diagnostics Article Diplopia Is Frequent and Associated with Motor and Non-Motor Severity in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up Diego Santos García 1, * , Lucía Naya Ríos 1 , Teresa de Deus Fonticoba 2 , Carlos Cores Bartolomé 1 , Lucía García Roca 1 , Maria Feal Painceiras 1 , Cristina Martínez Miró 1 , Hector Canfield 2 , Silvia Jesús 3,4 , Miquel Aguilar 5 , Pau Pastor 5 , Marina Cosgaya 6 , Juan García Caldentey 7 , Nuria Caballol 8 , Inés Legarda 9 , Jorge Hernández Vara 10 , Iria Cabo 11 , Lydia López Manzanares 12 , Isabel González Aramburu 4,13 , María A. Ávila Rivera 14 , Víctor Gómez Mayordomo 15 , Víctor Nogueira 16 , Víctor Puente 17 , Julio Dotor 18 , Carmen Borrué 19 , Berta Solano Vila 20 , María Álvarez Sauco 21 , Lydia Vela 22 , Sonia Escalante 23 , Esther Cubo 24 , Francisco Carrillo Padilla 25 , Juan C. Martínez Castrillo 26 , Pilar Sánchez Alonso 27 , Maria G. Alonso Losada 28 , Nuria López Ariztegui 29 , Itziar Gastón 30 , Jaime Kulisevsky 4,31 , Marta Blázquez Estrada 32 , Manuel Seijo 11 , Javier Rúiz Martínez 33 , Caridad Valero 34 , Mónica Kurtis 35 , Oriol de Fábregues 10 , Jessica González Ardura 36 , Ruben Alonso Redondo 37 , Carlos Ordás 38 , Luis M. López Díaz 39 , Darrian McAfee 40 , Pablo Martinez-Martin 4 and Pablo Mir 3,4,† on behalf of the COPPADIS Study Group  1 CHUAC, Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain;  lucia.naya.rios@gmail.com (L.N.R.); Carlos.Cores.Bartolome@sergas.es (C.C.B.); Citation: Santos García, D.; Naya lucia.garcia.roca@gmail.com (L.G.R.); mjfealpainceiras@gmail.com (M.F.P.); Ríos, L.; de Deus Fonticoba, T.; Cores Cristina.Martinez.Miro@sergas.es (C.M.M.); canfield.hector@gmail.com (H.C.) 2 CHUF, Complejo Hospitalario Universitario de Ferrol, 15006 A Coruña, Spain; terecorreomovil@gmail.com Bartolomé, C.; García Roca, L.; Feal 3 Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Painceiras, M.; Martínez Miró, C.; Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Canfield, H.; Jesús, S.; Aguilar, M.; 41013 Seville, Spain; smaestre-ibis@us.es (S.J.); pmir@us.es (P.M.) et al. Diplopia Is Frequent and 4 CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), Associated with Motor and 28031 Madrid, Spain; isagaramburu@gmail.com (I.G.A.); jkulisevsky@santpau.cat (J.K.); Non-Motor Severity in Parkinson’s pmm650@hotmail.com (P.M.-M.) Disease: Results from the COPPADIS 5 Hospital Universitari Mutua de Terrassa, 08221 Terrassa, Barcelona, Spain; miquelaguilar@gmail.com (M.A.); Cohort at 2-Year Follow-Up. paupastor@mutuaterrassa.es (P.P.) 6 Hospital Clínic de Barcelona, 08036 Barcelona, Spain; marinacosgaya@gmail.com Diagnostics 2021, 11, 2380. https:// 7 Centro Neurológico Oms 42, 07003 Palma de Mallorca, Spain; juangcaldentey@hotmail.com doi.org/10.3390/diagnostics11122380 8 Consorci Sanitari Integral, Hospital Moisés Broggi, 08970 Sant Joan Despí, Barcelona, Spain; nuriacaballol@hotmail.com Academic Editor: Benedetta Nacmias 9 Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain; ines.legarda@ssib.es 10 Hospital Universitario Vall d’Hebron, 08035 Barcelona, Spain; hernandezvarajorge76@gmail.com (J.H.V.); Received: 23 November 2021 odefabregues@gmail.com (O.d.F.) Accepted: 14 December 2021 11 Complejo Hospitalario Universitario de Pontevedra (CHOP), 36071 Pontevedra, Spain; icabol@yahoo.es (I.C.); Published: 17 December 2021 manuel.seijo.martinez@sergas.es (M.S.) 12 Hospital Universitario La Princesa, 28006 Madrid, Spain; Lydia.veladesojo@salud.madrid.org 13 Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain Publisher’s Note: MDPI stays neutral 14 Consorci Sanitari Integral, Hospital General de L’Hospitalet, L’Hospitalet de Llobregat, 08906 Barcelona, with regard to jurisdictional claims in published maps and institutional affil- Spain; asuncion.avila@sanitatintegral.org 15 Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain; vicmayordomo@gmail.com iations. 16 Hospital Da Costa, Burela, 27880 Lugo, Spain; victor.nogueira.fernandez@sergas.es 17 Hospital del Mar, 08003 Barcelona, Spain; Vpuente@parcdesalutmar.cat 18 Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; juliodotor@gmail.com 19 Hospital Infanta Sofía, 28703 Madrid, Spain; carmenborrue@hotmail.com 20 Institut d’Assistència Sanitària (IAS)—Institut Català de la Salut, 17190 Girona, Spain; Copyright: © 2021 by the authors. berta_solano@hotmail.com Licensee MDPI, Basel, Switzerland. 21 Hospital General Universitario de Elche, 03203 Elche, Spain; mariaalsa@hotmail.com This article is an open access article 22 Fundación Hospital de Alcorcón, 28922 Madrid, Spain; lvela@fhalcorcon.es distributed under the terms and 23 Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, 43500 Tarragona, Spain; sescalant@yahoo.es conditions of the Creative Commons 24 Complejo Asistencial Universitario de Burgos, 09006 Burgos, Spain; esthercubo@gmail.com Attribution (CC BY) license (https:// 25 Hospital Universitario de Canarias, 38320 Santa Cruz de Tenerife, Spain; fcarpad@gobiernodecanarias.org 26 Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain; jcmcastrillo@gmail.com creativecommons.org/licenses/by/ 27 Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain; PISANCHEZAL@GMAIL.COM 4.0/). Diagnostics 2021, 11, 2380. https://doi.org/10.3390/diagnostics11122380 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 2380 2 of 14 28 Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), 36213 Vigo, Spain; gemavarita@gmail.com 29 Complejo Hospitalario de Toledo, 45004 Toledo, Spain; nlariztegui@gmail.com 30 Complejo Hospitalario de Navarra, 31008 Pamplona, Spain; itziar.gaston.zubimendi@cfnavarra.es 31 Hospital de Sant Pau, 08041 Barcelona, Spain 32 Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; marta.blazquez.estrada@gmail.com 33 Hospital Universitario Donostia, 20014 San Sebastián, Spain; JAVIER.RUIZMARTINEZ@osakidetza.eus 34 Hospital Arnau de Vilanova, 46015 Valencia, Spain; carivalero@icloud.com 35 Hospital Ruber Internacional, 28034 Madrid, Spain; mkurtis@ruberinternacional.es 36 Hospital de Cabueñes, 33394 Gijón, Spain; jessardura@yahoo.es 37 Universitario