Association of Plasma Levels of Nitric Oxide Oxidative Metabolites with Acute Stroke in Patients Presenting to the Emergency Department of a Low-Middle Income Country.

INTRODUCTION: Acute stroke incites an inflammatory reaction in the brain's microvasculature, activating formation of nitric oxide oxidative metabolites, nitrate and nitrite (NOx, collectively), measurable in plasma. Our objectives were to investigate plasma NOx in patients with acute stroke presenting to the Emergency Department (ED) and to determine if it could (i) differentiate between ischemic and hemorrhagic stroke; (ii) predict clinical outcomes. METHODS: A cross-sectional study was conducted in the ED of Aga Khan University Hospital, from January 1 to December 31, 2016. Participants were enrolled if they had clinical acute stroke with confirmatory brain imaging to differentiate between ischemia and hemorrhage. Clinical demographic information, ancillary blood, and diagnostic specimens were collected as per standard of care since the center follows stroke algorithmic guidelines. Plasma NOx analysis was performed using high performance liquid chromatography. Clinical outcomes were assessed using Barthel Index and Modified Rankin Score. Data was analyzed using SPSS 19 and expressed in medians with interquartile ranges. Nonparametric tests were applied for comparing among groups. Pearson's correlation was used to determine associations with aforementioned stroke severity and disability scales. RESULTS: Seventy-five patients were enrolled, with median age of 57 years (IQR 47-66 years), 53 (71%) were males, and 46 (61%) had ischemic stroke. Overall, median NOx was 20.8 µM (IQR 13.4-35.3); there was no statistically significant difference between NOx in ischemic versus hemorrhagic stroke (21.2 µM vs. 17.9 µM; p=0.2). However, there was a significant positive correlation between NOx levels and aforementioned acute stroke scales [r(73)=0.417, p=0.0001], for both. CONCLUSION: Although plasma NOx could not differentiate between ischemia and hemorrhage, higher levels of the biomarker did show associations with poststroke disability scales. Further study with more patients in a multicenter trial is warranted to establish the real biomarker potential of plasma NOx in acute stroke.

Making prescriptions "talk" to stroke and heart attack survivors to improve adherence: Results of a randomized clinical trial (The Talking Rx Study).

BACKGROUND: We developed and tested the effectiveness of a tailored health information technology driven intervention: "Talking Prescriptions" (Talking Rx) to improve medication adherence in a resource challenged environment. METHODS: We conducted a parallel, randomized, controlled, assessor-blinded trial at the Aga Khan University (AKU), Karachi, Pakistan. Adults with diagnosis of cerebrovascular accident (CVA) or coronary artery disease (CAD) diagnosed least one month before enrollment, on anti-platelets and statins, with access to a mobile phone were enrolled. The intervention group received a) Daily Interactive Voice Response (IVR) call services regarding specific statin and antiplatelet b) Daily tailored medication reminders for statin and antiplatelet and c) Weekly lifestyle modification messages for a period of 3 months. We assessed Medication adherence to statin and antiplatelets by a validated version of the 8-item Morisky Medication Adherence scale 8 (MMAS-8) at 3 months by a blinded assessment officer. Analysis was conducted by intention-to-treat principle (ITT). RESULTS: Between April 2015 and December 2015, 197 participants (99 in intervention and 98 in the usual care group) enrolled in the Talking Rx Study. The dropout rate was 9.6%. Baseline group characteristics were similar. At baseline, the mean MMAS-8 was 6.68 (SD = 1.28) in the intervention group and 6.77 (SD = 1.36) in usual care group. At end of follow-up, the mean MMAS-8 increased to 7.41(0.78) in the intervention group compared with 7.38 (0.99) in usual care group with mean difference of 0.03 (S.D 0.13) (95% C.I [-0.23, 0.29]), which was not statistically significant. (P-Value = 0.40) CVA patients showed a relatively greater magnitude of adherence via the MMAS-8 at the end of follow up where the mean MMAS-8 increased to 7.29 (S.D 0.82) in the intervention group as compared to 7.07(S.D 1.24) in usual care group with mean difference of 0.22 (SD = 0.22) 95% C.I (-0.20, 0.65) with (P-value = 0.15). Around 84% of those on intervention arm used the service, calling at least 3 times and listening to their prescriptions for an average of 8 minutes. No user was excluded due to technologic reasons. CONCLUSION: The use of a phone based medication adherence program was feasible in LMIC settings with high volume clinics and low patient literacy. In this early study, with limited follow up, the program did not achieve any statistically significant differences in adherence behavior as self-reported by the MMAS-8 Scale. TRIAL REGISTRATION: Clinical Trials.gov NCT02354040.

