Background Patients with Parkinson’s disease (PD) frequently develop cardiovascular autonomic dysfunctions, including blood pressure (BP) fluctuations and orthostatic hypotension (OH) in the early stage, and hallucinations or cognitive impairment in the middle stage to late stage. The current study aimed to determine whether OH, BP fluctuations and cerebral white matter hyperintensities (WMHs) on MRI are associated with the development of hallucinations and cognitive impairment.Methods In this joint cross-sectional case–control study conducted across two institutions, we analysed the systolic BP coefficient of variation (SBP-CV) and nocturnal BP dipping using ambulatory BP monitoring and OH prevalence in 121 patients with PD and 21 hospital controls. The association between these factors and hallucinations/psychosis or cognitive impairment was analysed using multivariable logistic regression models. Then, we conducted mediation analyses of the relationship between abnormal BP fluctuations and cognitive impairment in PD, with WMHs evaluated using the Fazekas scale as the intermediate factor.Results Patients with PD were characterised by large SBP-CV without pulse rate-CV elevation, neurogenic OH and riser pattern of nocturnal BP dipping. Neurogenic OH was significantly associated with hallucinations/psychosis (adjusted OR: 6.22; 95% CI 2.47 to 15.64; p<0.001), and large SBP-CV was significantly associated with hallucinations/psychosis (adjusted OR: 2.15; 95% CI 1.32 to 3.53/5 points; p=0.002) and cognitive impairment (adjusted OR: 1.79; 95% CI 1.15 to 2.78/5 points; p=0.010). Periventricular hyperintensity (PVH) was associated with cognitive impairment (adjusted OR: 5.80; 95% CI 1.81 to 18.61; p=0.003), but not with BP fluctuations. The ORs for SBP-CV in cognitive impairment in PD were very similar across multivariable analyses that included PVH or deep WMH as mediator variables.Conclusions Large BP fluctuations in PD were associated with hallucinations and cognitive impairment, but WMHs did not mediate this relationship.

Adult-onset neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease that is pathologically characterized by eosinophilic hyaline intranuclear inclusions, mainly in astrocytes, and cerebral white matter degeneration. However, the pathogenesis underlying these neuropathological findings remains unclear. We previously reported an autopsy case of adult-onset NIID with characteristic perivascular findings. In that case, the perivascular areas were preserved despite cerebral white matter damage but dense glial fibrillary acidic protein-immunoreactive astrocytic processes were observed around the blood vessels. The present study examined 2 additional cases and confirmed that the above findings were common in patients with adult-onset NIID. To investigate the underlying pathophysiology behind these findings, immunohistochemistry was performed for proteins located in the astrocytic end-feet. In the cerebral white matter of all NIID cases, there was an altered distribution of aquaporin 4 (AQP4) with increased AQP4-immunopositive areas compared to control cases. These results suggest that the interaction between astrocytes and blood vessels, particularly involving water homeostasis, may be impaired in the cerebral white matter of patients with NIID.

Lateral trunk flexion is a common form of postural abnormality in Parkinson's disease and could be associated with verticality misperception. However, the mechanisms underlying lateral trunk flexion and verticality misperception in Parkinson's disease remain unclear. In the current study, we examined whether lateral trunk flexion is associated with verticality misperception in patients with Parkinson's disease. We also identified the brain regions involved in lateral trunk flexion and altered verticality perception. In this cross-sectional study, we evaluated the verticality perception using the subjective visual vertical test in 81 patients with Parkinson's disease and 14 age-matched healthy controls. According to the 97.5th percentile upper reference limit of the body tilt angle in the healthy controls, patients with Parkinson's disease were grouped into 37 patients with lateral trunk flexion and 44 patients without lateral trunk flexion. The mean of absolute subjective visual vertical angles was compared between patients with Parkinson's disease with lateral trunk flexion, those without lateral trunk flexion, and the healthy controls, and the impact of verticality misperception on lateral trunk flexion was evaluated using multivariate logistic regression models. We further performed a voxel-wise comparison of regional cerebral blood flow using N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography (height threshold of P < 0.001, uncorrected for multiple comparisons, extent threshold of 100 voxels) to identify the brain regions associated with lateral trunk flexion, and to investigate the relationship between verticality misperception and regional hypoperfusion. The mean of absolute subjective visual vertical angles was larger in patients with Parkinson's disease with and without lateral trunk flexion than in healthy controls (P < 0.001 and P < 0.001). Additionally, the subjective visual vertical angle was associated with the presence of lateral trunk flexion (odds ratio 2.25, 95% confidence interval 1.51-3.36, P < 0.001). The regional cerebral blood flow in patients with Parkinson's disease with lateral trunk flexion was decreased in the right inferior parietal lobule, right superior parietal lobule, right superior temporal gyrus, and right dorsal posterior cingulate cortex compared with those without lateral trunk flexion. The subjective visual vertical angle was inversely correlated with regional cerebral blood flow in these regions, except for the dorsal posterior cingulate cortex. Our study reveals that hypofunction in the right temporoparietal association cortices is involved in verticality misperception and the development of lateral trunk flexion in patients with Parkinson's disease. These results provide insights into potential therapeutic targets for addressing lateral trunk flexion.

