Determining the clinical profile of Parkinson s disease among Egyptian population; A National, Cross sectional, Collaborative Study

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1 Clinical Study Protocol Determining the clinical profile of Parkinson s disease among Egyptian population; A National, Cross sectional, Collaborative Study EMRA student-led national research collaborative Final protocol Version no.1 Date of release 17/04/2017 Contact information Website: FB group: 1: info@emra-collaborative.org 2: ahmed01251@medicine.zu.edu.eg Tel 1: Tel 2:

2 Principal investigator Co-Principal investigator Ahmed Negida Faculty of Medicine, Zagazig University Tel: Ahmed Elgebaly Faculty of Medicine, Al-Azhar University Hussien Ahmed Faculty of Medicine, Zagazig University Dr. Abdelrahman Ibrahim Abushouk, MBBCh Faculty of Medicine, Ain Shams University Lead coordinators Electronic data managers Senior supervisors (alphabetically) Mahmoud Atef Morsi Faculty of Medicine, Menoufia University Tel: Dr. Safwat Alnahrawy, MBBCh Faculty of Medicine, Tanta University Bilal Mansour Faculty of Medicine, Al-Azhar University Dr. Mohamed Ahmed El-hendy, MBBCh Faculty of Medicine, Al-Azhar University, Cairo Dr. Ali S Shalash, MD, PhD Movement Disorder Unit, Neurology department Faculty of Medicine, Ain Shams University Prof. Hatem Samir, MD, PhD Movement Disorder Unit, Neurology department Kasr Al-ainy school of Medicine, Cairo University Dr. Mohamed Abdel-Daim, PhD Pharmacology department, Faculty of veternary Medicine, Suez Canal University Member of the national ethics Committee Academy of Scientific Research and Technology Dr. Shaimaa Eljafary, MD, PhD Movement Disorder Unit, Neurology department Kasr Al-ainy school of Medicine, Cairo University Dr. Wael Mohamed, MD, PhD Neuroscience research unit, Pharmacology department, Faculty of Medicine, Menoufia University 2

3 Ain Shams University Alexandria University Al-Azhar University (Cairo) Al-Azhar University (Cairo) Females Al-Azhar University (Damietta) Al-Azhar University (Assiut) Assiut University Beni Suef University Kasr Al-ainy School of Medicine Mansoura University Menia University Menoufia University Local Coordinators Doaa Alaa Tel: Mohamed Mamdouh Eissa Tel: Dr. Attia Mohamed Attia, MBBCh Tel: Asmaa Sameh Rashwan Tel: Doaa Emadeldin Tel: Aly Mogheeth Tel: Muhammad Shawqi Tel: Randa Nabil Abdelazeem Tel: Mariam Bakr Tel: Osama Abunar Tel: Hesham Mohamed Ali Tel: Mohamed El-Semany Tel:

4 Misr University of Science and Technology October university Suez Canal University Tanta University Zagazig University Ahmad Ali Hassanen Tel: Omar Mohamed El Zahar Tel: Salma Fala Tel: Dr. Shorouk El mesery, MBBCh Tel: Dr. Osama Mokhtar, MBBCh Tel:

5 1. Working Teams This multicenter study will be delivered using a collaborative network model. The study teams are divided into three groups: 1.1. Steering committee This team will be responsible for study concept and design, protocol writing, study dissemination, Redcap system and monitoring the study, performing the analysis and drafting the final manuscript Local Leaders This team will be responsible for gaining ethical approval from their anticipated institution, organize working teams to prevent overlapping and monitoring the study on their level Data collectors This team is composed of all collaborators who collect the data for the study; they are the most vital part. Each team is composed of two students. Each hospital has at least one neurologist as a supervisor to help working teams access hospital data and ensure data accuracy. 2. Authorship The final manuscript will be published in an international peer-reviewed journal using the group name Egyptian Parkinson s disease group as a single author and all collaborators will gain PubMed citation under the group name as non-author contributors. The contribution of all collaborators will be described in the acknowledgment. Following publication of this project, the identified patient data will be made available on a public portal to allow for secondary analyses. 5

6 3. Abstract Introduction Parkinson's disease is the second most common neurodegenerative disorder affecting about 1-3% of population above 50 years. The epidemiology of PD is variable from a population to another due to the implication of multiple genetic, environmental, and dietary factors in the pathogenesis and course of the disease. The aim of this study is to investigate the epidemiological and clinical features of PD among Egyptian population. Methods and analysis This is a multicenter, national, cross-sectional study. Any hospital in Egypt performing routine follow up of PD, and any patient with Parkinson's disease according to the UK brain bank diagnostic criteria is eligible to enter the study. Investigators will collect observational data on PD patients for a 3-week period during a 6-month window. The primary outcomes of the study are pattern of early symptoms of the disease, Unified Parkinson's disease rating scale (UPDRS) part III, and quality of life of PD patients. The secondary outcomes include non-motor symptoms, drug sufficiency, and caffeine consumption. Ethics and dissemination Centers will process the required ethical approvals from the corresponding ethics committee or institutional review board. An oral informed consent will be taken from each patient in the presence of a third party. During the study, patient IDs and will be kept secure. Following the study, the deidentified IPD will be shared upon request with other investigators to allow for secondary analyses. Study registration The protocol of this study was registered on (Registration number: NCT ). Keywords Parkinson's disease, Clinical profile, Population, Egypt 6

7 4. Introduction Parkinson s disease is the second most common neurodegenerative disorder, affecting >1% of population above 60 years. The cardinal pathological features of Parkinson s disease are death of dopaminergic neurons and the formation of Lewy bodies [1]. The diagnosis of PD depends on the presence of one or more of the four most common motor symptoms including (rigidity, tremors, postural instability, and bradykinesia) [2]. In addition, PD patients experience a variety of non-motor symptoms such as anxiety, depression, mood swinging, dementia, sleep disturbances, psychosis, hallucinations and orthostatic hypotension [3, 4]. To date, there is no cure for PD and current pharmaceutical therapies only target symptomatic relief. Studying the epidemiology of PD plays a key role, not only in health care planning, but also as a tool to investigate the cause and risk factors of the disease. The incidence rate of PD (per 100,000 person-years) in the Unites States is 12.3 persons and it increases to 44 persons among population over 50 years [5]. The prevalence of PD in Africa is 160 per 100,000 people and is expected to increase by 200% within two decades after 2005 if the population structure follows the current predictions [6]. The Egyptian population is demographically characterized by large family units and high rates of birth and consanguinity marriage. Former studies on Arab and North African populations showed that such demographic structure can increase the risk of familial PD, both autosomal dominant and autosomal recessive types. Moreover, as a developing country, the population is aging at a faster rate than the developed countries, with an expected three-time increase in the elderly population within the next 40 years. Therefore, the burden of PD will increase, probably beyond the capabilities of the Egyptian healthcare system. There is a documented association in the literature between exposure to pesticides and the risk of PD. Being an agricultural country, about 120,000 Egyptian citizens are annually involved in spraying 10 to 60 thousand tons of pesticides in cotton fields, mainly in May, July, and September. These individuals are employed by the Egyptian ministry of agriculture and they are usually unequipped with the proper knowledge on safe handling of such chemicals. Moreover, household use of insecticides and rodenticides 7

8 increases the exposure to organophosphates and carbamates among Egyptian citizens. Despite these genetic and environmental risk factors, few former studies were published about the prevalence of PD in some Egyptian governorates and districts. Therefore, we designed this study to investigate the clinical profile of PD among Egyptian patients on a nationwide scale. 5. Aims and objectives The aim of this study is to determine the epidemiological and clinical features of Parkinson s disease among the Egyptian population. The primary objectives of this study are: To determine early symptoms of Parkinson's disease onset in Egyptian population To measure the quality of life in PD patients within Egypt The secondary objectives of this study are: To estimate the prevalence and pattern of caffeine intake in Egyptian population with PD To investigate the association between caffeine intake and age at disease onset in Egyptian population with PD To investigate the association between quality in life and treatment sufficiency in Egyptian population with PD To investigate the association between caffeine intake and quality of life in Egyptian population with PD 6. Patient and Methods This study is a national, collaborative, cross sectional study. This study is delivered through social media and professional networks within Egypt. We use the collaboration methodology to enroll potential centers to perform this study Study setting This study will be conducted in self-selected (registered) centers. Eligible center is defined as a university hospital, teaching hospital, governmental or 8

9 private clinic, where PD patients are attending for treatment and follow up. Eligible centers should be registered on the study website before 1 st, July 2017 (see appendix) Study population The target population is defined as patients with Parkinson's disease, those who meet the Parkinson s disease diagnostic criteria of UK Parkinson's Disease Society Brain Bank [7]. Patients, who meet these criteria, within the registered centers are included in this study Exclusion criteria We will exclude patients with the following conditions: Patients with vascular Parkinsonism (history of stroke) Patients with treatment induced Parkinsonism Patients with a history of exposure to the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) 6.4. Data entry Data will be submitted to the Research Electronic Data Capture (RedCap) system of Al Azhar University, Egypt ( Each collaborating team will be assigned unique username and password to access RedCap system. Data collection is designed to allow entry of individual patient data electronically and uploading a scan of the data collection forms. Data will be double-checked by the steering committee to avoid data entry errors Study variables and outcome measures We will collect the following data variables and measures from each eligible patient: Age at disease onset Time to diagnosis Initial motor symptom Side of initial motor symptoms Clinical subtype of the disease Pattern of levodopa treatment Levodopa equivalent dose per day 9

10 Duration of levodopa treatment from disease onset Non-motor symptoms measured by the non-motor symptoms questionnaire Quality of life including mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. The Parkinson's disease quality of life questionnaire (PDQ-39) will be used. Caffeine consumption measured by the Caffeine use questionnaire developed by Millar and colleagues. Motor functions measured by the Unified Parkinson's disease rating scale Part III will be included (if available) 6.6. Statistical analyses and power calculation Assuming the recruitment of 15 patients within a 3-week period from 30 centers. This will give a total of 450 patients, which allows for detecting a 5(±3)% rate of early disease symptoms in the population with a confidence level of 95% and 5% margin of error. Data will be presented as mean and standard deviation for continuous variables and frequencies and percentages for categorical variables. Data normality will be examined using the Kolmogorov-Smirnov test. Chi-square test and student t-test will be employed the test the significance of differences in categorical and continuous variables, respectively. Multivariate analysis will be conducted to compare caffeine consumption and quality of life in PD patient groups (classified according to early disease symptoms). An alpha level below 0.05 will be considered for statistical significance. Statistical analysis will be conducted using Stata statistical package (version 14) for windows. 7. Discussion In this protocol, we have presented the detailed design and objectives of our cross-sectional study, targeted at nationwide assessment of the clinical profile of PD among the Egyptian population. The definition of study population, the ethical soundness of the protocol, and the means for data collection were given attention in the design process. Moreover, we reported the exact methods of data entry and provided prospective solutions for possible challenges in our statistical analysis. 10

11 In a systematic review by Benamer et al. (2008) on the clinical profile of PD among Arabs, the authors found only three epidemiological studies, conducted in Tunisia, Libya, and Saudi Arabia. The review reported that PD has an incidence of 4.5 per 100,000 person-years, with a prevalence that ranges from 27 to 43 per 100,000 persons. It concluded that the clinical features of PD in Arabs are not different from those reported in other populations and highlighted the need for further epidemiological studies on PD clinical profile within Arab populations. After surveying the literature, we identified four epidemiological studies, recently published from Egypt, on the epidemiology of PD. In 2012, Khedr and colleagues conducted a community-based survey in Assiut governorate, Egypt to identify the prevalence and clinical profile of PD within the Egyptian population. The authors estimated a crude prevalence of 659/100,000 inhabitants, which increases with age, living in rural areas, and illiteracy. Moreover, the study showed that compared to other populations, these patients showed a high prevalence of mood/cognition dysfunction (84.4%) and gastrointestinal symptoms (90.9%). Another two cross sectional studies by El-Tallawy et al. (2013) and Khedr et al. (2015) were conducted on the Egyptian population in the New Valley and Qena governorates, respectively. These studies have reported crude prevalence rates, ranging from to 2748 per 100,000 individuals. These figures are relatively high, compared to those, reported in other Arab countries. Khedr et al. explained their findings by the presence of several sugar refining, paper making, and manganese production factories in Qena governorate, which partly drain their sewage into the Nile or its water canals. Excessive deposition of manganese within the brain tissue leads to manganism, a condition that shares multiple features with PD such as hypokinesia, rigidity, and psychotic symptoms. Table 1 shows a list of the cross-sectional studies, conducted within the Arab populations, on the epidemiology or clinical profile of PD. 11

12 Table 1 shows a summary of epidemiological studies on Parkinson's disease patients among the Arab population. Study ID/ Country Khedr et al (Assiut governorate Egypt) Screening Method Door to door study with face to face interviews PD Diagnostic approach The UK Parkinson s Disease Society Brain Bank Criteria Number of cases Total population Prevalence (per 10 5 persons) El-Tallawy et al (New Valley governorate- Egypt) Door to door study with face to face interviews The UK Parkinson s Disease Society Brain Bank Criteria 33 62, El-Tallawy et al (Red Sea governorate- Egypt) Door to door study with face to face interviews World Health Organization Diagnostic Criteria Not reported 33, Khedr et al (Qena governorate Egypt) Door to door study with face to face interviews The UK Parkinson s Disease Society Brain Bank Criteria Al Rajeh et al (Saudi Arabia) Door to door study with face to face interviews Presence of 2 of the 4 cardinal symptoms: Rigidity, hypokinesia, resting tremors, and postural instability. 6 23, Romdhane et al (Tunisia) Interview questionnaire Not reported 15 34, Ashok et al (Libya) Not reported Presence of 2 of the 4 cardinal symptoms: Rigidity, hypokinesia, resting tremors, and postural instability , Masalha et al (Arab Israel) Drug-tracer Patients on antiparkinsonian medications with further examination by neurologists ,

13 Another focus of our study is the assessment of non-motor symptoms (NMS) among the Egyptian PD patients, including cognitive impairment, sleep disturbances, neuropsychiatric disorders, sexual dysfunction, and gastrointestinal and cardiovascular symptoms. These symptoms can limit the effective treatment of motor manifestations; therefore, early management of NMS can supplement motor treatment, limit the financial impact of PD, and improve the quality of life for the patient and the caregiver. In our study, we are planning to use the Non-Motor Symptoms Scale (NMSS), which was designed to quantify the overall prevalence of NMS. Other important characteristics of PD that were not comprehensively investigated in Egyptian patients include the mean age at disease onset, time to PD diagnosis from the onset of symptoms, drug responsiveness, and quality of life. Therefore, in our study, we planned to identify these variables by using validated questionnaires such as the Parkinson's disease quality of life questionnaire (PDQ-39) and calculating the duration of Levodopa treatment and its current dosages Expected challenges and solutions The presence of cognitive impairment in some parkinsonian patients may increase the risk of recall bias; therefore, during the interviews, caregivers will be allowed to help their patients to ensure accurate data collection. To increase the participation of clinical neurologists in data collection, all practicing neurologists who contribute to data collection will be listed as collaborators in our published study. All used questionnaires or scales of assessment will be prospectively reviewed by expert neurologists and all open-ended questions will be coded and entered in a simple spread sheet. We excluded patients with vascular or treatment-related Parkinsonism due to the temporary nature of the condition. In summary, there are no sufficient data about the clinical profile of PD in Egypt. Therefore, we designed this nation-wide, cross sectional study to provide these data, which would provide better therapeutic management for PD patients and guide future planning of healthcare services in Egypt. 13

14 8. Ethical Considerations 8.1. Risk, benefit, and participant confidentiality The Study does not have any physical, psychological, social, legal, economic, or any other anticipated risks to study participants. In addition, participants will not receive a direct benefit from the study. Investigators will keep the privacy of patient data. Data submitted to the RedCap will not include patient name or national ID; instead, patient ticket number will be used as a unique number to avoid duplicate reporting of the patient data. We confirm that patient data will not be used outside this study Informed Consent Process We will comply with institutional guidelines of each registered center. The informed consent form, provided by the anticipated IRB or ethics committee, will be used by study collaborators. All eligible patients who agree to participate in the study will be asked to sign the informed consent Institutional Review Board Before starting data collection, collaborators of the registered centers should gain ethical approval from the anticipated local IRB or ethics committee of their institution. Investigators are advised to comply with institutional guidelines. In case of any changes to the study protocol, the ethics committee will be informed. 9. Publication and dissemination This project will be published using a collaborative publishing model. The final manuscript will be published in an international peer-reviewed journal using the group name Egyptian Parkinson s disease group as a single author and all collaborators will gain PubMed citation under the group name as non-author contributors. The contribution of all collaborators will be described in the acknowledgment. Following publication of this project, the identified patient data will be made available on a public portal to allow for secondary analyses. 14

15 10. Centers registration This study follows a collaborative model. Collaborators are required to register their centers and submit the institutional ethical approval before starting data collection. This study will be published using the collaborative published model. The manuscript(s) are published under a single group name as an author (Egyptian Parkinson s Disease Study Group). and all collaborators (see the working teams in the next section) will be listed with their institution in the acknowledgment section. 11. References 1. Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, et al (2008) Functional organization of the basal ganglia: Therapeutic implications for Parkinson s disease. Mov Disord 23: doi: /mds Jankovic J (2008) Parkinson s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79: doi: /jnnp Zindo FT, Barber QR, Joubert J, et al (2013) Steady progress on parkinson s disease. Eur J Med Chem 54: doi: /j.bmcl Ceravolo R, Frosini D, Rossi C, Bonuccelli U (2010) Impulse control disorders in Parkinson s disease: definition, epidemiology, risk factors, neurobiology and management. Park Relat Disord 15:S111 S115. doi: /S (09) Van Den Eeden SK (2003) Incidence of Parkinson s Disease: Variation by Age, Gender, and Race/Ethnicity. Am J Epidemiol 157: doi: /aje/kwg Dotchin C, Msuya O, Kissima J, et al (2008) The prevalence of Parkinson s disease in rural Tanzania. Mov Disord 23: doi: /mds Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55: