Anti-IgLON5 disease as a differential diagnosis of multiple system atrophy.

INTRODUCTION: Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a rare autoimmune encephalitis that can mimic progressive supranuclear palsy or corticobasal syndrome. Moreover, anti-IgLON5 disease can present with symptoms characteristic of multiple system atrophy (MSA), such as cerebellar ataxia and autonomic dysfunction. However, the clinical features of anti-IgLON5 disease resembling MSA have not been well established. METHODS: We enrolled 35 patients with suspected MSA for whom anti-IgLON5 antibody tests were requested. We evaluated immunoglobulin G (IgG) against IgLON5 using cell-based assays. We also summarized the clinical characteristics of patients who were positive for anti-IgLON5 antibodies. RESULTS: We identified serum and cerebrospinal fluid anti-IgLON5 antibodies in three patients. These patients had many clinical features characteristic of MSA, including parkinsonism, cerebellar ataxia, severe orthostatic hypotension, acute respiratory failure, sleep parasomnia, vocal cord paralysis, and pyramidal tract signs. Clinical features atypical for MSA were myorhythmia, horizontal eye movement restriction, fasciculations, and painful muscle cramps. CONCLUSION: Anti-IgLON5 disease may be an important differential diagnosis of MSA. A comprehensive physical examination, including assessments of eye movement, lower motor neuron signs, and atypical involuntary movements, is important to avoid misdiagnosis.

[Paraneoplastic Disorders of Peripheral Nervous System].

Paraneoplastic disorders of the peripheral nervous system are immune-mediated neurological syndromes associated with tumors. Several clinical phenotypes have been associated with these disorders. Sensory neuronopathy is the most well-known clinical phenotype, and is caused by neuronal cell injury to the dorsal root ganglia. Symptoms of the peripheral nervous system usually lead to the discovery of tumors. Antineuronal antibodies are occasionally identified in the serum and/or cerebrospinal fluid of these patients. The prevalence of small-cell lung cancer is notable in these patients. Early tumor resection, coupled with the initiation of immunotherapy, may prove effective in improving and stabilizing clinical symptoms.

[A case of autoimmune glial fibrillary acidic protein astrocytopathy with various symptoms such as optic disc edema and cerebellar ataxia].

A 59-year-old man had developed visual abnormality, nausea, headache, and weight loss since three months before. The ophthalmologist found severe optic disc edema in both eyes, and referred him to our hospital. The patient had mild cerebellar ataxia. Increased cerebrospinal fluid pressure, increased protein and cell counts, positive oligoclonal band, and contrast-enhanced head MRI showed multiple linear perivascular radial gadolinium enhancement around bilateral lateral ventricles. His subjective and objective findings significantly improved with steroid treatment. The cerebrospinal fluid was found to be positive for glial fibrillary acidic protein (GFAP) antibodies, and a diagnosis of GFAP astrocytopathy was obtained. When optic edema or radial contrast effects was observed on contrast-enhanced MRI, GFAP astrocytopathy should be considerd. Prompt immunotherapy is required to circumvent the development of permanent visual impairment.

Case report: Atypical case of autoimmune glial fibrillary acidic protein astrocytopathy following COVID-19 vaccination refractory to immunosuppressive treatments.

A 54-year-old Japanese man presented with headache and fever the day after SARS-CoV-2 vaccination. He became deeply unconscious within a week. Brain MRI showed periventricular linear enhancements and a few spotty lesions in the cerebral white matter. Cerebrospinal fluid (CSF) testing showed mild pleocytosis. He was treated with intravenous methylprednisolone and plasma exchange. However, the white matter lesions enlarged to involve the brainstem and cerebellum, and long cord spinal lesions appeared. Anti-glial fibrillary acidic protein (GFAP) antibody was positive in the CSF and serum, and he was therefore diagnosed as autoimmune GFAP-astrocytopathy (GFAP-A). In addition, high-dose immunoglobulin therapy was administered twice, but his symptoms did not improve; the white matter lesions enlarged further, and modified Rankin Scale score increased to 5. A brain biopsy specimen showed infiltration of macrophages and CD4 + lymphocytes together with neuron and oligodendrocytic injuries and glial scar. Although GFAP-A generally responds well to steroids, the present case developed GFAP-A following SARS-CoV-2 vaccination, with refractory to intensive immunosuppressive therapy and atypical pathologic findings of infiltration of CD4 + lymphocytes and demyelination.

