIg treatments in some patients.

Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy.

BACKGROUND AND OBJECTIVES: Deposition of myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibodies in the sural nerve is a key feature in anti-MAG neuropathy. Whether the blood-nerve barrier (BNB) is disrupted in anti-MAG neuropathy remains elusive.We aimed to evaluate the effect of sera from anti-MAG neuropathy at the molecular level using our in vitro human BNB model and observe the change of BNB endothelial cells in the sural nerve of anti-MAG neuropathy. METHODS: Diluted sera from patients with anti-MAG neuropathy (n = 16), monoclonal gammopathies of undetermined significance (MGUS) neuropathy (n = 7), amyotrophic lateral sclerosis (ALS, n = 10), and healthy controls (HCs, n = 10) incubated with human BNB endothelial cells to identify the key molecule of BNB activation using RNA-seq and a high-content imaging system, and exposed with a BNB coculture model to evaluate small molecule/IgG/IgM/anti-MAG antibody permeability. RESULTS: RNA-seq and the high-content imaging system showed the significant upregulation of tumor necrosis factor (TNF-α) and nuclear factor-kappa B (NF-κB) in BNB endothelial cells after exposure to sera from patients with anti-MAG neuropathy, whereas the serum TNF-α concentration was not changed among the MAG/MGUS/ALS/HC groups. Sera from patients with anti-MAG neuropathy did not increase 10-kDa dextran or IgG permeability but enhanced IgM and anti-MAG antibody permeability. Sural nerve biopsy specimens from patients with anti-MAG neuropathy showed higher TNF-α expression levels in BNB endothelial cells and preservation of the structural integrity of the tight junctions and the presence of more vesicles in BNB endothelial cells. Neutralization of TNF-α reduces IgM/anti-MAG antibody permeability. DISCUSSION: Sera from individuals with anti-MAG neuropathy increased transcellular IgM/anti-MAG antibody permeability via autocrine TNF-α secretion and NF-κB signaling in the BNB.

[A Patient Developing Guillain-Barré Syndrome After Receiving the BNT162b2 COVID-19 mRNA Vaccine].

We report a 71-year-old woman who presented with paresthesia, progressive weakness, difficulty walking, diarrhea, and bladder dysfunction one week after she received the BNT162b2 COVID-19 vaccine. Her neurological signs and symptoms gradually worsened up to 27 days after onset, after which her weakness slowly improved without immunotherapy. Analysis of serial cerebrospinal fluid specimens showed gradually increasing protein levels. Results of a nerve conduction study suggested functional axonal disturbance. The clinical findings together with the monophasic clinical course were consistent with Guillain-Barré syndrome. Her previous history was negative for symptomatic infection. Serological and bacterial tests, including the presence of anti-glycolipid antibodies, were negative for prior infection. Few cases have been reported on the development of Guillain-Barré syndrome after the BNT162b2 vaccine. Our patient's syndrome was characterized by atypical proximal weakness of the dominant lower limb. (Received January 28, 2022; Accepted April 4, 2022; Published August 1, 2022).

[Acute sarcoid myopathy and neuropathy aggravated by ustekinumab administration in an elderly woman with psoriasis and systemic sarcoidosis].

A 72-year old woman, who had a history of psoriasis and psoriatic arthritis from age of 69, was admitted because of acute progression of dyspnea and generalized muscle weakness after initiation of ustekinumab. She had been diagnosed as having lung and eye sarcoidosis ten months before admission. Nerve conduction studies revealed multiple mononeuropathy and needle electromyography showed myogenic changes with spontaneous activities. Muscle pathology showed non-caseating epithelioid granuloma and high expression of HLA-class I in myofibers. Diagnosis of sarcoid myopathy and neuropathy aggravated by ustekinumab was made, and ustekinumab administration was discontinued, resulting in slight improvement of her respiratory and neuro-muscular symptoms, but her symptoms remained severely disabled. Treatment with oral steroids further improved her clinical symptoms and she became able to walk independently. We considered that ustekinumab inhibited IL-12 and IL-23 signaling, which caused an imbalance in Th1/Th17 differentiation and activation of Th1 cell differentiation, thereby promoting the development of sarcoid myopathy and neuropathy.

Spinal cord sarcoidosis in Japan: utility of cerebrospinal fluid examination and nerve conduction study for diagnosis and prognosis prediction.

