Risk Factors for Therapeutic Intervention of Remdesivir in Mild to Moderate COVID-19-A Single-Center Retrospective Study of the COVID-19 Fourth Pandemic Period in Wakayama, Japan.

Background and Objectives: The incidence of coronavirus disease 2019 (COVID-19) has increased in Wakayama, Japan, due to the spread of the highly infectious B.1.1.7 variant. Before this event, the medical systems were almost unaffected. We aimed to assess the clinical characteristics of patients hospitalized with COVID-19 and the risk factors for therapeutic intervention of remdesivir during the fourth pandemic period in Wakayama, Japan. Materials and Methods: This single-center retrospective study enrolled 185 patients with mild to moderate COVID-19 hospitalized in our hospital without intensive care between 14 March and 31 May 2021. Results: In this period, 125 (67.6%) of the 185 patients had the B.1.1.7 variant. Sixty-three patients (34.1%) required remdesivir treatment. Age upon admission and length of hospitalization were significantly different between remdesivir treatment and careful observation groups (mean (standard deviation); 59.6 (14.7) versus 45.3 (20.6) years; p < 0.001 and median (interquartile range); 10 (9-12) versus 9 (8-10) years; p < 0.001). One patient was transferred to another hospital because of disease progression. At hospital admission, age ≥60 years (odds ratio (OR) 6.90, p < 0.001), a previous history of diabetes mellitus (OR 20.9, p = 0.002), B.1.1.7 variant (OR 5.30; p = 0.005), lower respiratory symptoms (OR 3.13, p = 0.011), headache (OR 3.82, p = 0.011), and fever ≥37.5 °C (OR 4.55, p = 0.001) were independent risk factors to require remdesivir treatment during the admission. Conclusions: Many patients with mild to moderate COVID-19 required the therapeutic intervention of remdesivir during the fourth pandemic period in Wakayama, Japan. From the clinical data obtained at admission, these risk factors could contribute to a prediction regarding the requirement of remdesivir treatment in cases of mild to moderate COVID-19.

Three-year follow-up of rheumatoid meningitis with matrix metalloprotease-9 levels in the serum and cerebrospinal fluid as indicators of disease activity: A case report.

Rheumatoid meningitis (RM) is an extra-articular complication of rheumatoid arthritis (RA). Although reports of RM sine arthritis exist, most patients with this presentation were diagnosed with RA within one year of RM onset. There are no established biomarkers reflecting the disease activity of RM. This case report highlights the elevation of matrix metalloprotease (MMP)-9 levels during the acute phase of RM and decline during remission. Additionally, this is the first case report of RA diagnosed three years after the onset of RM. It is important to further validate the utility of MMP-9 and conduct long-term follow-up of RM sine arthritis.

Effect of istradefylline on postural abnormalities in patients with Parkinson's disease: An association study of baseline postural angle measurements with changes in Unified Dystonia Rating Scale total score.

In our previous study, istradefylline treatment in patients with Parkinson's disease (PD) improved postural abnormalities (PAs), as seen from a decrease in the mean Unified Dystonia Rating Scale (UDRS) total score from week 0 to week 24. A subgroup analysis based on baseline clinical characteristics investigated the association between improvement in the UDRS total score and istradefylline treatment. However, the association between an objective assessment of PAs and improvement in the UDRS total score is unclear. This ad hoc analysis investigated the association between improvement in the UDRS total score after istradefylline treatment and baseline trunk and neck angles, objective assessments of PAs, measured from patients' photographs taken in the previous study. The patients (n = 31) were stratified into groups based on the trunk forward flexion angle (TFFA), trunk lateral flexion angle (TLFA), and neck flexion angle (NFA) values at baseline. From week 0 to week 24, significant improvements in the UDRS total score were found in median percent change (-8.33% [interquartile range: -43.97, 0.00], P = 0.039) in patients with equal to or above the median TFFA values, and in median change (-|1.50 [-9.25, 0.00], P = 0.015) and median percent change (-13.33% [-50.47, 0.00], P = 0.009) in patients with equal to or above the median TLFA values. Patients with more advanced PAs showed more consistent improvements in the UDRS total score with istradefylline. Baseline TFFA and TLFA values, which are objective values, may be useful to assess the istradefylline effectiveness in patients with PD and PAs.