[Adult-onset COVID-19-associated Fulminant Acute Encephalopathy with Elevated Cerebrospinal Fluid Interleukin-8: A Case Report].

A 26-year-old woman receiving immunosuppressive therapy for polymyositis was infected with COVID-19 (an omicron mutant strain) and presented with fever. On the second day after the onset, she was admitted to our hospital and developed status epilepticus. Brain magnetic resonance imaging on admission revealed abnormal symmetric hyperintensities in the bilateral putamen and around the dorsal horns of the lateral ventricle. Three days after admission, brain computed tomography revealed marked cerebral edema and herniation. The cerebrospinal fluid (CSF) cell count was normal, and the reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was negative. Interleukin (IL)-2, 6, and 10 levels were within the normal range in both serum and CSF, whereas IL-8 levels in the CSF were markedly higher compared to serum levels. She had fulminant acute encephalopathy, suspected to be in the early stages of acute necrotizing encephalopathy (ANE). Steroid pulse therapy and intravenous infusions of remdesivir were ineffective, and the patient died of sepsis on the 26th day after admission. We demonstrated that ANE may occur even in patients infected with Omicron strains and speculated that the pathogenesis in this case might be associated with intrathecal IL-8 production by microglial activation.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Unfractionated Heparin Safety in COVID-19: Incidence and Risks of Bleeding Complications in Japan.

AIM: Several studies have shown the efficacy and safety of low-molecular-weight heparin use in coronavirus disease 2019 (COVID-19), but that of unfractionated heparin (UFH) has not been investigated. We investigated the prevalence of bleeding complications during UFH administration, its impact on mortality, and the risk factors of bleeding outcomes associated with UFH. METHODS: This retrospective cohort study was conducted at a single-center tertiary care hospital, including hospitalized patients with COVID-19. The primary outcomes were measured as the prevalence of bleeding complications during hospitalization, and the secondary outcomes were thromboembolic events and 60-day mortality rates. Logistic regression analysis and propensity score matching were used to assess risk factors for bleeding complications and their impact on mortality. RESULTS: Among 1035 included patients, 516 patients were treated with UFH. Twelve (2.3%) patients in the UFH group experienced major bleeding. The prevalence of major bleeding in patients treated with therapeutic-dose UFH was 9.2%. Logistic regression analysis showed that age ≥ 60 years (adjusted odds ratio [aOR], 3.89; 95% confidence interval [CI], 1.01-15.0; P＜.05) and COVID-19 severity (aOR, 35.9; 95% CI, 4.57-282; P ＜.05) were associated with major bleeding complications. After propensity score matching, 11 major and 11 non-major bleeding cases (including minor bleeding) were matched. The 60-day cumulative mortality rate between the two groups did not differ significantly (P=.13, log-rank test). CONCLUSIONS: The incidence of major bleeding in COVID-19 patients using therapeutic-dose UFH was relatively high. Critical COVID-19 and older age were risk factors for bleeding complications.

A Case of Anti-IgLON5 Disease Showing an Improvement in Dysautonomia, Including Vocal Cord Palsy, via Combined Immunotherapy.

Anti-IgLON5 disease shows various neurological manifestations, of which dysautonomia is one of the major symptoms and is rarely improved by immunotherapy. We herein report a patient with anti-IgLON5 disease who showed several autonomic failures, including vocal cord palsy for four months. The patient presented with cognitive impairments, bulbar symptoms accompanied by myorhythmia in the pharynx and tongue, cerebellar ataxia with tremor, motor neuron symptoms in the limbs, gastrointestinal dysfunction, orthostatic hypotension, non-rapid eye movement sleep disorder on polysomnography, and severe vocal cord palsy. Combined immunotherapy improved his symptoms, including vocal cord palsy, suggesting that combined immunotherapy might improve dysautonomia in anti-IgLON5 disease.

[Clinical features and pathogenesis of Glial fibrillary acidic protein (GFAP) antibody-associated disorders].