Pattern of neurological diseases in adult outpatient neurology clinics in tertiary care hospital.

OBJECTIVES: The burden of neurological diseases in developing countries is rising although little is known about the epidemiology and clinical pattern of neurological disorders. The objective of this study was to understand the burden of disease faced by neurologists a in tertiary care setting. RESULTS: A prospective observational study was conducted of all presentations to neurology clinics at Aga Khan University Hospital Karachi over a period of 2 years. A total of 16,371 out-patients with neurological diseases were seen during the study period. The mean age of the study participants were 46.2 ± 18.3 years and 8508 (52%) were male. Headache disorders were present in 3058 (18.6%) of patients followed by vascular diseases 2842 (17.4%), nerve and root lesions 2311 (14.1%) and epilepsies 2055 (12.5%). Parkinson's disease was more prevalent in male participants 564 (70.8%) as compared to female 257 (62.1%) (p = 0.002). Migraines and vertigo disease were more diagnosed in females as compared to males. Epilepsies were seen more in younger age groups. Parkinson's disease was seen in 50.9% of participants between the ages of 45 and 65 years, and the frequency increased with age.

Quality of life after stroke in Pakistan.

BACKGROUND: There is very little information about the quality of life (QOL) of stroke survivors in LMIC countries with underdeveloped non communicable health infrastructures, who bear two thirds of the global stroke burden. METHODOLOGY: We used a sequential mix methods approach. First, a quantitative analytical cross-sectional study was conducted on 700 participants, who constituted 350 stroke survivor and their caregiver dyads. QOL of stroke survivor was assessed via Stroke Specific Quality of Life Scale (SSQOLS) whereas QOL of caregivers was assessed through RAND-36. In addition; we assessed complications, psychosocial and functional disability of stroke survivors. Following this quantitative survey, caregivers were qualitatively interviewed to uncover contextually relevant themes that would evade quantitative surveys. Multiple linear regression technique was applied to report adjusted ß-coefficients with 95% C.I. RESULTS: The QOL study was conducted from January 2014 till June 2014, in two large private and public centers. At each center, 175 dyads were interviewed to ensure representativeness. Median age of stroke survivors was 59(17) years, 68% were male, 60% reported depression and 70% suffered post-stroke complications. The mean SSQOLS score was 164.18 ± 32.30. In the final model severe functional disability [adjß -33.77(-52.44, -15.22)], depression [adjß-23.74(-30.61,-16.82)], hospital admissions [adjß-5.51(-9.23,-1.92)] and severe neurologic pain [adjß -12.41(-20.10,-4.77)] negatively impacted QOL of stroke survivors (P < 0.01). For caregivers, mean age was 39.18 ± 13.44 years, 51% were female and 34% reported high stress levels. Complementary qualitative study revealed that primary caregivers were depressed, frustrated, isolated and also disappointed by health services. CONCLUSION: The QOL of Stroke survivors as reported by SSQOLS score was better than compared to those reported from other LMIC settings. However, Qualitative triangulation revealed that younger caregivers felt isolated, depressed, overwhelmed and were providing care at great personal cost. There is a need to develop cost effective holistic home support interventions to improve lives of the survivor dyad as a unit. TRIAL REGISTRATION: NCT02351778 (Registered as Observational Study).

Facilitators and barriers to NCD prevention in Pakistanis-invincibility or inevitability: a qualitative research study.