[Varicella-zoster virus infection with concomitant lower cranial polyneuropathy in the absence of fever, headache and meningeal signs].

We present varicella-zoster virus (VZV) infection with concomitant lower cranial polyneuropathy in the absence of meningeal symptoms. Physical examination showed involvement of cranial nerves IX and X in Case 1 and of cranial nerves IX, X, and XI in Case 2. Cerebrospinal fluid (CSF) analysis revealed mild lymphocytic pleocytosis, normal protein levels, and absence of VZV-DNA based on polymerase chain reaction (PCR) analysis. Serum anti-VZV antibody testing showed positive results in both cases, which confirmed the diagnosis of VZV infection. VZV infection accompanied by lower cranial polyneuropathy is rare; therefore, it is important to consider VZV reactivation as an etiopathogenetic contributor to pharyngeal palsy and hoarseness. We emphasize the importance of serological analysis for precise diagnosis in VZV infection with multiple lower cranial nerve palsies because the VZV-DNA PCR test may show negative results in patients without meningitis symptoms or in those with normal CSF protein levels.

Predictive value of the neutrophil-to-lymphocyte ratio for treatment response in patients diagnosed with definite or probable autoimmune encephalitis/encephalopathy.

Introduction: Autoimmune encephalitis/encephalopathy (AE) is a complex and heterogeneous disease, making it difficult to predict the prognosis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential prognostic tool, but its usefulness remains a matter of debate. This study aimed to explore prognostic factors in cases of clinically definite or probable AE, including those with autoantibody-negative, or unknown status. Methods: Data on patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status, were retrospectively collected from the admission records of our department between January 2013 and December 2022. These patients were then categorized into either a good- or poor-response group, based on their short-term treatment response. Clinical characteristics, auxiliary examinations, and treatments were compared between the two groups. A multivariable logistic regression model was constructed to identify independent predictors of poor short-term treatment response by Akaike information criterion backward stepwise method. Results: A total of 31 patients were included in the final analysis, with 18 of them included in the poor-response group. In the univariable analysis, the poor-response group had a higher proportion of patients with a modified Rankin Scale (mRS) high score upon admission, female, epileptic seizures, or NLRs of 3.93 or higher than the good-response group (all p < 0.10). Furthermore, the multivariable logistic regression analysis revealed that the mRS score upon admission [OR: 5.51, 95% confidence intervals (CI): 1.29-23.50, p = 0.02], epileptic seizures (OR: 10.01, 95% CI: 1.16-86.66, p = 0.04), and NLRs of 3.93 or higher (OR: 11.37, 95% CI: 1.12-114.68, p = 0.04) were significantly associated with poor short-term treatment response. Conclusion: The NLR may play a supplementary role in predicting the short-term treatment response in patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status.

Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

Acute Oropharyngeal Palsy Following Bilateral Adie's Tonic Pupils Associated with Anti-GT1a and GQ1b IgG Antibodies.

A 36-year-old man was admitted to our hospital with complaints of dysphagia and photophobia. A neurological examination showed oropharyngeal palsy and bilateral mydriasis with loss of light reflexes in the absence of external ophthalmoplegia. Bilateral pupils were supersensitive to pilocarpine 0.1%, which was compatible with Adie's tonic pupils. Serum IgG reacted with GQ1b, GT1a, GalNAc-GD1a, and GD3. Intravenous high-dose immunoglobulin therapy improved his neurological symptoms within three weeks. To our knowledge, there is no medical literature describing acute oropharyngeal palsy with Adie's tonic pupils. We recommend evaluating antiganglioside antibodies to clarify the cause of oropharyngeal palsy and Adie's tonic pupils.

Efficacy and safety of istradefylline in patients with Parkinson's disease presenting with postural abnormalities: Results from a multicenter, prospective, and open-label exploratory study in Japan.

