[LEMS: Clinical Significance of Pathogenic Autoantibodies].

Approximately 90% of patients with Lambert-Eaton myasthenic syndrome (LEMS) are positive for P/Q-type voltage-gated calcium channels (VGCCs) antibodies, and can be broadly divided into two groups: paraneoplastic, especially with small cell lung carcinoma and, non-paraneoplastic, without cancer. Under the Japanese LEMS diagnostic criteria 2022, abnormal electrophysiological results is mandatory for diagnosis in addition to muscle weakness. Contrastingly, autoantibodies are useful for diagnosing the etiology and influence treatment strategies. We comprehensively reviewed the MG/LEMS 2022 practice guidelines. Moreover, we presented a case of PCD without LEMS that was positive for P/Q-type VGCCs antibodies_and discussed the clinical significance of the autoantibodies.

Paraneoplastic Cerebellar Degeneration With P/Q-VGCC vs Yo Autoantibodies.

BACKGROUND AND OBJECTIVES: Paraneoplastic cerebellar degeneration (PCD) is characterized by a widespread loss of Purkinje cells (PCs) and may be associated with autoantibodies against intracellular antigens such as Yo or cell surface neuronal antigens such as the P/Q-type voltage-gated calcium channel (P/Q-VGCC). Although the intracellular location of the target antigen in anti-Yo-PCD supports a T cell-mediated pathology, the immune mechanisms in anti-P/Q-VGCC-PCD remain unclear. In this study, we compare neuropathologic characteristics of PCD with anti-P/Q-VGCC and anti-Yo autoantibodies in an archival autopsy cohort. METHODS: We performed neuropathology, immunohistochemistry, and multiplex immunofluorescence on formalin-fixed and paraffin-embedded brain tissue of 1 anti-P/Q-VGCC, 2 anti-Yo-PCD autopsy cases and controls. RESULTS: Anti-Yo-PCD revealed a diffuse and widespread PC loss together with microglial nodules with pSTAT1+ and CD8+granzymeB+ T cells and neuronal upregulation of major histocompatibility complex (MHC) Class I molecules. Some neurons showed a cytoplasmic immunoglobulin G (IgG) staining. In contrast, PC loss in anti-P/Q-VGCC-PCD was focal and predominantly affected the upper vermis, whereas caudal regions and lateral hemispheres were spared. Inflammation was characterized by scattered CD8+ T cells, single CD20+/CD79a+ B/plasma cells, and an IgG staining of the neuropil in the molecular layer of the cerebellar cortex and neuronal cytoplasms. No complement deposition or MHC-I upregulation was detected. Moreover, synaptophysin was reduced, and neuronal P/Q-VGCC was downregulated. In affected areas, axonal spheroids and the accumulation of amyloid precursor protein and glucose-regulated protein 78 in PCs indicate endoplasmatic reticulum stress and impairment of axonal transport. In both PCD types, calbindin expression was reduced or lost in the remaining PCs. DISCUSSION: Anti-Yo-PCD showed characteristic features of a T cell-mediated pathology, whereas this was not observed in 1 case of anti-P/Q-VGCC-PCD. Our findings support a pathogenic role of anti-P/Q-VGCC autoantibodies in causing neuronal dysfunction, probably due to altered synaptic transmission resulting in calcium dysregulation and subsequent PC death. Because disease progression may lead to irreversible PC loss, anti-P/Q-VGCC-PCD patients could benefit from early oncologic and immunologic therapies.

Neuropathology of SCA34 showing widespread oligodendroglial pathology with vacuolar white matter degeneration: a case study.

Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant inherited ataxia due to mutations in ELOVL4, which encodes one of the very long-chain fatty acid elongases. SCA38, another spinocerebellar ataxia, is caused by mutations in ELOVL5, a gene encoding another elongase. However, there have been no previous studies describing the neuropathology of either SCA34 or 38. This report describes the neuropathological findings of an 83-year-old man with SCA34 carrying a pathological ELOVL4 mutation (NM_022726, c.736T>G, p.W246G). Macroscopic findings include atrophies in the pontine base, cerebellum, and cerebral cortices. Microscopically, marked neuronal and pontocerebellar fiber loss was observed in the pontine base. In addition, in the pontine base, accumulation of CD68-positive macrophages laden with periodic acid-Schiff (PAS)-positive material was observed. Many vacuolar lesions were found in the white matter of the cerebral hemispheres and, to a lesser extent, in the brainstem and spinal cord white matter. Immunohistological examination and ultrastructural observations with an electron microscope suggest that these vacuolar lesions are remnants of degenerated oligodendrocytes. Electron microscopy also revealed myelin sheath destruction. Unexpectedly, aggregation of the four-repeat tau was observed in a spatial pattern reminiscent of progressive supranuclear palsy. The tau lesions included glial fibrillary tangles resembling tuft-shaped astrocytes and neurofibrillary tangles and pretangles. This is the first report to illustrate that a heterozygous missense mutation in ELOVL4 leads to neuronal loss accompanied by macrophages laden with PAS-positive material in the pontine base and oligodendroglial degeneration leading to widespread vacuoles in the white matter in SCA34.