BACKGROUND: Non-communicable diseases (NCD) are the leading causes of death globally. In Pakistan, they are among the top ten causes of mortality, especially in the productive age group (30-69 years). Evidence suggests that health perceptions and beliefs strongly influence the health behavior of an individual. We performed focus group interviews to delineate the same so as to design the user interface of a non-invasive stroke risk monitoring device. METHODS: It was a qualitative study, designed to explore how health perceptions and beliefs influence behavior for NCD prevention. Four focus group discussions (FGD) were conducted with 30 stable participants who had diabetes mellitus, ischemic heart disease, blood pressure, and stroke. The data was collected using a semi-structured interview guide designed to explore participants' perceptions of their illnesses, self-management behaviors and factors affecting them. The interviews were transcribed and content analysis was done using steps of content analysis by Morse and Niehaus [10]. RESULTS: Medication adherence, self-monitoring of blood sugars and blood pressures, and medical help seeking were the commonly performed self-management behaviors by the participants. Personal experience of illness, familial inheritance of disease, education and fear of premature death when life responsibilities were unfulfilled, emerged as strong facilitators of self-management behaviors. A sense of personal invincibility, Fatalism or inevitability, lack of personal threat realization, limited knowledge, inadequate health education, health care and financial constraints appeared as key barriers to the self-management of chronic disease in participants. CONCLUSIONS: Behavioural interventional messaging will have to engender a sense of personal vulnerability and yet empower self-efficacy solutions at the individual level to deal with both invincibility and inevitability barriers to adoption of healthy behavior.

Using a tailored health information technology- driven intervention to improve health literacy and medication adherence in a Pakistani population with vascular disease (Talking Rx) - study protocol for a randomized controlled trial.

BACKGROUND: Vascular disease, manifesting as myocardial infarction and stroke, is a major cause of morbidity and mortality, especially in low- and middle-income countries. Current estimates are that only one in six patients have good adherence to medications and very few have sufficient health literacy. Our aim is to explore the effectiveness and acceptability of Prescription Interactive Voice Response (IVR) Talking Prescriptions (Talking Rx) and SMS reminders in increasing medication adherence and health literacy in Pakistani patients with vascular disease. METHODS: This is a randomized, controlled, single center trial. Adult participants, with access to a cell phone and a history of vascular disease, taking multiple risk-modifying medications (inclusive of anti-platelets and statins) will be selected from cerebrovascular and cardiovascular clinics. They will be randomized in a 1:1 ratio via a block design to the intervention or the control arm with both groups having access to a helpline number to address their queries in addition to standard of care as per institutional guidelines. Participants in the intervention group will also have access to Interactive Voice Response (IVR) technology tailored to their respective prescriptions in the native language (Urdu) and will have the ability to hear information about their medication dosage, correct use, side effects, mechanism of action and how and why they should use their medication, as many times as they like. Participants in the intervention arm will also receive scheduled SMS messages reminding them to take their medications. The primary outcome measure will be the comparison of the difference in adherence to anti-platelet and statin medication between baseline and at 3-month follow-up in each group measured by the Morisky Medication Adherence Scale. To ascertain the impact of our intervention on health literacy, we will also compare a local content-validated and modified version of Test of Health Literacy in Adults (TOFHLA) between the intervention and the control arm. We estimate that a sample size of 86 participants in each arm will be able to detect a difference of 1 point on the MMAS with a power of 90 % and significance level of 5 %. Accounting for an attrition rate of 15 %, we plan to enroll 100 participants in each arm (total study population = 200). We hypothesize that a linguistically tailored health IT intervention based on IVR and SMS will be associated with an improvement in adherence (to anti-platelet and lipid-lowering medications) and an improvement in health literacy in Pakistani patients with vascular disease. DISCUSSION: This innovative study will provide early data for the feasibility of the use of IT based prescriptions in an lower middle incorme country setting with limited numeracy and literacy skills. TRIAL REGISTRATION: Clinical Trials.gov: NCT02354040 - 2 February 2015.

Translating knowledge for action against stroke--using 5-minute videos for stroke survivors and caregivers to improve post-stroke outcomes: study protocol for a randomized controlled trial (Movies4Stroke).

