Case report: MRI-negative myelitis following COVID-19 with SEP abnormalities: a case series and literature review.

Coronavirus Disease 2019 (COVID-19) is known to have various, neurological manifestations. We herein report three patients with MRI-negative myelitis following COVID-19 with abnormal somatosensory evoked potentials (SEPs). Decreased amplitude of the cortical potential and prolonged latency in the SEPs contributed to diagnosing myelitis in the present patients. The SEP findings improved as the neurological symptoms improved. Despite a delay in initiating immunosuppressive treatment after myelitis onset, all the patients improved clinically. In the light of recent progress in COVID-19 research, several hypotheses can be made to explain the pathophysiology underlying MRI-negative myelitis, including antibody-binding and microglial synapse elimination.

Dopa-responsive dystonia in spinocerebellar ataxia 6: A case report.

Spinocerebellar ataxia 6 (SCA6) often presents with pure cerebellar ataxia. It is rarely accompanied by extrapyramidal symptoms, such as dystonia and parkinsonism. Here, we describe a case of SCA6 with dopa-responsive dystonia for the first time. A 75-year-old woman was admitted to the hospital with slowly progressive cerebellar ataxia and dystonia in the left upper limb for the past six years. Genetic testing confirmed the diagnosis of SCA6. Her dystonia improved with oral levodopa, and she was able to raise her left hand. Oral levodopa administration may provide early-phase therapeutic benefits for SCA6-associated dystonia.

An Autopsy Case of Elderly Onset Brainstem Acute Disseminated Encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM), which is a disease that causes multifocal inflammatory demyelination of the central nervous system, occurs predominantly in children and young adults. We report an autopsy case of an elderly man with brainstem ADEM that progressed over a period of about 3 months. An 82-year-old man developed disturbance of consciousness, dysphagia, and ataxic gait over a period of about 3 months. He was admitted to another hospital for aspiration pneumonia and recovered but was transferred to our hospital due to prolonged disturbance of consciousness. The patient was able to follow simple commands but had a tendency to somnolence. In addition to meningeal stimulation signs, the patient had left-dominant upper and lower limb ataxia and right-dominant limb spasticity. Brain FLAIR/T2-weighted imaging showed high-intensity lesions from the brainstem to the middle cerebellar peduncle bilaterally, medulla oblongata and upper cervical spinal cord, and T1-weighted imaging revealed contrast-enhanced lesions in the left middle cerebellar peduncle and cervical spinal cord. Although spinal fluid examination revealed elevated proteins, other laboratory tests indicated no evidence of infection, vasculitis, collagen diseases or tumors, and anti-ganglioside, anti-AQP4 and anti-MOG antibodies were negative. After admission, the patient again developed aspiration pneumonia, which progressed to acute respiratory distress syndrome, and he died on the 15th day of hospitalization. Autopsy findings indicated acute and subacute demyelination mainly in the brainstem and cerebellum, and perivascular lymphocyte and macrophage infiltration in the areas of demyelination. A postmortem diagnosis of ADEM was made based on the generally monophasic course of the disease and the absence of regenerating myelinated sheaths. There are very few reports of elderly patients with brainstem ADEM. ADEM should be considered as a differential diagnosis in patients with brainstem encephalitis.

Differential immunophenotypes of neuronal cytoplasmic inclusions in the dentate gyrus of multiple system atrophy and their association with clinicopathological features.

Although hippocampal pathologies of multiple system atrophy (MSA) and their association with dementia have been reported, no studies have reported clinicopathological differences among MSA patients with and without neuronal cytoplasmic inclusions (NCIs) in the dentate gyrus (dntNCIs). We investigated hippocampal NCI pathology in 18 MSA patient autopsies, focusing on phosphorylated α-synuclein (pAS)- and phosphorylated tau (pT)-positive dntNCIs. There were 8 MSA patients without and 10 with dntNCIs. The latter group was subclassified by immunophenotype: those with pAS-positive dntNCIs (pAS-dntNCI subtype), those with pT-positive dntNCIs (pT-dntNCI subtype), and those with both types of dntNCIs. MSA patients with dntNCIs survived longer with prolonged tracheostomy and had dementia more frequently than those without dntNCIs. The brain weights of patients with dntNCIs were lower than those without dntNCIs. The presence of dementia was similar among the dntNCI subtypes. The pAS-dntNCI subtype was associated with longer survival and smaller brain weights; the pT-dntNCI subtype exhibited more frequent tau pathologies than the pAS-dntNCI subtype. Thus, MSA with dntNCIs is a possible pathological subtype of longer survivors that correlates with longer disease duration, prolonged tracheostomy, and high frequency of dementia. Understanding clinicopathological differences in MSA patients with and without dntNCIs may lead to improved personalized management strategies.

