Evidence-Based Neurology E-Book
104,99 €
Mehr erfahren.
- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Serie: Evidence-Based Medicine
- Sprache: Englisch
From an expert editor team drawn from the Cochrane Neurological Network, Evidence-Based Neurology provides specialists and those in training with the skills and knowledge to apply evidence-based practice in the clinical setting.
- fills the gap between guidelines and primary studies as well as between primary and secondary scientific medical literature
- summarizes the most recent and important findings on treatments for neurological patients
- measures the benefit and, when applicable, the risk of harm inherent in specific neurological interventions
- now includes new non-clinical topics of interest to neurologists such as education and research
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 1172
Veröffentlichungsjahr: 2015
Ähnliche
Table of Contents
Cover
Title Page
Copyright
Contributors
Part 1: Evidence-based neurology: introduction
Chapter 1: Evidence-based neurology in health education
Introduction
Objectives
Topic selection
Tutorial
Post-tutorial
The critically appraised topic (CAT)
Resources
The evidence to support an evidence-based health curriculum
References
Chapter 2: Evidence-based medicine in health research
Introduction
Using evidence-based principles to develop and answer clinical research questions
Sound research design with the end result in mind
Resources for clinical investigators
Summary
References
Chapter 3: Evidence and ethics
Introduction
The current ethical framework in health care
References
Part 2: Evidence-based neurology in the hospital
Chapter 4: Thunderclap headache
Background
Case scenario
Framing answerable clinical questions
Critical review of the evidence
Conclusions
Future research needs
References
Chapter 5: Coma
Background
Monitoring of a comatose patient
Management
Clinical examination and scales
Neuroimaging
Electrophysiology
Biomarkers
Combining various parameters to predict outcome
Conclusion
References
Chapter 6: Acute ischemic stroke and transient ischemic attack
Background
Mechanism and pathophysiology
Epidemiology
Clinical scenario
Framing clinical questions and general approach to searching evidence
Critical review of the evidence
Epidemiology
Diagnosis
Evaluation
Framing clinical questions and general approach to searching evidence
Treatment
References
Chapter 7: Spinal cord compression
Introduction
Spinal cord compression due to tumor – metastatic spinal cord compression
Clinical questions: management of acute metastatic spinal cord compression
Spinal cord compression due to infection – spondylodiscitis
Clinical questions: management of spinal cord compression due to infection
Spinal cord compression due to degenerative disease – cervical and thoracic spondylotic myelopathy
Clinical questions: management of spinal cord compression due to degenerative disease
Spinal cord compression due to trauma – traumatic spinal cord injury
Clinical questions: management of spinal cord compression due to traumatic injury
Summary
References
Chapter 8: Delirium
Introduction
Methodology
Clinical questions and evidence
Summary
Acknowledgments/Disclosures
References
Chapter 9: Status epilepticus
Background
Framing clinical questions and search for evidence
Critical review of the evidence for each question
Summary
Acknowledgements
References
Chapter 10: Raised intracranial pressure
Introduction
Methodology
Summary
Disclosures
Acknowledgments
References
Chapter 11: Traumatic brain injury
Critical review of each question
Control of intracranial hypertension
References
Chapter 12: Myasthenia gravis
Introduction
Framing of clinical question and search strategy
Clinical scenario
Critical review of the evidence for each question
Clinical scenario
Critical review of the evidence for each question
Conclusions
References
Chapter 13: Acute visual loss
Non-arteritic ischemic optic neuropathy
Arteritic anterior ischemic optic neuropathy or giant cell arteritis
Retinal vascular occlusion syndromes
Terson's syndrome
Stroke
Optic nerve disorders
Neuromyelitis optica
Idiopathic intracranial hypertension
Non-physiologic vision loss
References
Chapter 14: Secondary prevention of stroke
What can be done to prevent further strokes in stroke survivors?
Vascular risk factor modification for secondary stroke prevention
Hypertension
Dyslipidemia
Diabetes
Smoking cessation
Antithrombotic agents in stroke survivors with atrial fibrillation
Antiplatelet agents in stroke survivors without atrial fibrillation
Endarterectomy for symptomatic carotid disease
Endovascular treatment (angioplasty and stenting) for carotid stenosis
Obstructive sleep apnea management
Lifestyle management (eating a balanced diet, limiting salt intake, moderating alcohol consumption, increasing physical activity, and optimizing weight)
Disclosure
References
Part 3: Evidence-based neurology in the clinic
Chapter 15: Central nervous system infections
Bacterial meningitis
CNS tuberculosis
HSV encephalitis
Cryptococcal meningitis
References
Chapter 16: Evidence-based neuro-oncology
Introduction
Best pre-operative medical management
Best surgical treatment in primary brain tumours
Best oncological treatment in primary brain tumours
Best treatment of brain metastasis?