Glial fibrillary acidic protein (GFAP) antibody-associated disorders (AD) were recently proposed to be immune-mediated neurological disorders. The pathogenesis of GFAP antibody-AD is poorly understood. Pathologically, there is a marked infiltration of large numbers of lymphocytes, including CD8+ and CD4+ T cells, into the meningeal and brain parenchyma, especially around the perivascular areas. GFAP-specific cytotoxic T cells are considered to be the effector cells of GFAP antibody-AD. The common phenotype of GFAP antibody-AD includes meningoencephalitis with or without myelitis. During the clinical disease course, patients present with consciousness disturbances, urinary dysfunction, movement disorders, meningeal irritation, and cognitive dysfunction. The detection of GFAP antibodies in the cerebrospinal fluid (CSF) by cell-based assay is essential for a diagnosis of GFAP antibody-AD. The CSF can be examined for lymphocyte-predominant pleocytosis and elevated protein levels. Brain linear perivascular radial enhancement patterns are observed in about half of GFAP antibody-AD patients. Spinal cord magnetic resonance imaging is used to detect longitudinal extensive spinal cord lesions. Although corticosteroid therapy is generally effective, some patients have a poor prognosis and relapse.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Following SARS-CoV-2 Infection.

We herein report the first case of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy after coronavirus disease 2019 (COVID-19). A 23-year-old man experienced fatigue, a fever, and headache 14 days after the resolution of COVID-19. He was severely disoriented and admitted to our hospital. On admission, the patient exhibited disorientation, headache, neck stiffness, myoclonus of both upper limbs, dysuria, and pyramidal signs. A blood examination revealed hyponatremia, and a cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis. The CSF test results were positive for anti-GFAPα antibodies. The patient was treated with methylprednisolone pulse therapy, followed by oral prednisolone, which quickly ameliorated his neurological abnormalities.

A retrospective study of autoimmune cerebellar ataxia over a 20-year period in a single institution.

BACKGROUND: It is important to differentiate autoimmune cerebellar ataxia (ACA) from neurodegenerative CA, but this is sometimes difficult. We performed a retrospective study in a single institution in Japan over a 20-year period to reveal the clinical features of ACA. METHODS: Patients with CA as the primary neurological symptom were enrolled from those admitted to the Department of Neurology, Hokkaido University Hospital between April 2002 and March 2022. ACA was diagnosed retrospectively according to the following criteria: (1) CA being the predominant symptom; (2) identification of cancer within 2 years of onset; (3) improvement in cerebellar symptoms following immunotherapy; and (4) ruling out alternative causes of CA. Patients fulfilling criteria (1), (2), and (4) were classified as paraneoplastic cerebellar degeneration (PCD), while those fulfilling (1), (3), and (4) were classified as non-PCD and enrolled as patients with ACA. Neurodegenerative diseases, e.g., multiple system atrophy (MSA), were confirmed retrospectively based on generally used diagnostic criteria and enrolled. Furthermore, the ACA diagnostic criteria proposed by Dalmau and Graus were applied retrospectively to the ACA patients to examine the validity of the diagnoses. RESULTS: Among the 243 patients with CA, 13 were enrolled as ACA; five were PCD and eight were non-PCD. Eight of these cases met the proposed diagnostic criteria by Dalmau and Graus. MSA was the most prevalent disease among CA patients, with 93 cases. The incidence of cerebellar atrophy was significantly lower in ACA (3/13) than in MSA (92/92). Cerebrospinal fluid (CSF) pleocytosis was significantly more frequent in ACA than in MSA (4/13 vs. 2/55, respectively). However, there was no significant difference in the presence of oligoclonal bands, increased protein in CSF, and laterality differences in ataxia. CONCLUSION: ACA was present in ~ 5% of Japanese CA patients. The absence of cerebellar atrophy, despite the presence of CA, strongly supports ACA over MSA. While CSF pleocytosis was observed more often in ACA, the positivity rate was only ~ 30%. Since ACA is treatable, further studies are needed to identify additional clinical features and accurate diagnostic biomarkers.

Reverse Shock Index multiplied by Glasgow Coma Scale score as a point-of-care severity assessment for initial trauma management: A nationwide cohort study.

