Dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography as imaging markers of prediagnostic Parkinson's disease.

OBJECTIVE: The objective of this study was to examine whether prediagnostic features of Parkinson's disease (PD) were associated with changes in dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography. METHODS: Prediagnostic features of PD (risk estimates, University of Pennsylvania Smell Identification Test, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire, and finger-tapping scores) were assessed in a large cohort of older U.K. residents. A total of 46 participants were included in analyses of prediagnostic features and MDS-UPDRS scores with the striatal binding ratio on dopamine reuptake transporter-single-photon emission computed tomography and nigral hyperechogenicity on transcranial sonography. RESULTS: The striatal binding ratio was associated with PD risk estimates (P = .040), University of Pennsylvania Smell Identification Test (P = .002), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores (P = .024), tapping speed (P = .024), and MDS-UPDRS motor scores (P = .009). Remotely collected assessments explained 26% of variation in the striatal binding ratio. The inclusion of MDS-UPDRS motor scores did not explain additional variance. The size of the nigral echogenic area on transcranial sonography was associated with risk estimates (P < .001) and MDS-UPDRS scores (P = .03) only. CONCLUSIONS: The dopamine reuptake transporter-single-photon emission computed tomography results correlated with motor and nonmotor features of prediagnostic PD, supporting its potential use as a marker in the prodromal phase of PD. Transcranial sonography results also correlated with risk scores and motor signs. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Identification of Prodromal Parkinson Disease: We May Be Able to But Should We?

Parkinson disease (PD) remains a progressive and incurable disease. Research over the past decade provides strong evidence of a detectible phase before the clinical diagnosis, known as the prodromal phase of PD (pPD). In this article, we review the debate about disclosure of risk of progression to PD and related disorders to individuals through the perspectives of the pillars of medical ethics: beneficence, nonmaleficence, autonomy, and justice. There is evidence that lifestyle modification may have positive effects on onset and progression of PD, providing justification of potential benefit. From a societal perspective, a diagnosis of pPD could allow targeted recruitment to disease-modifying trials. Regarding nonmaleficence, direct evidence that catastrophic reactions are scarce is largely derived from studies of monogenic conditions, which may not be generalizable. Diagnosis of PD can be traumatic, and appropriate communication and evaluation of circumstances to weigh up disclosure is crucial. Future research should therefore examine the potential harms of early and of false-positive diagnoses and specifically examine these matters in diverse populations. Autonomy balances the right to know and the right not to know, so an individualized patient-centered approach and shared decision-making is essential, acknowledging that knowledge of being in the prodromal phase could prolong autonomy in the longer term. Distributive justice brings focus toward health care and related planning at the individual and societal level and affects the search for disease modification in PD. We must acknowledge that waiting for established disease states is likely to be too little, too late and results in failures of expensive trials and wasted participant and researcher effort. Ultimately, clinicians must arrive at a decision with the patient that solicits and integrates patients' goals, taking into account their individual life circumstances, perspectives, and philosophies, recognizing that one size cannot fit all.

Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation.

OBJECTIVES: To characterize associations between antiepileptic drugs with sedating or anesthetic effects (third-line antiepileptic drugs) vs. other antiepileptic agents, and short-term outcomes, in status epilepticus. Furthermore, to evaluate the role of adverse hemodynamic and respiratory effects of these agents in status epilepticus treatment. DESIGN: Retrospective comparative analysis. SETTING: Tertiary academic medical center with two emergency departments and two neurologic intensive care units. PATIENTS: Adults admitted with a diagnosis of status epilepticus defined as seizures lasting continuously >5 mins, or for discrete periods in succession. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 126 patients with 144 separate status epilepticus admissions, 57 were female (45%) with mean age 54.7 ± 15.7 yrs. Status epilepticus was convulsive in 132 cases (92%). Status epilepticus etiologies included subtherapeutic antiepileptic drugs (43%), alcohol or other nonantiepileptic drug (13%), and acute central nervous system disease (12%). Third-line antiepileptic drugs were administered in 47 cases (33%). Seventy-eight status epilepticus episodes (54%) had good outcomes (Glasgow Outcome Score = 1, 2) at the time of hospital discharge. On univariate analysis, poor outcome (Glasgow Outcome Score > 2) was associated with older age (mean 59.8 ± 15.5 vs. 50.5 ± 13.8 yrs, p < .001), acute central nervous system disease (21% vs. 4%, p = .001), mechanical ventilation (76% vs. 53%, p = .004), longer duration of ventilation (median 10 days [range 1-56] vs. 2 days [range 1-10], p < .001), treatment with vasopressors (35% vs. 5%, p < .001), and treatment with third-line antiepileptic drugs (51% vs. 17%, p < .001). Death was associated with acute central nervous system disease, prolonged ventilation, treatment with vasopressors, and treatment with third-line antiepileptic drugs. Predictors of poor outcome among all status epilepticus episodes were older age (odds ratio 1.06; 95% confidence interval 1.03-1.09; p < .001), treatment with third-line antiepileptic therapy (odds ratio 5.64; 95% confidence interval 2.31-13.75; p < .001), and first episode of status epilepticus (odds ratio 3.73; 95% confidence interval 1.38-10.10; p = .010). Among status epilepticus episodes treated by third-line antiepileptic drugs, predictors of poor outcome were older age (odds ratio, 1.09; 95% confidence interval 1.01-1.18; p = .038) and longer ventilation (odds ratio, 1.47; 95% confidence interval 1.08-2.00; p = .015). Predictors of mortality among all status epilepticus episodes were treatment with third-line antiepileptic drugs (odds ratio, 12.08; 95% confidence interval 2.30-63.39; p = .003) and older age (odds ratio, 1.06; 95% confidence interval 1.00-1.12; p = .045). CONCLUSIONS: Third-line antiepileptic drug therapies with sedating or anesthetic effects predicted poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and duration of mechanical ventilation induced by these agents may be contributing factors, especially when pentobarbital is used. These findings may inform decision making on drug therapy in status epilepticus and help develop safer and more effective treatment strategies to improve outcome.

Improving estimation of Parkinson's disease risk-the enhanced PREDICT-PD algorithm.

We previously reported a basic algorithm to identify the risk of Parkinson's disease (PD) using published data on risk factors and prodromal features. Using this algorithm, the PREDICT-PD study identified individuals at increased risk of PD and used tapping speed, hyposmia and REM sleep behaviour disorder (RBD) as "intermediate" markers of prodromal PD in the absence of sufficient incident cases. We have now developed and tested an enhanced algorithm which incorporates the intermediate markers into the risk model. Risk estimates were compared using the enhanced and the basic algorithm in members of the PREDICT-PD pilot cohort. The enhanced PREDICT-PD algorithm yielded a much greater range of risk estimates than the basic algorithm (93-609-fold difference between the 10th and 90th centiles vs 10-13-fold respectively). There was a greater increase in the risk of PD with increasing risk scores for the enhanced algorithm than for the basic algorithm (hazard ratios per one standard deviation increase in log risk of 2.75 [95% CI 1.68-4.50; p < 0.001] versus 1.47 [95% CI 0.86-2.51; p = 0.16] respectively). Estimates from the enhanced algorithm also correlated more closely with subclinical striatal DaT-SPECT dopamine depletion (R2 = 0.164, p = 0.005 vs R2 = 0.043, p = 0.17). Incorporating the previous intermediate markers of prodromal PD and using likelihood ratios improved the accuracy of the PREDICT-PD prediction algorithm.

Slow Motion Analysis of Repetitive Tapping (SMART) Test: Measuring Bradykinesia in Recently Diagnosed Parkinson's Disease and Idiopathic Anosmia.

BACKGROUND: Bradykinesia is the defining motor feature of Parkinson's disease (PD). There are limitations to its assessment using standard clinical rating scales, especially in the early stages of PD when a floor effect may be observed. OBJECTIVE: To develop a quantitative method to track repetitive tapping movements and to compare people in the early stages of PD, healthy controls, and individuals with idiopathic anosmia. METHODS: This was a cross-sectional study of 99 participants (early-stage PD = 26, controls = 64, idiopathic anosmia = 9). For each participant, repetitive finger tapping was recorded over 20 seconds using a smartphone at 240 frames per second. From each video, amplitude between fingers, frequency (number of taps per second), and velocity (distance travelled per second) was extracted. Clinical assessment was based on the motor section of the MDS-UPDRS. RESULTS: People in the early stage of PD performed the task with slower velocity (p < 0.001) and with greater frequency slope than controls (p = 0.003). The combination of reduced velocity and greater frequency slope obtained the best accuracy to separate early-stage PD from controls based on metric thresholds alone (AUC = 0.88). Individuals with anosmia exhibited slower velocity (p = 0.001) and smaller amplitude (p < 0.001) compared with controls. CONCLUSION: We present a simple, proof-of-concept method to detect early motor dysfunction in PD. Mean tap velocity appeared to be the best parameter to differentiate patients with PD from controls. Patients with anosmia also showed detectable differences in motor performance compared with controls which may suggest that some were in the prodromal phase of PD.