BACKGROUND Carbamazepine (CBZ) is a common therapy for seizures, neuropathic pain, and painful tonic spasms following spinal cord disease; however, it is associated with rare autoimmune complications, including drug-induced lupus erythematosus (DILE). Diagnosis of DILE can be challenging, especially when onset occurs after a prolonged latency period. Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune disease characterized by recurrent inflammation of the central nervous system, frequently coexists with other autoimmune disorders. This report describes a case of DILE in a 61-year-old woman with NMOSD involving the cervical and thoracic spinal cord after 14 years of CBZ therapy. CASE REPORT A 61-year-old woman with aquaporin-4-IgG-positive NMOSD involving the cervical and thoracic spinal cords had received CBZ for 14 years to control painful tonic spasms. She presented with fatigue, weight loss, intermittent fever, and pleural effusion. Laboratory testing showed a high antinuclear antibody titer (1: 640) and elevated anti-single-stranded DNA, anti-DNA, and anti-histone antibodies. Chest imaging demonstrated pleural effusion and pleural thickening; malignancy and infection were excluded. Discontinuation of CBZ led to resolution of symptoms, normalization of inflammatory markers, and a decline in lupus-related autoantibodies, confirming the diagnosis of DILE. No recurrence was observed during a 30-month follow-up period. CONCLUSIONS This report describes a rare delayed-onset autoimmune adverse effect of CBZ that developed 14 years after treatment initiation. It highlights the importance of clinical awareness of potential autoimmune associations, particularly when CBZ is used in patients with preexisting autoimmune disorders such as NMOSD.

Objective: The aim of the RIN-2 study was a compassionate use of rituximab (RTX) for patients who completed the RIN-1 study, a multicentre, randomised, double-blind, placebo-controlled trial of RTX. We also investigated the long-term safety and efficacy of RTX. Methods: A study design was a prospective open-label extension study following the RIN-1 study. RTX was infused repeatedly under monthly monitoring of CD19-positive and CD 20-positive B cell lymphocyte subsets from 24 weeks after an infusion.Results: Thirty-three (87%) of 38 patients of the RIN-1 study were enrolled from February 2016 to March 2019 at six sites in Japan. In RIN-2, RTX was administered three times (median, range 1-5 times), and the interval of RTX administrations were 9.5 [2.5] months (mean [SD]). The observation period was 20.5 [10.1] months. During the trial, three patients dropped out due to two withdrawals and one adverse event. During the study, 28 (90%) of 31 patients were treated with RTX monotherapy. Neuromyelitis optica (NMO) relapses were observed in two patients. The annualized relapse rate (ARR) was 0.035 counts per person-years, ~1/10th compared with 0.321 in the placebo arm of the RIN-1 study. We observed 14 severe adverse events in six (18%) and 156 adverse events, of which 135 were grade 1, 11 were grade 2 and 10 were grade 3.Conclusions: Under B cell monitoring, the interval of RTX re-infusion was elongated to nine months, and NMO relapses were suppressed with 0.035 of ARR.

Background Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). Research design and methods The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. Results A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein epsilon 4 carriers, but not in non-carriers, and the factor interaction (intervention x epsilon 4 genotype) was highly significant (P< 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57],P= 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P= 0.048). Conclusions Cognitive function deteriorated in epsilon 4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