BACKGROUND: Severe trauma patients often require emergent interventions, such as massive transfusion, resuscitative procedures, and surgical procedures, and consume considerable human and medical resources. However, few practical indices can be easily used for emergent interventions. In recent years, it has become clear that rSIG (Reverse Shock Index multiplied by Glasgow Coma Scale [GCS] score), which can be easily calculated from vital signs, is a promising predictor of mortality. However, it is unclear whether rSIG is useful for emergent interventions. METHODS: Data collected by the Japan Trauma Data Bank for adult patients admitted directly from the scene of trauma between April 2019 and December 2020 were analysed. The outcomes were massive transfusion, resuscitative procedures, surgical procedures and emergent interventions. Emergent interventions were defined as the composite outcome of massive transfusion, resuscitative procedures, and surgical procedures. The ability of rSIG to predict massive transfusion was compared with that of the ABC score and FASILA score by receiver-operating characteristic curve analysis. The ability of rSIG to predict resuscitative and surgical procedures was compared with that of the Shock Index (SI), GCS, Triage Revised Trauma score (T-RTS), and Previous Simple Prediction (PSP) score. The ability of rSIG to predict emergent interventions was compared with that of T-RTS, PSP, ABC, and FASILA. In addition to rSIG, rSIM (Reverse Shock Index multiplied by best motor response score) was also analysed as a supplement. RESULTS: The study included 32,201 patients, 6,371 of whom required emergent interventions. The area under the receiver-operating characteristic curve (AUROC) for massive transfusion was highest for rSIG (0.846 [95 % confidence interval 0.832-0.859]) and significantly higher for rSIG than for rSIM, ABC and FASILA (all p < 0.0001). AUROCs for resuscitative and surgical procedures were highest for rSIG (0.777 [0.769-0.785] and 0.731 [0.720-0.741], respectively) and significantly higher than those for rSIM, SI, GCS, T-RTS, and PSP (all p < 0.0001). The AUROC for emergent interventions was highest for rSIG (0.760 [0.753-0.768]) and significantly higher for rSIG than for rSIM, T-RTS, PSP, ABC, or FASILA (all p < 0.0001). CONCLUSIONS: rSIG is a simple and effective point-of-care predictor of emergent interventions during initial management of trauma.

Emergence of quasi-1D spin-polarized states in ultrathin Bi films on InAs(111)A for spintronics applications.

The discovery, characterization, and control of heavy-fermion low-dimensional materials are central to nanoscience since quantum phenomena acquire an exotic and highly tunable character. In this work, through a variety of comprehensive experimental and theoretical techniques, it was observed and predicted that the synthesis of ultrathin Bi films on the InAs(111)A surface produces quasi-one-dimensional spin-polarized states, providing a platform for the realization of a unique spin-transport regime in the system. Scanning tunneling microscopy and low-energy electron diffraction measurements revealed that the InAs(111)A substrate facilitates the formation of the Bi-dimer phase of 2√3 × 3 periodicity with an admixture of the Bi-bilayer phase under submonolayer Bi deposition. X-ray photoelectron spectroscopy (XPS) measurements have shown the chemical stability of the Bi-induced phases, while spin and angle resolved photoemission spectroscopy (SARPES) observations combined with state-of-the-art DFT calculations have revealed that the electronic spectrum of the Bi-dimer phase holds a quasi-1D hole-like spin-split state at the Fermi level with advanced spin texture, whereas the Bi-bilayer phase demonstrates metallic states with large Rashba spin-splitting. The band structure of the Bi/InAs(111)A interface is discovered to hold great potential as a high-performance spintronics material fabricated in the ultimate two-dimensional limit.

Measuring auditory event-related potentials at the external ear canal: A demonstrative study using a new electrode and error-feedback paradigm.

Although ear canal electroencephalogram (EEG) recording has received interest from basic and applied research communities, evidence on how it can be implemented in practice is limited. The present study involving eight male participants including the authors presents the utility of our ear canal electrode and method by demonstrating both comparability of ear canal EEG to those at nearby sites and distinctiveness that ear canal event-related potentials (ERPs) could have. For this purpose, we used the balanced noncephalic electrode reference and an experimental paradigm with an error-feedback sound. Clear auditory ERPs were detected at the ear canal sites with a sufficiently low noise level comparable with those at conventional sites. The N1c, a temporal maximum subcomponent, spread over the bilateral temporal sites, including the ear canals and earlobes. While consecutive signals are generally highly similar between the ear canal and the earlobe, the N1c was larger at the ear canal than the earlobe, as demonstrated by the conventional frequentist and the hierarchical Bayesian modelling approaches. Although an evident caveat is that our sample was limited in terms of size and sex, the general capability indicates that the structure of our ear canal electrode provides EEG measurement that can be used in basic and applied settings. Our experimental method can also be an ERP-based test that conveniently assesses the capability of existing and future ear canal electrodes. The distinctive nature of the ERPs to the error-feedback sound may be utilized to examine the basic aspects of auditory ERPs and to test the processes involved in feedback-guided behaviour of participants.