Intracranial dural arteriovenous fistula mimicking neuromyelitis optica spectrum disorder: A case report.

Neuromyelitis optica spectrum disorder (NMOSD) is an immune-mediated disorder. It often develops acute myelopathy due to longitudinally extensive transverse myelitis (LETM), although other disorders can cause an LETM-like lesion. Here, we report a 76-year-old patient presenting with acute-onset, progressive myelopathy, which proved to be caused by an intracranial dural arteriovenus fistula (dAVF). Magnetic resonance imaging (MRI) revealed a longitudinally extensive spinal cord lesion, which was further extended rostrally to the medulla. Although cord surface flow voids were absent on T2-weighted MRI, abnormally congested peri-spinal veins showed up with gadolinium contrast. Angiography confirmed dAVF in the posterior fossa, which drained into the peri-spinal veins. Intracranial dAVF should be considered as a differential diagnosis of NMOSD, because it is not immunologically but is surgically treatable.

Self-remitting cerebral cortical encephalitis associated with myelin oligodendrocyte glycoprotein antibody mimicking acute viral encephalitis: A case report.

A 22-year-old woman acutely developed recurrent convulsive seizures followed by fever and headache. Cerebrospinal fluid study showed leukocytosis without hypoglycorrhachia. These clinical features suggested acute viral or aseptic encephalitis. The patient was treated only with an antiviral agent and improved immediately with good prognosis. Afterwards, the characteristic brain MRI findings required us to check the patient's serum, and the final diagnosis of myelin oligodendrocyte glycoprotein (MOG) antibody-positive cerebral cortical encephalitis (CCE) was confirmed. Most previously reported cases with MOG antibody-positive CCE clinically showed fever and/or headache, and some were initially misdiagnosed of having central nervous system infection. All previously reported cases were treated with immunotherapy. However, our case showed the very benign clinical course and improved rapidly without any immunotherapy. We should be reminded that MOG-antibody-positive CCE could be self-remitting and mimic acute viral or aseptic encephalitis. In addition, the characteristic neuroradiological findings could be an important clue to the correct diagnosis of CCE.

Intrathecal IgG Synthesis and Persistent Inflammation Are Associated with White Matter Lesions in HIV-negative Patients with Cryptococcal Meningoencephalitis.

Objective Cryptococcal meningoencephalitis (CM) causes significant morbidity and mortality in human immunodeficiency virus (HIV)-negative and HIV-positive populations. White matter lesions (WMLs) have been reported in both populations of CM patients; however, the mechanisms underlying WML formation remain unknown. We herein report the relationship between the intrathecal immune response and the development of WMLs in HIV-negative patients with CM. Methods Eleven consecutive HIV-negative patients with CM who presented at one of three emergency hospitals in Japan from April 2001 to March 2018 were enrolled. For all patients, we retrospectively assessed the relationships between clinical and laboratory information and the presence of WMLs. Results At presentation, 6 patients had WMLs on magnetic resonance imaging (MRI). The cerebrospinal fluid immunoglobulin G (CSF IgG) index was significantly higher in the patients with WMLs than in those without WMLs (mean, 1.34 vs. 0.70, p=0.017). The time from the symptom onset to initial neuroimaging was also significantly longer in the patients with WMLs than in those without WMLs (median, 31.5 vs. 7.0 days; p=0.008). The clinical outcome was comparable among the patients with and without WMLs. Conclusion In HIV-negative patients with CM, a persistent, aberrant immune response to Cryptococcus, such as intrathecal IgG synthesis, may induce WML formation.

[Paraneoplastic Cerebellar Degeneration with Lambert-Eaton Myasthenic Syndrome: A Report of an Effectively Treated Case and Systematic Review of Japanese Cases].

A 63-year-old female who developed dizziness, diplopia and subsequent gait disturbance from September X-1 year was analyzed. The first neurological findings in May X year revealed cerebellar ataxia, weakness in the proximal limbs, decreased tendon reflexes, and autonomic symptoms (ADL:mRS 3). Furthermore, an incremental phenomenon was observed in the repetitive nerve stimulation test, and she was diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) based on the serum P/Q-type calcium channel (VGCC) antibody positivity. In addition, small cell lung cancer was detected by chest CT and bronchoscopy, and her cerebellar ataxia was diagnosed as paraneoplastic cerebellar degeneration (PCD). Therefore, the patient underwent chemotherapy and radiotherapy from June in X year. Six months after initiation of treatment, her cerebellar ataxia had almost disappeared and she could walk without assistance (ADL:mRS 1). The P/Q-type VGCC antibodies were also negative at that time. Cases wherein cerebellar ataxia resolved almost completely in parallel with disappearance of the serum P/Q-type VGCC antibodies are of great interest. We conducted a systematic literature review of PCD-LEMS cases in Japan reported since P/Q-type calcium channel antibody measurement was reported in 1995. As a result, 13 cases (including our study) that concurrently displayed cerebellar ataxia and LEMS were selected. The average age of the 13 patients (10 males and 3 females) was 61.5 years. Small cell carcinoma was complicated in 11 patients (10 in the lung and 1 in the oropharynx); in the other 2 patients, cancer was not found at the time of reporting (the observation period was as short as 1-2 months). The time from onset to treatment ranged between 1 week and 10 months. While 1 of the 13 patients developed cerebellar ataxia during the subsequent course of the treatment, the remaining 12 had already developed cerebellar ataxia and LEMS symptoms, although their main neurologic finding was cerebellar ataxia and they were subsequently diagnosed with LEMS after electrophysiological testing and autoantibody detection. Small cell carcinoma was found in 11 patients. We define the pathology following such a certain clinical course as PCD-LEMS. The P/Q-type VGCC antibodies were positive in 11 of the 13 cases, although their antibody titers were not necessarily very high. Treatment for the associated small cell carcinoma might have improved the neurological findings in 9 of the 11 PCD-LEMS patients. The P/Q-type VGCC antibodies were measured before and after the treatment. The PCD-LEMS symptoms improved in all patients and their antibody titers decreased. These findings indicate that P/Q-type VGCC antibodies are involved in the pathology of PCD-LEMS. Appropriate and timely treatment, at least in PCD-LEMS patients in Japan, that actively treats any associated cancer can be expected to improve not only life prognosis but also cerebellar ataxia. (Received October 15, 2018; Accepted November 5, 2018; Published January 1, 2019).