Spinal cord sarcoidosis (SCS) is rare, and its diagnosis is challenging. We examined clinical, laboratory, and imaging features in patients with SCS to obtain useful clues for diagnosis and prognosis. Eleven consecutive patients (four males, seven females) at a single Japanese institution were investigated. Median age at onset was 66 years old. The most frequent site affected, other than the nervous system, was the respiratory system. While histological confirmation of non-caseating granulomas was often found there, no patient had respiratory symptoms. Peripheral nerve involvement was detected in 64% of patients. Soluble IL-2 receptor (sIL-2R) levels in serum and cerebrospinal fluid (CSF) were elevated in 64% and 45% of patients, respectively, and this finding was more common than elevation of angiotensin-converting enzyme (ACE). 18F-fluorodeoxyglucose (FDG) positron emission tomography showed abnormally high uptake in spinal lesions of all examined patients. Although corticosteroids were administrated to all patients, and immuno-suppressants were prescribed to six (55%), the modified Rankin Scale was unchanged or worsened in four (36%) patients during the follow-up period. Neurological exacerbation of myelopathy was seen in four (36%) patients. Complete response rate was only seen in 9%. High levels of cell count, protein, ACE, and sIL-2R in CSF were significantly more frequent in patients with a marked improvement after immunotherapy than in the other patients. These results suggest that high serum and CSF sIL-2R, high uptake of FDG, and peripheral nerve involvement are indicative of SCS. Given that SCS is commonly intractable, CSF abnormalities may predict efficacy of immunotherapies.

[Clinical and long-term characteristics of the subtypes of chronic inflammatory demyelinating polyneuropathy].

OBJECTIVE: To clarify the clinical and long-term characteristic of each subtype of chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We evaluated data from 30 consecutive CIDP patients who met the criteria proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society. RESULTS: Patients were classified as having typical CIDP (t-|CIDP) (10/30, 33%), multifocal acquired demyelinating sensory and motor (MADSAM) (12/30, 40%), DADS (4/30, 13%), sensory CIDP (3/30, 10%) or motor CIDP (1/30, 3%). Nerve conduction studies showed more prolonged distal motor latencies/F-wave latencies and slower motor nerve conduction in the typical CIDP group than in the MADSAM group. Intravenous immunoglobulin (IVIg) was effective in 80% (8/10) of t-|CIDP, 100% (12/12) of MADSAM, 100% (4/4) of DADS, and 100% (3/3) of sensory CIDP cases. Maintenance therapy with immunoglobulin was administered in patients with t-|CIDP (5/10, 50%), MADSAM (9/12, 75%), DADS (1/4, 25%), and sensory CIDP (2/3, 67%). There were no patients with CIDP, in whom CIDP subtype was transformed from the initial diagnosis during five years of follow-up. DISCUSSION: Percentage of MADSAM was the most common phenotype in our cohort of CIDP patients, and IVIg/immunoglobulin maintenance was effective for MADSAM as well as t-|CIDP in contrast to findings from the previous reports.

[Intravenous immunoglobulin-induced eczematous eruption in autoimmune neuromuscular diseases].

BACKGROUND: Intravenous immunoglobulin (IVIg) have been administrated for the long time in patients with several autoimmune neuromuscular diseases. Eczematous eruption has been described as IVIg-induced adverse effect. OBJECTIVE: The purpose of this study is to clarify the incidence and characteristic of IVIg-induced eczematous eruption in autoimmune neuromuscular disease. METHODS: We retrospectively collected the data from 92 patients with autoimmune neuromuscular diseases, including 35 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 8 patients with multifocal motor neuropathy (MMN), 25 patients with myositis, 15 patients with Guillain-Barré syndrome (GBS), and 9 patients with myasthenia gravis (MG), who have administrated IVIg in Yamaguchi University Hospital. RESULTS: There are 10 patients (6 CIDP/4 MMN), who had an eczematous skin reaction after IVIg infusion. The frequencies of IVIg-induced eczematous eruption were significantly higher in patients with multifocal acquired demyelinating sensory and motor (MADSAM) and MMN than in patients with GBS, myositis, and MG. In addition, corticosteroids or immunosuppressive drugs had been administrated before IVIg treatment more frequently in patients with myositis and MG than in those with MADSAM and MMN. CONCLUSION: MADSAM or MMN patients had more frequently IVIg-induced eczematous eruption than other autoimmune neuromuscular diseases. Pathophysiology of MADAM and MMN is considered to be cell-mediated immunity against the peripheral nerve and the accumulation of IgG in both epidermis and dermis of the hand after IVIg may induce the infiltration of inflammatory cells around the vessels in the skin, causing eczematous eruption in MADSAM and MMN.

Sensory Ataxic Guillain-Barré Syndrome with Dysgeusia after mRNA COVID-19 Vaccination.

Guillain-Barré syndrome (GBS) has occasionally occurred in people who have received coronavirus disease 2019 (COVID-19) vaccines. Dysgeusia is rare symptom of GBS. We herein report a rare case of sensory ataxic GBS with dysgeusia just after the second dose of the Pfizer-BioNTech COVID-19 vaccine. Although autoantibodies against glycolipids were not detected, immunotherapy with intravenous immunoglobulin and methylprednisolone pulse therapy effectively ameliorated the symptoms. Our report suggests that the COVID-19 vaccine may induce various clinical subtypes of GBS, including a rare variant with sensory ataxia and dysgeusia.

Exploring lipophilic compounds that induce BDNF secretion in astrocytes beyond the BBB using a new multi-cultured human in vitro BBB model.

