A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Transcranial Direct Current Stimulation on Different Targets to Modulate Cortical Activity and Dual-Task Walking in Individuals With Parkinson's Disease: A Double Blinded Randomized Controlled Trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation to modulate cortical activity for improving motor function. However, the information of tDCS stimulation on different brain regions for dual-task walking and cortical modulation in Parkinson's disease (PD) has not yet been compared. OBJECTIVE: The objective of this study was to investigate the effects of different tDCS targets on dual-task gait performance and cortical activity in patients with PD. METHODS: A total of 36 participants were randomly assigned to primary motor cortex (M1) tDCS, dorsal lateral prefrontal cortex (DLPFC) tDCS, cerebellum tDCS, or Sham tDCS group. Each group received 20 min of tDCS stimulation, except for the Sham group. Gait performance was measured by the GAITRite system during dual-task walking and single walking. Corticomotor activity of the tibialis anterior (TA) was measured using transcranial magnetic stimulation (TMS). The functional mobility was assessed using the timed up and go (TUG) test. RESULTS: All participants showed no significant differences in baseline data. Following the one session of tDCS intervention, M1 (p = 0.048), DLPFC (p < 0.001), and cerebellum (p = 0.001) tDCS groups demonstrated significant improvements in dual-task gait speed compared with a pretest. The time × group interaction [F(3, 32) = 5.125, p = 0.005] was detected in dual-task walking speed. The post hoc Tukey's test showed that the differences in gait speed were between the Sham tDCS group and the DLPFC tDCS group (p = 0.03). Moreover, DLPFC tDCS also increased the silent period (SP) more than M1 tDCS (p = 0.006) and Sham tDCS (p = 0.002). CONCLUSION: The results indicate that DLPFC tDCS exerted the most beneficial effects on dual-task walking and cortical modulation in participants with PD. CLINICAL TRIAL REGISTRATION: [http://www.thaiclinicaltrials.org/show/TCTR20200909005], Thai Clinical Trials Registry [TCTR20200909005].

Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia.

The AFG3L2 gene encodes AFG3-like protein 2, which is a subunit of human mitochondrial ATPases associated with various cellular protease activities (m-AAA). The clinical spectrum of AFG3L2 mutations is broad. Dominant AFG3L2 mutations can cause autosomal dominant spinocerebellar ataxia type 28 (SCA28), whereas biallelic AFG3L2 mutations may lead to spastic ataxia 5 (SPAX5). However, the role of AFG3L2 mutations in autosomal recessive spinocerebellar ataxia (SCAR) remains elusive. The aim of this study is to delineate the clinical features and spectrum of AFG3L2 mutations in a Taiwanese cohort with cerebellar ataxia. Mutational analyses of AFG3L2 were carried out by targeted resequencing in a cohort of 133 unrelated patients with molecularly undetermined cerebellar ataxia. We identified one single patient carrying compound heterozygous mutations in AFG3L2, p.[R632*];[V723M] (c.[1894C > T];[2167G > A]). The patient has suffered from apparently sporadic and slowly progressive cerebellar ataxia, ptosis, and ophthalmoparesis since age 55 years. These findings expand the clinical spectrum of AFG3L2 mutations and suggest a new subtype of late-onset SCAR caused by biallelic AFG3L2 mutations.

Fibroblast Growth Factor 20 Gene Polymorphism in Parkinson's Disease in Asian Population: A Meta-Analysis.

Parkinson's disease (PD) is a neurodegenerative disease with the pathological hallmark of Lewy bodies and Lewy neurites composed of α-synuclein. The SNP rs591323 is one of the risk loci located near the FGF20 gene that has been implicated in PD. The variation of FGF20 in the 3' untranslated region was shown to increase α-synuclein expression. We examined the association of rs591323 with the risk of PD in a Taiwanese population and conducted a meta-analysis, including our study and two other studies from China, to further confirm the role of this SNP in Taiwanese/Chinese populations. A total of 586 patients with PD and 586 health controls (HCs) were included in our study. We found that the minor allele (A) and the AA + GA genotype under the dominant model are significantly less frequent in PD than in controls. The meta-analysis consisted of 1950 patients with PD and 2073 healthy controls from three studies. There was significant association between rs591323 and the risk of PD in the additive (Z = -3.96; p < 0.0001) and the dominant models (Z = -4.01; p < 0.0001). Our study results and the meta-analysis support the possible protective role of the rs591323 A allele in PD in Taiwanese/Chinese populations.

COVID-19 Vaccination for Persons with Parkinson's Disease: Light at the End of the Tunnel?