Summary
References
Chapter 17: Epilepsy
Background
AED Treatment After First Seizure
Summary
AED monotherapy for partial epilepsy
Addition of second-line AEDs
Summary
AED withdrawal for people in remission
Summary
Surgery
Summary
Summary
Generalised epilepsy
Carbamazepine for generalised epilepsy
Conclusion
Additional treatments
Summary
Abbreviations
References
Chapter 18: Cognitive disorders: mild cognitive impairment and Alzheimer's disease
Introduction
Framing the clinical questions
Search strategy
Clinical questions
Conclusion
References
Chapter 19: Evidence-based treatment of Parkinson's disease
Background
Clinical questions
Search strategy
Critical review of the evidence
References
Chapter 20: Therapies for multiple sclerosis
Introduction
Methods
Clinically isolated syndrome
Interferon-beta and glatiramer acetate for relapsing-remitting multiple sclerosis
Natalizumab and fingolimod
The newest oral therapies: Teriflunomide and dimethyl fumarate
Secondary progressive MS
Primary progressive MS
Dalfampridine
Conclusions
References
Chapter 21: Amyotrophic lateral sclerosis
Background
Framing answerable clinical questions
General approach to the search for evidence
Critical review of the evidence for each question
Multidisciplinary care
Conclusions
References
Chapter 22: Peripheral nerve disorders
Introduction
Treatment for CIDP
Treatment for Guillain–Barré syndrome
Treatment for multifocal motor neuropathy
Treatment for diabetic polyneuropathy
References
Chapter 23: Critical illness neuromyopathy
Background
Clinical features and diagnosis
Framing of clinical question and search strategy
Clinical scenario
Critical review of the evidence for each question
Conclusions
References
Chapter 24: Muscle disorders
Introduction
Critical review of the evidence for each disorder
References
Chapter 25: Sleep disorders
Background
Framing clinical questions
Critical review of evidence
Conclusion
References
Chapter 26: Acute migraine attacks
Background
Case scenario
Framing answerable clinical questions
Critical review of the evidence
Conclusion
Future research needs
References
Chapter 27: Therapy of vestibular disorders, nystagmus and cerebellar ataxia
Introduction
Principles of the pharmacotherapy of vertigo, dizziness, ocular motor disorders, and nystagmus
Peripheral vestibular disorders
Vestibular paroxysmia
Acknowledgements
References
Chapter 28: Neuro-ophthalmology
Introduction
Optic neuritis
Arteritic anterior ischemic optic neuropathy
Non-arteritic anterior ischemic optic neuropathy
Acknowledgement
References
Chapter 29: Therapeutic connection in neurorehabilitation: theory, evidence and practice
Background
Defining therapeutic connection
Framing clinical questions
Approach to searching the evidence
Chapter summary
Conclusion
References
Part 4: Telemedicine feature
Chapter 30: Evidence-based teleneurology practice
Introduction to the chapter
Methodology
Clinical Questions
Chapter summary
Acknowledgements
Disclosures
References
Index
End User License Agreement
Pages
vii
viii
ix
3
4
5
6
7
9
10
11
12
13
14
15
16
17
18
19
20
23
24
25
26
27
28
29
30
31
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
53
54
55
56
57
58
59
60
61
62
63
64
65
67
68
69
70
71
72
73
75
76
77
78
79
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
235
236
237
238
239
240
241
242
243
244
245
246
247
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
267
268
269
270
271
272
273
274
275
276
277
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
321
322
323
324
1
21
129
319
325
326
327
328
329
330
331
332
333
334
335
Guide
Cover
Table of Contents
Part 1
Begin Reading
List of Illustrations
Chapter 4: Thunderclap headache
Figure 4.1 Likelihood of thunderclap headache (TCH) in selected common and uncommon conditions. Data from epidemiologic studies are of variable quality, but summarized together to demonstrate general principles [17, 19, 20, 23, 25]. 95% confidence intervals are not shown. The percent likelihood of TCH given diagnosis refers to best literature estimate [18, 22, 24, 25]. For example, while CI is very common, the likelihood of TCH is low; whereas SAH is much less common, but more likely to present with TCH. CAD cervical artery dissection, CI cerebral infarction, CVST cerebral venous sinus thrombosis, ICH intracerebral hemorrhage, SAH subarachnoid hemorrhage, SIH spontaneous intracranial hypotension.
Chapter 16: Evidence-based neuro-oncology
Figure 16.1 MRI ‘pseudo-progression’. (a) Serial MRI scans demonstrating Gadolinium enhanced T1 weighted image after concomitant chemo-radiation. (b) Development of new focus of enhancement during adjuvant chemotherapy with Temozolomide ? Tumour progression. (c) Enhancement resolves on follow-up without changing treatment plan of completion of adjuvant Temozolomide.
Chapter 21: Amyotrophic lateral sclerosis
Figure 21.1 Criteria for the diagnosis of ALS/MND. EMG: electromyography; NCV: nerve conduction velocity; LMN: lower motor neurone; MN: upper motor neurone.
Chapter 26: Acute migraine attacks
Figure 26.1 Data (mean and 95% CI) for headache response at 2 hour (a) and pain-free at 2 hour (b) are shown for each triptan. Absolute and placebo-subtracted outcomes are presented with the hatched region being the 95% CI envelope for sumatriptan 100 mg.
Figure 26.2 Data (mean and 95% CI) for headache recurrence from 2–24 hours (a) and sustained pain-free (b) are presented with the hatched region being the 95% CI envelope for sumatriptan 100 mg. For naratriptan, the recurrence rate is given for the interval 4–24 hours post dose (as presented in the original publications) and for 2–24 hours post dose (after recalculating the data).
Chapter 27: Therapy of vestibular disorders, nystagmus and cerebellar ataxia
Figure 27.1 Peak values of cochlear blood flow with curve fitted by nonlinear regression and calculated corresponding oral dosage (peak mean ± SD; *:
p
< 0.05)) showing a sigmoid increase of blood in an animal model. This correlates with the increasing dosages currently used for the treatment of Menière's disease
Figure 27.2 Cranial MRI in a patient with vestibular paroxysmia ((a) Constructive interference in steady-state sequence, (b): Time-of-flight) shows contact between the right eighth cranial nerve (CN 8) and the anterior inferior cerebellar artery (AICA). Intraoperative micrographs demonstrate the vascular contact (c) and the considerable compression of the eighth nerve after removal of the arteries (d, circle).
Figure 27.3 Effects of 4-aminopyridine in episodic ataxia type 2. (a) Number of attacks of ataxia per month. 4-Aminopyridine significantly reduced the number of attacks of ataxia per month (
p
= 0.03). (b) Patient-reported quality of life (vestibular disorders activities of daily living scale (VDADL) score as a measure of the burden of disease). 4-Aminopyridine significantly reduced the VDADL score (
p
= 0.022).
Figure 27.4 Effects of acetyl-dl-leucine (Tanganil
TM
) on cerebellar ataxia. Value changes on (a) Scale for the assessment and rating of ataxia (SARA) and spinocerebellar ataxia functional index (SCAFI) sub-score items in terms of (b) eight-meter walk (8MW), (c) PATA word count in 10 seconds and (d) nine-hole-peg-test (9HPT) of the dominant and nondominant hand before and during the therapy with acetyl-DL-leucine (5 g per day) (mean ± SD) These changes have a significant impact on functioning and quality of life of patients with cerebellar ataxia.
Chapter 28: Neuro-ophthalmology
Figure 28.1 The risk of developing clinically definite multiple sclerosis after an initial episode of optic neuritis in the ONTT. Patients are divided into groups based on the presence of lesions on their initial MRI scan of the brain. By 10–15 years, the difference between those with one or two lesions and those with three or more lesions is no longer statistically significant.
Figure 28.2 The course of vision after onset in an eye affected by non-arteritic anterior ischemic optic neuropathy, in a large observational study in the left graph, and a prospective study in the right graph. Slightly under half of subjects have some improvement by 3–6 months, with no further improvement beyond that point.
Chapter 29: Therapeutic connection in neurorehabilitation: theory, evidence and practice
Figure 29.1 Summary of search findings.
