Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Stereo-electroencephalography evidence of an eccentrically located seizure-onset zone around a polymorphous low-grade neuroepithelial tumor of the young: illustrative case.

BACKGROUND: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a newly identified low-grade brain tumor with frequent epileptic presentation. Despite the facilitated use of invasive electroencephalography owing to the growing availability of stereo-electroencephalography (SEEG), intracranial features of tumor-related seizures are still scarcely described. This report provides the first description of SEEG-recorded seizures in PLNTY to provide an insight into its surgical strategy. OBSERVATIONS: Spontaneous clinical seizures were recorded with SEEG in a young adult patient with drug-resistant epilepsy associated with a PLNTY in the left lateral temporal cortex. The seizure onset was characterized by low-voltage fast activity (LVFA) and showed eccentric localization with respect to the tumor: LVFA was localized in the anterior portion of the tumor and spread toward the adjacent polar cortex. The language risks associated with the resection of the posterior temporal cortex could thus be minimized. LESSONS: PLNTY can show a focal and eccentric seizure-onset zone around the tumor. The present findings serve to improve the functional and seizure outcomes using the staged invasive approach in PLNTY.

Postoperative striatal degeneration: a hitherto unrecognized impact of frontal disconnection surgery for drug-resistant epilepsy. Illustrative cases.

BACKGROUND: Frontal disconnection surgery is a useful surgical option for patients with frontal epilepsy whose seizure onset zones are exceedingly large and thus are not amenable to conventional resective surgery. While it has the advantage of avoiding sequelae stemming from a large resection cavity, the impact of radical anatomofunctional disconnection of such a vast frontal region is not fully understood. OBSERVATIONS: The authors have identified secondary degeneration in the striatum ipsilateral to the frontal disconnection surgery in two adult patients who had otherwise favorable postoperative outcomes following the surgery. On serial postoperative magnetic resonance imaging, the striatum showed transient restricted diffusion in the caudate head and rostral putamen around several weeks postoperatively and subsequent atrophy in the caudate head. The affected striatal regions (i.e., the anterior portion of the striatum) were congruent with the known fronto-striatal connectivity corresponding to the disconnected frontal regions anterior to the primary and supplementary motor areas. Both patients achieved 1-year seizure freedom without apparent disability related to the surgery. LESSONS: The benign postoperative course despite the marked degenerative changes in the ipsilateral striatum supports the feasibility of the frontal disconnection surgery in otherwise inoperable patients with broad frontal epileptogenicity.

Impact of COVID-19 pandemic on epilepsy care in Japan: A national-level multicenter retrospective cohort study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study. METHODS: This study included monthly data on the frequency of (1) visits by outpatients with epilepsy, (2) outpatient electroencephalography (EEG) studies, (3) telemedicine for epilepsy, (4) admissions for epilepsy, (5) EEG monitoring, and (6) epilepsy surgery in epilepsy centers and clinics across Japan between January 2019 and December 2020. We defined the primary outcome as epilepsy-center-specific monthly data divided by the 12-month average in 2019 for each facility. We determined whether the COVID-19 pandemic-related factors (such as year [2019 or 2020], COVID-19 cases in each prefecture in the previous month, and the state of emergency) were independently associated with these outcomes. RESULTS: In 2020, the frequency of outpatient EEG studies (-10.7%, p<0.001) and cases with telemedicine (+2,608%, p=0.031) were affected. The number of COVID-19 cases was an independent associated factor for epilepsy admission (-3.75*10-3 % per case, p<0.001) and EEG monitoring (-3.81*10-3 % per case, p = 0.004). Further, the state of emergency was an independent factor associated with outpatient with epilepsy (-11.9%, p<0.001), outpatient EEG (-32.3%, p<0.001), telemedicine for epilepsy (+12,915%, p<0.001), epilepsy admissions (-35.3%; p<0.001), EEG monitoring (-24.7%: p<0.001), and epilepsy surgery (-50.3%, p<0.001). SIGNIFICANCE: We demonstrated the significant impact that the COVID-19 pandemic had on epilepsy care. These results support those of previous studies and clarify the effect size of each pandemic-related factor on epilepsy care.

Comparison of Acute Withdrawal and Slow Taper of Antiseizure Medications during Video Electroencephalographic Monitoring: Efficacy for Shortening of Hospital Stay.