Postural abnormalities in Parkinson's disease (PD) can devastatingly impair the quality of life, especially in patients with advanced disease, and are generally refractory to dopaminergic agents. The objective of this exploratory study was to investigate the efficacy and safety of istradefylline for the treatment of postural abnormalities in PD. In this open-label, 24-week, single-arm prospective trial, PD patients with postural abnormalities experiencing the wearing-off phenomenon on levodopa-containing therapies were enrolled and received a starting dose of 20 mg/day istradefylline orally for 4 weeks, which was then increased to 40 mg/day. The primary endpoint was the change from baseline to week 24 in the 14-item Unified Dystonia Rating Scale (UDRS) total score. Pivotal secondary endpoints were changes in the sub-items of UDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, and adverse drug reactions (ADRs). Overall, 24/31 enrolled patients completed the study; mean (standard deviation) age and duration of motor complications were 73.3 (7.7) years and 3.2 (4.4) years, respectively. Mean (95% confidence interval [CI]) change in the UDRS total score was 4.84 (1.97, 7.71; P = 0.002), with significant improvements in the neck, right distal arm and hand, and trunk severity scores. Mean (95% CI) change in the MDS-UPDRS part III score was 7.84 (4.34, 11.34; P < 0.001). The most common ADRs were malaise, dyskinesia exacerbation, and visual hallucinations in 2 (6.5%) patients each. This exploratory study demonstrated that istradefylline could be efficacious for postural abnormalities and was generally well tolerated in patients with PD experiencing the wearing-off phenomenon with levodopa-containing therapies.

Validation of the Japanese Version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS).

Introduction: The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (PD)-Rating Scale (QUIP-RS) was developed to assess the severity of impulsive and compulsive behaviors (ICBs) in PD. We aimed to validate the Japanese version of QUIP-RS and determine the characteristics of ICBs in Japan. Methods: We translated the QUIP-RS into Japanese, back-translated it to English, and obtained confirmation from the original author that the questionnaire remained appropriate. The participants for the validation study were 161 PD patients, identified by continuous sampling at two institutions, who were diagnosed with ICBs through a semistructured interview and completed the QUIP-RS-J. Sensitivity, specificity, and cutoff values were calculated using receiver operating characteristic (ROC) curves. Interinstitutional reliability and test-retest reliability were also assessed for a subset of participants. Results: Twenty-six (16.1%) participants were diagnosed with ICB. The optimal cutoff value of the QUIP-RS-J total score was 6, with area under the curve (AUC) = 0.889 and sensitivity/specificity of 0.92/0.71. Each subscale also showed high AUC (0.89-1.00), sensitivity (0.92-1.00), and specificity (0.71-1.00). Compared with the English version, the optimal cutoff point for binge eating was higher and hypersexuality lower. The total score tended to be higher when described by an informant. Conclusion: The present study validated the Japanese version of QUIP-RS. Use of QUIP-RS-J enables standardized assessment of ICBs and can be used in clinical research, including international multicenter studies.

An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

Effects of zonisamide on experimental tremors in rats.

OBJECTS: To study the effect of zonisamide on experimental tremors in rats. METHODS: Effect of zonisamide on harmaline- or oxotreorine-induced tremors, and tacrine-induced tremulous jaw movements (TJMs) was studied. RESULTS: Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors dose-dependently. Zonisamide also significantly suppressed tacrine-induced TJMs, and this effect was not lost under conditions of monoamine-depletion or dopaminergic blockade. CONCLUSION: The anti-tremor effects of zonisamide may be achieved by a non-dopaminergic mechanism. Since it effectively suppressed tremors that are based on different kinds of tremors, we propose a novel perspective of clinical potential of zonisamide as a non-specific, anti-tremor drug.

[Amyotrophic lateral sclerosis associated with extrapyramidal symptoms or signs].