In The Lancet Neurology, Masayuki Tahara and colleagues1Tahara M Oeda T Okada K et al.Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2020; 19: 298-306Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar reported the results of a trial comparing rituximab, an anti-CD20 monoclonal antibody, with placebo in patients with neuromyelitis optica spectrum disorder (NMOSD) who were seropositive for aquaporin 4 antibody. Patients from eight hospitals in Japan were randomly assigned to rituximab (n=19) or placebo (n=19). The primary outcome measure was time to first relapse within 72 weeks. Seven relapses were recorded in the placebo group versus none in the treatment group. Disease duration is recognised to have an effect on relapse rate in patients with NMOSD. Patients with shorter disease duration exhibit significantly higher relapse rates.2Tackley G O'Brien F Rocha J et al.Neuromyelitis optica relapses: race and rate, immunosuppression and impairment.Mult Scler Relat Disord. 2016; 7: 21-25Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar The average disease duration in Tahara and colleagues' study was 119 months in the treatment group and 80 months in the placebo group. As such, their analysis might provide an overestimate of rituximab-mediated relapse suppression. Tahara and colleagues do report that disease activity was in fact higher in the treatment group than in the placebo group in the 2 years preceding trial enrolment. However, little data regarding previous therapy—another factor influencing relapse rate2Tackley G O'Brien F Rocha J et al.Neuromyelitis optica relapses: race and rate, immunosuppression and impairment.Mult Scler Relat Disord. 2016; 7: 21-25Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar—are presented, making interpretation of baseline demographics difficult. Although patients taking alternative immunosuppression in the 3 months before treatment allocation were excluded from the study, this criterion leaves the past history of immunosuppression unknown. Exclusion of patients with recent plasma exchange or pulsed steroid therapy might further confound the differential baseline relapse rates. I declare no competing interests. Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trialRituximab prevented relapses for 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This study is limited by its small sample size and inclusion of participants with mild disease activity. However, our results suggest that rituximab could be useful maintenance therapy for individuals with NMOSD who are AQP4 antibody-positive. Full-Text PDF Factors affecting relapse rate in patients with neuromyelitis optica spectrum disorder – Authors' replyWe thank Fraser S Brown for his letter concerning disease activity and participant background in our randomised clinical trial (RIN-1 study)1 in patients with neuromyelitis optica spectrum disorder (NMOSD). Full-Text PDF

We read with interest the report in The Lancet Neurology by Masayuki Tahara and colleagues of the RIN-1 study,1Tahara M Oedo T Okada K et al.Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2020; 19: 298-306Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar a randomised placebo-controlled trial investigating the safety and efficacy of rituximab in patients with neuromyelitis optica spectrum disorder (NMOSD). Although several case series, open-label trials, and retrospective studies have shown efficacy of rituximab in patients with NMOSD,2Damato V Evoli A Iorio R Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis.JAMA Neurol. 2016; 73: 1342-1348Crossref PubMed Scopus (147) Google Scholar randomised trial data are scarce, and the RIN-1 study fills this evidence gap and is of considerable importance. The RIN-1 trial provides a dosing scheme for rituximab for clinicians treating patients with NMOSD,3Hartung H-P Aktas O Old and new breakthroughs in neuromyelitis optica.Lancet Neurol. 2020; 19: 280-281Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar but further clarification is needed. Tahara and colleagues propose a regimen that entails induction with a dose adjusted for body surface area every week for 4 weeks, followed by a maintenance phase of 1000 mg rituximab at visits eight and 14 (corresponding to 24 weeks and 48 weeks, respectively, after randomisation).1Tahara M Oedo T Okada K et al.Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2020; 19: 298-306Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar Tahara and colleagues outline that the maintenance doses were given every 2 weeks and without review of lymphocyte subset analysis, which differs from current clinical practice.4Ciron J Audoin B Bourre B et al.Recommendations for the use of rituximab in neuromyelitis optica spectrum disorders.Rev Neurol. 2018; 174: 255-264Crossref PubMed Scopus (35) Google Scholar, 5Kim S-H Kim W Li XF et al.Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years.Arch Neurol. 2011; 68: 1412-1420Crossref PubMed Scopus (220) Google Scholar Regarding the treatment effect, a secondary outcome of the RIN-1 trial was the rate of oral steroid reduction, which was 75·1% for patients assigned rituximab and 65·3% in those allocated placebo.1Tahara M Oedo T Okada K et al.Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2020; 19: 298-306Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar According to Tahara and colleagues, the oral prednisolone dose was fixed between visits two and four, then reduced by 10% every visit to 2 mg/day. It is unclear to us how the rate of reduction could differ between the two groups. More detail is needed if steroid dosing was increased (and for what duration) for possible relapses, or other indications, during the trial period. In view of the robust evidence base supporting rituximab as a treatment option for patients with NMOSD, further randomised controlled trials assessing the efficacy of rituximab are unlikely to be undertaken. In this context, Tahara and colleagues have a unique opportunity to clarify and refine their findings to guide clinicians in their treatment of NMOSD. We declare no competing interests.

