Cytomegalovirus-associated encephalomyelitis in an immunocompetent adult: a two-stage attack of direct viral and delayed immune-mediated invasions. case report.

BACKGROUND: It is clinically rare to find cytomegalovirus (CMV)-associated encephalomyelitis in immunocompetent adults. Here, we present the case of an adult patient who developed acute transverse myelitis that was followed by immune-mediated disseminated encephalomyelitis. CASE PRESENTATION: A 38-year-old man developed acute paraplegia with paresthesia below the level of the T7-8 dermatome. Both brain and spinal cord MRIs performed at admission appeared normal. Corticosteroid therapy was initiated, with the later addition of high-dose intravenous immunoglobulins. After polymerase chain reaction analysis indicated the presence of CMV DNA in his cerebrospinal fluid (CSF), anti-viral therapy was added. Forty days after symptom onset, despite an initial positive response to this therapy, he developed dysarthria and truncal ataxia. Repeated magnetic resonance imaging scans demonstrated progressively expanding lesions involving not only the spinal cord but also the cerebral white matter, suggestive of extensive immune-mediated demyelination involving the central nervous system (CNS), as is observed in acute disseminated encephalomyelitis (ADEM). CONCLUSION: This case report underscores the importance of careful patient observation following the initial diagnosis of a CMV-associated CNS infection, such as transverse myelitis, on the possibility that post-infectious ADEM may appear.

Good's syndrome with opportunistic infection of the central nervous system: a case report.

BACKGROUND: Immunodeficiency with a thymoma (Good's syndrome) is a rare condition occurring in patients with adult-onset hypogammaglobulinemia that is progressive after the removal of thymoma. Recently, we encountered a patient with Good's syndrome who suddenly developed opportunistic encephalitis 4 years after the resection of thymoma without a history of infectious complications. CASE PRESENTATION: A 58-year-old man, who underwent surgery to remove a thymoma at the age of 54, was admitted because of speech difficulties. A brain MRI showed multiple lesions involving the frontal lobes, but the CSF finding was normal. Acyclovir was empirically administered, and fever as well as his neurological symptoms fully recovered within a few days. However, 1 week after admission, motor aphasia and mild right hemiparesis reappeared. MRI showed that the lesion involving the left cingulate gyrus expanded in size, and revealed an abnormal signal intensity lesion in the left corona radiata. Laboratory examination found increased CMV pp65 antigen-positive lymphocytes in serum. Antiviral therapy using ganciclovir and immunoglobulin replacement therapy was started. The patient has since been free from any neurological symptoms for 1 year, and lesions demonstrated by MRI are gradually improving. CONCLUSION: Early recognition of this rare condition and prompt initiation of therapy are crucially important. Awareness of immunodeficiency in a patient after removal of thymoma may help neurologists to consider the possibility that opportunistic infection may be the cause of cerebral lesions.

Efficacy and Safety of Elobixibat in Parkinson's Disease with Chronic Constipation: CONST-PD Study.

BACKGROUND: Chronic constipation is a common digestive complication of Parkinson's disease (PD). OBJECTIVES: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD. METHODS: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed. RESULTS: The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported. CONCLUSIONS: Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation. TRIAL REGISTRATION INFORMATION: Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).

Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72.

BACKGROUND: A GGGGCC hexanucleotide repeat expansion in C9ORF72 occurs on a chromosome 9p21 locus that is linked with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in white populations. The diseases resulting from this expansion are referred to as 'c9FTD/ALS'. It has been suggested that c9FTD/ALS arose from a single founder. However, the existence of c9FTD/ALS in non-white populations has not been evaluated. RESULTS: We found two index familial ALS (FALS) patients with c9FTD/ALS in the Japanese population. The frequency of c9FTD/ALS was 3.4% (2/58 cases) in FALS. No patients with sporadic ALS (n=110) or control individuals (n=180) had the expansion. Neuropathological findings of an autopsy case were indistinguishable from those of white patients. Although the frequency of risk alleles identified in white subjects is low in Japanese, one patient had all 20 risk alleles and the other had all but one. The estimated haplotype indicated that the repeat expansion in these patients was located on the chromosome with the risk haplotype identified in white subjects. CONCLUSIONS: C9ORF72 repeat expansions were present in a Japanese cohort of ALS patients, but they were rare. Intriguingly, Japanese patients appear to carry the same risk haplotype identified in white populations.