BACKGROUND: Two thirds of the global mortality of stroke is borne by low and middle income countries (LMICs). Pakistan is the world's sixth most populous country with a stroke-vulnerable population and is without a single dedicated chronic care center. In order to provide evidence for a viable solution responsive to this health care gap, and leveraging the existing >70% mobile phone density, we thought it rational to test the effectiveness of a mobile phone-based video intervention of short 5-minute movies to educate and support stroke survivors and their primary caregivers. METHODS: Movies4Stroke will be a randomized control, outcome assessor blinded, parallel group, single center superiority trial. Participants with an acute stroke, medically stable, with mild to moderate disability and having a stable primary caregiver will be included. After obtaining informed consent the stroke survivor-caregiver dyad will be randomized. Intervention participants will have the movie program software installed in their phone, desktop, or Android device which will allow them to receive, view and repeat 5-minute videos on stroke-related topics at admission, discharge and first and third months after enrollment. The control arm will receive standard of care at an internationally accredited center with defined protocols. The primary outcome measure is medication adherence as ascertained by a locally validated Morisky Medication Adherence Scale and control of major risk factors such as blood pressure, blood sugar and blood cholesterol at 12 months post discharge. Secondary outcome measures are post-stroke complications and mortality, caregiver knowledge and change in functional outcomes after acute stroke at 1, 3, 6, 9 and 12 months. Movies4Stroke is designed to enroll 300 participant dyads after inflating 10% to incorporate attrition and non-compliance and has been powered at 95% to detect a 15% difference between intervention and usual care arm. Analysis will be done by the intention-to-treat principle. DISCUSSION: Movies4Stroke is a randomized trial testing an application aimed at supporting caregivers and stroke survivors in a LMIC with no rehabilitation or chronic support systems. TRIAL REGISTRATION: NCT02202330 (28 January 2015).

Building global capacity for brain and nervous system disorders research.

The global burden of neurological, neuropsychiatric, substance-use and neurodevelopmental disorders in low- and middle-income countries is worsened, not only by the lack of targeted research funding, but also by the lack of relevant in-country research capacity. Such capacity, from the individual to the national level, is necessary to address the problems within a local context. As for many health issues in these countries, the ability to address this burden requires development of research infrastructure and a trained cadre of clinicians and scientists who can ask the right questions, and conduct, manage, apply and disseminate research for practice and policy. This Review describes some of the evolving issues, knowledge and programmes focused on building research capacity in low- and middle-income countries in general and for brain and nervous system disorders in particular.

A randomized controlled behavioral intervention trial to improve medication adherence in adult stroke patients with prescription tailored Short Messaging Service (SMS)-SMS4Stroke study.

BACKGROUND: The effectiveness of mobile technology to improve medication adherence via customized Short Messaging Service (SMS) reminders for stroke has not been tested in resource poor areas. We designed a randomized controlled trial to test the effectiveness of SMS on improving medication adherence in stroke survivors in Pakistan. METHODS: This was a parallel group, assessor-blinded, randomized, controlled, superiority trial. Participants were centrally randomized in fixed block sizes. Adult participants on multiple medications with access to a cell phone and stroke at least 4 weeks from onset (Onset as defined by last seen normal) were eligible. The intervention group, in addition to usual care, received reminder SMS for 2 months that contained a) Personalized, prescription tailored daily medication reminder(s) b) Twice weekly health information SMS. The Health Belief Model and Social Cognitive theory were used to design the language and content of messages. Frontline SMS software was used for SMS delivery. Medication adherence was self-reported and measured on the validated Urdu version of Morisky Medication Adherence Questionnaire. Multiple linear regression was used to model the outcome against intervention and other covariates. Analysis was conducted by intention-to-treat principle. RESULTS: Two hundred participants were enrolled. 38 participants were lost to follow-up. After 2 months, the mean medication score was 7.4 (95 % CI: 7.2-7.6) in the intervention group while 6.7 (95 % CI: 6.4-7.02) in the control group. The adjusted mean difference (Δ) was 0.54 (95 % CI: 0.22-0.85). The mean diastolic blood pressure in the intervention group was 2.6 mmHg (95 % CI; -5.5 to 0.15) lower compared to the usual care group. CONCLUSION: A short intervention of customized SMS can improve medication adherence and effect stroke risk factors like diastolic blood pressure in stroke survivors with complex medication regimens living in resource poor areas. TRIAL REGISTRATION: Clinicaltrials.gov NCT01986023 last accessed at https://clinicaltrials.gov/ct2/show/NCT01986023.

Improving medication adherence in stroke patients through Short Text Messages (SMS4Stroke)-study protocol for a randomized, controlled trial.

