Effects of theophylline on ADCY5 activation-From cellular studies to improved therapeutic options for ADCY5-related dyskinesia patients.

We show the effects of the three purine derivatives, caffeine, theophylline, and istradefylline, on cAMP production by adenylyl cyclase 5 (ADCY5)-overexpressing cell lines. A comparison of cAMP levels was performed for ADCY5 wild-type and R418W mutant cells. ADCY5-catalyzed cAMP production was reduced with all three purine derivatives, while the most pronounced effects on cAMP reduction were observed for ADCY5 R418W mutant cells. The gain-of-function ADCY5 R418W mutant is characterized by an increased catalytic activity resulting in elevated cAMP levels that cause kinetic disorders or dyskinesia in patients. Based on our findings in ADCY5 cells, a slow-release formulation of theophylline was administered to a preschool-aged patient with ADCY5-related dyskinesia. A striking improvement of symptoms was observed, outperforming the effects of caffeine that had previously been administered to the same patient. We suggest considering theophylline as an alternative therapeutic option to treat ADCY5-related dyskinesia in patients.

Low serum uric acid levels and levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND: Levodopa is the most used and effective medication for motor symptoms of Parkinson disease (PD), its long-term use is associated with the appearance of levodopa-induced dyskinesia (LID). Uric acid (UA) is believed to play an important neuroprotective role in PD. OBJECTIVE: To investigate if serum UA levels are related with the presence of LIDs in PD patients. Also, we investigated the associations among UA levels and clinical features of PD. METHODS: We enrolled 81 PD patients (dyskinesia = 48; no dyskinesia = 33) in the present study. A blood sample was collected to evaluate serum UA levels, clinical evaluation included the following instruments: Montreal Cognitive Assessment (MoCA), Beck Depression Inventory II (BDI-II), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (HY), and the sub-item 4.1 of MDS-UPDRS IV (score ≥ 1). Additional relevant clinical information was obtained by a clinical questionnaire. RESULTS: Serum UA levels were lower in the dyskinesia group when compared with the no dyskinesia group. The same result was found in the UA levels of both men and women. The multivariate analysis showed lower uric acid levels were significantly associated with having dyskinesia (odds ratio [OR] = 0.424; 95% confidence interval [CI]: 0.221-0.746; p = 0.005). Additional analysis verified that serum UA levels are inversely correlated with depressive symptoms, disease duration, MDS-UPDRS IV and time spent with dyskinesia. A positive correlation was found with age at onset of PD symptoms. CONCLUSIONS: The present study provides a possible role of serum UA levels in LID present in PD patients.

ANTECEDENTES: A levodopa é a medicação mais utilizada e eficaz para os sintomas motores da doença de Parkinson (DP); seu uso a longo prazo está associado ao aparecimento de discinesia induzida por levodopa (LID). Acredita-se que o ácido úrico desempenhe um importante papel neuroprotetor na DP. OBJETIVO: Investigar se os níveis séricos de AU estão relacionados com a presença de LID em pacientes com DP. Além disso, investigamos as associações entre os níveis de AU e as características clínicas da DP. MéTODOS: Foram incluídos 81 pacientes com DP (discinesia = 48; sem discinesia = 33) no presente estudo. Uma amostra de sangue foi coletada para avaliar os níveis séricos de AU, a avaliação clínica incluiu os seguintes instrumentos: Avaliação Cognitiva de Montreal (MoCA), Inventário de Depressão de Beck (BDI-II), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (HY) e o subitem 4.1 da MDS-UPDRS IV (escore ≥ 1). Informações clínicas relevantes adicionais foram obtidas por meio de um questionário clínico. RESULTADOS: Os níveis séricos de AU foram menores no grupo com discinesia quando comparados ao grupo sem discinesia. O mesmo resultado foi encontrado nos níveis de AU de homens e mulheres. A análise multivariada mostrou que níveis mais baixos de ácido úrico foram significativamente associados a ter discinesia (odds ratio [OR] = 0,424; intervalo de confiança (IC) de 95%: 0,221­0,746; p = 0,005). Análises adicionais verificaram que os níveis séricos de AU estão inversamente correlacionados com sintomas depressivos, duração da doença, MDS-UPDRS IV e tempo gasto com discinesia. Uma correlação positiva foi encontrada com a idade de início dos sintomas da DP. CONCLUSõES: O presente estudo fornece um possível papel dos níveis séricos de AU na LID presente em pacientes com DP.