Case report: Young-onset large vessel ischemic stroke due to hyperhomocysteinemia associated with the C677T polymorphism on 5,10-methylenetetrahydrofolate reductase and multi-vitamin deficiency.

Hyperhomocysteinemia is an important risk factor for cerebral infarction. Herein, we report on a 30-year-old man previously diagnosed with epilepsy who presented with right hemiplegia and total aphasia. Magnetic resonance imaging showed a fronto-temporal ischemic lesion due to occlusion of the left middle cerebral artery. Clinical testing and imaging demonstrated that he had hyperhomocysteinemia induced by multiple factors including the C677T polymorphism on 5.10-methylenetetrahydrofolate reductase (MTHFR), and multiple vitamin deficiencies. The C677T polymorphism on MTHFR is closely related to hyperhomocysteinemia and folate deficiency in epileptic patients who are taking multiple anti-convulsants. Given hyperhomocysteinemia can independently cause stroke at a young age, physicians should periodically examine plasma homocysteine and serum folic acid levels in epileptic patients who are on long-term regimens of multiple anti-epileptic drugs.

Two rare diseases, acute calcific retropharyngeal tendinitis, and crowned dens syndrome, mimicking meningitis: A case report.

We report two rare cases. One involved acute calcific retropharyngeal tendinitis, an inflammatory condition of the longus colli tendon triggered by the deposition of calcium hydroxyapatite crystals. The other involved crowned dens syndrome, caused by pseudogout of the atlantoaxial junction following deposition of calcium pyrophosphate dehydrate or calcium hydroxyapatite. Although these two diseases involve different mechanisms, the common symptoms of neck pain and fever resemble those of meningitis. Accurate diagnosis can thus be difficult without background knowledge of these conditions. Cerebrospinal fluid examination and cervical computed tomography are useful for distinguishing these pathologies from meningitis.

Investigating the efficacy and safety of elobixibat, an ileal bile acid transporter inhibitor, in patients with Parkinson's disease with chronic constipation: a multicentre, placebo-controlled, randomised, double-blind, parallel-group stud (CONST-PD).

INTRODUCTION: Chronic constipation worsens the quality of life (QOL) of patients with Parkinson's disease (PD). Elobixibat, an ileal bile acid transporter inhibitor, is a useful laxative, but its effect on chronic constipation in patients with PD remains unclear. Therefore, we designed a placebo-controlled, randomised, double-blind study to investigate the efficacy and safety of elobixibat in patients with PD with chronic constipation. METHODS AND ANALYSIS: The study will consist of 2-week observation and 4-week treatment periods. Patients with clinically established PD will record the status of spontaneous bowel movements and use of rescue medications/concomitant medications in a Bowel Movement Diary from the start of the observation period at visit 1 (week -2). At visit 2 (week 0), patients will be assessed for final registration based on the diary records and physical examinations, and allocated to either the elobixibat or placebo group. Daily intake of the investigational drug will be recorded in the diary. Patients will undergo laboratory tests and answer constipation-related, PD-related and QOL-related questionnaires at visits 2 and 4 (week 4). Subjective symptoms and objective findings will be collected at visits 2, 3 (week 2) and 4. Since patients' motor function might be improved by treatment of constipation, the use of dopamine preparations will also be monitored. Bowel movement data and other parameters will be compared between groups.Safety information will be collected as adverse events, specifically focusing on those occurring in association with study conduct. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the Helsinki Declaration, the Clinical Trials Act of the Japan Ministry of Health, Labour and Welfare, and related laws and regulations. The study was approved by the Juntendo University Certified Review Board. The results will be disseminated through an online study registry (Japan Registry of Clinical Trials), presented at scientific conferences, and published in medical journals. TRIAL REGISTRATION NUMBER: JPRN-jRCTs031200172; Pre-results.