List of Tables
Chapter 1: Evidence-based neurology in health education
Table 1.1 Objectives of evidence-based neurology curriculum
Table 1.2 PICO acronym [8]
Chapter 4: Thunderclap headache
Table 4.1 Risk of secondary pathology following evaluation for thunderclap headache
Table 4.2 Differential diagnosis of thunderclap headache
Chapter 5: Coma
Table 5.1 Common etiologies of coma
Table 5.2 Commonly used tools for neurologic monitoring
Table 5.3 Indications for continuous electroencephalogram (cEEG) monitoring
Chapter 6: Acute ischemic stroke and transient ischemic attack
Table 6.1 ABCD
2
risk stratification score
Table 6.2 Risk of stroke after TIA based on ABCD
2
score
Chapter 8: Delirium
Table 8.1 2010 National Institute for Health and Clinical Excellence (NICE). Recommendations for prevention of delirium in at-risk adults
Chapter 10: Raised intracranial pressure
Table 10.1 Major pathophysiologic categories of raised intracranial pressure (ICP)
Table 10.2 Overview of methods to control ICP
Chapter 11: Traumatic brain injury
Table 11.1 Conservative treatment versus surgical evacuation of acute subdural haematoma in patients with acute severe TBI
Table 11.2 Effect on outcome and management of serial brain CTS policy
Table 11.3 Antiepileptic drugs for acute TBI
Chapter 16: Evidence-based neuro-oncology
Table 16.1 Recursive partitioning analysis for high-grade glioma
Table 16.2 Cytochrome P450 enzyme inducers and inhibitors
Table 16.3 Current randomised controlled trials of concomitant and adjuvant chemotherapy with Temozolomide and control groups in primary disease and Temozolomide alone at recurrence
Table 16.4 Current randomised controlled trials of surgery, whole brain radiotherapy and focal radiation for brain metastases
Chapter 17: Epilepsy
Table 17.1 Comparisons of antiepileptic drug monotherapy in partial and generalised epilepsy (results of systematic reviews)
Table 17.2 Effects of additional drug treatment and dose–response in people not responding to usual treatment: results of systematic reviews
Table 17.3 Risk of seizure recurrence after AED withdrawal
Table 17.4 Effects of vagus nerve stimulation
Chapter 18: Cognitive disorders: mild cognitive impairment and Alzheimer's disease
Table 18.1 Efficacy and harm of cholinesterase inhibitors for mild to moderate AD
Table 18.2 Efficacy and harm of ChEIs and NMDA for mild to moderate AD
Table 18.3 Efficacy and harm of memantine for moderate to severe AD
Table 18.4 Efficacy and harm of cholinesterase inhibitor (donepezil) for moderate to severe AD
Table 18.5 Efficacy and harm of neuroleptics for agitation in AD
Table 18.6 Efficacy and harm of atypical antipsychotics for agitation in AD
Table 18.7 Efficacy and harm of antidepressant for agitation in AD based on reference
Chapter 20: Therapies for multiple sclerosis
Table 20.1 Disease-modifying therapies for multiple sclerosis
Chapter 21: Amyotrophic lateral sclerosis
Table 21.1 Summary of modified Escorial criteria (Airlie House Revision) of diagnosis of ALS/MND
Chapter 23: Critical illness neuromyopathy
Table 23.1 Overview of intensive insulin therapy studies on CINM
Chapter 25: Sleep disorders
Table 25.1 Treatment of excessive daytime sleepiness
Table 25.2 Treatment of cataplexy
Chapter 26: Acute migraine attacks
Table 26.1
The International Classification of Headache Disorders
, 3rd Edition
Table 26.2 Nonspecific acute treatments for migraine
Table 26.3 Meta-analysis of triptans: NNTs of 2-hours pain-free and 24-hours sustained pain-free and NNH
Table 26.4 Proposed rational hierarchy for the use of triptans
Table 26.5 Recommendations for the use of ergotamine
Table 26.6 Prophylactic drugs with data on ≥50% reduction in migraine attacks
Chapter 27: Therapy of vestibular disorders, nystagmus and cerebellar ataxia
Table 27.1 Relative frequency of different vertigo syndromes diagnosed in an interdisciplinary special outpatient clinic for dizziness (
n
= 17,718 patients)
Table 27.2 Frequency of congenital and/or acquired ocular oscillations in a total of 4854 consecutive patients seen in a neurological dizziness unit. DBN was the most frequent fixation nystagmus
Table 27.3 Summary of the clinical features, pathophysiology, etiology, site of lesion, and current treatment options for common forms of central nystagmus
Table 27.4 Current ongoing randomized multicenter investigator initiated clinical trials at the German Center for Vertigo and Balance Disorders, Munich
Chapter 28: Neuro-ophthalmology
Table 28.1 Traditional criteria for diagnosing giant cell arteritis
Table 28.2 Using age, symptoms, and signs to determine the probability of giant cell arteritis
Table 28.3 Likelihood ratios for giant cell arteritis from tests
Table 28.4 Biopsy length in patients with negative versus positive results
Table 28.5 Strategies used in studies of treatment for non-arteritic AION
Chapter 29: Therapeutic connection in neurorehabilitation: theory, evidence and practice
Table 29.1 Summary of included studies
Table 29.2 Overview of terms adopted and related definitions for included studies
Evidence-Based Neurology: Management of Neurological Disorders
Second Edition
Edited by
Bart M. Demaerschalk, MD, MSc, FRCP(C)
Professor of Neurology Department of Neurology Mayo Clinic College of Medicine Phoenix, AZ USA
Dean M. Wingerchuk, MD, MSc, FRCP(C)
Professor of Neurology Department of Neurology Mayo Clinic College of Medicine Scottsdale, AZ USA
This edition first published 2015 © 2015 by John Wiley & Sons Ltd.
BMJ Books is an imprint of BMJ Publishing Group Limited, used under licence by John Wiley & Sons.
Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA
For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell
The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.
Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.
The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.
Library of Congress Cataloging-in-Publication Data applied for.