Lucus Augusti (HULA), 27003 Lugo, Spain; alonso_1408@hotmail.es 38 Hospital Rey Juan Carlos, 28933 Madrid, Spain; carlos.ordas@quironsalud.es 39 Complejo Hospitalario Universitario de Orense (CHUO), 32005 Orense, Spain; Luis.Manuel.Lopez.Diaz@sergas.es 40 University of Maryland School of Medicine, Baltimore, MD 21201, USA; mcafeed@sas.upenn.edu * Correspondence: diegosangar@yahoo.es; Tel.: +34-646-173-341 † Collaborators of the COPPADIS Study Group is provided in the Supplementary Material. Abstract: Background and objective: Diplopia is relatively common in Parkinson’s disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. Patients and Methods: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as “with diplopia” or “without diplopia” according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. Results: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269–4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012–1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson’s Disease Rating Scale–III (OR = 1.039; 95%CI, 1.023–1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001–1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716). Conclusions: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity. Keywords: changes; motor; Parkinson’s disease; phenotype; PIGD; Tremor 1. Introduction Parkinson’s disease (PD) is a complex disorder with a wide variety of symptoms that have a negative impact on a patient’s quality of life (QoL) and a patient’s independence for activities of daily living (ADL) [1]. Visual impairment is reported by some patients with PD, with double vision as one of the most common complaints. Diplopia is relatively common in PD but is still understudied [2]. Its prevalence in PD ranges from 10% to 30% and is usually limited to specific situations, such as reading and looking around [2–8]. A recent review concluded that diplopia in PD patients is usually intermittent and binocular, and the review also identified an older age, a longer disease duration, a greater disease severity, a cognitive decline, a presence of visual hallucinations, and a higher levodopa equivalent daily dose (LEDD) as risk factors contributing to it [4]. Moreover, diplopia could have a significant impact on QoL [5]. Possible comorbidities of diplopia include myasthenia gravis and vascular disease [7]. Very recently, Hamedani et al. found, using data from 26,790 PD patients and 9257 controls in the Fox Insight Study, that 28.2% of all the PD patients reported diplopia at least once during the study (period prevalence) Diagnostics 2021, 11, 2380 3 of 14 and identified to be older, to be non-white, to have a longer disease duration, and to have greater motor, non-motor, and daily activity limitations as factors associated with diplopia. Despite diplopia being frequent in PD, it is under-recognized [8]. On the other hand, since it is easy to identify by asking the patient, diplopia could be considered as a simple clinical marker of disease severity. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. 2. Methods PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort [9] were included in this study. Methodology regarding COPPADIS-2015 study can be consulted at https://bmcneurol.biomedcentral.com/articles/ 10.1186/s12883-016-0548-9 (accessed on 15 December 2021) [10]. This is a longitudinal- prospective, 5-year follow-up study designed to analyze natural progression of PD in which patients diagnosed with PD according to UK PD Brain Bank criteria without dementia were included [10]. Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment was collected. Motor status, non-motor symptoms (NMS), QoL, and disability were assessed at V0 and at V2 using different validated scales: Hoenh & Yahr (H&Y); UPDRS-III and UPDRS-IV; Freezing of Gait Questionnaire [FOGQ]); Parkinson’s Disease Cognitive Rating Scale (PD-CRS); Non-Motor Symptoms Scale (NMSS); Beck Depression Inventory-II (BDI-II); Parkinson’s Disease Sleep Scale (PDSS); Neuropsychiatric Inventory (NPI); Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS); Visual Analog Scale-Pain (VAS-Pain); Visual Analog Fatigue Scale (VAFS]); the 39-item Parkinson’s disease Questionnaire (PDQ-39); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8); ADLS (Schwab & England Activities of Daily Living Scale). In patients with motor fluctuations, the motor assessment was made during the OFF state (without medication in the last 12 h) and during the ON state. The assessment was only performed without medication in patients without motor fluctuations. The same evaluation as for the patients, except for the motor assessment, was performed in control subjects at V0 and at V2 (2 years ± 1 month). Furthermore, motor (H&Y, UPDRS-III, UPDRS-IV) and non-motor assessment (NMSS and ADLS) was conducted in PD patients at 1 year ± 1 month (V1) [10]. LEED was calculated based on the literature [11]. 2.1. Diplopia Definition Patients were classified as “with diplopia” or “without diplopia” according to item 15 of the NMSS [12] at V0, V1, and V2. In the control group, it was done based on the evaluation at V0 and at V2. This item is one of the 30 items of this scale and is included in domain 4 (Perceptual problems/hallucinations; items 13, 14, and 15). Symp- toms were assessed over the last month. Each symptom scored with respect to severity (0 = None; 1 = Mild, symptoms present but causes little distress or disturbance to the patient; 2 = Moderate, some distress or disturbance to the patient; 3 = Severe, major source of dis- tress or disturbance to the patient) and frequency (1 = Rarely, <1/week; 2 = Often, 1/week; 3 = Frequent, several times per week; 4 = Very frequent, daily or all the time). For each item, the score is calculated as frequency x severity, being the range from 0 (without the symptom) to 12 (the most frequent and severe). Specifically, the question of item 15 is: “Does the patient experienced double vision? (2 separate real objects and not blurred vision)”. Patients with a NMSS-item 15 score = 0 at V0, V1, and V2 were considered as “without diplopia”, whereas patients with a NMSS-item 15 score ≥ 1 (from 1 to 12) in at least one of the three visits were considered as “with diplopia”. The same was applied in the controls but only for visits V0 and V2. Diplopia burden was also calculated in PD patients. The score at V0, V1, and V2 and the sum of the score from the three visits Diagnostics 2021, 11, 2380 4 of 14 (NMSS-DiplopiaV0+V1+V2 , from 0 to 36) was calculated. Patients reporting diplopia in the three visits were defined as patients with “persisting diplopia”. Based on previously published studies [5,6], the relationship between diplopia and visual hallucinations was explored. Patients were classified as “with visual hallucinations” or “without visual hallucinations” according to the item 13 of the NMSS [12]: “Does the patient indicate that he/she sees things that are not there?”