DJ-1 associates with synaptic membranes.

Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons. Although many reports have suggested that genetic factors are implicated in the pathogenesis of PD, molecular mechanisms underlying selective dopaminergic neuronal degeneration remain unknown. DJ-1 is a causative gene for autosomal recessive form of PARK7-linked early-onset PD. A number of studies have demonstrated that exogenous DJ-1 localizes within mitochondria and the cytosol, and functions as a molecular chaperone, as a transcriptional regulator, and as a cell protective factor against oxidative stress. However, the precise subcellular localization and function of endogenous DJ-1 are not well known. The mechanisms by which mutations in DJ-1 contributes to neuronal degeneration also remain poorly understood. Here we show by immunocytochemistry that DJ-1 distributes to the cytosol and membranous structures in a punctate appearance in cultured cells and in primary neurons obtained from mouse brain. Interestingly, DJ-1 colocalizes with the Golgi apparatus proteins GM130 and the synaptic vesicle proteins such as synaptophysin and Rab3A. Förster resonance energy transfer analysis revealed that a small portion of DJ-1 interacts with synaptophysin in living cells. Although the wild-type DJ-1 protein directly associates with membranes without an intermediary protein, the pathogenic L166P mutation of DJ-1 exhibits less binding to synaptic vesicles. These results indicate that DJ-1 associates with membranous organelles including synaptic membranes to exhibit its normal function.

Inversely polarized thermo-electrochemical power generation via the reaction of an organic redox couple on a TiO2/Ti mesh electrode.

We demonstrate thermo-electrochemical (TEC) conversion using a biocompatible redox couple of lactic acid and pyruvic acid on earth-abundant TiO2. The TEC cell exhibited a positive Seebeck coefficient of 1.40 mV K-1. DFT calculations figured out that the adsorption of intermediate species and protons on TiO2 controls both the redox reaction and current polarity.

Herpes Zoster Radiculomyelitis With Aquaporin-4 Antibodies: A Case Report and Literature Review.

Background: The relationship between varicella-zoster virus (VZV)-associated myelitis and aquaporin-4 immunoglobulin-G (AQP4-IgG) remains unknown. Case Report: We report a case of acute radiculomyelitis with longitudinal extensive hyperintensity signals traversing the brainstem until the upper thoracic cord in a 55-year-old healthy woman following herpes zoster infection in the left C4-T3 dermatome. VZV-specific IgG in the cerebrospinal fluid (CSF) and AQP4-IgG positivity on enzyme-linked immunosorbent assay (ELISA) were undetectable. Thus, she was diagnosed with immune-competent VZV radiculomyelitis. Forty-two months later, she experienced a relapse, and AQP4-IgG positivity was detected on ELISA. A cell-based assay (CBA) showed AQP4-IgG positivity not only at the time of recurrence but also retrospectively at 1 month after the initial symptoms. We concluded that AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) was concurrent with VZV myelitis. After the second attack, she was treated with azathioprine and has had no relapse since then. Conclusion: We reported a case of VZV radiculomyelitis with confirmed concurrent AQP4-IgG positivity. NMOSD induced by herpes zoster has been recently identified, but distinguishing it from VZV myelitis can be difficult and whether these two diseases aggravate each other is unknown. Awareness of the potentially varied presentation of VZV myelitis can enable earlier recognition and proper treatment.