BACKGROUND: Stroke is a major cause of morbidity and mortality, especially in low and middle income countries. Medical management is the mainstay of therapy to prevent recurrence of stroke. Current estimates are that only 1 in 6 patients have perfect adherence to medication schedules. Using SMS (Short Messaging Service) as reminders to take medicines have been used previously for diseases such as diabetes and HIV with moderate success. We aim to explore the effectiveness and acceptability of SMS in increasing adherence to medications in patients with stroke. METHODS: This will be a randomized, controlled, assessor blinded single center superiority trial. Adult participants with access to a cell phone and a history of stroke longer than 1 month on multiple risk modifying medications will be selected from Neurology and Stroke Clinic. They will be randomized into two parallel groups in a 1:1 ratio via block technique with one group receiving the standard of care as per institutional guidelines while the parallel group receiving SMS reminders for each dose of medicine in addition to the standard of care. In addition intervention group will receive messages for lifestyle changes, medication information, risk factors and motivation for medication adherence. These will bemodeled on Social Cognitive Theory and Health Belief Model and will be categorized by Michies Taxonomy of Behavioral Change Communication. Patient compliance to medicines will be measured at baseline and then after 2 months in each group by using the Morisky Medication Adherence Scale. The change in compliance to medication regimen after the intervention and the difference between the two groups will be used to determine the effectiveness of SMS reminders as a tool to increase medication compliance. The acceptability of the SMS will be determined by a tool designed for this study whose attributes are based Rogers Diffusion of innovation theory. A sample size of 86 participants in each arm will be sufficient to detect a difference of 1 point on the MMAS with a power of 90 % and significance level of 5 % between the two groups; using an attrition rate of 15 %, 200 participants in all will be randomized. DISCUSSION: The SMS for Stroke Study will provide evidence for feasibility and effectiveness of SMS in improving post stroke medication adherence in an LMIC setting. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01986023 11 /11/2013.

Diagnostic TCD for intracranial stenosis in acute stroke patients: experience from a tertiary care stroke center in Karachi, Pakistan.

BACKGROUND: Stroke is a common cause of morbidity and mortality around the world. Intracranial large artery atherosclerosis (ICAD) is a frequent etiology of stroke in the South Asian population. There is a need for widely available screening tools to identify patients that are at high risk of stroke due to ICAD for aggressive risk management. This study describes the experience of using the transcranial Doppler (TCD) as a screening tool for this purpose at a tertiary care hospital in a developing country. METHODS: 86 Patients admitted with stroke due to ICAD underwent TCD for six arteries (Right and left middle cerebral arteries, right and left anterior cerebral arteries, right and left posterior cerebral arteries) in addition to the magnetic resonance angiography (MRA) that is done routinely at the stroke center. Arteries were labeled with either <50 or >50% stenosis by TCD using two separate criteria. These findings were compared with those from the MRA which was used as the gold standard. The proportion of patients that had complete exams (all six arteries insonated by TCD) was reported. The success rate of each TCD criteria in detecting arteries with >50% stenosis was also calculated. RESULTS: There was an attempt to visualize 516 arteries (86 patients with 6 arteries each) of which 375 (72.7%) were successfully insonated. 38 of the 86 (55.8%) patients had complete examinations. MRA reported 43 (8.3%) arteries as stenosed >50%. The TCD did not categorize any artery as stenosed using either criterion and hence failed to classify any stenosed artery correctly. The positive predictive and sensitivity was 0 for this study and the negative predictive value was 93.3%. CONCLUSIONS: This study indicates the poor sensitivity of TCD to be a reliable screening tool for the presence of ICAD in the South Asian population in a real life clinical setting.

Study Protocol: Validation and Adaptation of community-worker-administered stroke symptom questionnaire in a periurban Pakistani community to determine disease burden.

BACKGROUND: Stroke is the second leading cause of mortality and the leading cause of disability in the world today. The disease burden is on the rise in developing nations, but there is scarcity of data from these regions to inform policy decisions. Stroke burden can be determined by clinical diagnosis alone in the public health context and is a far more feasible way to assess disease status in low- to middle-income countries like Pakistan. We aim to translate and adapt a validated stroke symptom questionnaire, train community health workers in its administration, and verify it against assessment by two trained neurologists. METHODS/DESIGN: This is a prospective study, which we aim to carry out in Ibrahim Hyderi, a periurban slum of Karachi. We translated into Urdu the questionnaire for verifying stroke free status (QVSFS), which is an internationally validated tool to assess the same. Two community health workers (CHW) will be identified and will receive training by neurologists, which will include teaching regarding stroke pathophysiology, symptomatology, and detection. They will be familiarized with the QVSFS, and their questionnaire administration will be assessed through roleplay. We intend to recruit 322 subjects from the same community and the CHWs will gather data on them. The same subjects will later be assessed by two trained neurologists, and the findings collaborated to validate those obtained by the CHWs. Sensitivity, specificity, positive and negative predictive values, and Cohen's kappa will be determined for the CHW-administered questionnaire tested against assessment by two neurologists together and separately for the two CHWs. Data analysis will be done using SPSS version 19.0. DISCUSSION: The results of this study will determine if and how well CHW-administered questionnaires are at assessing stroke status in a community. This will facilitate use of the same as a practical alternative for stroke surveillance in the country. TRIAL REGISTRATION: NCT02073955.

Study protocol: asymptomatic intracranial atherosclerotic disease in pakistanis.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is the most frequent subtype of ischemic stroke globally. It is important to describe the determinants of early ICAD as a strategy to prevent strokes from clinically evident and progressive ICAD. Our objective is to report the determinants of asymptomatic ICAD by linking the presence or absence of ICAD on magnetic resonance angiogram (MRA) with detailed risk assessment in asymptomatic adults. METHODS: This is an observational cross-sectional analytical study. We plan to recruit 200 adult participants from the radiology departments of two tertiary care centers of Karachi, Pakistan. The participants will first be screened for the absence of stroke symptoms via the Questionnaire for Verifying Stroke Free Status (QVSFS). QVSFS negative will be participants will be eligible. After written informed consent, participants will undergo detailed medical, sociodemographic, lifestyle, and anthropometric evaluation by a detailed interview. They will, in addition, undergo MRA to study the presence, degree, and distribution of asymptomatic ICAD. All MRA scans will be reviewed centrally by vascular neurologists blinded to clinical information. These images would be reviewed on DICOM Viewer 3.0 used for calculating the degree of stenosis using Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study defined criteria employing electronic calipers. A sample size of 200 will achieve 80% power for detecting a minimum difference of 20% in the prevalence of exposure factors (medical and lifestyle) between asymptomatic ICAD positive and ICAD negative persons. This study will generate regional data on risks for ICAD development and prevention in a high-risk susceptible population. Study ID: NCT02072876.

Can trained field community workers identify stroke using a stroke symptom questionnaire as well as neurologists? Adaptation and validation of a community worker administered stroke symptom questionnaire in a peri-urban Pakistani community.

BACKGROUND: Stroke is a leading cause of morbidity and mortality worldwide. There is a paucity of data from South Asia where stroke is highly prevalent. Validated tools administrable by community health workers (CHWs) are required to identify stroke in the community in a resource-strapped region such as this. METHODS: The study was conducted in a transitional slum in Karachi, Pakistan. Questionnaire to Verify Stroke-Free Status (QVSFS) was adapted and translated into Urdu. Two CHWs, trained by a neurologist, selected 322 community-dwelling subjects using purposive sampling. Each CHW collected data independently, which was validated by a vascular neurologist who directly examined each participant. To assess the effect of audit and feedback, data from the final 10% of the subjects were collected after a second training session for the CHWs. Sensitivity, specificity, and Cohen kappa were determined for the CHW-administered questionnaire against neurovascular assessment. RESULTS: Mean age of participants was 56.5 years with 71% of participants being women. The sensitivity and specificity of the questionnaire of detecting stroke was 77.1% (confidence interval [CI], 64.1-86.9) and 85.8% (CI, 83.5-87.5), respectively. The chance-corrected agreement using the Cohen kappa statistic was .51 (CI, .38-.60). Kappa ranged from .37 to .58 for each of the 7 stroke symptoms. Hemianesthesia (72.9%) and hemiplegia (64.6%) were the most sensitive symptoms. The performance and agreement improved from moderate to substantial after audit and feedback. CONCLUSIONS: We found a reasonable sensitivity and specificity and moderate agreement between CHW-administered QVSFS and assessment by a vascular neurologist.