ISBN: 9780470657782
Contributors
Amelia K. Adcock, MD
Assistant Professor of Neurology
West Virginia University
Morgantown, West Virginia, USA
Maria I. Aguilar, MD
Associate Professor of Neurology
Cerebrovascular Diseases Center
Mayo Clinic Hospital Phoenix
AZ, USA
Miguel Arango
The University of Western Ontario and
The London Health Sciences Centre
London, Ontario, Canada
Kevin M. Barrett
Department of Neurology
Mayo Clinic
Jacksonville, FL, USA
Jason J.S. Barton, MD, PhD, FRCPC
Professor
Departments of Medicine (Neurology), Ophthalmlogy and Visual Sciences, Psychology
University of British Columbia
Vancouver, Canada
Andrea J. Boon, MD
Department of Physical Medicine
Mayo Clinic
Rochester, MN, USA
Thomas Brandt, MD, FRCP, FANA
Department of Neurology, German Center for Vertigo and Balance Disorders and Institute for Clinical Neurosciences
University Hospital Munich
Munich, Germany
Miguel Bussière, MD, PhD, FRCP
Assistant Professor
Neurology and Interventional Neuroradiology, Division of Neurology
Grey Nuns Hospital
Edmonton, AB, Canada
Richard J. Caselli, MD
Consultant, Professor of Neurology
Department of Neurology, Mayo College of Medicine
Mayo Clinic
Scottsdale, AZ, USA
Nicholas D. Child, MB, ChB
Deep Brain Stimulation Fellow
Department of Neurology
Mayo Clinic College of Medicine
Rochester, MN, USA
Bart M. Demaerschalk, MD, MSc, FRCP(C)
Professor of Neurology
Department of Neurology
Mayo Clinic
Phoenix, AZ, USA
P. James B. Dyck
Department of Neurology
Mayo Clinic
Rochester, MN, USA
William David Freeman, MD
Associate Professor
Departments of Neurology, Neuosurgery, and Critical Care
Mayo Clinic Florida
Jacksonville, FL, USA
Gloria von Geldern
Section of Infections of the Nervous System, NINDS
National Institutes of Health
Bethesda, MD, USA
Brent P. Goodman, MD
Department of Neurology
Mayo Clinic
Scottsdale, AZ, USA
Robin Grant
Consultant Neurologist
Division of Clinical Neurosciences
Western General Hospital
Edinburgh, UK
Gord Gubitz, MD, FRCPC
Division of Neurology, Department of Medicine
Dalhousie University
Halifax, Nova Scotia, Canada
Rashmi B. Halker, MD
Assistant Professors, Department of Neurology
Mayo Clinic
Phoenix, AZ
Michael G. Hart
Neurosurgery Specialty Trainee
Department of neurosurgery
Addenbrooke's Hospital
Cambridge, UK
Nicola M. Kayes
Centre for Person Centred Research, Health and Rehabilitation Research Institute, School of Clinical Sciences
AUT University
Auckland, New Zealand
Paula Kersten
Centre for Person Centred Research, Health and Rehabilitation Research Institute, School of Clinical Sciences
AUT University
Auckland, New Zealand
Salah G. Keyrouz, MD
Department of Neurology and Neurological Surgery
Washington University School of Medicine
St. Louis, MO, USA
Bryan T. Klassen, MD
Assistant Professor of Neurology
College of Medicine
Mayo Clinic
Rochester MN, USA
Lawrence Korngut, MD, FRCP
Clinical Assistant Professor (Neurology)
Director, Calgary ALS and Motor Neuron Disease Clinic
Clinical Neurosciences
South Health Campus
Calgary, AB, Canada
Joyce Lee-Iannotti, MD
Vascular Neurology Fellow
Mayo Clinic Arizona
Scottsdale, AZ, USA
E. Anne MacGregor, MD
Centre for Neuroscience & Trauma, BICMS, Barts and
the London School of Medicine and Dentistry
London, UK
Anthony G. Marson
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine
University of Liverpool
Liverpool, Merseyside, UK
Kathryn M. McPherson
Centre for Person Centred Research, Health and Rehabilitation Research Institute, School of Clinical Sciences
AUT University
Auckland, New Zealand
Avindra Nath
Section of Infections of the Nervous System, NINDS
National Institutes of Health
Bethesda, MD, USA
Cumara B. O'Carroll, MD, MPH
Assistant Professor of Neurology
Department of Neurology,
Mayo Clinic
Phoenix, AZ, USA
Bhavesh M. Patel, MD
Assistant Professor
Department of Critical Care Medicine
Mayo Clinic
Phoenix, AZ, USA
Naresh P. Patel, MD
Associate Professor
Department of Neurological Surgery
Mayo Clinic
Phoenix, AZ, USA
Christopher A. Payne, BS
Trinity College
Dublin, Ireland
Kameshwar Prasad
Department of Neurology
All India Institute of Medical sciences
New Delhi, India
Manya Prasad
Department of Community Medicine
Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences
Rohtak, Haryana, India
Corina Puppo
Emergency Department, Clinics Hospital
University of the Repúblic School of Medicine
Montevideo, Uruguay
Sridharan Ramaratnam
Department of Neurology
SIMS Hospitals
Chennai, Tamil Nadu, India
Bappaditya Ray, MBBS, MD
Department of Neurology
The University of Oklahoma Health Sciences Center
Oklahoma City, OK, USA
Todd J. Schwedt, MD
Associate Professor of Neurology
Mayo Clinic
Phoenix, AZ, USA
Jonathan H. Smith, MD
Assistant Professor of Neurology
University of Kentucky
Lexington, KY, USA
Charlene H. Snyder, DP, NP-BC
Nurse Practitioner, Associate Department of Neurology, and Assistant Professor of Neurology
Mayo College of Medicine
Mayo Clinic
Scottsdale, AZ, USA
Byron Roderick Spencer
Blue Sky Neurology (Division of Carepoint)
Denver, CO, USA
Michael Strupp, MD, FANA
Department of Neurology
German Center for Vertigo and Balance Disorders and Institute for Clinical Neurosciences
University Hospital Munich
Munich, Germany
Martin Sutton-Brown, MD, FRCPC
Clinical Assistant Professor
Department of Medicine (Neurology)
University of British Columbia
Vancouver, Canada
Greg Thaera
Mayo Clinic
Scottsdale, AZ, USA
Jennifer A. Tracy
Assistant Professor, Department of Neurology
Mayo Clinic
Rochester, MN, USA
Bert B. Vargas, MD
Assistant Professors, Department of Neurology
Mayo Clinic
Phoenix, AZ
Kenneth A. Vatz
Department of Neurology
Chicago, IL, USA
Joseph L. Verheijde, PhD, MBA, PT
Associate Professor of Biomedical Ethics, College of Medicine
Mayo Clinic
Scottsdale, AZ, USA
Walter Videtta
Intensive Care Unit,
Hospital Posadas,
Buenos Aires, Argentina
Dean M. Wingerchuk, MD, MSc, FRCP(C)
Professor of Neurology
Mayo Clinic
Scottsdale, AZ, USA
Bryan K. Woodruff, MD
Consultant
Assistant Professor of Neurology
Department of Neurology, Mayo College of Medicine
Mayo Clinic
Scottsdale, AZ, USA
Part 1Evidence-based neurology: introduction
Chapter 1Evidence-based neurology in health education
Lawrence Korngut1, Miguel Bussière2 and Bart M. Demaerschalk3
1Calgary ALS and Motor Neuron Disease Clinic, Clinical Neurosciences, South Health Campus, Calgary, AB, Canada
2Neurology and Interventional Neuroradiology, Division of Neurology, Grey Nuns Hospital, Edmonton, AB, Canada
3Department of Neurology, Mayo Clinic, Phoenix, AZ, USA
Introduction
Clinical neurology trainees undergo a lengthy and complex process requiring integration of many fundamental skills that coalesce into sound diagnosis and decision making. Beyond the core knowledge of anatomy, physiology, biochemistry, pathology, and the medical sciences, there is an essential requirement for the clinical student, in the arena of evidence-based clinical practice, to acquire skills and expertise in the principles and practice of critical appraisal and to have a working knowledge of the best evidence from the diverse multiple subspecialties that comprise neurology today. Maintaining competence in the current best evidence over a neurologist's career is essential to making accurate diagnoses, providing high-quality neurological care, and selecting appropriate tests and therapies.