Several COVID-19 vaccines have recently been approved for emergency use according to governmental immunization programs. The arrival of these vaccines has created hope for people with Parkinson's disease (PD), as this can help to mitigate their risk of becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can lead to serious, life-threatening disease, at least among those with more advanced PD. However, both persons with PD and physicians looking after these individuals have expressed concerns about the vaccine's efficacy and safety in the specific context of PD and its symptomatic treatment. Here, we discuss our perspective on these concerns, based on our interpretation of the literature plus the unfolding experience with widespread vaccination in the population at large. Because the benefits and risks of COVID-19 vaccines do not appear to be different than in the general population, we recommend COVID-19 vaccination with approved vaccines to persons with PD, unless there is a specific contraindication. Some caution seems warranted in very frail and terminally ill elderly persons with PD living in long-term care facilities.

Colonic Leucine-Rich Repeat Kinase 2 Expression Is Increased and Associated With Disease Severity in Patients With Parkinson's Disease.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise a common genetic risk factor for Parkinson's disease (PD) and inflammatory bowel disease (IBD). We investigated the expression of LRRK2 in colonic biopsies obtained from a cohort of PD patients and healthy controls. METHODS: A cohort of 51 PD patients and 40 age- and gender-matched controls who have colonic biopsied samples were recruited. Among these participants, 26 individuals (12 PD patients and 14 controls) had a series of colon biopsies. For the patients with PD, the first biopsies were taken before the PD diagnosis. The colonic expression of LRRK2 was assayed by immunohistochemical staining. RESULTS: The fraction of LRRK2-positive cells among the total cell count in biopsied colonic tissues was significantly higher in PD patients than controls (0.81% ± 0.53% vs. 0.45% ± 0.39%; P = 0.02). Colonic LRRK2 immunoreactivity was higher in those with LRRK2 genetic variants compared to those with wild type LRRK2 (2.44% ± 1.15% vs. 0.21 ± 0.13%, P < 0.01). Age had no effect on LRRK2 expression (P = 0.96). LRRK2 expression correlated with disease severity in regards to motor symptoms measured by the UPDRS part III scores (r = 6335, P < 0.001) and cognitive dysfunction measured by the mini-mental status examination scores (r = -0.5774, P < 0.001). PD patients in the prodromal phase had a steeper increase in colonic LRRK2 expression compared to controls during the serial colon biopsy assessment (P < 0.01). CONCLUSION: Colonic LRRK2 expression was increased in PD patients compared to controls, and the expression level correlated with disease severity.

Tardive syndrome: An update and mini-review from the perspective of phenomenology.

Tardive syndrome (TS) is a group of movement disorders caused by the long-term use of dopamine receptor blocking agents. The phenotypic presentation of TS is diverse, ranging from the most well-characterized symptom of tardive dyskinesia to other symptoms, including dystonia, akathisia, myoclonus, parkinsonism, tremor, and tics. These tardive symptoms are distinct not only in their phenomenology but also in their clinical outcomes. However, our knowledge of the pathophysiology and management of TS is almost exclusively based on tardive dyskinesia. First-generation antipsychotics have a higher risk of inducing TS and have largely been replaced by second-generation antipsychotics with a lower risk of TS. However, patients with off-label use of second-generation antipsychotics are still at risk of developing TS. Thus, the management of TS remains a challenging and important issue for physicians. In this review, we update the information on the epidemiology, phenomenology, and treatment of TS from the perspective of the specific form of TS.

Genetic Analysis of EGLN1 C127S Variant in Taiwanese Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder related to nigrostriatal dopaminergic neuron degeneration and iron accumulation. As a cellular oxygen sensor, prolyl hydroxylase domain containing protein 2 (PHD2, encoded by egl-9 family hypoxia inducible factor 1, EGLN1) modifies hypoxia-inducible factor alpha (HIF-α) protein for proteasomal destruction under normoxic condition. In addition, 2-oxoglutarate- (OG-) dependent dioxygenase activity of PHD2 is involved in the oxygen and iron regulation of iron-responsive element binding protein 2 (IRP2) stability. Previously increased expression of EGLN1 was found in the substantia nigra of the parkinsonian brain. We investigated the possible role of c.380 G > C (p.C127S) of EGLN1 gene in Taiwanese patients with PD. 479 patients and 435 healthy controls were recruited. Polymerase chain reaction and BsmAI restriction enzyme analysis were applied for analysis. An association between CC genotype and reduced PD risk in the recessive model (CC vs. GG + GC) was found. Our study provides a link between EGLN1 c.380 G > C SNP and the development of PD.

Altered Gut Microbiome and Intestinal Pathology in Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder arising from an interplay between genetic and environmental risk factors. Studies have suggested that the pathological hallmarks of intraneuronal α-synuclein aggregations may start from the olfactory bulb and the enteric nervous system of the gut and later propagate to the brain via the olfactory tract and the vagus nerve. This hypothesis correlates well with clinical symptoms, such as constipation, that may develop up to 20 years before the onset of PD motor symptoms. Recent interest in the gut-brain axis has led to vigorous research into the gastrointestinal pathology and gut microbiota changes in patients with PD. In this review, we provide current clinical and pathological evidence of gut involvement in PD by summarizing the changes in gut microbiota composition and gut inflammation associated with its pathogenesis.

Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson's disease.

OBJECTIVE: Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson's disease (PD). Here, we evaluate gut microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD. METHODS: Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3-V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1ß, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls. RESULTS: Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 [95% confidence interval 0.474 to 0.758], P < 0.01). Altered microbiota was correlated with plasma concentrations of IFNγ and TNFα. There was a correlation between Bacteroides and plasma level of TNFα (rho = 0.638 [95% CI: 0.102-0.887], P = 0.02); and a correlation between Verrucomicrobia abundance and plasma concentrations of IFNγ (rho = 0.545 [95% CI - 0.043-0.852], P = 0.05). The elevated plasma cytokine responses were confirmed in an additional independent 120 patients with PD and 120 controls (TNFα: PD vs. control 8.51 ± 4.63 pg/ml vs. 4.82 ± 2.23 pg/ml, P < 0.01; and IFNγ: PD vs. control: 38.45 ± 7.12 pg/ml vs. 32.79 ± 8.03 pg/ml, P = 0.03). CONCLUSIONS: This study reveals altered gut microbiota in PD and its correlation with clinical phenotypes and severity in our population. The altered plasma cytokine profiles associated with gut microbiome composition alterations suggest aberrant immune responses may contribute to inflammatory processes in PD.

Anti-NMDAR encephalitis with ovarian teratomas: Review of the literature and two case reports.

OBJECTIVE: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a paraneoplastic syndrome associated with ovarian teratomas. Anti-NMDAR encephalitis patients typically present with prominent psychiatric symptoms, seizures, and involuntary movements; further, they rapidly progress to unresponsiveness with central hypoventilation and dysautonomia. CASE REPORT: This paper presents two anti-NMDAR encephalitis cases with ovarian teratomas and reviews 13 anti-NMDAR encephalitis clinical case reports in Taiwan, of which six involved ovarian tumors, five being mature teratomas. Patients presented with acute onset of psychiatric symptoms and subsequently developed coma within a few days. Anti-NMDAR encephalitis usually occurs in young women and is often associated with ovarian tumors, specifically teratomas. Ovarian cystectomy or oophorectomy was performed, which markedly improved cognitive function. CONCLUSION: Paraneoplastic neurological conditions associated with ovarian teratomas represent a fascinating disease process. Identifying the gynecological cause of a neurological condition, particularly in young women, followed by prompt treatment can remarkably improve clinical conditions and, thus, be lifesaving.

Impact of code stroke on thrombolytic therapy in patients with acute ischemic stroke at a secondary referral hospital in Taiwan.

BACKGROUND: Efficacy of thrombolytic therapy decreases with time elapsed from symptom onset. We sought to identify the impact of code stroke on the thrombolytic therapy. METHODS: Code stroke is activated by the emergency physician when a patient is eligible for thrombolytic therapy. We retrospectively reviewed patients with acute ischemic stroke between January 2011 and December 2014. RESULTS: In total, 1809 patients were enrolled. Code stroke was activated in 233 of 351 patients arriving at the emergency room (ER) within 3 h of symptom onset, and in 21 patients arriving >3 h. The sensitivity, specificity, and positive and negative predictive values of code stroke were 76%, 46%, 72%, and 51%, respectively. Thrombolytic therapy was provided to 58 patients, accounting for 3.4% of all cerebral infarcts. Code stroke was activated in 40 of these patients. The most common reasons for excluding thrombolytic therapy were: National Institute of Health Stroke Scale (NIHSS) < 6, intracranial hemorrhage (ICH), and age >80 years. Mean liaison-to-neurological evaluation time was only 6 min. Code stroke activation significantly reduced all the intervals, except for the onset-to-ER and door-to-order times. During the 4-year study period, there were significant reductions of the door-to-neurology liaison time by 28 min and door-to-laboratory time by 22 min. The proportion of door-to-needle time within 60 min improved from 33% in 2011 to 67% in 2014. Improved NIHSS scores during hospitalization were most prominent in tPA-treated patients. Symptomatic ICH occurred in 3.6% patients arriving within 3 h. Death occurred in 50% of patients received tPA treatment on family's request, and only 13% of those patients had favorable outcome. CONCLUSION: Code stroke is effective in reducing in-hospital delays. The accuracy of code stroke activation has acceptable sensitivity but low specificity. Rapid patient assessment by neurologists increases the number of patients eligible for thrombolytic therapy.

Common Neurological Disorders Involving Inpatient Liaisons at a Secondary Referral Hospital in Taiwan: A Retrospective Cross-Sectional Study.

BACKGROUND AND PURPOSE: The requirement for neurology liaison is increasing in accordance with the growing health care demands associated with aging populations. The aim of this study was to characterize the nature of neurological inpatient liaisons (NILs) to help plan for the appropriate use of neurology resources. METHODS: This was a retrospective cross-sectional study of NILs in a secondary referral hospital over a 12-month period. RESULTS: There were 853 neurological consultations with a liaison rate of 3% per admission case. Chest medicine, gastroenterology, and infectious disease were the three most frequent specialties requesting liaison, and altered consciousness, seizure, and stroke were the three most frequent disorders for which a NIL was requested. Infection was the most common cause of altered consciousness. Epilepsy, infection, and previous stroke were common causes of seizure disorders. Acute stroke accounted for 44% of all stroke disorders. Electroencephalography was the most recommended study, and was also the most frequently performed. Ninety-five percent of emergency consultations were completed within 2 hours, and 85% of regular consultations were completed within 24 hours. The consult-to-visit times for emergency and regular consultations were 44±47 minutes (mean±standard deviation) and 730±768 minutes, respectively, and were shorter for regular consultations at intensive care units (p=0.0151) and for seizure and stroke disorders (p=0.0032). CONCLUSIONS: Altered consciousness, seizure, and stroke were the most common reasons for NILs. Half of the patients had acute neurological diseases warranting immediate diagnosis and treatment by the consulting neurologists. Balancing increasing neurologist workloads and appropriate health-care resources remains a challenge.

A possible case of acute disseminated encephalomyelitis after Japanese encephalitis.

PURPOSE: Acute disseminated encephalomyelitis (ADEM) is a monophasic demyelination disease of central nervous system (CNS) with presentations of impaired consciousness, neurologic deficits and diffuse white matter lesions on magnetic resonance imaging (MRI). Predisposing infection can be identified in around 50 to 77% of all patients with ADEM. Post-infectious autoimmune events associated with Japanese encephalitis have been limited to case reports of Guillain-Barre syndrome after Japanese encephalitis and Japanese encephalitis virus vaccine-related ADEM. We herein report the first possible patient with Japanese encephalitis developed a subsequent ADEM after recovery from Japanese encephalitis. CASE REPORT: A 50-year-old man suffered from an acute onset of headache, fever, and disturbance of consciousness. Japanese encephalitis was diagnosed by virological and image study. He recovered gradually and was discharged about 1.5 months later. However, another episode of consciousness impairment with violent behavior occurred 21 days after discharge. Acute disseminated encephalomyelitis was confirmed by brain MRI which showed newly developed diffuse white matter lesions. His clinical symptoms and abnormal brain lesions on MRI improved gradually after combination of high-dose intravenous methylprednisolone and oral steroid therapy. CONCLUSION: Our patient is a possible case of ADEM developing after Japanese encephalitis. High dose steroid therapy resulted in good outcome of ADEM.

Genetic analysis of HLA-DRA region variation in Taiwanese Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder comprising both motor and cognitive disability. The pathogenesis of the disease is still unclear; however, neuroinflammation seemed to play a role. A recent genome-wide association study (GWAS) reported an association between HLA-DRA rs3129882 and the development of PD in Caucasian populations. In this study, we observe no association between this single nucleotide polymorphism and PD in a Taiwanese population. The possible reasons include different ethnicity with genomic differences and environmental factors in different geographical regions.

Analyses of transthyretin concentration in the cerebrospinal fluid of patients with Guillain-Barré syndrome and other neurological disorders.

BACKGROUND: Guillain-Barré syndrome (GBS) is an autoimmune inflammatory polyradiculoneuropathy that causes acute areflexic paralysis with a high risk of respiratory failure. Previously, using two-dimensional gel electrophoresis and mass spectrometry, we found that the transthyretin level was altered in the cerebrospinal fluid (CSF) of GBS patients when compared to that in CSF of control patients. METHODS: We used enzyme-linked immunosorbent assay (ELISA) to measure the transthyretin levels in the CSF and serum from 22 GBS, 4 Miller-Fisher syndrome (MFS), 9 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 22 multiple sclerosis (MS), 10 Alzheimer's disease (AD), and 6 viral meningitis (VM) patients, and 18 controls. RESULTS: The results show that CSF transthyretin concentration of the GBS patients is significantly higher than that of the control, MS, AD and VM patients (p<0.05), although not significantly different from that of MFS and CIDP patients. CONCLUSION: The increased CSF transthyretin level may be explained by barrier dysfunction or decreased CSF flow in the GBS patients along with increased intrathecal synthesis of transthyretin that might be a protective response to nerve damage.