A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34.

IMPORTANCE: Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified. OBJECTIVE: To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTS: Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURES: Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing. RESULTS: Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCE: Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

CADASIL with a novel NOTCH3 mutation (Cys478Tyr).

Recently, an increasing number of NOTCH3 mutations have been described to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here, we report 2 CADASIL patients from a Japanese family, who were found to possess a novel NOTCH3 mutation. The proband only had chronic headache, and her mother had previously suffered a minor stroke. Although the patients' clinical symptoms were mild, their distinctive magnetic resonance imaging (MRI) features suggested CADASIL. Genetic analysis revealed that both patients had a novel heterozygous NOTCH3 mutation (p.Cys478Tyr) leading to stereotypical cysteine loss. The present finding suggests that genetic testing for NOTCH3 mutations in patients with distinctive MRI features, even if the symptoms are as mild as chronic headache, should help to broaden the mutational and clinical spectrum of CADASIL.

Late-phase thromboembolism after catheter ablation for paroxysmal atrial fibrillation.

BACKGROUND: The aim of this study was to investigate the incidence and predictors (which have not previously been fully elucidated) of late-phase thromboembolism (TE) after catheter ablation (CA) for paroxysmal atrial fibrillation (AF). METHODS AND RESULTS: We studied 1,156 consecutive patients (61±10 years; 891 men; CHADS2score, 0.8±1.0) after CA for symptomatic paroxysmal AF and examined the details of late-phase TE. During a follow-up of 49.5±21.9 months (median, 47 months; range, 6-113 months) after CA, 9 patients (0.78%) developed late-phase TE, all of which were ischemic stroke. Of these, 5 patients with AF recurrence experienced cardioembolism; the AF was asymptomatic at recurrence. The remaining 4 without AF recurrence experienced cardioembolism (n=1), small-vessel occlusion (n=1), large-artery atherosclerosis (n=1), and stroke of other determined etiology (n=1). On Kaplan-Meier analysis patients with structural heart disease (P=0.003), AF recurrence after the final CA (P=0.01), prior stroke (P=0.002), CHADS2score ≥2 (P=0.0002), left ventricular ejection fraction <50% (P<0.0001), and spontaneous echo contrast on transesophageal echocardiogram (P=0.0004) had a significantly higher risk of late-phase TE. Multivariate analysis indicated that CHADS2score ≥2 (HR, 4.49; 95% CI: 1.08-22.56; P=0.04) independently predicted late-phase TE. CONCLUSIONS: The incidence of TE was low after CA for paroxysmal AF, but CHADS2score ≥2 independently increased the risk of late-phase TE.

Overlapping demyelinating syndromes and anti­N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: To report the clinical, radiological, and immunological association of demyelinating disorders with anti­Nmethyl- D-aspartate receptor (NMDAR) encephalitis. METHODS: Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. RESULTS: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p50.011). INTERPRETATION: Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis.

Motor nerve conduction study in cauda equina with high-voltage electrical stimulation in multifocal motor neuropathy and amyotrophic lateral sclerosis.

In this study we aim to establish a motor nerve conduction study (NCS) for the cauda equina and examine its usefulness in multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS). NCS of the tibial nerve proximal to the knee was performed with an optimized high-voltage electrical stimulation (HV-ES) method in 21 normal subjects, 5 with MMN, and 11 with ALS. HV-ES, but not magnetic stimulation, could supramaximally stimulate the cauda equina. Cauda equina motor conduction time determined by HV-ES, but not that with F-waves, correlated well with cauda equina length on magnetic resonance imaging. HV-ES revealed proximal lesions in 4 MMN patients but in none of the ALS patients. Importantly, 1 patient with "MMN without conduction block (CB)" had a CB in the cauda equina. Cauda equina motor conduction is better evaluated by HV-ES than with F-wave study or magnetic stimulation. HV-ES can help to distinguish MMN and "MMN without CB" from ALS.