Leucine-rich Glioma-inactivated 1 Encephalitis Followed by Isaacs Syndrome: Alternating Presence of Pathogenic Autoantibodies to Leucine-rich Glioma-inactivated 1 and Contactin-associated Protein-like 2.

The coexistence of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) autoantibodies in the same individual is surprisingly often observed. We herein report the first case of LGI1 encephalitis followed by Isaacs syndrome in which LGI1 and CASPR2 antibodies in the serum and cerebrospinal fluid (CSF) were measured during the entire disease course. After the resolution of limbic encephalitis, LGI1 antibodies disappeared from the CSF simultaneously with the appearance of CASPR2 antibodies in the serum. The alternating presence of these pathogenic autoantibodies along with the clinical and phenotypic alternations suggested that LGI1 encephalitis was associated with CASPR2 autoantibody production in the peripheral tissue, leading to CASPR2-associated Isaacs syndrome.

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions.

We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.

Tufted astrocyte-like glia in two autopsy cases of multiple system atrophy: Is it a concomitant neurodegenerative disorder with multiple system atrophy and progressive supranuclear palsy?

Tufted astrocytes are one of the core histopathological features of progressive supranuclear palsy (PSP). To our knowledge, only three cases of multiple system atrophy (MSA) with PSP pathology have been reported. Here, we report two autopsy cases of MSA associated with the appearance of tufted astrocyte-like glia (TuALG). Clinically, the patients' symptoms were atypical of MSA; one showed vertical gaze palsy, and the other was a long-term survivor who progressed to a bedridden state shortly after the onset of the disease. These neuropathological observations were characterized by the copresence of MSA-specific changes and TuALG in some of the cerebral cortices but few or none of the other PSP tau pathologies. These cases might emphasize the significance of TuALG in non-PSP neurodegenerative disorders.

Saccharopinuria accompanied by hyperammonemia and hypercitrullinemia presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia.

We report a case of saccharopinuria with hyperammonemia and hypercitrullinemia in a Japanese woman who presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia. Blood amino acid analysis revealed an increase in citrulline, cystine, and lysine levels, and urine amino acid analysis showed increased citrulline and cystine levels. Urine metabolomics revealed an increased saccharopine level, leading to the definitive diagnosis of saccharopinuria. In western blots of liver biopsy samples, normal citrin levels were observed, suggesting that adult-onset citrullinemia type 2 (CTLN2) was not present. In addition, decreased argininosuccinate synthetase (ASS) levels were observed, and ASS1 gene, a causative gene for citrullinemia type 1 (CTLN1), was analyzed, but no gene mutations were found. Because the causes of hypercitrullinemia were not clear, it might be secondary to saccharopinuria. Muscle biopsy findings of the biceps brachii revealed diminished cytochrome c oxidase (COX) activity, mitochondrial abnormalities on electron microscopy and p62- positive structures in immunohistochemical analyses. Saccharopinuria is generally considered a benign metabolic variant, but our case showed elevated lysine and saccharopine levels causing ornithine circuit damage, mitochondrial dysfunction, and autophagy disorders. This may lead to so far unknown neurological disorders.

Midbrain atrophy related to parkinsonism in a non-coding repeat expansion disorder: five cases of spinocerebellar ataxia type 31 with nigrostriatal dopaminergic dysfunction.

BACKGROUND: Spinocerebellar ataxia type 31 (SCA31) is caused by non-coding pentanucleotide repeat expansions in the BEAN1 gene. Clinically, SCA31 is characterized by late adult-onset, pure cerebellar ataxia. To explore the association between parkinsonism and SCA31, five patients with SCA31 with concomitant nigrostriatal dopaminergic dysfunction (NSDD) development, including three cases of L-DOPA responsive parkinsonism, were analyzed. METHODS: To assess regional brain atrophy, cross-sectional and longitudinal imaging analyses were retrospectively performed using magnetic resonance imaging (MRI) planimetry. The midbrain-to-pons (M/P) area ratio and cerebellar area were measured on midsagittal T1-weighted MRI in five patients with SCA31 with concomitant NSDD (NSDD(+)), 14 patients with SCA31 without NSDD (NSDD(-)), 32 patients with Parkinson's disease (PD), and 15 patients with progressive supranuclear palsy (PSP). Longitudinal changes in the M/P area ratio were assessed by serial MRI of NSDD(+) (n = 5) and NSDD(-) (n = 9). RESULTS: The clinical characteristics assessed in the five patients with NSDD were as follows: the mean age at NSDD onset (72.0 ± 10.8 years), prominence of bradykinesia/akinesia (5/5), rigidity (4/5), tremor (2/5), dysautonomia (0/5), vertical gaze limitation (1/5), and abnormalities on 123I-ioflupane dopamine transporter scintigraphy (3/3) and 3-Tesla neuromelanin MRI (4/4). A clear reduction in the midbrain area and the M/P area ratio was observed in the NSDD(+) group (p < 0.05) while there was no significant difference in disease duration or in the pons area among the NSDD(+), NSDD(-), and PD groups. There was also a significant difference in the midbrain and pons area between NSDD(+) and PSP (p < 0.05). Thus, mild but significant midbrain atrophy was observed in NSDD(+). A faster rate of decline in the midbrain area and the M/P area ratio was evident in NSDD(+) (p < 0.05). CONCLUSION: The clinical characteristics of the five patients with SCA31 with concomitant NSDD, together with the topographical pattern of atrophy, were inconsistent with PD, PSP, and multiple system atrophy, suggesting that SCA31 may manifest NSDD in association with the pathomechanisms underlying SCA31.