Feasibility of a wearable inertial sensor to assess motor complications and treatment in Parkinson's disease.

BACKGROUND: Wearable sensors-based systems have emerged as a potential tool to continuously monitor Parkinson's Disease (PD) motor features in free-living environments. OBJECTIVES: To analyse the responsivity of wearable inertial sensor (WIS) measures (On/Off-Time, dyskinesia, freezing of gait (FoG) and gait parameters) after treatment adjustments. We also aim to study the ability of the sensor in the detection of MF, dyskinesia, FoG and the percentage of Off-Time, under ambulatory conditions of use. METHODS: We conducted an observational, open-label study. PD patients wore a validated WIS (STAT-ONTM) for one week (before treatment), and one week, three months after therapeutic changes. The patients were analyzed into two groups according to whether treatment changes had been indicated or not. RESULTS: Thirty-nine PD patients were included in the study (PD duration 8 ± 3.5 years). Treatment changes were made in 29 patients (85%). When comparing the two groups (treatment intervention vs no intervention), the WIS detected significant changes in the mean percentage of Off-Time (p = 0.007), the mean percentage of On-Time (p = 0.002), the number of steps (p = 0.008) and the gait fluidity (p = 0.004). The mean percentage of Off-Time among the patients who decreased their Off-Time (79% of patients) was -7.54 ± 5.26. The mean percentage of On-Time among the patients that increased their On-Time (59% of patients) was 8.9 ± 6.46. The Spearman correlation between the mean fluidity of the stride and the UPDRS-III- Factor I was 0.6 (p = <0.001). The system detected motor fluctuations (MF) in thirty-seven patients (95%), whilst dyskinesia and FoG were detected in fifteen (41%), and nine PD patients (23%), respectively. However, the kappa agreement analysis between the UPDRS-IV/clinical interview and the sensor was 0.089 for MF, 0.318 for dyskinesia and 0.481 for FoG. CONCLUSIONS: It's feasible to use this sensor for monitoring PD treatment under ambulatory conditions. This system could serve as a complementary tool to assess PD motor complications and treatment adjustments, although more studies are required.

Reliability and Discriminative Validity of Wearable Sensors for the Quantification of Upper Limb Movement Disorders in Individuals with Dyskinetic Cerebral Palsy.

Background-Movement patterns in dyskinetic cerebral palsy (DCP) are characterized by abnormal postures and involuntary movements. Current evaluation tools in DCP are subjective and time-consuming. Sensors could yield objective information on pathological patterns in DCP, but their reliability has not yet been evaluated. The objectives of this study were to evaluate (i) reliability and (ii) discriminative ability of sensor parameters. Methods-Inertial measurement units were placed on the arm, forearm, and hand of individuals with and without DCP while performing reach-forward, reach-and-grasp-vertical, and reach-sideways tasks. Intra-class correlation coefficients (ICC) were calculated for reliability, and Mann-Whitney U-tests for between-group differences. Results-Twenty-two extremities of individuals with DCP (mean age 16.7 y) and twenty individuals without DCP (mean age 17.2 y) were evaluated. ICC values for all sensor parameters except jerk and sample entropy ranged from 0.50 to 0.98 during reach forwards/sideways and from 0.40 to 0.95 during reach-and-grasp vertical. Jerk and maximal acceleration/angular velocity were significantly higher for the DCP group in comparison with peers. Conclusions-This study was the first to assess the reliability of sensor parameters in individuals with DCP, reporting high between- and within-session reliability for the majority of the sensor parameters. These findings suggest that pathological movements of individuals with DCP can be reliably captured using a selection of sensor parameters.

[Analysis of the risk factors for poor prognosis and recurrence in patients with anti-NMDAR encephalitis].