Antiepileptic medications (ASMs) are withdrawn at the epilepsy monitoring unit to facilitate seizure recordings. The effect of rapid tapering of ASMs on the length of hospital stay has not been well documented. We compared the mean length of hospital stay between patients who underwent acute ASM withdrawal and slow dose tapering during long-term video electroencephalography (EEG) monitoring. We retrospectively investigated 57 consecutive patients admitted to the epilepsy monitoring unit regarding the mean length of hospital stay in the acute ASM withdrawal group (n = 30) and slow-taper group (n = 27). In the acute-withdrawal group, all ASMs were discontinued once the patients were admitted. In the slow-taper group, the doses of ASMs were gradually reduced by 15-30% daily. We also evaluated the safety of the acute-withdrawal and slow-taper protocols. The mean lengths of hospital stay were 3.8 ± 1.92 and 5.2 ± 0.69 days in the acute-withdrawal and slow-taper groups, respectively (p < 0.005). No severe adverse events, including status epilepticus, were observed. Acute ASM withdrawal has the advantage of significantly reducing the length of hospital stay over slow tapering, without any severe adverse effects.

Characteristics of olfactory dysfunction in patients with temporal lobe epilepsy.

OBJECTIVE: To determine the characteristics of olfactory dysfunction in patients with temporal lobe epilepsy (TLE). METHODS: Odor identification was assessed using the odor stick identification test for Japanese (OSIT-J, full score 12 points) in 65 patients with TLE and in 74 controls. RESULTS: The mean OSIT-J score was significantly lower in patients with TLE (mean ±â€¯SD = 8.1 ±â€¯2.8; median = 9) than in the control subjects (mean ±â€¯SD = 10.6 ±â€¯1.1; median = 11) (P < 0.005). Olfactory dysfunction (hyposmia/anosmia) was associated with bilateral seizure foci and older age of onset in TLE. Patients who underwent temporal lobectomy for hippocampal sclerosis did not show significant decline after long-term recovery. The Indian ink part of OSIT-J was useful for the detection of olfactory deficits in patients with TLE (sensitivity = 47%, specificity = 93%). Patients with TLE tended to have preserved olfactory ability for stimulating odors and for familiar odors of daily life. SIGNIFICANCE: We observed characteristic odor identification deficits for individual odors used in OSIT-J. Our study findings provide deeper insight into the underlying mechanism of olfactory function in patients with TLE and may be beneficial in the clinical management of these patients.

Elderly-Onset Multiple System Atrophy with Lewy Body Pathology: A Case Report.

An 81-year-old woman presented with a 2-year history of progressive dysarthria and gait disturbance. Subsequently, she developed orthostatic hypotension, obstructive sleep apnea, right-sided resting tremor, and rigidity. Together with characteristic findings of imaging studies, she was diagnosed with multiple system atrophy (MSA). Despite progressive dysphagia and repeated choking episodes, the patient elected not to use artificial feeding or tracheostomy. She died suddenly at age 91 after 12 years of illness. The autopsy revealed neuropathological features of both MSA and of Parkinson's disease. The peripheral autonomic ganglia revealed both pre- and postganglionic involvement by synucleinopathy, which may have underscored the sudden death of the patient. The patient survived 10 years after onset, despite the presence of multiple poor prognostic factors in MSA including the onset of old age and early appearance of orthostatic hypotension and falls, in addition to the complication of PD pathology found by autopsy. Multidisciplinary team approach and her preserved cognitive function may have been contributory to the long-term survival.

PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

Intrafamilial phenotypic variation in spinocerebellar ataxia type 23.

BACKGROUND: Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. CASE PRESENTATIONS: We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. CONCLUSIONS: We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.

Improvement of Blood Plasmalogens and Clinical Symptoms in Parkinson's Disease by Oral Administration of Ether Phospholipids: A Preliminary Report.

Introduction. Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). With the ageing of population, the frequency of PD is expected to increase dramatically in the coming decades. L-DOPA (1,3,4-dihydroxyalanine) is the most effective drug in the symptomatic treatment of PD. Nonmotor symptoms in PD include sleep problems, depression, and dementia, which are not adequately controlled with dopaminergic therapy. Here, we report the efficacy of oral administration of scallop-derived ether phospholipids to some nonmotor symptoms of PD. METHODS: Ten (10) patients received oral administration of 1 mg/day of purified ether phospholipids derived from scallop for 24 weeks. Clinical symptoms and blood tests were checked at 0, 4, 12, 24, and 28 weeks. The blood levels of plasmalogens in patients with PD were compared with those of 39 age-matched normal controls. RESULTS: Initial levels of plasma ethanolamine ether phospholipids in PD and ethanolamine plasmalogen of erythrocyte from PD were lower than those of age-matched normal controls. Oral administration of 1 mg/day of the purified ether phospholipids increased plasma ether phospholipids in PD and increased the relative composition of ether phospholipids of erythrocyte membrane in PD. The levels of ether phospholipids in peripheral blood reached to almost normal levels after 24 weeks. Furthermore, some clinical symptoms of PD improved concomitantly. CONCLUSION: 1 mg/day of oral administration of purified ether phospholipids derived from scallop can increase ether phospholipids in peripheral blood and concomitantly improve some clinical symptoms of PD.

Study of the Anatomical Features of the Offending Arteries Involved in Glossopharyngeal Neuralgia.

BACKGROUND: The anatomic features of the posterior inferior cerebellar arteries (PICAs) and the anterior inferior cerebellar arteries (AICAs) as offending arteries involved in glossopharyngeal neuralgia (GPN) are important to dictate the best surgical approach. OBJECTIVE: To study and classify the anatomic features of the offending arteries. METHODS: All clinical data and surgical videos from 18 GPN cases that were surgically treated during the past 10 yr were retrospectively reviewed. RESULTS: Among these 18 patients, the offending arteries involved were the PICA in 12 (66.7%), AICA in 4 (22.2%), and both PICA and AICA in 2 (11.1%). The PICA were then classified into the following groups based on their anatomic features: type I: the PICA formed an upward loop at the level of the glossopharyngeal nerve and passed between the glossopharyngeal and vestibulocochlear nerves; type II: the PICA formed an upward loop at the level of the glossopharyngeal nerve and passed between the glossopharyngeal and vagus nerves or between the rootlets of the vagus nerve; and type III: the PICA passed between the glossopharyngeal and vestibulocochlear nerves without forming a loop. The AICA had only one running pattern. CONCLUSION: The offending arteries involved in GPN, mainly the PICA and/or AICA, were classified into 4 different types based on their anatomic features.

Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis.

BACKGROUND: A subset of familial forms of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene coding Cu/Zn-superoxide dismutase (SOD1). Mutant SOD1 proteins are susceptible to misfolding and abnormally accumulated in spinal cord, which is most severely affected in ALS. It, however, remains quite controversial whether misfolding of wild-type SOD1 is involved in more prevalent sporadic ALS (sALS) cases without SOD1 mutations. METHODS: Cerebrospinal fluid (CSF) from patients including sALS as well as several other neurodegenerative diseases and non-neurodegenerative diseases was examined with an immunoprecipitation assay and a sandwich ELISA using antibodies specifically recognizing misfolded SOD1. RESULTS: We found that wild-type SOD1 was misfolded in CSF from all sALS cases examined in this study. The misfolded SOD1 was also detected in CSF from a subset of Parkinson's disease and progressive supranuclear palsy, albeit with smaller amounts than those in sALS. Furthermore, the CSF samples containing the misfolded SOD1 exhibited significant toxicity toward motor neuron-like NSC-34 cells, which was ameliorated by removal of the misfolded wild-type SOD1 with immunoprecipitation. CONCLUSIONS: Taken together, we propose that misfolding of wild-type SOD1 in CSF is a common pathological process of ALS cases regardless of SOD1 mutations.

Neuromyelitis optica spectrum disorder with massive basal ganglia involvement: a case report.

BACKGROUND: Occurrence of basal ganglia involvement in neuromyelitis optica spectrum disorders (NMOSD) has rarely been reported and none documented pathologically. CASE PRESENTATION: A 73-year-old female was clinically diagnosed with a NMOSD based on the clinical and radiological features and positive serum autoantibodies to AQP4. One month before her death, she became acutely ill with disturbed consciousness and right hemiparesis, and was diagnosed and treated as having basal ganglia infarction based on the brain CT. She made a partial recovery but later died from heart failure. At autopsy, the corresponding basal ganglia process revealed a large fresh area of necrosis. Histologically, several pathological signatures of NMOSD could be recognized in the lesion, including inflammatory cell infiltrations by B and T lymphocytes, perivascular complement and fibrinogen deposition, and the appearance of numerous phagocytosed corpora amylacea within the infiltrating macrophages. CONCLUSIONS: The present case illustrates that basal ganglia may be directly involved in the pathological processes of NMOSD, although the possibility of modification of the lesions by superimposed regional ischemia could not be excluded.

A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis.

Dominant mutations in the gene encoding copper and zinc-binding superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS). Abnormal accumulation of misfolded SOD1 proteins in spinal motoneurons is a major pathological hallmark in SOD1-related ALS. Dissociation of copper and/or zinc ions from SOD1 has been shown to trigger the protein aggregation/oligomerization in vitro, but the pathological contribution of such metal dissociation to the SOD1 misfolding still remains obscure. Here, we tested the relevance of the metal-deficient SOD1 in the misfolding in vivo by developing a novel antibody (anti-apoSOD), which exclusively recognized mutant SOD1 deficient in metal ions at its copper-binding site. Notably, anti-apoSOD-reactive species were detected specifically in the spinal cords of the ALS model mice only at their early pre-symptomatic stages but not at the end stage of the disease. The cerebrospinal fluid as well as the spinal cord homogenate of one SOD1-ALS patient also contained the anti-apoSOD-reactive species. Our results thus suggest that metal-deficiency in mutant SOD1 at its copper-binding site is one of the earliest pathological features in SOD1-ALS.

Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis.

Aquaporin-4 (AQP4) is abundantly expressed in the central nervous system and is involved in the water balance in the cellular environment. Previous studies have reported that AQP4 expression is upregulated in rat models of amyotrophic lateral sclerosis (ALS), a fatal disease that affects motor neurons in the brain and spinal cord. In this study, we report that astrocytic AQP4 overexpression is evident during the course of disease in the spinal cord of an ALS mouse model, as well as in tissue from patients with ALS. AQP4 overexpression appears to be specifically associated with ALS because it was not induced by other experimental manipulations that produced acute or chronic gliosis. In order to examine the contribution of AQP4 to ALS disease development, we crossed AQP4 knockout mice with a mouse model of ALS. Significant improvement in blood-brain barrier (BBB) permeability was observed in the AQP4-deficient ALS mouse model. However, the time to disease onset and total lifespan were reduced in the AQP4-deficient ALS mouse model. The contradictory results suggest that changes in AQP4 may be context-dependent and further studies are required to understand the precise contribution of brain water balance in ALS.

An Autopsy Case of Respiratory Failure Induced by Repetitive Cervical Spinal Cord Damage due to Abnormal Movement of the Neck in Athetoid Cerebral Palsy.

We herein report the clinical and autopsy findings of a 48-year-old right-handed man with athetoid cerebral palsy who suffered from cervical myelopathy due to abnormal neck movement, and who died of respiratory failure. Pathologically, the external appearance of the ventral surface of the cervical spinal cord revealed a linear indentation running obliquely at the level between the C4 and C5 segments. In the most severely compressed lesion, the gray matter was predominantly affected and severely atrophic. Microscopically, clusters of oligodendrocytes associated with thinly myelinated axons were also observed in the lateral funiculus. The latter findings are unique, and could be interpreted as regenerative and/or restorative phenomena of the central nervous system following chronic repetitive spinal cord compression.

Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis.

BACKGROUND: Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (SOD1-ALS) with accumulation of misfolded SOD1 proteins as intracellular inclusions in spinal motor neurons. Oligomerization of SOD1 via abnormal disulfide crosslinks has been proposed as one of the misfolding pathways occurring in mutant SOD1; however, the pathological relevance of such oligomerization in the SOD1-ALS cases still remains obscure. METHODS: We prepared antibodies exclusively recognizing the SOD1 oligomers cross-linked via disulfide bonds in vitro. By using those antibodies, immunohistochemical examination and ELISA were mainly performed on the tissue samples of transgenic mice expressing mutant SOD1 proteins and also of human SOD1-ALS cases. RESULTS: We showed the recognition specificity of our antibodies exclusively toward the disulfide-crosslinked SOD1 oligomers by ELISA using various forms of purified SOD1 proteins in conformationally distinct states in vitro. Furthermore, the epitope of those antibodies was buried and inaccessible in the natively folded structure of SOD1. The antibodies were then found to specifically detect the pathological SOD1 species in the spinal motor neurons of the SOD1-ALS patients as well as the transgenic model mice. CONCLUSIONS: Our findings here suggest that the SOD1 oligomerization through the disulfide-crosslinking associates with exposure of the SOD1 structural interior and is a pathological process occurring in the SOD1-ALS cases.

Coexistence of Copper in the Iron-Rich Particles of Aceruloplasminemia Brain.

The interaction between iron and copper has been discussed in association with human health and diseases for many years. Ceruloplasmin, a multi-copper oxidase, is mainly involved in iron metabolism and its genetic defect, aceruloplasminemia (ACP), shows neurological disorders and diabetes associated with excessive iron accumulation, but little is known about the state of copper in the brain. Here, we investigated localization of these metals in the brains of three patients with ACP using electron microscopes equipped with an energy-dispersive x-ray analyzer. Histochemically, iron deposition was observed mainly in the basal ganglia and dentate nucleus, and to lesser degree in the cerebral cortex of the patients, whereas copper grains were not detected. X-ray microanalysis identified two types of iron-rich particles in their brains: dense bodies, namely hemosiderins, and their aggregated inclusions. A small number of hemosiderins and most inclusions contained a significant amount of copper which was enough for distinct Cu x-ray images. These copper-containing particles were observed more frequently in the putamen and dentate nucleus than the cerebral cortex. Coexistence of iron and copper was supported by good correlations in the molecular ratios between these two metals in iron-rich particles with Cu x-ray image. Iron-dependent copper accumulation in iron-rich particles may suggest that copper recycling is enhanced to meet the increased requirement of cuproproteins in iron overload brain. In conclusion, the iron-rich particles with Cu x-ray image were found in the ACP brain.