Immunoglobulin G4-related Disease Accompanied by Peripheral Neuropathy: A Report of Two Cases.

Due to its rarity and the limited literature, the clinicopathological characteristics of peripheral nerve involvement in immunoglobulin G4 (IgG4)-related disease are unknown. We present two cases of IgG4-related disease, accompanied by peripheral neuropathy, presenting as unilateral ptosis (case 1) and sclerosing cholangitis (case 2), respectively. In both cases, sural nerve biopsy indicated vasculitis as the underlying pathophysiology; the peripheral neuropathy was refractory to corticosteroid therapy. In contrast to the previously proposed pathomechanism of IgG4-related neuropathy (direct lymphoplasmacytic infiltration), the pathological findings in our cases suggest that vasculitis occurs secondary to systemic autoimmune conditions.

Effects of oral care on prolonged viral shedding in coronavirus disease 2019 (COVID-19).

AIM: To assess the effects of oral care on prolonged viral shedding in coronavirus disease 2019 (COVID-19) patients. METHODS AND RESULTS: We evaluated the clinical course of eight COVID-19 patients, including their duration of viral shedding, by PCR testing of nasopharyngeal swabs. The average time from the onset of symptoms until the virus was no longer detectable was 31.6 ± 11.8 days (mean ± SD; range 17-53). Thus, it took 15.1 ± 14.7 (1-40) days from the time of clinical recovery for the virus to become undetectable. In two patients who had mental retardation and psychiatric disorders, the viral shedding period continued for 44 days or 53 days. These two patients did not voluntarily brush their teeth. When they were instructed on the importance of oral care, including tooth brushing and gargling, their tests for the coronavirus became negative. CONCLUSION: Most of the patients with COVID-19 had a viral shedding period of 30 days or less. In cases of prolonged viral shedding (≥44 days), noninfectious viral nucleic acid may have accumulated in uncleaned oral cavities and continued to be detected. We propose that tooth brushing and gargling remove such viral nucleic acid and improve the accuracy of PCR testing.

Cerebral white matter tau-positive granular glial pathology as a characteristic pathological feature in long survivors of multiple system atrophy.

INTRODUCTION: It is unclear whether tau-positive granular glial pathology is a characteristic feature of MSA. We aimed to analyse the prevalence and significance of tau-positive granular glial pathology in MSA. METHODS: Fourteen MSA cases were clinicopathologically investigated, focusing on tau-positive granular glial pathology in the frontal and temporal white matter and putamen. RESULTS: In five MSA cases, the temporal white matter showed AT8-positive granular glial pathology; this pathology was detected in the frontal white matter in three cases. AT8-positive granular glia in the white matter were associated with long disease duration with long-term tube feeding and/or long-term tracheotomy. Alpha-synuclein-positive glial cytoplasmic inclusion intensity was not associated with AT8-positive granular glial pathology. The tau isoform of AT8-positive granular glia in the cerebral white matter exhibited three-repeat, not four-repeat, tau. Ten MSA patients showed tau-positive granular glial pathology in the putamen; the tau isoform was predominantly three-repeat tau and four-repeat tau in cases with disease duration ≥13 years and < 13 years, respectively. CONCLUSIONS: Tau-positive granular glia in the putamen is a characteristic pathological feature of MSA. Tau-positive granular glia appear in the cerebral white matter in MSA patients and are associated with long disease duration with long-term tube feeding and/or long-term tracheotomy.