Background Pharmacological prevention against relapses in patients with neuromyelitis optica spectrum disorder (NMOS D) is developing rapidly. We aimed to investigate the safety and efficacy of rituximab, an anti-C D20 monoclonal antibody, against relapses in patients with NMOSD. Methods We did a multicentre, randomised, double-blind, placebo-controlled clinical trial at eight hospitals in japan. Patients aged 16-80 years with NMOSD who were seropositive for aquaporin 4 (AQP4) antibody, were taking 5-30 mg/day oral steroids, and had an Expanded Disability Status Scale (EDSS) score of 7.0 or less were eligible for the study. Individuals taking any other immunosuppressants were excluded. Participants were randomly allocated (1:1) either rituximab or placebo by a computer-aided dynamic random allocation system. The doses of concomitant steroid (converted to equivalent doses of prednisolone) and relapses in previous 2 years were set as stratification factors. Participants and those assessing outcomes were unaware of group assignments. Rituximab (375 mg/m(2)) was administered intravenously every week for 4 weeks, then 6-month interval dosing was done (1000 mg every 2 weeks, at 24 weeks and 48 weeks after randomisation). A matching placebo was administered intravenously. Concomitant oral prednisolone was gradually reduced to 2-5 mg/day, according to the protocol. The primary outcome was time to first relapse within 72 weeks. Relapses were defined as patient-reported symptoms or any new signs consistent with CNS lesions and attributable objective changes in MRI or visual evoked potential. The primary analysis was done in the full analysis set (all randomly assigned patients) and safety analyses were done in the safety analysis set (all patients who received at least one infusion of assigned treatment). The primary analysis was by intention-to-treat principles. This trial is registered with the UMIN clinical trial registry, UMIN000013453. Findings Between May 10, 2014, and Aug 15, 2017, 38 participants were recruited and randomly allocated either rituximab (n=19) or placebo (n=19). Three (16%) patients assigned rituximab discontinued the study and were analysed as censored cases. Seven (37%) relapses occurred in patients allocated placebo and none were recorded in patients assigned rituximab (group difference 36.8%, 95% CI 12- 3-65. 5; log-rank p=0.0058). Eight serious adverse events were recorded, four events in three (16%) patients assigned rituximab (lumbar compression fracture and infection around nail of right foot [n=1], diplopia [n=1], and uterine cancer In=11) and four events in two (11%) people allocated to placebo (exacerbation of glaucoma and bleeding in the right eye chamber after surgery and visual impairment and asymptomatic white matter brain lesion on MRI En=11); all patients recovered. No deaths were reported. Interpretation Rituximab prevented relapses for 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This study is limited by its small sample size and inclusion of participants with mild disease activity. However, our results suggest that rituximab could be useful maintenance therapy for individuals with NMOSD who are AQP4 antibody-positive. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

INTRODUCTION:Patients with Parkinson's disease (PD) frequently lose weight, even in the early stages of the disease. Our objective was to clarify the association between low body mass index (BMI) and life prognosis in PD. METHODS:We conducted a retrospective cohort study of 651 PD patients (380 females), with a primary endpoint of survival. Because of sex differences in BMI, male and female data were separated. We compared survival times between underweight (BMI < 18.5) and non-underweight (BMI ≥ 18.5) patients and calculated hazard ratios (HRs) adjusted for other relevant factors. To investigate the semi-quantitative relationship between relative risk of death and BMI, we divided patients into lower, middle, and upper thirds of BMI and calculated the HRs of the lower and upper thirds, with reference to the middle third. RESULTS:Seventy-nine patients (41 females) died over a mean (standard deviation) observation period of 39 (26) months. Underweight patients had poorer life prognosis than non-underweight patients and the difference was larger in males than in females (adjusted HR 3.8 (95% confidence interval 1.9-7.9) in males and 1.8 (0.9-3.5) in females). In males, the relationship between survival and BMI was much poorer in the bottom third and slightly poorer in the top third compared with the middle third. In females, the higher the BMI, the better the survival prognosis; however, the difference was not statistically significant. CONCLUSION:Low BMI had a significant impact on the life prognosis of PD patients, especially males.