The reverse shock index multiplied by the Glasgow Coma Scale score can predict the need for initial resuscitation in patients suspected of sepsis.

For patients suspected of sepsis, early recognition of the need for initial resuscitation is key in management. This study evaluated the ability of a modified shock index - the reverse shock index multiplied by the Glasgow Coma Scale score (rSIG) - to predict the need for initial resuscitation in patients with sepsis. This retrospective study involved adults with infection who were admitted to a Japanese tertiary care hospital from an emergency department between January and November 2020. The rSIG, modified Early Warning Score (MEWS), quick Sequential Organ Failure Assessment (qSOFA), and original shock index (SI) values were recorded using initial vital signs. The primary outcome was the area under the receiver-operating characteristic curve (AUROC) for the composite outcome consisting of vasopressor use, mechanical ventilation, and 72-h mortality. Secondary outcomes were the AUROCs for each component of the primary outcome and 28-day mortality. As a result, the primary outcome was met by 67 of the 724 patients (9%). The AUROC was significantly higher for the rSIG than for the other tools (rSIG 0.84 [0.78 - 0.88]; MEWS 0.78 [0.71 - 0.84]; qSOFA 0.72 [0.65 - 0.79]; SI 0.80 [0.74 - 0.85]). Compared with MEWS and qSOFA, the rSIG also had a higher AUROC for vasopressor use and mechanical ventilation, but not for 72-h mortality or in-hospital mortality. The rSIG could be a simple and reliable predictor of the need for initial resuscitation in patients suspected of sepsis.

Anti-N-methyl-d-aspartate receptor encephalitis preceded by meningitis lasting up to 60 days.

Long-lasting meningitis complicated by N-methyl-d-aspartate receptor (NMDAR) encephalitis has not been discussed widely in the literature. Herein, we present two cases of anti-NMDAR encephalitis preceded by meningitis. The patients had 60- and 22-day periods of preceding meningitis, which improved with intravenous methylprednisolone and plasmapheresis. No tumors were detected in either of the patients. Although meningitis preceding anti-NMDAR encephalitis is not rare, our patients, especially those who had it for a duration of 60 days, had longer durations of meningitis. This manuscript foregrounds that anti-NMDAR encephalitis might be included in the differential diagnosis of long-lasting meningitis.

[Autoimmune encephalitis and paraneoplastic neurological syndromes presenting atypical parkinsonism: a scoping review].

Recent studies have demonstrated that atypical parkinsonism can be presented in autoimmune encephalitis and paraneoplastic neurological syndromes. However, it is unclear which anti-neural antibodies are involved and when these diseases should be suspected. To address these clinical questions, we conducted a scoping review and analyzed 38 articles. The literature shows that many anti-neural antibodies, including unknown ones, have been reported in progressive supranuclear palsy, corticobasal syndrome, and multiple system atrophy. Moreover, the following symptoms and signs suggest the possibility of autoimmune encephalitis and paraneoplastic neurological syndromes: early onset, acute or subacute progression, the presence of a neoplasm, significant weight loss, abnormal cerebrospinal fluid findings, the absence of typical brain magnetic resonance imaging findings, and the existence of atypical physical examination signs.

[Autoimmune Parkinsonism and Related Disorders].

Autoimmune parkinsonism and related disorders are immune-mediated central nervous system disorders that present with extrapyramidal signs such as involuntary movements, hypokinesia, and rigidity. Patients commonly have neurological signs other than the extrapyramidal signs. Some patients show a slowly progressive clinical course with neurological symptoms resembling those of neurodegenerative disorders. Occasionally, specific autoantibodies targeting the basal ganglia or related sites are detected in their serum or cerebrospinal fluid. These autoantibodies are important diagnostic markers for these disorders.