[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.

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.

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.

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 glial fibrillary acidic protein astrocytopathy associated with breast cancer: a case report.

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is an autoimmune inflammatory central nervous system disorder characterized by the detection of autoantibodies that recognize GFAP in CSF. The pathogenesis of GFAP-A is poorly understood. Some patients had a neoplasm detected and GFAP expressed by neoplasms is plausible as immunogen triggering paraneoplastic neurological autoimmunity. CASE PRESENTATION: We report a case of 76-year-old female patient with GFAP-A complicated with breast cancer. She presented with altered consciousness, nuchal rigidity, speech disturbances, and weakness. Her clinical symptoms were improved by immunotherapy and cancer treatments. Immunohistochemical analysis showed that the restricted tumor expressed GFAP. The infiltration of CD3 + T cells were observed in the peritumoral and intratumoral areas. The most common infiltrating lymphocytes were CD8 + T cells. CD4 + T cells and CD20 + B cells were also observed in the predominant peritumoral area. CONCLUSIONS: These results suggest that GFAP-A may occur in a paraneoplastic neurological syndrome associated with breast cancer.

Possible Chronic Graft-versus-host Disease in the Central Nervous System Manifesting as Cerebellar Ataxia after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia.

A 44-year-old woman was admitted to our hospital with a fever, dizziness, and gait disturbance after undergoing allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia followed by graft-versus-host disease. She presented with cerebellar ataxia, nystagmus, and numbness of the lower extremities. Brain magnetic resonance imaging and perfusion scintigraphy showed progressive cerebellar involvement. Cerebrospinal fluid tests showed mildly elevated protein and IgG levels without pleocytosis. Anti-ganglioside antibodies were detected, but their levels did not follow the patient's clinical course. The patient did not respond sufficiently to steroids or other immunotherapies. We herein report the clinical characteristics of this case and a literature review.

[Anti-NMDAR Encephalitis with Poor Recovery on Steroid Pulse and IVIg: Second-Line Immunotherapies and Prediction of Prognosis].

Most patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis improve slowly with first-line immunotherapies (steroids, intravenous immunoglobulins, or plasma exchange) and, if necessary, tumor removal. However, the remaining refractory patients require second-line immunotherapies, such as rituximab or cyclophosphamide. We discuss the identification of patients who should receive second-line immunotherapies and the timing of the transition to these immunotherapies based on a review of the literature and our treatment experience.

Autopsy findings of a patient with severe COVID-19 treated with long-term extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) therapy in patients with coronavirus disease 2019 (COVID-19) has a low frequency of use, and thus pathological findings in such patients are valuable. In this case report, a 62-year-old man with a history of hypertension presented with a runny nose. After an at-home COVID-19 positive test, he developed dyspnea and fever. Once admitted to our hospital, his oxygenation worsened, and ECMO was initiated. He died from respiratory failure 69 days after ECMO induction. Macroscopically, the lungs gained mass, were partially consolidated, and were airless. Histological analysis revealed diffuse bronchial epithelial metaplasia and adenoid metaplasia in the alveolar epithelium. Although the lung parenchyma was partially preserved, there was organizing and fibrosis that filled pulmonary alveolus due to COVID-19 and changes resulting from disuse and long-term ECMO.

Smoking and severe illness in hospitalized COVID-19 patients in Japan.

BACKGROUND: The aim of this study was to identify associations between smoking status and the severity of COVID-19, using a large-scale data registry of hospitalized COVID-19 patients in Japan (COVIREGI-JP), and to explore the reasons for the inconsistent results previously reported on this subject. METHODS: The analysis included 17 666 COVID-19 inpatients aged 20-89 years (10 250 men and 7416 women). We graded the severity of COVID-19 (grades 0 to 5) according to the most intensive treatment required during hospitalization. The smoking status of severe grades 3/4/5 (invasive mechanical ventilation/extracorporeal membrane oxygenation/death) and separately of grade 5 (death) were compared with that of grade 0 (no oxygen, reference group) using multiple logistic regression. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and other factors considering the potential intermediate effects of comorbidities. RESULTS: Among men, former smoking significantly increased the risk of grade 3/4/5 and grade 5, using grade 0 as a reference group, with age- and admission-date-adjusted ORs (95% CI) of 1.51 (1.18-1.93) and 1.65 (1.22-2.24), respectively. An additional adjustment for comorbidities weakened the ORs. Similar results were seen for women. Current smoking did not significantly increase the risk of grade 3/4/5 and grade 5 in either sex. CONCLUSIONS: The severity of COVID-19 was not associated with current or former smoking per se but with the comorbidities caused by smoking. Thus, smoking cessation is likely to be a key factor for preventing smoking-related disease and hence for reducing the risk of severe COVID-19.