To investigate the risk factors of poor prognosis and recurrence in patients with anti-NMDAR encephalitis. A single center, observational cohort study was used to retrospectively analyze 44 patients with anti NMDAR encephalitis hospitalized in the Department of Neurology of Beijing Tong Ren Hospital from January 2014 to October 2020. The results showed that the interval from onset to immunotherapy in the poor prognosis group was significantly longer than that in the good prognosis group (t=2.045,P=0.047), and the course of disease in the poor prognosis group was significantly longer than that in the good prognosis group (t=4.127,P=0.000 2). The number of patients with clinical manifestations of dyskinesia was significantly increased (Fisher exact test: P=0.014). The patients with abnormal brain MRI in the poor prognosis group were significantly more than those in the good prognosis group (Fisher exact test: P=0.017), and the patients with slow wave>50% in the poor prognosis group were significantly more than those with slow wave <50% (Fisher exact test: P<0.001). Patients with the first onset of immunotherapy time <3 months, long course of disease, high intracranial pressure, and high cerebrospinal fluid protein are prone to relapse. Bivariate logistic regression analysis showed that patients with dyskinesia, abnormal brain MRI, and slow wave EEG more than 50% were risk factors for poor prognosis (OR values were 4.687, 4.978, and 24.500, respectively; P values were 0.018, 0.016, and 0.000, respectively). The time of first-line immunotherapy for the first onset<3 months was the risk factor for recurrence (OR 17.231, P=0.010). In conclusion, dyskinesia, abnormal brain MRI and slow wave of EEG more than 50% may be the risk factors for poor prognosis of patients. The duration of immunotherapy less than 3 months after the first onset might be the risk factor for recurrence.

Scapular Dyskinesis in the Athletic Patient: A Sport-Specific Review.

¼: Scapular dyskinesis is an alteration of normal scapular kinematics. It is essential that each patient be evaluated holistically and that sport-related factors be taken into account. ¼: The presentation of scapular dyskinesis may be highly variable depending on the underlying etiology or associated pathology, but the onset of symptoms is often gradual. ¼: Sport-specific literature on scapular dyskinesis is most commonly reported in the context of baseball, swimming, and tennis. Treatment is most often conservative and involves physical therapy directed at the scapular stabilizers.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Association between the General Movement Optimality Score and clinical features in newborns during hospitalization: A cross-sectional study.

AIMS: To describe the General Movements (GMs) of hospitalized newborns to verify if their global and detailed GMA are related and if their GMs are associated with clinical features. METHODS: Cross-sectional study. Thirty-eight preterm and full-term newborns, who were hospitalized in the neonatal intermediate care unit of a reference hospital, were included. Prechtl's General Movement Assessment (GMA), including the General Movement Optimality Score (GMOS) list, was used as an assessment tool. Clinical variables, such as preterm birth, birthweight, length of hospitalization, Apgar scores, pregnancy problems, admission at neonatal intensive care unit, use of invasive mechanical ventilation, and brain imaging findings were also collected. Newborns were videoed at a single time for 3 min before discharge. RESULTS: Most newborns presented GMs with normal or poor repertoire quality. GMOS ranged from 17 to 42 points. Scores were lower in abnormal GMs. Abnormal GMs were associated with preterm birth, length of hospital stay >30 days and birthweight <2500 g. Accordingly, lower GMOSs were also associated with preterm birth, a birthweight <2500 g and a hospital stay >30 days but also with the invasive mechanical ventilation application. CONCLUSION: Preterm and full-term newborns presented normal or abnormal GMs during hospitalization. Preterm birth, low birthweight, longer hospital stay and a time period of invasive ventilation were associated with worse GM behaviors.

Gut Microbiome Composition in Dystonia Patients.

Dystonia is a movement disorder in which patients have involuntary abnormal movements or postures. Non-motor symptoms, such as psychiatric symptoms, sleep problems and fatigue, are common. We hypothesise that the gut microbiome might play a role in the pathophysiology of the (non-)motor symptoms in dystonia via the gut-brain axis. This exploratory study investigates the composition of the gut microbiome in dystonia patients compared to healthy controls. Furthermore, the abundance of neuro-active metabolic pathways, which might be implicated in the (non-)motor symptoms, was investigated. We performed both metagenomic and 16S rRNA sequencing on the stool samples of three subtypes of dystonia (27 cervical dystonia, 20 dopa-responsive dystonia and 24 myoclonus-dystonia patients) and 25 controls. While microbiome alpha and beta diversity was not different between dystonia patients and controls, dystonia patients had higher abundances of Ruminococcus torques and Dorea formicigenerans, and a lower abundance of Butyrivibrio crossotus compared to controls. For those with dystonia, non-motor symptoms and the levels of neurotransmitters in plasma explained the variance in the gut microbiome composition. Several neuro-active metabolic pathways, especially tryptophan degradation, were less abundant in the dystonia patients compared to controls. This suggest that the gut-brain axis might be involved in the pathophysiology of dystonia. Further studies are necessary to confirm our preliminary findings.

Occurrence of involuntary movements after prolonged misuse of zolpidem: a case report.

Zolpidem is a non-benzodiazepine agent used for short-term treatment of insomnia. Several cases of dependence and withdrawal from zolpidem are reported in the literature. Furthermore, involuntary movements after prolonged zolpidem misuse have been described. In this case report, a 69-year-old Italian woman with no history of diagnosed psychiatric or neurologic diseases developed uncontrolled movements and a depressive-anxious syndrome after twelve-year zolpidem misuse. The underlying mechanisms of involuntary movements occurring after long-term zolpidem intake are unknown; yet, we suggest that zolpidem might induce an increase in dopamine release through inhibition of gamma-aminobutyric acid neurons tonically suppressing dopamine cells. Future studies on the occurrence of persistent disorders after long-term benzodiazepine or Z-drug abuse are needed and clinicians should pay attention to the risk of tardive syndromes related to zolpidem misuse, especially in the case of long-term intake of over-therapeutic dosages.

Efficacy of rehabilitation robot-assisted gait training on lower extremity dyskinesia in patients with Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND: Robot-assisted training is used as a new rehabilitation training method for the treatment of motor dysfunction in neurological diseases. Robot-assisted gait training (RAGT) has been reported to treat motor dysfunction in patients with Parkinson's disease (PD). The purpose of this study was to summarize previous clinical studies comparing the effectiveness of RAGT and conventional training for lower extremity dyskinesia in PD patients. METHODS: PubMed, Cochrane library, Scopus, Embase, EBSCO, Web of Science, CNKI, and Wanfang databases were searched. This study included all randomized controlled trials (RCTs) compared lower extremity RAGT with conventional training on motor impairment in PD patients. The retrieval time limit is from the establishment of the database to October 2022. Two researchers independently screened the literature, extracted data, assessed the risk of bias of included studies, and then used RevMan 5.3 software for meta-analysis. RESULTS: A total of 14 RCTs with 572 patients were included. The results showed that compared with the control group, RAGT significantly improved the motor function evaluation-related indicators 10MWT, 6MWT, TUG and UPDRS III, 10MWT [MD= 0.08, 95 % CI (0.01, 0.14), P = 0.03], 6MWT [MD= 42.83, 95 % CI (22.05, 63.62), P < 0.0001], TUG[MD= -1.81, 95 % CI (-2.55, -1.08), P < 0.0001], UPDRS III [MD= - 3.82, 95 % CI (-4.27, -3.37), P < 0.00001]; For the balance function evaluation index BBS [MD= 3.33, 95 % CI (2.76, 3.89), P < 0.00001], the above results were significantly different significance. CONCLUSION: The currently limited evidence suggests that RAGT provides evidence for the effectiveness of lower extremity motor function and balance dysfunction, and RAGT can significantly improve motor and balance function in PD patients.

Monochorea after acute contralateral pontine infarction: A case report.

RATIONALE: Chorea is a hyperkinetic movement characterized by random, brief, and involuntary muscle contractions. In stroke, a common cause of chorea, basal ganglia are anatomical locations that can cause chorea when a stroke occurs, and chorea is less frequently triggered by a stroke in other anatomical brain regions. Herein, we report a rare case of monochorea after acute contralateral pontine infarction. PATIENT CONCERNS: A 32-year-old man visited the emergency room due to dysarthria and right hemiparesis that occurred approximately 6 hours and 30 minutes before the visit. A brain magnetic resonance image confirmed a diffusion restriction lesion in the left pons. The patient was initially diagnosed with acute infarction at the left pons and began to receive medical treatment with an antiplatelet agent and statin with admission. DIAGNOSIS: Approximately 14 hours after the onset of the initial stroke symptoms, the patient complained of involuntary movement in the right arm for the first time. Intermittent, irregular involuntary movements were observed in the distal part of the right arm. This symptom was unpredictable and random, and a similar symptom was not observed in other parts of the patient's body. Clinically, post-stroke monochorea was suspected. INTERVENTIONS AND OUTCOMES: The symptom improved from day 5 without specific medical treatment for chorea. LESSONS: The monochorea caused by the pontine lesion in this case was triggered by the direct lesions of the corticospinal tract, and its underlying pathophysiology remains unclear. However, abnormal movements can occur due to inadequate downstream activation or inhibition of the corticospinal tract, which is induced by functional abnormalities of the motor cortex. This case suggests that further investigation is needed on the mechanisms of direct corticospinal tract lesions for chorea.

Mimic of transient ischemic attack by anemia-induced asterixis: A novel differential diagnosis of stroke with critical pitfalls.

As most cases of asterixis with metabolic causes are asymptomatic, they have not been considered in the differential diagnosis of stroke. However, an asterixis occasionally resembles a transient ischemic attack (TIA). On the other hand, reports have indicated that anemia is an independent risk factor for brain ischemia. Therefore, both asterixis and anemia are important considerations for stroke diagnosis. A 79-year-old man with frequent leg palsy was initially diagnosed with recurrent TIA at the anterior cerebral artery (ACA) with a tiny callosal infarction and aspirin was prescribed immediately. However, subsequent careful physical examination revealed asterixis at both the wrist and knee joints. Laboratory testing and colonoscopy revealed severe anemia secondary to colon cancer. Blood transfusion immediately improved the asterixis and gait, thus confirming that anemia contributed to the patient's symptoms. This novel etiology of asterixis may be accompanied by misleading anemia-induced brain ischemic lesions detectable on magnetic resonance imaging (MRI). Anemia-induced asterixis should be considered as a novel differential diagnosis of a stroke to avoid pitfalls leading to unnecessary stroke treatment for patients with anemia.

[Encephalopathy GNAO1]. / Entsefalopatiya GNAO1.

OBJECTIVE: To study the clinical picture of all patients with GNAO1 encephalopathy detected in the Russian Federation. This publication is a multicenter study combining data from epileptological centers in Moscow, Novosibirsk, St. Petersburg, Nizhny Novgorod, Tyumen. MATERIAL AND METHODS: Nine patients were included, aged 2 to 19 years, with 4 mutations. Male to female sex ratio = 5:4. RESULTS: 8 patients (5 with mutation c.607G>A (p.Gly203Arg), 1 - c.155A>G (Gln52Arg), 1 - c.485G>A (p.Arg162Gln)) had a variant of epileptic encephalopathy, developmental encephalopathy, 1 patient had torsion dystonia without epilepsy (mutation c.713A>G (p.Asp238Gly)). Epileptic seizures in 8 children with epileptic encephalopathy GNAO1 in 100% debuted at 1 month of life, becoming the earliest symptom of the disease. Motor development delayed in 100% of cases. Mental development was not affected only in the case of the dystonic variant. Hyperkinesis (dystonia, choreoathetosis, ballism) followed later, from 2 to 8 months. They were more severe than epilepsy. 4 patients with the c.607G>A (p.Gly203Arg) mutation developed repeated dystonic storms that were resistant to most drugs. CONCLUSION: Epilepsy in GNAO1 is difficult to treat, but temporary or complete remission is possible. Effective drug strategies for the treatment of hyperkinesis have not yet been developed. Expansion of indications for surgical therapy (DBS) of hyperkinesis in this syndrome is desirable.

Development of a Clinical Framework for the Assessment of Dyskinesia and Function in the Upper Limb in Children with Cerebral Palsy.

OBJECTIVE: Dyskinesia in cerebral palsy (CP) is a complex movement disorder that can significantly impact upper limb function. Despite a range of available tools, there is no consensus on best practice assessment of upper limb function in children with CP and dyskinesia. This study aimed to develop a clinical framework for the assessment of the impact of dyskinesia on upper limb function in children with CP. DESIGN: Modified Delphi study using expert consensus. METHODS: An expert panel of six highly experienced Australian therapists ranked assessment tools sourced from existing evidence-based literature using a five-point Likert scale. Tools rated as important for use "most" or "all" of the time, by 80% of respondents were accepted into the framework following two survey rounds and a third stage discussion. RESULTS: Of 21 tools, 12 were included in the framework under five categories: (i) screening for dyskinesia; (ii) measuring the severity of dyskinesia; (iii) Classifying upper limb functional ability; (iv) measuring upper limb functional ability; and (v) measuring upper limb movement. CONCLUSIONS: The framework for assessing the impact of dyskinesia on upper limb function in CP aims to guide clinicians to improve assessment consistency and facilitate individualized goal-directed management. Further studies with a larger number of expert clinicians and researchers will further strengthen the utility of the framework.

[Idiopathic (Oral) and Tardive Dyskinesia: Pathogenesis, Epidemiology, and Treatment].

Etymologically, dyskinesia is a combination of the prefix "dys-," which means 'abnormality' and the suffix "-kinesia," which means 'movement.' In a broad sense, dyskinesia indicates hyperkinetic involuntary movements. In a narrow sense, as a general term, dyskinesia refers to combinations of one or more of the following movements: chorea, dystonia, tremor, ballism, athetosis, tics, and myoclonus. In this article, we describe the pathogenesis, epidemiology, and treatment of idiopathic (oral) and tardive dyskinesia.