TDP-43 mutation in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Accumulating evidence has shown that 43kDa TAR-DNA-binding protein (TDP-43) is the disease protein in ALS and frontotemporal lobar degeneration. We previously reported a familial ALS with Bumina bodies and TDP-43-positive skein-like inclusions in the lower motor neurons; these findings are indistinguishable from those of sporadic ALS. In three affected individuals in two generations of one family, we found a single base-pair change from A to G at position 1028 in TDP-43, which resulted in a Gln-to-Arg substitution at position 343. Our findings provide a new insight into the molecular pathogenesis of ALS.

Cervico-shoulder dystonia following lateral medullary infarction: a case report and review of the literature.

BACKGROUND: Secondary cervical dystonia is induced by organic brain lesions involving the basal ganglia, thalamus, cerebellum, and brain stem. It is extremely rare to see cervical dystonia induced by a medullary lesion. CASE PRESENTATION: We report a case of an 86-year-old Japanese woman who developed cervical dystonia following lateral medullary infarction. She developed sudden-onset left upper and lower extremity weakness, right-side numbness, and dysarthria. Brain magnetic resonance imaging revealed an acute ischemic lesion involving the left lateral and dorsal medullae. A few days after her stroke, she complained of a taut sensation in her left neck and body, and cervico-shoulder dystonia toward the contralateral side subsequently appeared. Within a few weeks, it disappeared spontaneously, but her hemiplegia remained residual. CONCLUSIONS: To date, to the best of our knowledge, there has been only one reported case of cervical dystonia associated with a single medullary lesion. It is interesting to note the similarities in the clinical characteristics of the previously reported case and our patient: the involvement of the dorsal and caudal parts of the medullary and associated ipsilateral hemiplegia. The present case may support the speculation that the lateral and caudal regions of the medulla may be the anatomical sites responsible for inducing cervical dystonia.

Deep cerebral venous thrombosis mimicking influenza-associated acute necrotizing encephalopathy: a case report.

BACKGROUND: Acute necrotizing encephalopathy is one of the most devastating neurological complications of influenza virus infection. Acute necrotizing encephalopathy preferentially affects the thalamus bilaterally, as does deep cerebral venous thrombosis, which can lead to misdiagnosis. CASE PRESENTATION: A 52-year-old Japanese woman infected with seasonal influenza B virus presented to the emergency care unit in our hospital with progressive alteration of her level of consciousness. Bilateral thalamic lesions were demonstrated by magnetic resonance imaging, leading to a tentative diagnosis of acute necrotizing encephalopathy. However, she had deep cerebral venous thrombosis, and the presence of diminished signal and enlargement of deep cerebral veins on T2*-weighted imaging contributed to a revised diagnosis of deep cerebral venous thrombosis. Anticoagulant therapy was initiated, leading to her gradual recovery, with recanalization of the deep venous system and straight sinus. CONCLUSIONS: To the best of our knowledge, these results represent the first report of deep cerebral venous thrombosis associated with influenza infection. It is clinically important to recognize that deep cerebral venous thrombosis, although rare, might be one of the neurological complications of influenza infection. In the presence of bilateral thalamic lesions in patients with influenza infection, deep cerebral venous thrombosis should be considered in addition to acute necrotizing encephalopathy. Delays in diagnosis and commencement of anticoagulant therapy can lead to unfavorable outcomes.

Acute psychosis as an initial manifestation of hypothyroidism: a case report.

INTRODUCTION: Hypothyroidism is one of the most important causes of treatable dementia, and psychosis occasionally associated with it is known as myxedema madness. We report a case of a 90-year-old patient who developed myxedema madness acutely without overt clinical symptoms and signs suggestive of hypothyroidism. CASE PRESENTATION: A 90-year-old Japanese man, a general practitioner, was admitted to our emergency room because of acute-onset lethargy, delusions, and hallucinations. He had been actively working until 3 days before the admission. Upon admission, his general physical examination was unremarkable. However, a blood investigation showed the presence of hypothyroidism, and computed tomography revealed pleural effusion and ascites. Electroencephalography revealed diffuse slow waves with a decrease of α-wave activity. A single-photon emission computed tomography scan revealed a decrease of cerebral blood flow in both frontal lobes. The patient was soon treated with thyroid hormone replacement therapy. Following normalization of his thyroid function, both pleural effusion and ascites diminished and his electroencephalographic activity improved simultaneously; however, he did not recover from his psychosis. CONCLUSIONS: Myxedema madness should be kept in mind in the differential diagnosis of acute psychosis in elderly patients, particularly the oldest patients as in our case, because manifestations of hypothyroidism often may be indistinguishable from the aging process.

A CLCN1 mutation in dominant myotonia congenita impairs the increment of chloride conductance during repetitive depolarization.

Myotonia congenita is caused by mutation of the CLCN1 gene, which encodes the human skeletal muscle chloride channel (ClC-1). The ClC-1 protein is a dimer comprised of two identical subunits each incorporating its own separate pore. However, the precise pathophysiological mechanism underlying the abnormal ClC-1 channel gating in some mutants is not fully understood. We characterized a ClC-1 mutation, Pro-480-Thr (P480T) identified in dominant myotonia congenita, by using whole-cell recording. P480T ClC-1 revealed significantly slowed activation kinetics and a slight depolarizing shift in the voltage-dependence of the channel gating. Wild-type/mutant heterodimers exhibited similar kinetic properties and voltage-dependency to mutant homodimers. Simulating myotonic discharge with the voltage clamp protocol of a 50 Hz train pulse, the increment of chloride conductance was impaired in both wild-type/mutant heterodimers and mutant homodimers, clearly indicating a dominant-negative effect. Our data showed that slow activation gating of P480T ClC-1 impaired the increment of chloride conductance during repetitive depolarization, thereby accentuating the chloride conductance reduction caused by a slight depolarizing shift in the voltage-dependence of the channel gating. This pathophysiology may explain the clinical features of myotonia congenita.

PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy.

Mutations in PTEN-induced putative kinase 1 (PINK1) cause recessive form of Parkinson's disease (PD). PINK1 acts upstream of parkin, regulating mitochondrial integrity and functions. Here, we show that PINK1 in combination with parkin results in the perinuclear mitochondrial aggregation followed by their elimination. This elimination is reduced in cells expressing PINK1 mutants with wild-type parkin. Although wild-type PINK1 localizes in aggregated mitochondria, PINK1 mutants localization remains diffuse and mitochondrial elimination is not observed. This phenomenon is not observed in autophagy-deficient cells. These results suggest that mitophagy controlled by the PINK1/parkin pathway might be associated with PD pathogenesis.

Chronological changes in MRI and CSF biochemical markers in Creutzfeldt-Jakob disease patients.

BACKGROUND: There are currently no markers for evaluating chronological changes in Creutzfeldt-Jakob disease (CJD). We examined if chronological changes in biochemical markers in cerebrospinal fluid (CSF) and diffusion-weighted magnetic resonance imaging (DWI) were utilizable for this purpose. METHODS: Ten independent patients were divided into two groups of 5 patients each. We analyzed CSF biochemical markers, DWI and the clinical course in one group. In the remaining group, only the CSF biochemical markers were analyzed before and after the onset of akinetic mutism. RESULTS: The level of total tau (t-tau) protein in CSF in the early phase after disease onset was 2,655 +/- 423.9 pg/ml, reaching a mean peak of 14,675 +/- 1,240 pg/ml in the middle phase and gradually declining after that. Just before patients deteriorated into akinetic mutism, t-tau protein titers reached a maximum (8,786 +/- 2,975 pg/ml). There were dramatic changes in t-tau protein levels throughout the clinical course, unlike the other markers. DWI was not always utilizable, because of discordance with clinical symptoms seen in this study. Four cases exhibited peaks in t-tau protein levels while the patients fell into akinetic mutism except 1 case. CONCLUSION: Our results suggest that t-tau protein is the most sensitive marker of disease progression in CJD patients.

TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation.

Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.