The Usefulness of Swallowing Pressure Assessment in the Identification of Mild Pharyngeal Weakness of Myasthenia Gravis: A Case Report.

Despite the clinical impact of dysphagia in myasthenia gravis (MG), a standard protocol for diagnosing dysphagia reliably has not yet been established. High-resolution manometry (HRM) provides precise information on pharyngeal pressure. We hypothesized that swallowing pressure assessment using HRM during the edrophonium chloride (EC) test could identify mild bulbar symptoms with no abnormalities on videoendoscopic (VE) and videofluorographic (VF) examination of swallowing, and we tested this hypothesis on a 72-year-old female patient diagnosed with ocular MG who developed slight pharyngeal discomfort over 3 months. The patient's ocular symptoms were stable with pyridostigmine medication. VE and VF revealed no abnormalities. The swallowing pressure along the pharynx was measured using HRM during the EC test. HRM parameters, including velopharyngeal contractile integral and meso-hypopharyngeal contractile integral, were evaluated. These parameters were assessed for three swallows using 3 mL of water. After EC injection, the values of the velopharyngeal contractile integral (78.0 ± 5.4 vs. 134.7 ± 1.3 mm Hg cm·s) and the meso-hypopharyngeal contractile integral were both higher (130.6 ± 1.5 vs. 284.2 ± 11.9 mm Hg cm·s) than those observed before EC injection. Chest computed tomography revealed a thymoma that had not been observed in previous examinations. The patient was diagnosed with thymoma-associated MG. Intravenous immunoglobulin therapy improved the mild dysphagia. We concluded that swallowing pressure assessment during the EC test may be helpful in identifying mild bulbar symptoms in patients with MG.

Autoimmune glial fibrillary acidic protein astrocytopathy resembling isolated central nervous system lymphomatoid granulomatosis.

We report two patients with meningoencephalomyelitis without evidence of extra central nervous system (CNS) involvement. Brain MRI showed linear perivascular radial gadolinium enhancement patterns and spinal cord MRI showed longitudinal extensive T2-hyperintensity lesions. Pathological findings from brain biopsies were angiocentric T-cell predominant lymphoid infiltrates that lacked Epstein-Barr virus-positive atypical B cells. The patients were initially suspected to have isolated CNS-lymphomatoid granulomatosis (LYG). Thereafter, glial fibrillary acidic protein (GFAP)-immunoglobulin G were detected in their cerebrospinal fluid. This finding suggested autoimmune GFAP astrocytopathy. We speculate there is a link between isolated CNS-LYG and autoimmune GFAP astrocytopathy.

[Longitudinally Extensive Transverse Myelitis Caused by Granulomatous Primary Central Nervous System Vasculitis with Characteristic Brain Magnetic Resonance Image: A Case Report].

We report a case of primary central nervous system vasculitis (PCNSV) with longitudinally extensive transverse myelitis. A 47-year-old woman presented with malaise, progressive cognitive impairment, and lower limb spasticity. Diffuse hyperintense areas in the deep cerebral white matter on the diffusion-weighted image and T2-weighted images were observed during brain magnetic resonance imaging. Gadolinium-enhanced T1-weighted images showed multiple linear enhancements. A sagittal T2-weighted image displayed a longitudinal extensive lesion of transverse myelitis in the spinal column from the upper cervical (C7) to the thoracic region (Th12). On brain biopsy, the patient was diagnosed as having granulomatous primary angiitis of the central nervous system (PCNSV). This case suggests that PCNSV could show longitudinally extensive transverse myelitis. (Received 14 January, 2021; Accepted 18 February, 2021; Published 1 August, 2021).

[Differentiating Between HTLV-1 Associated Myelopathy and Amyotrophic Lateral Sclerosis: A Case Report].