Clinical characteristics of children and adults with anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVES: To investigate the clinical characteristics of children and adults with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. METHODS: Patients who tested positive for the anti-NMDAR antibody (by a cell-based assay) in the cerebrospinal fluid were enrolled. They were divided into two groups based on age (<16 years or older). RESULTS: Three children (two males and one female) and four adults (one male and three females) were examined. The age at onset was 3.0 ± 1.41 years (range: 2-5 years) for the children and 31.8 ± 6.80 years (range: 20-36 years) for the adults. The follow-up duration was 82.7 ± 23.80 months (range: 52-110 months) for the children and 61.5 ± 12.54 months (range: 43-78 months) for the adults. Prodromal symptoms such as fever and headache were observed in three adults. Two children received influenza vaccination before the onset of encephalitis. Brain magnetic resonance imaging abnormalities were observed in three children and one adult. Basal ganglia lesions were observed in two children and one adult, and the two children showed dystonia. Two children and one adult without neoplasms experienced recurrences. The modified Rankin Scale scores at the final follow-up tended to be worse in children than in adults. CONCLUSION: Three patients had basal ganglia lesions, and two of them showed dystonia. Dystonia with basal ganglia lesions has been rarely reported in anti-NMDAR encephalitis but should be noted as a significant symptom, which severely affects the activities of daily life.

Chronic demyelinating neuropathy with anti-myelin-associated glycoprotein antibody without any detectable M-protein.

Previous case reports and studies have shown that anti-myelin-associated glycoprotein (MAG) antibody can be detected in patients with polyneuropathy without any detectable M-protein. Nevertheless, the frequency of and related factors have not yet been adequately investigated. The objectives of this study are to examine the prevalence of anti-MAG antibody in patients with demyelinating neuropathy without M-protein and to determine their clinical characteristics. From January, 2004, to September, 2016, consecutive patients with chronic demyelinating neuropathy were recruited. Anti-MAG antibody presence was tested at the first evaluation. We determined the prevalence of anti-MAG antibody without M-protein among included patients and evaluated the clinical characteristics. A total of 44 patients were included in the present study (12 women; median age at first visit 60 years [interquartile range 47-67 years]; median duration between onset and first visit 9 months [3-26 months]). M-protein was found in eight patients (18%) at the first evaluation. Anti-MAG antibody was present in 2 of remaining 36 (5.6 [95% confidence interval 0-13.0] %) patients without M-protein. Patients with anti-MAG antibody exhibited slowly progressive and distal dominant neuropathy with elevated serum IgM levels and refractory to immunotherapy. There were no differences in clinical features between patients having anti-MAG antibody without M-protein, and those with M-protein. One patient with the anti-MAG antibody showed a delayed appearance of M-protein during a 4-year follow-up after diagnosis. The prevalence of the anti-MAG antibody in chronic demyelinating neuropathy without any detectable M-protein was 5.6%. Anti-MAG antibody may be detectable earlier than M-protein.

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presented as T-Lymphoid Hyperplasia Involving the Central Nervous System.

We herein report a case of T-cell/histiocyte-rich large B-cell lymphoma which initially presented as a self-limiting T-lymphoproliferative disorder involving multiple extranodal and extrapulmonary organs, such as the salivary gland, the liver, and the central nervous system. Repeated biopsies only revealed polyclonal T-lymphocytosis without the presence of atypical B-cells. Angiocentric cellular infiltration was absent, thus ruling out lymphomatoid granulomatosis. A recurrence in the lymphatic system finally revealed a small population of pathognomonic atypical B-cells, which led to the diagnosis. The clinical dilemma in the diagnosis and management of this indeterminate condition points to limitations in the current nosology.

Prevalence and clinical characteristics of corticobasal syndrome with an initial symptom outside of the upper limb.

Although typical corticobasal syndrome (CBS) presents with asymmetric upper limb symptoms, the prevalence and clinical characteristics of patients with symptoms beginning in other sites are unknown. From January 1997 through April 2016, consecutive patients with CBS who fulfilled the modified Cambridge criteria were recruited. Their medical records were reviewed to determine the body part, where the initial symptoms developed and the clinical characteristics. A total of 24 patients [13 female participants, median age at onset: 64 (IQR 60-74) years, and median duration between onset and evaluation: 38 (17-53) months] met the criteria. The initial symptom involved the unilateral upper limb in 14 cases (58%), unilateral lower limb in five (21%), gait in four (17%), and visual field in one (4%). Over a median of 59 (IQR 40-68) months of follow-up, the duration between the onset and the time for need of assistance in walking was significantly shorter in the patients with lower limb (p = 0.018 with log-rank test) or gait (p = 0.025) onset than in those with upper limb onset. About a half of the CBS patients initially complained of symptoms other than the upper limb. The most common area of origin of the initial symptom after the upper limb was the lower limb followed by gait. Such patients need assistance in walking earlier than those with upper limb-onset CBS. Patients with lower limb- or gait-onset CBS are not rare and may have unfavorable outcome.

Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.

OBJECTIVE: The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT. METHODS: To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. RESULTS: We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aß)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aß in Pittsburgh compound-B positron emission tomography imaging. INTERPRETATION: Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT.