5-2-1 Criteria: A Simple Screening Tool for Identifying Advanced PD Patients Who Need an Optimization of Parkinson's Treatment

Objective 5- (5 times oral levodopa tablet taken/day) 2- (2 hours of OFF time/day) 1- (1 hour/day of troublesome dyskinesia) criteria have been proposed by a Delphi expert consensus panel for diagnosing advanced Parkinson's disease (PD). The aim of the present study is to compare quality of life (QoL) in PD patients with “5-2-1 positive criteria” vs QoL in PD patients without “5-2-1 positive criteria” (defined as meeting ≥1 of the criteria). Methods This is a cross-sectional, observational, monocenter study. Three different instruments were used to assess QoL: the 39-Item Parkinson's Disease Quality of Life Questionnaire Summary Index Score (PDQ-39SI); a subjective rating of perceived QoL (PQ-10); and the EUROHIS-QOL 8-Item Index (EUROHIS-QOL8). Results From a cohort of 102 PD patients (65.4 ± 8.2 years old, 53.9% males; disease duration 4.7 ± 4.5 years), 20 (19.6%) presented positive 5-2-1 criteria: 6.9% for 5, 17.6% for 2, and 4.9% for 1. 37.5% (12/32) and 25% (5/20) of patients with motor complications and dyskinesia, respectively, presented 5-2-1 negative criteria. Both health-related (PDQ-39SI, 25.6 ± 14 vs 12.1 ± 9.2; p < 0.0001) and global QoL (PQ-10, 6.1 ± 2 vs 7.1 ± 1.3; p=0.007; EUROHIS-QOL8, 3.5 ± 0.5 vs 3.7 ± 0.4; p=0.034) were worse in patients with 5-2-1 positive criteria. Moreover, nonmotor symptoms burden (Non-Motor Symptoms Scale total score, 64.8 ± 44.8 vs 39.4 ± 35.1; p < 0.0001) and autonomy for activities of daily living (ADLS scale, 73.5 ± 13.1 vs 89.2 ± 9.3; p < 0.0001) were worse in patients with 5-2-1 positive criteria. Patient's principal caregiver's strain (Caregiver Stain Index, 4.3 ± 3 vs 1.5 ± 1.6; p < 0.0001), burden (Zarit Caregiver Burden Inventory, 28.4 ± 12.5 vs 10.9 ± 9.8; p < 0.0001), and mood (Beck Depression Inventory II, 12.2 ± 7.2 vs 6.2 ± 6.1; p < 0.0001) were worse in patients with 5-2-1 positive criteria as well. Conclusions QoL is worse in patients meeting ≥1 of the 5-2-1 criteria. This group of patients and their caregivers are more affected as a whole. These criteria could be useful for identifying patients in which it is necessary to optimize Parkinson's treatment.


Introduction
In Parkinson's disease (PD), effective management is key at all stages and often requires individual customization of therapy as the disease progresses [1]. However, in the absence of a biomarker, a diagnostic test, or a gold standard index to determine the severity of PD (based on the motor and nonmotor symptoms), clinicians often rely on varied clinical evaluation and medical history to determine staging in PD [2]. Recently published systematic reviews and consensus articles acknowledge the growing need to establish guidelines for the different treatment approaches for advanced PD patients [3][4][5][6][7][8]. At this stage, it is important to ensure timely referral of patients to a movement disorder specialist before deterioration of quality of life (QoL) and development of complications of advancing disease [9,10]. Previous studies have observed that motor fluctuations are frequent even during the first years after the diagnosis of PD. Motor fluctuations also are related to a greater NMS burden, a worse QoL, and less functional independence for activities of daily living [11,12]. Having an easy tool to identify which patients are worse is necessary for clinical practice because the adjustment of symptomatic treatment will improve the patients' quality of life and autonomy.
In this context, 5-(5 times oral levodopa tablet taken/ day) 2-(2 hours of OFF time/day) 1 (1 hour/day of troublesome dyskinesia) criteria have recently been proposed by a Delphi expert consensus panel for diagnosing advanced PD [8,13]. However, these criteria have been only applied in one cohort of advanced PD patients under levodopa infusion therapy (ADEQUA Study) [14]. e objective of the present study was to compare functional dependency in PD patients with vs without "5-2-1 positive criteria" (defined as meeting ≥1 of the criteria). Moreover, nonmotor symptoms (NMS) burden, patients' QoL, and the patient's principal caregiver status was also compared between both groups to determine if 5-2-1 criteria could be a useful screening tool for identifying advanced PD patients who need an optimization of Parkinson's treatment.

Methods
A subgroup of PD patients from the COPPADIS cohort-2015 were included in this study. Methodology about the COPPADIS-2015 study has been previously published [15].
is is a multicenter, observational, longitudinal-prospective, 5-year follow-up study that was designed to analyze disease progression in a Spanish population of PD patients.
e data for the present study (cross-sectional study) were obtained from the baseline evaluation of PD patients assessed at one center (CHUF, Ferrol, Spain), that was from January 2016 to October 2017. All patients included were diagnosed according to UK PD Brain Bank criteria. Exclusion criteria were: non-PD parkinsonism, dementia, age <18 or >75 years, inability to read or understand the questionnaires, to be receiving any advanced therapy (continuous infusion of levodopa or apomorphine, and/or with deep brain stimulation), and presence of comorbidity, sequelae, or any disorder that could interfere with the assessment [15].
Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment was collected. ). In patients with motor fluctuations, the motor assessment was conducted during the OFF state (without medication in the last 12 hours) and during the ON state. However, in patients without motor fluctuations, the assessment was only performed without medication (first thing in the morning without taking medication in the previous 12 hours). Strain and burden (Caregiver Strain Index (CSI) and Zarit Caregiver Burden Inventory (ZCBI)), mood (BDI-II), and QoL (PQ-10 and EUROHIS-QOL8) were also assessed in the patient's principal caregiver. e information about the criteria of the 5-2-1 concept (frequency of daily levodopa tablet intake, OFF time, and dyskinesia time and severity of dyskinesia) had been collected at baseline evaluation after UPDRS-IV application and asked directly to the patients. A patient with 5-2-1 positive criteria was considered when at least 1 of the 3 criteria was positive [13].
Considering functional independency for activities of daily living as the gold standard, the 5-2-1 criteria were applied with the aim of knowing sensitivity and specificity of 5-2-1 criteria for detection of functional dependency. Functional dependency was defined to be present if the ADLS score was less than 80% (80% � completely independent in most chores; 70% � not completely independent) [16].