. The same criteria as previously explained were considered for defining visual hallucinations. 2.2. Serum Biomarkers Determination Serum biomarkers (SB) collected from the COPPADIS cohort were analyzed for know- ing if there was a relationship between any of them and the presence of diplopia. Blood sample collection for the determination of different SB included S-100b protein, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric acid, ultrasensitive CRP (US-CRP), ferritin, and iron. SB levels were de- termined from frozen blood samples obtained from subjects participating in the COPPADIS- 2015 study from 9 centers of Spain. The extraction of the sample was carried out no longer than 3 months after the first clinical assessment (V0) in the absence of infections and/or fever. The analysis was conducted at a common laboratory: REFERENCE LABORATORY (www.reference-laboratory.es, accessed on 15 December 2021). Different methods were used: visible spectrophotometry (iron); immunoluminescence (S-100b protein, ferritin, vitamin B12, and homocysteine); enzimoimmunoassay (IL-1, IL-2, and TNF-α); immunoas- say (US-CRP); mass spectrometry (methylmalonic acid); enzymatic technique (uric acid). Outliers were excluded from the analysis. 2.3. Data Analysis Data were processed using SPSS 20.0 for Windows. For comparisons between groups, the Student’s t-test, Mann–Whitney–Wilcoxon test, chi-square test, or Fisher test were used as appropriate (distribution for variables was verified by one-sample Kolmogorov– Smirnov test). Since multiple analysis on the same dependent variable (diplopia) were conducted, Bonferroni correction was applied to reduce the instance of a false positive. Binary regression models were used for determining independent factors associated with diplopia (diplopia as dependent variable). Any variables with univariate associations with p-values < 0.20 were included in a multivariable model, and a backwards selection process was used to remove variables individually until all remaining variables were significant at the 0.10 level. A p-value < 0.05 was considered significant. 2.4. Standard Protocol Approvals, Registrations, and Patient Consents Approval from the Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/534; 2 December 2014) was obtained. A written informed consent from all partici- pants was signed. COPPADIS-2015 was classified by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios) as a Post-authorization Prospective Follow-up study with the code COH-PAK-2014-01. 3. Results At the baseline, 691 PD patients (62.59 ± 8.92 years old; 60.2% males) and 206 controls (60.98 ± 8.34 years old; 50% males) were considered valid for the analysis. The frequency of diplopia in PD patients was: 13.6% (94/691) at V0; 14.2% (86/604) at V1; 17.1% (86/502) at V2 (Figure 1A). At V0 and at V2, diplopia was significantly less frequent (p < 0.0001) in the controls than in patients (1.9% at V0 and 0.8% at V2 in the controls). In the group (N = 481; 62.62 ± 8.54 years old, from 35 to 75; 59.2% males) with assessments carried out in all the visits (V0, V1, and V2), 24.9% (120/481) of the patients reported diplopia at least once during the study (period prevalence); specifically, 11.8% (57/481) in only one visit, 6% (29/481) in two out of the three visits, and 7.1% (34/481) in all three visits (i.e., persisting diplopia) (Figure 1B). Regarding the diplopia burden in PD patients, as Diagnostics 2021, 11, 2380 5 of 14 expected, the NMSS-DiplopiaV0+V1+V2 score was higher in patients with persisting diplopia: diplopia in one visit, 2.64 ± 2.83 (N = 57); diplopia in two out of the three visits, 7.03 ± 6.51 (N = 29); persisting diplopia, 13.52 ± 6.76 (N = 34) (p < 0.0001). Figure 1. (A) Percentage of patients and controls reporting diplopia at different visits: V0, V1, V2. (B) Prevalence of diplopia during the follow-up period in all patients who completed the three visits (N = 481; V1, V2, V3) and percentage of cases presenting diplopia in only 1 visit, 2 visits, and all visits. With regard to visual hallucinations, they were more frequent in PD patients with diplopia than in those without diplopia in all the visits: at V0, 45.7% vs. 9.4% (p < 0.0001); at V1, 51.2% vs. 11% (p < 0.0001); at V2, 53.5% vs. 13% (p < 0.0001) (Figure 2A). The patients with persisting diplopia presented visual hallucinations (at least once from V0 to V2) in up to 85.3% of the cases compared to 20.8% of those without diplopia in any visit (p < 0.0001) (Figure 2B). A moderate correlation was observed between the NMSS-DiplopiaV0+V1+V2 score and the NMSS-Visual hallucinationsV0+V1+V2 score (r = 0.503; p < 0.0001). At V0, patients with diplopia (N = 120), when compared to those without diplopia (N = 361), had a more severe disease in general with worse motor (UPDRS-IV, FOGQ) and non-motor status (PD-CRS, NMSS, PDSS, VAS-PAIN, VASF-Physical, VASF-Mental) and QoL (PDQ-39SI, EUROHIS-QoL), and had a greater dependency for ADL (ADLS) (Table 1). However, there were no differences between both groups regarding age, gender, and time from symptoms onset. With regard to cognition, the PD-CRS total score and the score on the posterior-cortical sub-domain were significantly lower at the baseline in the PD patients with diplopia compared to those without diplopia (Table 2). There were also no differences in relation to the molecular markers analyzed between both groups (data not shown due to lack of interest). When changes in the symptoms from the baseline visit to the end of the follow-up were analyzed, it was observed that, in the patients with Diagnostics 2021, 11, 2380 6 of 14 diplopia compared to those without diplopia, the mean score on the UPDRS-III and NPI increased from V0 to V2 in +6.06 ± 11.31 vs. +2.23 ± 9.41 (p = 0.007) and in +2.12 ± 12.35 vs. −0.03 ± 7.22 (p = 0.44), respectively, although it was not significant after the Bonferroni correction. Figure 2. (A) Number of patients reporting visual hallucinations at V0, V1, and V2 when they were divided in patients with vs. without diplopia. (B) Percentage of patients reporting visual hallucinations at least once during the follow-up according to the times who reported diplopia. Diagnostics 2021, 11, 2380 7 of 14 Table 1. PD-related variables in patients with diplopia compared to those ones without diplopia (N = 481). All Without Diplopia With Diplopia p (N = 481) (N = 361) (N = 120) At V0 (baseline) Age at baseline 62.62 ± 8.54 62.26 ± 8.78 63.69 ± 7.73 0.187 Gender (males) (%) 59 59.2 59 0.531 Time from symptoms onset 5.48 ± 4.26 5.27 ± 4.21 6.12 ± 4.35 0.312 Number of non-antipark. drugs 2.51 ± 2.34 2.46 ± 2.38 2.65 ± 2.25 0.212 Arterial hypertension (%) 32.2 29.1 41.7 0.008 Diabetes (%) 8.3 7.8 10 0.275 Dyslipemia (%) 32 31.6 33.3 0.401 Atrial fibrillation/arrhythmia (%) 4.2 3.9 5 0.38 Cardiopahy (%) 8.7 9.4 6.7 0.234 Smoking (%) 9.6 10.5 6.7 0.142 Alcohol consumption (%) 22.2 23.5 18.3 0.144 LEDD 575.3 ± 419.78 548.81 ± 408.93 653.66 ± 442.91 0.014 H&Y-OFF stage 1–2 (%) 91.1 92.2 87.8 0.112 UPDRS-III-OFF 22.37 ± 10.61 21.48 ± 10.36 24.98 ± 10.93 0.003 UPDRS-IV 2 ± 2.37 1.78 ± 2.32 2.66 ± 2.4 <0.0001 FOGQ 3.77 ± 4.6 3.24 ± 4.34 5.34 ± 5.23 <0.0001 PD-CRS 92.15 ± 15.77 93.47 ± 15.94 88.18 ± 14.61 0.001 NMSS 44.92 ± 37.87 38.14 ± 31.22 65.33 ± 47.71 <0.0001 BDI-II 8.25 ± 6.85 7.83 ± 6.58 9.52 ± 7.5 0.031 PDSS 117.27 ± 24.31 120.08 ± 21.84 108.84 ± 29.08 <0.0001 NPI 5.78 ± 7.89 5.44 ± 7.92 6.81 ± 7.74 0.023 QUIP-RS 4.35 ± 8.3 4.22 ± 8.09 4.78 ± 9.03 0.459 VAS-PAIN 2.55 ± 2.87 2.42 ± 2.86 2.95 ± 2.87 <0.0001 VASF-Physical 2.88 ± 2.7 2.64 ± 2.7 3.58 ± 2.59 <0.0001 VASF-Mental 2.11 ± 2.49 1.92 ± 2.47 2.69 ± 2.48 0.001 ADLS 88.48 ± 11.43 89.45 ± 8.78 85.58 ± 11.43 <0.0001 PDQ-39SI 16.64 ± 12.98 14.53 ± 11.59 22.97 ± 14.82 <0.0001 PQ-10 3.79 ± 0.7 3.87 ± 0.7 3.55 ± 0.64 0.054 EUROHIS-QoL 3.78 ± 0.53 3.83 ± 0.53 3.62 ± 0.52 <0.0001 Change at V2 (V2–V0) Number of non-antipark. drugs +0.51 ± 1.51 +0.47 ± 1.47 +0.63 ± 1.61 0.333 LEDD +194.37 ± 330.58 +190.15 ± 326.07 +206.85 ± 344.71 0.614 UPDRS-III-OFF +3.24 ± 10.08 +2.23 ± 9.41 +6.06 ± 11.31 0.007 UPDRS-IV +0.71 ± 2.51 +0.63 ± 2.41 +0.93 ± 2.77 0.394 FOGQ +1.16 ± 4.2 +1.11 ± 3.96 +1.31 ± 4.88 0.347 PD-CRS −1.6 ± 11.85 −1.17 ± 11.25 −2.87 ± 13.46 0.089 NMSS + 8.4 ± 34.82 +7.07 ± 25.77 +12.41 ± 53.49 0.618 BDI-II +0.35 ± 7.84 +0.09 ± 7.12 +1.12 ± 9.66 0.487 PDSS +0.52 ± 26.16 +0.64 ± 22.98 −0.14 ± 34.11 0.332 NPI +0.52 ± 8.85 −0.03 ± 7.22 +2.12 ± 12.35 0.044 QUIP-RS +0.21 ± 9.17 −0.03 ± 8.59 +1.01 ± 10.96 0.407 VAS-PAIN +0.34 ± 3.26 +0.38 ± 3.19 +0.22 ± 3.49 0.691 VASF-Physical +0.28 ± 3 +0.35 ± 2.85 +0.07 ± 3.44 0.499 VASF-Mental +0.06 ± 2.81 +0.07 ± 2.77 −0.02 ± 2.95 0.644 ADLS −4.13 ± 11.62 −3.74 ± 10.98 −5.34 ± 13.37 0.191 PDQ-39SI +3.48 ± 12.26 +3.16 ± 10.58 +4.45 ± 16.36 0.5 PQ-10 −0.14 ± 1.73 −0.11 ± 1.76 −0.21 ± 1.67 0.385 EUROHIS-QoL −0.01 ± 0.6 −0.01 ± 0.59 −0.03 ± 0.62 0.727 Results are expressed as mean ± SD or %. Mann–Whitney–Wilcoxon and chi-square tests were applied for assessing the relation with variables; a p ≤ 0.001 was considered significant (Bonferroni correction). ADLS, Schwab & England Activities of Daily Living Scale; BDI, Beck Depression Inventory-II; EUROHIS-QOL8, European Health Interview Survey-Quality of Life 8 Item-Index; FOGQ, Freezing Of Gait Questionnaire; H&Y, Hoenh & Yahr; LEED, levodopa equivalent daily dose; NMS, non-motor symptoms; NMSB, non-motor symptoms burden; NMSS, Non-Motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD, Parkinson’s disease; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire Summary Index; PDSS, Parkinson’s Disease Sleep Scale; QoL, Quality of life; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VAS-Pain, Visual Analog Scale-Pain. Diagnostics 2021, 11, 2380 8 of 14 Table 2. Cognitive function in patients with diplopia compared to those ones without diplopia (N = 481). All Without Diplopia With Diplopia p (N = 481) (N = 361) (N = 120) At V0 (baseline) PD-CRS total score 92.15 ± 15.77 93.47 ± 15.94 88.18 ± 14.61 0.001 PD-CSR FS sub-score 64.32 ± 14.48 65.15 ± 14.72 61.85 ± 13.46 0.037 Immediate verbal memory 8.05 ± 2.08 8.06 ± 8.03 8.03 ± 2.05 0.784 Sustained attention 8.59 ± 14.48 8.67 ± 1.72 8.35 ± 1.95 0.063 Working memory 7.13 ± 2.27 7.15 ± 2.25 7.07 ± 2.35 0.801 Clock drawing 9.04 ± 1.61 9.09 ± 1.68 8.91 ± 1.4 0.339 Delayed verbal memory 5.47 ± 2.79 5.43 ± 2.27 5.58 ± 2.95 0.677 Alternating verbal fluency 11.38 ± 4.54 11.71 ± 4.5 10.42 ± 4.15 0.006 Action verbal fluency 14.72 ± 5.74 15.12 ± 5.69 13.51 ± 5.78 0.003 PD-CRS PC sub-score 27.83 ± 3.14 28.32 ± 2.48 26.33 ± 4.27 <0.0001 Confrontation naming 18.25 ± 2.91 18.72 ± 2.08 16.83 ± 4.29 0.005 Clock copy 9.57 ± 1.03 9.6 ± 1.03 9.5 ± 1.02 0.638 Change at V2 (V2–V0) PD-CRS total score −1.6 ± 11.85 −1.17 ± 11.25 −2.87 ± 13.46 0.089 PD-CSR FS sub-score −1.42 ± 10.88 −0.96 ± 10.6 −2.77 ± 11.61 0.065 Immediate verbal memory −0.07 ± 2.45 +0.15 ± 2.58 −0.16 ± 2.02 0.306 Sustained attention −0.43 ± 2.01 −0.39 ± 1.93 −0.66 ± 2.33 0.16 Working memory −0.41 ± 2.09 −0.35 ± 2.13 −0.63 ± 1.93 0.292 Clock drawing −0.2 ± 1.96 −0.12 ± 1.93 −0.57 ± 2.05 0.05 Delayed verbal memory +0.36 ± 2.58 +0.46 ± 2.57 −0.09 ± 2.57 0.543 Alternating verbal fluency −0.41 ± 4.08 −0.34 ± 4.18 −0.69 ± 3.62 0.09 Action verbal fluency −0.46 ± 4.95 −0.44 ± 5.1 −0.53 ± 4.17 0.356 PD-CRS PC sub-score −0.17 ± 2.86 −0.19 ± 2.52 −0.1 ± 3.71 0.434 Confrontation naming +0.07 ± 2.34 −0.01 ± 2.1 +0.46 ± 3.21 0.839 Clock copy −0.25 ± 1.48 −0.2 ± 1.51 −0.48 ± 1.38 0.076 Results are expressed as mean ± SD. Mann–Whitney–Wilcoxon and chi-square tests were applied for assessing the relation with variables; a p ≤ 0.002 was considered significant (Bonferroni correction). FS, fronto-subcortical; PC, posterior-cortical; PD-CRS, Parkinson’s Disease Cognitive Rating Scale. Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269–4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012–1.024; p = 0.015), and a greater increase from V0 to V2 in the UPDRS-III (OR = 1.039; 95%CI, 1.023–1.083; p < 0.0001) and NPI (OR = 1.028; 95%CI, 1.001–1.057; p = 0.049) scores were indepen- dent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716) (Table 3). In the same model, when the variables were included individually as dichoto- mous variables, the next results were obtained (all models significant): to have a severe or very severe NMS burden at V0 (NMSS > 40), OR = 2.107 (95%CI, 1.195–3.714; p = 0.010); an increase from V0 to V2 in the UPDRS-III > 10 points, OR = 2.171 (95%CI, 1.094–4.297; p = 0.026). A significant OR for the NPI total score increase from V0 to V2 was not observed when cut-points were defined (increase in ≥5, >5, >10, >15, >20 points). Table 3. Binary regression model about factors associated with diplopia. OR a OR b 95% IC a 95% IC b pa pb At V0 (baseline) UPDRS-III-OFF 1.031 1.025 1.011–1.051 0.998–1.054 0.003 0.075 NMSS 1.018 1.009 1.012–1.024 1.002–1.017 <0.0001 0.015 PDSS 0.982 0.989 0.974–0.991 0.979–1.000 <0.0001 0.056 Visual hallucinations 4.076 2.264 2.628–6.324 1.269–4.039 <0.0001 0.006 Change at V2 (V2–V0) UPDRS-III 1.039 1.052 1.016–1.062 1.023–1.083 0.001 <0.0001 NPI 1.027 1.028 1.000–1.054 1.001–1.057 0.05 0.049 Dependent variable: diplopia (reporting at least once during the study). OR and 95% IC are shown. a , univariate analysis; b , multivariate analysis (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716). NMSS, Non-motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PDSS, Parkinson’s Disease Sleep Scale; UPDRS, Unified Parkinson’s Disease Rating Scale. Diagnostics 2021, 11, 2380 9 of 14 4. Discussion The present study observes that diplopia is frequent in PD patients, clearly much more frequent than in controls, and is associated with motor and non-motor severity, including visual hallucinations, which suggests that it could be used as a simple clinical marker of the disease state. In other words, a neurologist could ask about diplopia in clinical practice, and, if the patient’s response is positive, it should be taken into account that there is a greater probability of having a more advanced disease. The prevalence of diplopia during the period of our study, 2 years, was 24.9%. It seems to be in line with previous reports, ranging from 10% to 30% [4]. Schindlbeck et al. [3] detected binocular diplopia in 37 out of 125 PD patients (29.6%) who were screened for diplopia, visual hallucinations, problems with spatial perception, contrast sensitivity, presence of blurred vision, and history of ophthalmological comorbidities via interview. In a more recent longitudinal study, Hamedani et al. [8] reported a point prevalence diplopia of 18.1% in 26,790 PD patients and 6.3% in a control group, being present at least once in up to 28.2% of all the patients during the study (period prevalence). In our cohort, diplopia for each transversal analysis ranged from 13.6% to 17.1% in the patients and was very low in the controls. The inclusion/exclusion criteria of the study with a maximum age limit of 75 years and the absence of relevant comorbidities [10] could explain the low percentage in the controls. Other studies were designed to compare patients with diplopia previously selected versus without diplopia and controls but not to estimate the prevalence [5,6]. One important point is that diplopia was defined according to one specific question that asks for this symptom (item 18 from domain 4, “Perceptual problems/hallucinations”) from the NMSS, but a specific interview for trying to identify possible causes, differential diagnosis, and other visual symptoms was not specifically conducted. In fact, this is a post hoc analysis that was not initially considered in the COPPADIS study protocol [10]. However, as we previously reported [13], this methodology is not infrequent when scales are used (i.e., freezing of gait [14], motor fluctuations [15], dysphagia [16], etc.). Moreover, the NMSS is useful for detecting not only the presence of a symptom, such as the NMS-Quest [17], but the frequency and severity as well, being correct to separate the patients as those without the symptom (score = 0) versus those with the symptom (score ≥ 1). In the largest study to date to detect diplopia in PD, the NMSQuest was used, being present in 28.2% of all the PD patients compared to 9.1% of controls [8]. Using the NMSS with our methodology (only one visit), Martinez-Martin et al., identified 72 out of 411 (17.5%) patients as PD patients with double vision [18]. We found that diplopia was associated with motor and non-motor severity. Specif- ically, the patients with diplopia compared to those without diplopia presented a score on different scales that was indicative of a worse status in terms of motor complications, gait disturbances, global NMS burden, cognition, sleep, pain, fatigue, QoL, and disability. Conversely, there were no differences between both groups in age, time from symptoms onset, and total number of non-antiparkinsonian drugs when used as an indirect marker of comorbidity [19]. This finding suggests that asking about diplopia could be a simple clinical marker informing us of the possible condition of the patient, regardless of age and disease duration time, which is important in PD given the great variability in clinical presentation, from mild but long-term cases to very severe cases significantly affected from the beginning. The factors previously associated with diplopia are to be older, to be non-white, to have a longer disease duration, to have greater