This investigation was conducted to clarify the frequency and characteristics of ALS associated with extrapyramidal symptoms or signs in Wakayama prefecture. The questionnaires to survey ALS cases were mailed to all medical centers in Wakayama prefecture. A total of 252 cases were found to have motor neuron diseases. Among them, 204 cases fulfilled probable or definite according to El Escorial Criteria. In 10 of them, extrapyramidal signs were identified as follows: rigidity 50%, tremor 40% and akinesia 10%. Family history of ALS in these cases (20%) is higher than expected in usual ALS, and all of them are negative for SOD-1 mutation. Dementia and autonomic nervous symptoms were observed in several cases. Incidence of extrapyramidal signs in ALS resulted in 4.8%. The incidence of extrapyramidal signs is more frequent than expected by chance, suggesting that the degeneration of basal ganglia and/or substantia nigra may not be so rare in ALS.

Neutron activation analysis of scalp hair from ALS patients and residents in the Kii Peninsula, Japan.

The aim of this study was to evaluate the accumulation of transition metals in the scalp hair of amyotrophic lateral sclerosis (ALS) patients in the Koza/Kozagawa/Kushimoto (K) area (K-ALS) in the Kii Peninsula, Japan. Metal contents were measured in the unpermed, undyed hair samples of 88 K-residents, 20 controls, 7 K-ALS patients, and 10 sporadic ALS patients using neutron activation analysis at the Research Reactor Institute, Kyoto University. A human hair standard and elemental standards were used as comparative standards. The contents of Zn, Mn, and V were higher, while that of S was lower in K-ALS patients than in the controls. The content of Mn in K-ALS patients negatively correlated with clinical durations. The content of Al was significantly higher in K-residents than in the controls, with 15.9 % of K-residents having high Mn contents over the 75th percentile of the controls. The contents of Zn, Mn, and V were high in the scalp hair of K-ALS patients and correlated with the content of Al. The accumulation of these transition metals may chronically increase metal-induced oxidative stress, which may, in turn, trigger the neuronal degeneration associated with K-ALS.

Sensorimotor hemiparesis with secondary cervical dystonia following lateral caudal medullary infarction without signs and symptoms of Wallenberg syndrome.

We report the case of an 84-year-old woman who suddenly developed motor and both superficial and deep sensory hemiparesis on the left side, and cervical dystonia with a head tilt to the right side. A brain MRI showed an infarct in the left lateral caudal medulla. It is clinically important to recognize that the lateral caudal medullary infarction appears without signs and symptoms of lower cranial nerve palsies commonly involved in Wallenberg syndrome.

T2-low signal intensity in the cortex in multiple system atrophy.

To determine the clinical significance of T2-low signal intensity in the cortex of patients presenting parkinsonism, T2-weighted magnetic resonance (MR) images of the cortex of patients with multiple system atrophy (MSA), Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and compared with those of patients with amyotrophic lateral sclerosis (ALS) and age-matched normal controls. The MR images were gathered and presented randomly to three neurologists who were blind to information on the patients. There was a significant increase in the frequency of T2-low signal intensity in the cortex of patients with ALS and MSA. Particularly in those with MSA, the T2-low signal intensity was observed not only in the motor cortex but also in the frontal association cortex. The cortical T2-low signal intensity in MSA might reflect the spread of degenerative processes in the cortex.

[Isolated finger flexion caused by continuous muscle fiber activity].

We report two patients who presented with progressive involuntary flexion of fingers. Both of them were women (Case 1 and 2 were 23 year old and 86 year old, respectively), and developed involuntary finger flexions, particularly of the ring and little fingers, following a localized pain of their hands and forearms. The other neurological findings were not present. There was no abnormal finding in their serum, and anti-voltage-gated potassium channel antibodies were negative. Nerve conduction velocity studies revealed no obvious peripheral neuropathy or conduction block. EMG studies revealed continuous muscle fiber activities only in the flexor digitorum superficialis muscles in both patients. Additionally, in Case 1, neuromyotonic discharges at frequencies of 100-200 Hz were recorded only from the flexor digitorum superficialis muscle. The present findings are likely to be similar to those of a novel form of focal neuromytonia reported recently as 'isolated finger flexion'.