We present the case of a 72-year-old woman with slowly progressive spastic paraplegia and painful muscle spasms of the lower limbs. Spastic paraplegia began in the left lower extremity and extended to the right lower extremity 4 months later. We considered the diagnosis of amyotrophic lateral sclerosis (ALS) because of the left-dominant spastic paraplegia of bilateral lower limbs and due to the presence of fasciculation, hyperreflexias, and pathological reflexes. However, cerebrospinal fluid (CSF) examination revealed that cell count and protein values were increased. The patient also had an increased titer of anti-HTLV-1 antibodies in serum and CSF and was diagnosed with HTLV-1 associated myelopathy (HAM). She was treated with steroids, and her symptoms improved. Distinguishing HAM from ALS may be difficult because HAM may present with unilateral spastic paralysis and may be accompanied by fasciculation. Careful and accurate evaluation is necessitated to differentiate between these conditions for a conclusive diagnosis. (Received 1 March, 2021; Accepted 26 April, 2021; Published 1 September, 2021).

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for status epilepticus: study protocol for a multicenter non-inferiority designed randomized control trial.

BACKGROUND: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE. METHODS: This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is "continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance." In both groups, diazepam is initially administered at 1-20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000-3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes. DISCUSSION: The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031190160 . Registered on December 13, 2019.

[Paraneoplastic Disorders of the Central Nervous System].

Paraneoplastic neurological syndromes (PNS) are neurological disorders that occur as indirect immune-mediated responses to malignancies. The increased number of patients with PNS correlates with the discovery of an increasing number of novel autoantibodies associated with PNS. The use of immune checkpoint inhibitors that have expanded the range of cancers strongly associated with PNS has likely increased the frequency of PNS diagnoses. This article presents an overview of the pathophysiology, diagnosis, therapy, and prognosis of PNS.

Self-remitting Elevation of Adenosine Deaminase Levels in the Cerebrospinal Fluid with Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: A Case Report and Review of the Literature.

A 29-year-old man presented with a high-grade fever, headache, and urinary retention, in addition to meningeal irritation and myoclonus in his upper extremities. A cerebrospinal fluid (CSF) examination showed pleocytosis and high adenosine deaminase (ADA) levels with no evidence of bacterial infection, including Mycobacterium tuberculosis. T2-weighted brain magnetic resonance imaging showed transient hyper-intensity lesions at the splenium of the corpus callosum (SCC), bilateral putamen, and pons during the course of the disease. The CSF was positive for anti-glial fibrillary acidic protein (GFAP) antibodies. He was diagnosed with autoimmune GFAP astrocytopathy. The present case shows that the combination of an elevated ADA level in the CSF and reversible T2-weighted hyper-intensity on the SCC supports the diagnosis of autoimmune GFAP encephalopathy.

Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding: validation of endoscopy guidelines.

BACKGROUND: It remains unclear whether type of antiplatelet (AP) therapy, AP combination therapy, and AP continuing or switching strategy affect the risk of post-polypectomy bleeding (PPB). In this study, we sought to elucidate this risk. METHODS: We analyzed 1050 patients who underwent colonoscopic polypectomy: 525 AP users and 525 controls matched for age, sex, comorbidities, concomitant non-steroidal anti-inflammatory drugs use, and polyp characteristics who did not receive antithrombotics. PPB risk was evaluated by AP number, type, and continuing or switching strategies during the peri-endoscopic period. RESULTS: In multivariate analysis, bleeding risk increased significantly as the number of AP agents used increased (monotherapy, adjusted odds ratio [aOR], 3.7; dual antiplatelet therapy (DAPT), 4.6; triple antiplatelet therapy (TAPT), 11.1) compared with controls. With monotherapy, significantly increased PPB risk was found for aspirin (aOR 4.3), thienopyridine (aOR 6.3), and cilostazol (aOR 5.9), but not for eicosapentaenoic acid or other APs (beraprost, limaprost, sarpogrelate, dilazep, or dipyridamole). With DAPT, significantly increased PPB risk was found for combination aspirin plus cilostazol, but not aspirin plus other APs. Bleeding rates for continuing monotherapy were 4.3% for aspirin and 0% for thienopyridine, cilostazol, and other APs, respectively. CONCLUSIONS: Analysis of this large polypectomy dataset showed that the use of low-dose aspirin, thienopyridine, or cilostazol and a combination of these is associated with increased PPB risk. Although PPB risk was high with DAPT or TAPT, PPB rate in any antiplatelet monotherapy even with a continuing strategy was low at < 5%.

Clinicopathological findings of a mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT-ND1.

We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.