motor, non-motor, and daily activity limitations, to have visual hallucinations, to have cognitive decline, and to have a higher LEDD [3,8]. We found visual hallucinations as a symptom associated with diplopia in our cohort. In fact, the diplopia burden (frequency × severity) was correlated to the visual hallucinations burden. Visser et al., found visual hallucinations in 44% of 35 PD patients with diplopia compared to none of the 16 PD patients without diplopia and none of the 23 healthy controls [6]. Importantly, they analyzed the diplopia subtype, selective (i.e., diplopia of single objects) versus complete diplopia (i.e., diplopia of the entire visual field) and, although oculomotor abnormalities were equally prevalent in both subtypes, they Diagnostics 2021, 11, 2380 10 of 14 found that only the patients with selective diplopia had visual hallucinations. This finding would be in accordance with the previously reported finding by Nebe & Ebersbach [20], who suggested that the selective diplopia of isolated single objects and persons in PD is possibly related to hallucinosis and that minor ocular disturbances seem to be a triggering factor for this peculiar type of misperception. Unfortunately, the type of diplopia was not analyzed in our cohort. Very recently, Naumann et al. observed, in a cross-sectional study conducted in 50 non- demented PD patients with and without intermittent diplopia and in 24 healthy controls, that those with diplopia reported NMS more frequently, including more subjective cognitive problems and apathy, compared to those without diplopia [5]. Regarding cognition, visual function (pentagon copying; number location; cube analysis), but not executive function, memory, or language, was worse in the group of patients with diplopia compared to the PD patients without diplopia and controls [5]. Using the PD-CRS in a much larger sample, we observed differences at the baseline in posterior-cortical and global cognitive functions between both groups, patients with diplopia (N = 120) compared to those without diplopia (N = 361). Furthermore, to have visual hallucinations was an independent factor in the binary model associated with diplopia (OR = 2.264), as found by Schindlbeck et al. [3] in their cohort of 125 PD patients (OR = 3.5), but cognitive impairment was not. A greater NMS burden and an impairment in motor and neuropsychiatric symptoms in the short- term were the other independent factors associated with diplopia. On the basis of all this data, we suggest that asking about diplopia could be used as a very simple screening question for trying to identify PD patients that are more affected; i.e., if the answer is positive, motor and axial symptoms, NMS, QoL, autonomy for ADL, as well as visual hallucinations and psychosis should be exhaustively checked. Moreover, it is necessary to keep in mind an interaction between cognitive decline, visual impairment, and other visual symptoms, such as diplopia and visual hallucinations [21]. Finally, although this is the first study in which molecular markers were analyzed in relation to the presence of diplopia or not, any SB (i.e., inflammation, neurodegeneration, etc.) was associated with diplopia in our cohort (data not shown). Hopefully, some objective biomarkers, such as retinal changes in PD using Optical Coherence Tomography (OCT), could be useful in the future and are starting to be used in clinical trials [22]. The present study has very important limitations. As has previously been indicated, this is a post hoc analysis in which diplopia was considered based on an answer to a simple clinical question from the NMSS, but a complete neuro-ophthalmological assessment was not conducted [23], and the diplopia type and mechanism involved (motor-fluctuation related, visual hallucination related, convergence insufficiency, decompensated heteropho- ria, etc.) were not analyzed. Furthermore, it was not collected if the neurologists ruled out myasthenia gravis, microvascular disease, or other causes of diplopia in their clini- cal practice. However, the NMSS or other questionnaires were used in other studies as well [3,18,24–26]. To our knowledge, this is the second largest prospective longitudinal study about diplopia prevalence and the related factors in PD patients compared with con- trols conducted to date, after the Hamedani study [8]. Nevertheless, in the Hamedani study, a portion of the participants were recruited from education/research and online through digital marketing, and the response to the questionnaires was carried out by themselves without the supervision of the neurologist. On the other hand, the information at the 1-year and 2-year follow-up was obtained from 87.4% and 72.6% of the patients, respectively, the percentage being 60.2% after the 2-year follow-up in the controls. This limitation has been reported in other prospective studies, with maintenance rates from 61.9% to 89.3% [27,28]. In the Fox Insight Study, 26,790 PD patients were followed longitudinally and completed a median of five questionnaires at 90-day intervals (IQR: 2–7), but the information on the patient losses to follow-up was not provided [8]. For some variables, the information was not collected in all cases. Instead of a specific tool for assessing comorbidity, like the Charlson Index or others, the total number of non-antiparkinsonian medications was used as a surrogate marker of comorbidity [19], and the role of possible comorbidities Diagnostics 2021, 11, 2380 11 of 14 conditioning visual symptoms was not taken into account. Finally, the logistic regression model used to identify the independent factors associated with diplopia in our analysis only explains 25% of the variance, but it was either low as well or not provided in other studies [3,4,8]. In conclusion, diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity. In clinical practice, to ask about the presence of diplopia when a PD patient is evaluated could be useful for screening the disease severity. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/diagnostics11122380/s1. Author Contributions: D.S.G.: conception, organization, and execution of the project; statistical analysis; writing of the first draft of the manuscript; recruitment and/or evaluation of participants. L.N.R.: Collaboration in the preparation of the manuscript. Review and critique. H.C.: review and critique; recruitment and/or evaluation of participants. T.d.D.F.: review and critique; recruitment and/or evaluation of participants. C.C.B.: Collaboration in the preparation of the manuscript. Review and critique. L.G.R.: Collaboration in the preparation of the manuscript; review and critique. M.F.P.: Collaboration in the preparation of the manuscript; review and critique. C.M.M.: review and critique. S.J.: review and critique; recruitment and/or evaluation of participants. M.A.: review and critique; recruitment and/or evaluation of participants. P.P.: review and critique; recruitment and/or evalua- tion of participants. M.C.: review and critique; recruitment and/or evaluation of participants. J.G.C.: review and critique; recruitment and/or evaluation of participants. N.C.: review and critique; recruit- ment and/or evaluation of participants. I.L.: review and critique; recruitment and/or evaluation of participants. J.H.V.: review and critique; recruitment and/or evaluation of participants. I.C.: review and critique; recruitment and/or evaluation of participants. L.L.M.: review and critique; recruitment and/or evaluation of participants. I.G.A.: review and critique; recruitment and/or evaluation of participants. M.A.Á.R.: review and critique; recruitment and/or evaluation of participants. V.G.M.: review and critique; recruitment and/or evaluation of participants. V.N.: review and critique; recruit- ment and/or evaluation of participants. V.P.: review and critique; recruitment and/or evaluation of participants. J.D.: review and critique; recruitment and/or evaluation of participants. C.B.: review and critique; recruitment and/or evaluation of participants. B.S.V.: review and critique; recruitment and/or evaluation of participants. M.Á.S.: review and critique; recruitment and/or evaluation of participants. L.V.: review and critique; recruitment and/or evaluation of participants. S.E.: review and critique; recruitment and/or evaluation of participants. E.C.: review and critique; recruitment and/or evaluation of participants. F.C.P.: review and critique; recruitment and/or evaluation of participants. J.C.M.C.: review and critique; recruitment and/or evaluation of participants. P.S.A.: review and critique; recruitment and/or evaluation of participants. M.G.A.L.: review and critique; recruitment and/or evaluation of participants. N.L.A.: review and critique; recruitment and/or evaluation of participants. I.G.: review and critique; recruitment and/or evaluation of participants. J.K.: review and critique; recruitment and/or evaluation of participants. M.B.E.: review and critique; recruitment and/or evaluation of participants. M.S.: review and critique; recruitment and/or eval- uation of participants. J.R.M.: review and critique; recruitment and/or evaluation of participants. C.V.: review and critique; recruitment and/or evaluation of participants. M.K.: review and critique; recruitment and/or evaluation of participants. O.d.F.: review and critique; recruitment and/or evaluation of participants. J.G.A.: review and critique; recruitment and/or evaluation of participants. R.A.R.: review and critique; recruitment and/or evaluation of participants. C.O.: review and critique; recruitment and/or evaluation of participants. L.M.L.D.: review and critique; recruitment and/or evaluation of participants. D.M.: review and critique; review of English style. P.M.-M.: review and critique; supervision. P.M.: review and critique; recruitment and/or evaluation of participants. All authors have read and agreed to the published version of the manuscript. Funding: Fundación Curemos el Parkinson (www.curemoselparkinson.org, accessed on 15 December 2021). Santos García D. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, and Teva. Naya Ríos L: None. De Deus Fonticoba T: None. Cores Bartolomé C. has received honoraria for educational presentations and advice service by Lundbeck and UCB Pharma. García Roca L: None. Martínez Miró C: None. Feal Painceiras: None. Canfield H: None. Jesús S. has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon and holds the competitive contract “Juan Rodés” supported by the Instituto de Salud Carlos III. She has received grants from the Spanish Ministry of Economy Diagnostics 2021, 11, 2380 12 of 14 and Competitiveness (PI18/01898) and the Consejería de Salud de la Junta de Andalucía (PI-0459- 2018). Aguilar M: UCB and Schwabe with assistance to a Congress; Nutricia with assistance to a Congress and payment of lecture. Pastor P: None. Cosgaya M: None. García Caldentey J. has received honoraria for educational presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva. Caballol N. has received honoraria from Bial, Italfármaco, Qualigen, Zambon, UCB, Teva, and KRKA and sponsorship from Zambon, TEVA, and Abbvie for attending medical conferences. Legarda I. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Hernández Vara J. has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, Zambon, Italfarmaco, and Sanofi-Genzyme. Cabo I. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. López Manzanares L: Compensated advisory services, consulting, research grant support, or speaker honoraria: AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. González Aramburu I: None. Ávila Rivera MA. has received honoraria from Zambon, UCB Pharma, Qualigen, Bial, and Teva and sponsorship from Zambon and Teva for attending conferences. Gómez Mayordomo: Nogueira V: None. Puente V. has served as consultant for Abbvie and Zambon; has received grant/research from Abbvie. Dotor García-Soto J: Compensated advisory services, consulting, research grant support, or speaker honoraria: Merck, Sanofi-Genzyme, Allergan, Biogen, Roche, UCB, and Novartis. Borrué C: None. Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bial. Álvarez Sauco M. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Vela L. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Escalante S. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. Cubo E: Travel grants: Abbvie, Allergan, Boston; Lecturing honoraria: Abbvie, International Parkinson’s disease Movement Disorder Society. Carrillo Padilla F. has received honoraria from Zambon (SEN Congress assistance). Martínez Castrillo JC. has received research support from Lundbeck, Italfarmaco, Allergan, Zambon, Merz, and Abbvie. He has received speaking honoraria from AbbVie, Bial, Italfarmaco, Lundbeck, Krka, TEVA, UCB, Zambon, Allergan, Ipsen, and Merz. Sánchez Alonso P. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada MG. has received honoraria for educational presentations and advice service by Zambon and Bial. López Ariztegui N. has received honoraria for educational presentations and advice service by Abbvie, Italfarmaco, Zambon, and Bial. Gastón I. has received research support from Abbvie and Zambon and has served as a consultant for Abbvie, Exelts, and Zambon. Kulisevsky J: (1) Consulting fees: Roche, Zambon; (2) Stock/allotment: No; (3) Patent royalties/licensing fees: No; (4) Honoraria (e.g., lecture fees): Zambon, Teva, Bial, UCB; (5) Fees for promotional materials: No; (6) Research funding: Roche, Zambon, Ciberned; Instituto de SaludCarlos III; FundacióLa Maratóde TV3; (7) Scholarship from corporation: No; (8) Corporate laboratory funding: No; (9) Others (e.g., trips, travel, or gifts): No. Blázquez Estrada M. has received honoraria for educational presentations and advice service by Abbvie, Abbott, UCB Pharma, Allergan, Zambon, Bial, and Qualigen. Seijo M. has received honoraria for educational services from KRKA, UCB, Zambon, Bial, and travel grants from Daiichi and Roche. Ruiz Martínez J. has received honoraria for educational presentations, attending medical conferences, and advice service by Abbvie, UCB Pharma, Zambon, Italfarmaco, Bial, and Teva. Valero C. has received honoraria for educational services from Zambon, Abbvie and UCB. Kurtis M. has received honoraria from Bial, the Spanish Neurology Society, and the International and Movement Disorders Society. de Fábregues O. has received honoraria for educational presentations and advice service by Bial, Zambon, Abbvie, KRKA, and Teva. González Ardura J. has recieved honoraria for speaking from italofarma, Krka, Genzyme, UCB, Esteve, Psyma iberica marketing research SL and Ferrer, course grant from Teva and travel grant from Merck. Alonso Redondo R: None. Ordás C: None. López Díaz L. has received honoraria from UCB, Lundbeck, and KRKA. McAfee D: None. Martínez-Martin P. has received honoraria from National School of Public Health (ISCIII), Editori-al Viguera and Takeda Pharmaceuticals for lecturing in courses, and from the International Parkinson and Movement Disorder Society (MDS) for management of the Program on Rating Scales. Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon and have received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575], co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, Diagnostics 2021, 11, 2380 13 of 14 CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI- 0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and ap-proved by Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/534; 2 December 2014). Informed Consent Statement: Written informed consent from all participants in this study were obtained before the start of the study. Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. No computer coding was used in the completion of the current manuscript. Acknowledgments: We would like to thank all patients and their caregivers who collaborated in this study. Many thanks also to Fundación Española de Ayuda a la Investigación en Parkinson y otras Enfermedades Neurodegenerativas (Curemos el Parkinson; www.curemoselparkinson.org, accessed on 15 December 2021), Alpha Bioresearch (www.alphabioresearch.com, accessed on 15 December 2021), and other institutions for helping us. COPPADIS Study Group: Adarmes AD, Almeria M, Alonso Losada MG, Alonso Cánovas A, Alonso Frech F, Alonso Redondo R, Álvarez I, Álvarez Sauco M, Aneiros Díaz A, Arnáiz S, Arribas S, Ascunce Vidondo A, Aguilar M, Ávila MA, Bernardo Lambrich N, Bejr-Kasem H, Blázquez Estrada M, Botí M, Borrue C, Buongiorno MT, Cabello González C, Cabo López I, Caballol N, Cámara Lorenzo A, Canfield Medina H, Carrillo F, Carrillo Padilla FJ, Casas E, Catalán MJ, Clavero P, Cortina Fernández A, Cosgaya M, Cots Foraster A, Crespo Cuevas A, Cubo E, de Deus Fonticoba T, de Fábregues-Boixar O, Díez-Fairen M, Dotor García-Soto J, Erro E, Escalante S, Estelrich Peyret E, Fernández Guillán N, Gámez P, Gallego M, García Caldentey J, García Campos C, García Moreno JM, Gastón I, Gómez Garre MP, Gómez Mayordomo V, González Aloy J, González-Aramburu I, González Ardura J, González García B, González Palmás MJ, González Toledo GR, Golpe Díaz A, Grau Solá M, Guardia G, Hernández Vara J, Horta-Barba A, Idoate Calderón D, Infante J, Jesús S, Kulisevsky J, Kurtis M, Labandeira C, Labrador MA, Lacruz F, Lage Castro M, Lastres Gómez S, Legarda I, López Ariztegui N, López Díaz LM, López Manzanares L, López Seoane B, Lucas del Pozo S, Macías Y, Madrigal Lkhou E, Mata M, Martí Andres G, Martí MJ, Martínez Castrillo JC, Martinez-Martin P, McAfee D, Meitín MT, Menéndez González M, Méndez del Barrio C, Mir P, Miranda Santiago J, Morales Casado MI, Moreno Diéguez A, Nogueira V, Novo Amado A, Novo Ponte S, Ordás C, Pagonabarraga J, Pareés I, Pascual-Sedano B, Pastor P, Pérez Fuertes A, Pérez Noguera R, Planas-Ballvé A, Planellas L, Prats MA, Prieto Jurczynska C, Puente V, Pueyo Morlans M, Puig Daví A, Redondo Rafales N, Rodríguez Méndez L, Rodríguez Pérez AB, Roldán F, Ruíz De Arcos M, Ruíz Martínez J, Sánchez Alonso P, Sánchez-Carpintero M, Sánchez Díez G, Sánchez Rodríguez A, Santacruz P, Santos García D, Segundo Rodríguez JC, Seijo M, Sierra Peña M, Solano Vila B, Suárez Castro E, Tartari JP, Valero C, Vargas L, Vela L, Villanueva C, Vives B, Villar MD. 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