Data Analysis.
Data were processed using SPSS 20.0 for Windows. For comparisons between patients with and without 5-2-1 positive criteria, Student's t-test, Mann-Whitney U test, chi-square test, or Fisher test, as appropriate, were used (distribution for variables was verified by the one-sample Kolmogorov-Smirnov test). e p value was considered significant when it was <0.05.

Standard Protocol Approvals, Registrations, and Patient
Consents. For this study, we received approval from the appropriate local and national ethical standards committee. Written informed consents from all participants participating in this study were obtained before the start of the study. COPPADIS-2015 was classified by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios) as a Postauthorization Prospective Follow-Up study with the code COH-PAK-2014-01.

Discussion
e present study applies the 5-2-1 criteria for the first time in a general cohort of PD patients. is study also demonstrates that both health-related and global QoL are worse in those patients with 5-2-1 positive criteria. Moreover, patients' NMS burden was greater and autonomy for activities of daily living was also worse. Patient's principal caregiver strain, burden, and mood were worse in this group of patients as well. Currently, treatments for PD are symptomatic and the objective is to improve patients' autonomy and QoL [18]. In advanced PD patients, this is an even more necessary goal because QoL in them is worse [19]. Indeed, changes in QoL has been chosen as the principal variable in some studies with PD patients selected for receiving a second line therapy [20,21] and the use of PDQ-39 in routine care for PD has been suggested [22]. However, although some criteria have been proposed with the aim to define advanced PD [23][24][25], in many cases the criteria are not useful in daily clinical practice because their application is time-consuming and also because the concept of PD is too broad [26]. erefore, a quick screening tool that identifies which PD patients are worse and need optimized treatment, including possibly a second line therapy, would be ideal. e 5-2-1 criteria could be a useful screening tool. Firstly, its application is simple and would only need to know the number of medication doses and the time per day in the OFF state with disabling  dyskinesia. Secondly, these criteria seem to identify patients with worse QoL and with more requirements to improve their status. Being that patients in this cohort with 5-2-1 positive criteria presented a longer disease duration and they were more affected as a whole, it makes sense that patients with motor complications but with 5-2-1 negative criteria tended to have a better QoL compared to those with positive criteria. So, these criteria could differentiate between patients with more severe motor complications and those with less severe motor complications. In fact, the 5-2-1 criteria resulted in a high negative predictive value for functional dependency since only 7% of the patients were functionally dependent when the criteria were negative. Finally, it is easy to keep in mind the concept of 5-2-1 for application in real clinical practice.Previous studies have analyzed the reasons driving treatment modification in PD [27,28]. e most common reasons behind the anti-Parkinson drug therapy changes among neurologists were presence/worsening of motor or NMS. Patients attributed greater relevance than neurologists to NMS as a reason requiring treatment changes. In our study, patients with 5-2-1 positive criteria presented more severe motor and NMS. Specifically, mood, neuropsychiatric symptoms, sleep problems, fatigue, and pain were more severe in patients with 5-2-1 positive criteria and the percentage of patients with severe to very severe NMS burden was the double in this group compared to those patients with negative criteria. On the other hand, some studies have shown improvement in the caregiver status of patients with advanced PD after starting some second-line therapies [29,30]. An overburdened caregiver cares less which contributes to a worse QoL of the patient, so it is important to identify the problem and take action. In our study, 5-2-1 criteria served to identify the most overburdened and most poor-minded caregivers. e present study has some limitations. is is a crosssectional study and not a longitudinal study. Motor complications were assessed using the UPDRS-part IV applied by an expert neurologist on PD, but other more sensitive tools exist [31,32]. e statistical significance in the analysis for the subgroup of PD patients with motor fluctuations but 5-2-1 negative criteria was limited by the size of the sample (few patients). Our sample was not fully representative of the PD population due to inclusion and exclusion criteria (i.e., age limit, no dementia, no severe comorbidities, and no second line therapies). Finally, 5-2-1 criteria should be tested in a larger cohort of PD patients and follow-up after interventions in relation with the results of the test should be assessed.
As conclusion, the first application of 5-2-1 criteria in a cohort of PD patients demonstrates that QoL is worse in patients meeting ≥1 of the 5-2-1 criteria.
is group of patients and their caregivers were more severely burdened. ese criteria could be useful for identifying patients in which it is necessary to optimize Parkinson's treatment.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
D. Santos-García has received honoraria for educational presentations and advice service by AbbVie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial and Teva. T. de Deus Fonticoba has received honoraria for educational presentations and advice service by AbbVie. e other authors declare that they have no conflicts of interest.