Introduction A number of video-fluoroscopic swallowing study (VFSS) abnormalities have been reported in patients with Parkinson's disease (PD). However, the most crucial finding of subsequent aspiration pneumonia has not been validated fully. We conducted a retrospective and case-control study to determine the clinically significant VFSS findings in this population, and to propose a practical scale for predicting aspiration pneumonia in patients with PD. Methods We enrolled 184 PD patients who underwent VFSS because of suspected dysphagia. The patients who developed aspiration pneumonia within six months of the VFSS were assigned as cases and the patients without aspiration pneumonia at six months were designated as controls. Logistic regression analysis was performed to determine the prognostic VFSS features based on the data of swallowing 3 mL of jelly, which were used to make a PD VFSS scale (PDVFS). The validity of the new PDVFS was evaluated by ROC analysis. Additionally, we used the survival time analysis to compare time to death between groups, stratified by the PDVFS score. Results Twenty-five patients developed aspiration pneumonia. Among the previously-proposed VFSS features, mastication, lingual motility prior to transfer, aspiration, and total swallow time were identified as significant prognostic factors. We combined these factors to form the PDVFS. The PDVFS score ranges from 0 to 12, with 12 being the worst. ROC analysis revealed 92% sensitivity and 82% specificity at a cutoff point of 3. The higher PDVFS group showed shorter time-to-death than the lower PDVFS group (log rank P = 0.001). Conclusion Our newly developed VFSS severity scale (based on jelly swallowing) for patients with PD was easy to rate and could predict subsequent aspiration pneumonia and poor prognosis in patients with PD.

ObjectivesBrain acetylcholine is decreased even in patients with cognitively preserved Parkinson’s disease (PD). We investigated whether early and long-term use of donepezil prevents psychosis in non-demented PD patients.MethodsA double-blinded, placebo-controlled trial was conducted. A total of 145 non-demented PD patients were randomly assigned to receive 5 mg/day donepezil (n=72) or placebo (n=73) for 96 weeks. Medications for PD were not restricted, but antipsychotic drugs were not permitted throughout the study. The primary outcome measure was survival time to psychosis that was predefined by Parkinson’s Psychosis Questionnaire (PPQ) B score ≥2 or C score ≥2. Secondary outcome measures included psychosis developing within 48 weeks, total PPQ score, Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) and subgroup analysis by apolipoprotein ε4 genotyping.ResultsKaplan-Meier curves for psychosis development were very similar between the two groups, and the Cox proportional hazard model revealed an adjusted HR of 0.87 (95%CI 0.48 to 1.60). The changes in MMSE and WMS-1 (auditory memory) were significantly better with donepezil than in placebo. In the subgroup analysis, donepezil provided an HR of 0.31 (0.11–0.86) against psychosis in 48 weeks for apolipoprotein ε4 non-carriers.ConclusionsAlthough donepezil provided beneficial effects on PPQ, MMSE and auditory WMS score changes in 2 years, it had no prophylactic effect on development of psychosis in PD. Apolipoprotein ε4 may suppress the antipsychotic effect of donepezil.Trial registration numberUMIN000005403.

Psychosis is a common non-motor complication in Parkinson disease, and affects the quality of life of patients and their care-givers. This psychosis is caused by intrinsic (pathological and genetic) and extrinsic factors. Pathological factors include the severity of Lewy body pathology, degeneration of cholinergic neurons and overstimulation of serotonin receptors. Genetic factors include apolipoprotein ε4, cholecystokinin genotyping, and glucocerebrosidase mutations. Extrinsic factors that trigger psychosis include systemic inflammation and medication of risky drugs. To prevent such psychosis, it is important to examine systemic infection, cease high-risk drugs, and then consider prescription of anti-psychotic drugs. This review is to discuss pathogenesis and therapeutic strategy of psychosis in Parkinson disease.

Introduction: Anxiety disorders are a common non-motor symptom of Parkinson's disease (PD) with a reported prevalence ranging from 20% to 50%. Although anxiety is associated with Parkinson's disease, anxiety disorders can begin before the onset of motor symptoms, and have been linked to a possible abnormality of dopaminergic, serotonergic, and adrenergic neurons that precedes motor disturbance. Area covered: Several studies have reported the pharmacological treatment of depression in PD, but none have been randomized clinical trials with a primary outcome measure of anxiety. Two trials showed that pharmacological intervention with tricyclic antidepressants or selective serotonin reuptake inhibitors proved beneficial in treating anxiety in PD. However, the effect size was modest. Anxiety is associated with off-periods and improved by L-Dopa, especially in patients with high levels of anxiety. Expert opinion: Decreasing off-periods is important for managing anxiety in patients with motor fluctuations. Minor suggestive data indicate that tricyclic antidepressants and selective serotonin reuptake inhibitors can be helpful with modest effect sizes, but the former can cause additional side effects. Only one study has examined the use of benzodiazepines to treat anxiety in PD, and benzodiazepines cannot be recommended because they increase the risk of falling. Further clinical studies for pharmacological intervention against anxiety are required.