Brain-derived neurotrophic factor (BDNF) cannot cross the blood-brain barrier (BBB) when administered peripherally, which hinders its therapeutic potential. We utilized an in vitro BBB model-a tri-culture of a human endothelial cell line, a pericyte cell line, and an astrocyte cell line-to study the effect of twenty candidate lipophilic compounds on stimulating BDNF secretion in pericytes and astrocytes. The prostaglandin E2 receptor 4 agonist and sphingosine-1-phosphate receptor 5 agonist facilitated secretion of BDNF in the astrocyte, but did not decrease the transendothelial electrical resistance. These compounds may be promising agents for neurodegenerative and neuroinflammatory diseases.

[Treatment Options for Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): With a Focus on Immunoglobulin Treatment].

The disease state and clinical course of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are diverse, and the response to treatment varies from patient to patient. Therefore, it is necessary to select a treatment and determine the appropriate dose and dosage interval while monitoring the clinical course after treatment initiation. In this article, we will discuss points to be considered and the results of studies that can be used as references in order to make an appropriate choice at each stage of CIDP treatment.

[Atezolizumab-induced Guillain-Barré syndrome-like acute demyelinating polyneuropathy responsive to steroid therapy: a case report].

A 76-year-old man, who received atezolizumab for the treatment for small cell lung cancer, acutely developed limb weakness with sensory disturbance after the third course of the treatment. Nerve conduction studies were consistent with demyelinating polyneuropathy and acute demyelinating polyneuropathy caused by atezolizumab was suggested. Atezolizumab was immediately withdrawn, and intravenous immunoglobulin (IVIg) and methylprednisolone pulse therapies with subsequent oral administration of prednisolone were initiated, after which neurological deficits steadily improved. Although Guillain-Barré syndrome-like neuropathy caused by immune checkpoint inhibitor (ICI) was occasionally reported, this is the first case of acute demyelinating polyneuropathy triggered by atezolizumab, monoclonal antibody targeting programmed death-ligand 1. This case suggests that combined treatments with IVIg and corticosteroids are effective for neuropathy induced by atezolizumab as same as those by other ICI.

[Neuropathy presenting conduction block in ANCA-negative eosinophilic granulomatosis with polyangiitis].

A 74-year-old woman with a history of asthma and allergic rhinitis rapidly developed multiple mononeuropathy. Although anti-neutrophil cytoplasmic antibodies were negative, the presence of eosinophilia and eosinophilic infiltrations in the sural nerve led to a diagnosis of eosinophilic granulomatosis with polyangiitis. A motor nerve conduction study on admission revealed conduction block, which promptly disappeared after initiating immunotherapy without findings suggestive for remyelination or axonal degeneration. This electrophysiological change distinct from that of Wallerian degeneration. A biopsy of the sural nerve showed many eosinophil infiltrations and degranulation of eosinophilic cationic protein within nerve fascicles, whereas findings of necrotizing vasculitis were absent. These findings suggest that a direct effect of eosinophilic cationic protein, rather than ischemic damage due to vasculitis, was the main mechanism of transient nerve conduction failure in this patient.

[A 81-year old man of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody-positive myopathy associated with lung adenocarcinoma cancer].

An 81-year-old man, who had no history of taking statins, developed progressive muscle weakness of the limbs and dysphagia. Laboratory tests showed a high level of CK and positivity for serum 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. Tests for other autoantibodies to ARS and SRP were negative. A pathological analysis of the left biceps muscle revealed numerous necrotic and regenerated fibers with macrophage infiltration and deposition of C5b-9 complement in and around the myofibers. Chest CT showed a nodular shadow, which was suspected to be lung cancer, in the upper left lobe. A pathological analysis of a transbronchial lung biopsy specimen revealed lung adenocarcinoma with high level of HMGCR. He was diagnosed with HMGCR necrotizing myopathy associated with lung cancer, and both his muscle strength and dysphagia improved after three treatments with intravenous immunoglobulin (IVIg). He did not undergo surgery or radiation therapy because of interstitial pneumonia. This case suggests that a paraneoplastic mechanism caused the production of HMGCR antibodies, leading to myositis in this patient. Treatment with IVIg can be effective for patients with HMGCR antibody-positive paraneoplastic necrotizing myopathy that is refractory to corticosteroid therapy.

[Sarcoidosis in Central Nervous System].

Sarcoidosis with lesions in the central nervous system is a heterogeneous condition with diverse clinical presentations and various degrees of neurological disability. Although extremely rare among sarcoidosis cases, it is of relevance to routine clinical practice because it may be a differential diagnosis in brain tumors, meningitis, and myelopathy of unknown origin. Encephalic and myelopathic lesions of sarcoidosis are often resistant or only partially responsive to immunotherapies, including high-dose corticosteroids and immunosuppressants. This may lead to residual neurological disability in a certain number of cases. Several retrospective findings have recently shown superior therapeutic effects with infliximab. However, high-level evidence is warranted to confirm its efficacy to treat neurosarcoidosis.