[The frontal assessment battery at bed side(FAB) in patients with Parkinson's disease].

It is by no means easy to assess the frontal lobe function precisely in patients with neurological disorders. Recently, Dubois et al. (2000) reported a new bedside cognitive and behavioral battery for evaluating frontal lobe function. To evaluate the clinical efficacy of this frontal assessment battery at bedside (FAB), we performed both FAB and Hasegawa's dementia scale (HDS), a Japanese version of convenient clinical scaling of dementia resembling the Mini-Mental State Examination, in patients with Parkinson's disease (PD) and age-matched controls. The FAB global score was significantly lower in the PD patients compared to the controls. On the other hand, there was no significant difference in the scores of HDS between the PD patients and controls. In the PD patients, there was no correlation between the FAB scores and their age or duration of the illness. The FAB is likely to be useful and convenient battery for assessing frontal lobe function at bedside in the PD patients.

Environmental characteristics and oxidative stress of inhabitants and patients with amyotrophic lateral sclerosis in a high-incidence area on the Kii Peninsula, Japan.

OBJECTIVE: Although Oshima, in the Kii Peninsula of Japan, is located within a high incidence area of amyotrophic lateral sclerosis (ALS) (Koza/Kozagawa/Kushimoto area, K area), no patients with ALS were detected between 1960 and 1999. However, the incidence recently increased between 2000 and 2009. On Oshima, the source of drinking water was changed from a regional river/wells to the Kozagawa River in the K area in 1975. We speculate that this change in water source may have played a role in the recent increase in the incidence of ALS. The aim of this study is to find contributing factors that may have triggered the locally high incidence of ALS. METHODS: We investigated a possible association between the mineral content of drinking water and serum and oxidative stress markers among patients with ALS in the K area (K-ALS), residents of Oshima and controls. RESULTS: We found that the levels of Ca and Zn in the recent drinking water in Oshima are low and that the serum levels of Ca and Zn in the Oshima residents and patients with K-ALS were significantly lower, while the oxidative stress markers were significantly higher, than those of the controls. The serum Zn and urinary 8-OHdG/creatinine levels explained 60% and 58% of the variations among the three groups, respectively. The serum Zn levels were negatively correlated with the serum Cu levels in the patients with K-ALS, and the serum Cu levels exhibited a tendency to be positively correlated with the 8-OHdG/creatinine levels in both the patients with K-ALS (r: 0.64) and the residents free from K-ALS (r: 0.32, p<0.01). CONCLUSION: Taken together, we suggest that the low levels of Ca and Zn in the drinking water are possibly associated with an imbalance of metal metabolism in Oshima residents and an increase in oxidative stress markers in patients with K-ALS, although the causative relationship is not clear. This is a cross-sectional study, and a prospective study is needed in the future.

White matter hyperintensities in patients with multiple system atrophy.

INTRODUCTION: Although white matter hyperintensities (WMHs) are prevalent in the elderly, the clinical significance and the underlying pathophysiological mechanisms of WMHs in neurodegenerative disorders have not been fully clarified. OBJECTIVE: The present study aimed to determine the degree of WMHs in patients with multiple system atrophy (MSA), and analyze the predisposing factors for WMHs. METHODS: Two raters blinded to clinical information assessed cerebrovascular lesions in brain MRIs from patients with MSA and age-matched controls. Patients with Parkinson's disease (PD) were similarly studied as a disease control. The results obtained were compared with the clinical characteristics of the patients and statistically analyzed. RESULTS: WMHs in patients with MSA were statistically greater compared with PD patients or controls. There were no significant differences in either lacunar or territorial infarcts. Multiple linear regression analysis demonstrated that age, supine systolic blood pressure, and a drop in orthostatic blood pressure were significantly and independently correlated with WMH scores in MSA. CONCLUSIONS: The present study suggests that white matter is differentially involved in MSA. In addition to aging, cerebral hypoperfusions caused by fluctuations of blood pressure may be a significant contributing factor to WMHs in MSA, although the possibility that degenerative processes occurring in oligodendrocytes may be associated with WMHs should not be excluded.