Developing the skills necessary for critical appraisal is a difficult process, particularly when competing with the rigorous demands of a residency training program. An evidence-based curriculum in neurology education provides the opportunity for teaching the fundamentals of critical appraisal and engaging in discussion of current clinical questions, hot topics, and continued controversies. Fostering an understanding of what comprises an appropriately comprehensive rigorous literature search, the levels of evidence, the different types of studies, and the methodologies are difficult to consolidate outside of a formalized curriculum or graduate-level training in evidence-based medicine, health research methodology, and clinical epidemiology.
In this chapter, we discuss the development of an evidence-based neurology (EBN) curriculum in health education.
Objectives
Teaching and acquisition of critical appraisal skills is the primary objective of an evidence-based clinical practice curriculum. Fundamental critical appraisal skills include the following: awareness of a clinical knowledge gap, formulation of answerable questions based on clinical uncertainty, performance of a literature search, identification of the highest quality evidence from the search yield, and critical appraisal of the studies to address the original clinical question. Students should become familiar with the different classifications of clinical studies (e.g. prognosis, diagnosis, therapy or harm) and the main methodological and statistical questions that must be addressed in each type of study. The students should also be able to determine whether or not the study findings are worth considering given the methodological quality of the study and its generalizability in reference to the patient population in question.
Students should develop an understanding of both the importance and the limitations of clinical evidence. Emphasis should remain on high-quality patient care and the use of the current best evidence to guide clinical practice within the context of the patient's wishes and the clinician's judgment and reasoning. It must be emphasized that lack of evidence for efficacy does not necessarily mean lack of benefit with treatment, and vice versa for lack of evidence against certain therapies or diagnostic tests.
As a result of the evidence-based medicine, curriculum knowledge about best current evidence practices is accumulated and stored for future use. Owing to the discussion of common clinical scenarios and review of the relevant best evidence, the students develop a working knowledge of the current evidence (Table 1.1).
Table 1.1 Objectives of evidence-based neurology curriculum
Students of neurology should develop critical appraisal skills to
formulate answerable questions based on clinical uncertainty
perform an appropriate literature search
identify the best quality evidence from the studies identified
critically appraise the identified studies to answer the original clinical question
be familiar with prognostic, diagnostic, and therapeutic clinical studies and the key methodological and statistical questions that should be addressed in each type of study
determine whether the study findings are valid and useful, considering the methodological quality of the study and the applicability to a particular patient population
Students of neurology should develop a working understanding of the importance of high-quality evidence and also realize its limitations
Students should accumulate knowledge about best current evidence practices in neurology
The following sections describe an example of an EBN curriculum based on two longstanding, mature, and successful programs targeting clinical neurology residents: the EBN curriculum from the Western University (WU) in London, Canada [1–4]; and the Mayo Clinic Evidence-Based Clinical Practice, Research, Informatics, and Training (MERIT) Curriculum, Mayo Clinic, Phoenix, AZ [5, 6]. Another third valuable resource designed to help educators teach students of neurology to understand and use evidence-based medicine is the web-based American Academy of Neurology (AAN) Evidence-Based Medicine Curriculum [7].
Topic selection
Generating the clinical questions
Once annually EBN curriculum facilitators survey all neurology students and faculty members to generate a list of neurological questions for potential review. These clinical questions are then rank ordered by the trainees and facilitators according to multiple factors including clinical importance, relevance, frequency of occurrence, and interest. The most highly ranked questions are reviewed in the upcoming year. The topics are screened to ensure that they are congruent with the educational recommendations of the training program (post-graduate education committee): Royal College of Physicians and Surgeons of Canada Advisory Committee and/or Accreditation Council for Graduate Medical Education – Neurology Residency and American Board of Psychiatry and Neurology [1–6].
Preparing for the tutorial session
Students each select one or two clinical questions per academic year and prepare their critically appraised topic for general discussion with the group. For each clinical topic, a clinical scenario and a focused clinical question are formulated. A focused clinical question should include considerations of the specific patient group, the intervention or exposure, the method of comparison, and the outcome measures. The acronym PICO can serve as a helpful reminder [8] (Table 1.2).
Table 1.2 PICO acronym [8]
Patient or population
Intervention, prognostic factor or exposure
Comparison intervention
Outcome to measure or achieve
For a given clinical question, the presenting trainee performs a literature search and identifies studies representing the highest level of evidence [9]. Expert librarians and informatics specialists can be called upon to assist in efficient and comprehensive literature searching. Studies are evaluated according to the generally accepted hierarchy of clinical evidence. High-quality meta-analyses, systematic reviews, and randomized clinic trials are preferred over observational studies and case reports. One to four studies are selected for critical appraisal and discussion. A summary of this information is prepared in advance of the discussion in the form of a critically appraised topic (CAT) as described later. One week prior to the session, the presenting trainee circulates copies of the clinical scenario, focusing clinical question, search strategy, and articles for review to the participants. The pre-tutorial process is supervised by one of the facilitators. The faculty often provides instruction and advice on the search strategy and reasons for inclusion or exclusion of studies. Trainees are introduced to different search engines (e.g. PubMed [10], SUMSearch [11], Cochrane Library [12]). Discussions on Medical Subject Headings (MeSH headings), keywords, and their uses are helpful.
Flexibility is available to adjust the clinical topics to suit the needs and training level of the trainees. Semi-annual meetings of the curriculum trainees and facilitators allow for appropriate curriculum content changes and adjustment of group discussion objectives to cover specific epidemiological or biostatistical topics.
Tutorial
Each tutorial session focuses on a trainee presenting one clinical question. The session begins with a 5-min description of the clinical scenario and focused clinical question. This is followed by a 10-min presentation of the background topic including clinical information about the condition, treatment, or diagnostic test. The trainee then presents and discusses the search strategy for 5 min.
The following 45 min is dedicated to critical appraisal of the evidence.
The study type is identified (e.g. prognosis, diagnosis, therapy, or harm), and the appropriate rating scale or worksheet is utilized to assist the presenting trainee and faculty members guide the group through the critical appraisal process. Sample worksheets are available through the Western University Evidence-Based Neurology website [4]. These worksheets were derived from the Users' Guide to the Medical Literature [13] and relevant articles contained therein. The rating scales are generally divided into three sections: (1) analysis of the study methodology to determine its validity, (2) assessment of the final results including accuracy and clinical importance, and (3) appraisal of the applicability of these results to the target patient or patient population.
To engage the audience, it is helpful to divide into smaller groups of three or more participants (depending on number of trainees) to each completely assigned portions of a worksheet. For example, for a therapeutic article one group can determine whether the study addressed a focused clinical question, whether treatment allocation was randomized, and whether the randomization list was concealed. A second group could discuss the length of patient follow-up and whether an intention-to-treat analysis was employed. The whole group then discusses the interpretation of results and their applicability to the focus clinical question (5 min). The final conclusions of the group are summarized as “clinical bottom lines” (5 min). The presenting trainee's draft CAT is then reviewed, discussed, and edited. The final CAT reflects the opinion of the entire group.
Post-tutorial
The presenting trainee completes final revisions of the CAT based on the suggestions of the group at the tutorial and submits it for final review to the facilitators. The final CAT is collected and made available for review either in hard copy format, posted to a central repository on the intranet or Internet, or published in peer-reviewed journals.
All trainees are encouraged to utilize their evidence-based skills during their clinical rotations and in teaching sessions. Trainees are encouraged to ask about the evidence underlying their supervising faculty's medical decisions in a collegial manner and to review the literature as appropriate to enhance everyone's knowledge base.
The critically appraised topic (CAT)
The CAT begins with a short summary of the clinical scenario and focused clinical question. The literature search is briefly outlined. The clinical bottom lines are highlighted followed by the most relevant data, typically in table form, and the relevant references. The objective of the CAT is to summarize the tutorial topic and conclusions in a concise manner for future reference. The WU EBN Program maintains an online archive of CATs that assist in clinical decision making and implementation of evidence-based clinical practice [4]. Both the Mayo Clinic MERIT and WU EBN programs have published CATs in peer-reviewed print journals [6, 14–26].
Resources
Faculty
Most programs have two full-time neurologists with expertise in evidence-based medicine, clinical epidemiology, and biostatistics who are responsible for coordinating the tutorials and teaching evidence-based care principles and practice. All neurology and neurosurgery faculty are invited to attend tutorials, and special invitations are sometimes extended to other medical and surgical faculty, outside neurology, with particular interest or expertise on the topic of discussion at a given session. Teaching faculty from other departments or other academic institutions are occasionally invited to participate or teach on specific evidence-based medicine topics. Neurosurgery residents attend EBN tutorials when topics relevant to neurosurgical practice are discussed. Neurology residents have graded responsibilities and assume a greater teaching role as they gain experience and skill in EBN. Neurology trainees, residents, and fellows vary in total number from 10 to 14 per year, depending on the institution.
Medical librarians and informatics experts
If available, expert evidence-based medicine librarians and informatics specialists serve as valuable faculty additions and can be called upon to assist in the literature search. They may identify more useful or encompassing search terms, suggest additional specialized databases to search, and help finalize a list of relevant articles.
Time
EBN tutorial sessions range from 60 to 90 min in duration, depending on the program, and are held monthly throughout the typical 4- or 5-year neurology residency training program. Sessions are scheduled into protected educational time for neurology students, thus ensuring mandatory participation. Topics for discussion are generally decided upon early in the academic year, thus allowing ample informal research and preparatory time.
Space
EBN tutorials are generally held in an available university or hospital auditorium. Reference material on evidence-based medicine is made available in the departmental library. Computers, smartphones, and tablets with links to electronic databases are readily available.
Educational resource material
It is helpful to provide an introductory reference book on evidence-based medicine to each new student [27]. Other evidence-based references and educational material can be located in the departmental library. A compilation of all critically appraised topics reviewed is made available in print format (published, peer reviewed, or unpublished) or as a web-based searchable database for intra- or extra-institutional use [4].
Informatics
Students use smartphones, tablets, laptop computers, and digital projection units for presentations and tutorials. With Internet access and links to the commonly used searchable databases of the evidence-based literature, the departmental library based on the real and virtual neurology remains a focal point of the EBN curriculum.
The evidence to support an evidence-based health curriculum
An increasing number of medical residency training programs devote formal educational time to developing evidence-based clinical practice knowledge and skills. One of the core competencies on graduate medical education is Practice-based learning and improvement. This requires the clinical student to investigate and evaluate their care of patients, to appraise and assimilate scientific evidence, and to continuously improve patient care based on constant self-evaluation and lifelong learning. Residents/fellows are expected to develop skills and habits to be able to
Locate, appraise, and assimilate evidence from scientific studies related to their patients' health problems;
Use information technology to optimize learning.
Other than simply fulfilling a core competency, the question is, “Do these curricula improve knowledge of evidence-based neurology concepts and critical appraisal skills?” “Do they result in a change in clinical practice and patient health outcomes?” Several primarily nonrandomized or quasirandomized studies conducted over the past decade have attempted to address these questions. High-quality evidence is limited as a result of heterogeneity of the teaching method or intervention assessed, small sample sizes, heterogeneity of the outcome instruments or measures, and variability in the duration of the study or timing of the outcome assessment [28–30]. Systematic reviews of the available evidence suggest that post-graduate evidence-based medicine education results in significant improvements in a student's knowledge base but data are lacking, which significantly alter clinical decision making or patient outcomes [28–30].
References
1 Burneo, J.G. & Jenkins, M.E. (2007) Teaching evidence-based clinical practice to neurology and neurosurgery residents.
Clinical Neurology and Neurosurgery
,
109
, 418–421.
2 Burneo, J.G., Jenkins, M.E., Bussière, M. & UWO Evidence-based Neurology Group (2006) Evaluating a formal evidence-based clinical practice curriculum in a neurology residency program.
Journal of the Neurological Sciences
,
250
, 10–19.
3 Demaerschalk, B.M. & Wiebe, S. (2001) Evidence Based Neurology: an innovative curriculum for post-graduate training in the neurological sciences.
http://www.uwo.ca/cns/ebn
(accessed 21 September 2009).
4 University of Western Ontario's Evidence Based Neurology. (2001)
http://www.uwo.ca/cns/ebn
(accessed 21 September 2009).
5 Demaerschalk, B.M. & Wingerchuk, D.M. (2007) The MERITs of evidence-based clinical practice in neurology.
Seminars in Neurology
,
27
(4), 303–311.
6 Wingerchuk, D.M. & Demaerschalk, B.M. (2007) The evidence-based neurologist: critically appraised topics.
The Neurologist
,
13
, 1.
7 American Academy of Neurology Evidence Based Medicine Toolkit,
http://www.aan.com/education/ebm/
(accessed 21 September 2009).
8 Richardson, W.S., Wilson, M.C., Nishikawa, J. & Hayward, R.S. (1995) The well-built clinical question: a key to evidence-based decisions.
ACP Journal Club
,
123
, A12–A13.
9 University of Oxford Centre for Evidence-Based Medicine.
http://www.cebm.net/levels_of_evidence.asp
(accessed 23 February 2009)
10 U.S. National Library of Medicine PubMed.
http://www.ncbi.nlm.nih.gov/sites/entrez
(accessed 23 February 2009)
11 University of Texas Health Science Centre SUMSearch engine.
http://sumsearch.uthscsa.edu/
(accessed 23 February 2009).
12 The Cochrane Collaboration.
http://www.cochrane.org/index.htm
(accessed 23 February, 2009).
13 Guyatt, G.H. & Rennie, D. (2002)
Users' Guides to the Medical Literature. A Manual for Evidence-based Clinical Practice
. AMA Press, Chicago.
14 Zarkou, S., Aguilar, M.I., Patel, N.P., Wellik, K.E., Wingerchuk, D.M. & Demaerschalk, B.M. (2009) The role of corticosteroids in the management of chronic subdural hematomas: a critically appraised topic.
Neurologist
,
15
, 299–302.
15 Wingerchuk, D.M., Spencer, B., Dodick, D.W. & Demaerschalk, B.M. (2007) Migraine with aura is a risk factor for cardiovascular and cerebrovascular disease: a critically appraised topic.
Neurologist
,
13
, 231–233.
16 Demaerschalk, B.M. & Wingerchuk, D.M. (2007) Treatment of vascular dementia and vascular cognitive impairment.
Neurologist
,
13
, 37–41.
17 Hickey, M.G., Demaerschalk, B.M., Caselli, R.J., Parish, J.M. & Wingerchuk, D.M. (2007) “Idiopathic” rapid-eye-movement (REM) sleep behavior disorder is associated with future development of neurodegenerative diseases.
Neurologist
,
13
, 98–101.
18 Halker, R.B., Barrs, D.M., Wellik, K.E., Wingerchuk, D.M. & Demaerschalk, B.M. (2008) Establishing a diagnosis of benign paroxysmal positional vertigo through the dix-hallpike and side-lying maneuvers: a critically appraised topic.
Neurologist
,
14
, 201–214.
19 Hoerth, M.T., Wellik, K.E., Demaerschalk, B.M.
et al
. (2008) Clinical predictors of psychogenic nonepileptic seizures: a critically appraised topic.
Neurologist
,
14
, 266–270.
20 Khoury, J.A., Hoxworth, J.M., Mazlumzadeh, M., Wellik, K.E., Wingerchuk, D.M. & Demaerschalk, B.M. (2008) The clinical utility of high resolution magnetic resonance imaging in the diagnosis of giant cell arteritis: a critically appraised topic.
Neurologist
,
14
, 330–335.
21 Capampangan, D.J., Wellik, K.E., Aguilar, M.I., Demaerschalk, B.M. & Wingerchuk, D.M. (2008) Does prophylactic postoperative hypervolemic therapy prevent cerebral vasospasm and improve clinical outcome after aneurysmal subarachnoid hemorrhage?
Neurologist
,
14
, 395–398.
22 Almaraz, A.C., Bobrow, B.J., Wingerchuk, D.M., Wellik, K.E. & Demaerschalk, B.M. (2009) Serum neuron specific enolase to predict neurological outcome after cardiopulmonary resuscitation: a critically appraised topic.
Neurologist
,
15
, 44–48.
23 Khoury, J., Wellik, K.E., Demaerschalk, B.M. & Wingerchuk, D.M. (2009) Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of central nervous system sarcoidosis.
Neurologist
,
15
(2), 108–111.
24 Capampangan, D.J., Wellik, K.E., Bobrow, B.J.
et al
. (2009) Telemedicine versus telephone for remote emergency stroke consultations: a critically appraised topic.
Neurologist
,
15
, 163–166.
25 Jenkins, M.E. & Burneo, J.G. (2008) The return of evidence-based neurology to the Journal: It's all about patient care.
The Canadian Journal of Neurological Sciences
,
35
, 273–275.
26 Tartaglia, M.C., Pelz, D.M., Burneo, J.G., Jenkins, M.E. & University of Western Ontario Evidence Based Neurology Group (2009) Cerebral angiography and diagnosis of CNS vasculitis.
The Canadian Journal of Neurological Sciences
,
36
, 93–94.
27 Sackett, D.L., Strauss, S.E. & Richardson, W.S. (2000)
Evidence-based Medicine: How to Practice and Teach EBM
, 2nd edn. Churchill Livingstone, London.
28 Parkes, J., Hyde, C., Deeks, J. & Milne, R. (2001) Teaching critical appraisal skills in health care settings.
Cochrane Database of Systematic Reviews
, (3), CD001270 DOI: 10.1002/14651858.CD001270.
29 Coomarasamy, A. & Khan, K.S. (2004) What is the evidence that postgraduate teaching in evidence based medicine changes anything? A systematic review.
BMJ
,
329
, 1–5.
30 Flores-Mateo, G. & Argimon, J.M. (2007) Evidence based practice in postgraduate healthcare education: a systematic review.
BMC Health Services Research
,
7
, 119–127.
Chapter 2Evidence-based medicine in health research
Dean M. Wingerchuk
Professor of Neurology, Mayo Clinic, Scottsdale, AZ, USA
Introduction
Evidence-based medical practice combines use of the best available evidence that addresses a particular problem with clinical experience and the patient's values and circumstances [1]. Learning and teaching evidence-based medicine principles have become core components of undergraduate and postgraduate medical curricula, largely with the information “consumer” or “end-user,” in mind. That is, evidence-based medicine education largely aims to provide clinicians with fundamental skills that allow critical appraisal of medical literature, interpretation of quantitative evidence, and translation of evidence into practice (see Chapter 1). Clinical investigators provide the data that these practitioners will evaluate and translate to their clinics. Therefore, successful and truly impactful researchers must also possess a thorough understanding of the principles of evidence-based methodology. Such individuals will understand what data the “consumer” will need to change clinical practice with confidence. Possession of poor research design skills leads to undesirable outcomes such as studies with inadequate sample sizes, data marred by biases, and invalid or clinically irrelevant outcome measures. These methodological shortcomings waste both financial and patient resources and have an enormous impact on the effectiveness of global health research [2–6]. The aim of this chapter is to provide an overview of some guiding principles for effective clinical investigators and the implications of evidence-based practice on research publication and subsequent data use.
Using evidence-based principles to develop and answer clinical research questions
In their introductory evidence-based medicine book for clinicians, Straus and colleagues include a chapter entitled “Asking Answerable Clinical Questions” [1]. They suggest that clinicians learn to ask focused questions with four key components (also known as the PICO model): the patient (or problem or population), the intervention of interest, comparison interventions (if relevant), and the specific outcome measure that will be used to interpret the results. This approach provides a template that can be applied to any type of clinical questions, including those that address therapy, diagnosis, prognosis, or causation. The PICO approach has several advantages, a few of which include requiring attention to disease definitions and factors that modify treatment responses or disease course, careful consideration of clinically meaningful outcome measures, and facilitation of literature searches. The goal is to find the best quality evidence that applies to a particular patient and his or her circumstances.
Clinical investigators can also use this schema to guide protocol development. For example, after a thorough, targeted literature search (including systematic reviews published in the Cochrane Database of Systematic Reviews and current studies registered at the clinicaltrials.gov website), an investigator may summarize the current status of a therapeutic area and elect to design a new randomized controlled trial to “repurpose” an existing therapy. This approach of combining published literature with registered trials optimizes the chances that the proposed study will address an important knowledge gap and avoid unnecessary duplication. There may be residual uncertainty about the existence of unpublished data. In some instances, this could be mitigated by reviewing conference proceedings for abstracts that report relevant results but have not been followed by a full-text, peer-reviewed publication or by contacting investigators in the field to determine if they know of such studies. The requirement for posting new trials to clinicaltrials.gov promises to gradually reduce this potential bias.
That literature and the PICO framework also guide definition of eligibility criteria, choice of dose and frequency of the study drug, selection of the optimal comparison treatment, and definition of clinically meaningful outcome measures. The details of the protocol are then refined to account for key subgroups, secondary and exploratory outcome measures, and pragmatic considerations necessary for successful trial conduct. This systematic approach provides the greatest likelihood that the study results will contribute meaningfully to clinical practice and guide subsequent research.
Sound research design with the end result in mind
Among the main goals of scientific publication is dissemination of knowledge for use in clinical practice and upon which to build new research. In recent years, many leading academic medical journals have endorsed the use of formal guidelines to ensure transparent research reporting. The most widely known of these is the Consolidated Standards of Reporting Trials (CONSORT) checklist for randomized control trials, which was designed to enable readers to “… understand a trial's design, conduct, analysis and interpretation, and to assess the validity of its results” [7]. Similar requirements have been developed for diagnostic studies (STAR-D) [8] and systematic reviews and meta-analyses (PRISMA) [9]. Although these guidelines have been emphasized for reporting study results, investigators should refer to the pertinent guideline during protocol development to insure that study operations will adequately capture and record the data necessary for future reporting. In other words, the time to be cognizant of the reporting requirements is during protocol development. Some of the key principles of evidence-based research design relevant to therapeutic and diagnostic studies are considered next.
Therapeutic studies
The CONSORT checklist for reporting of therapeutic trials consists of 22 items under several headings: Title and Abstract, Background, Methods, Results, and Discussion [8]. The study author is instructed to include the term “randomized” in the report title if appropriate. The “Methods” section requires reporting of several key elements meant to reassure the consumer that potential sources of bias or threats to validity have been adequately addressed and, importantly, so that a study may be satisfactorily replicated using the reported methods. These key elements include study objectives and hypotheses, how subjects were ascertained (eligibility criteria; setting and location of recruitment), precise details of the study interventions (dose, route of administration, frequency, timing, etc.), clear definitions of primary and secondary outcome measures and any methods to enhance data quality (including training of assessors), and how the study sample size was determined. Details about subject and investigator blinding are crucial and frequently missing or inadequately described in trial reports [2, 3]. These details include randomization method; explicit description of steps taken to conceal treatment allocation; and how blinded status was maintained for subjects, investigators, and other relevant individuals. The consistency of reporting items such as randomization and allocation concealment methods remain mediocre despite use of the CONSORT schema, indicating that peer reviewers and editors have an opportunity for quality improvement.
The “Methods” section of the protocol must contain a description of the statistical analysis plan for the primary and key secondary outcomes. A priori definition of secondary or subgroup analyses is also highly desirable. Therefore, consultation with an experienced statistician and, if available, study methodologist is recommended very early in the study design phase.
Planning for eventual study reporting can assist in protocol design because it requires one to consider the sequential operations that govern a subject's progression through the trial process from identification to final evaluation. The CONSORT checklist includes a strong recommendation for use of a flow diagram in the study report. Required variables include the number of participants randomly assigned, receiving intended treatment and completing the protocol, and were included in the primary outcome analysis. The flow diagram allows the reader to easily track those who are lost to follow-up or do not contribute to the outcome analysis, factors that are sometimes not clearly reported.
In addition to completion of the flow diagram, the reporting requirements include recruitment and follow-up dates, baseline demographics and clinical characteristics of study groups, and the number of subjects in each group. It must clear how many subjects contribute to the statistical analyses and whether the analysis was performed by “intention-to-treat” methods; such methods should be specified. The primary and secondary outcomes must be reported with an estimate of the magnitude and precision (e.g. 95% confidence interval) of the effect. Subgroup and adjusted analyses are denoted as pre-planned or exploratory. Adverse event descriptions and rates are required for each intervention group. The CONSORT checklist also includes a section on study interpretation and context, in which investigators should discuss the results and sources of potential bias. Finally, the checklist requires a statement on generalizability (external validity) of the study findings, and that the results be placed in the context of current available evidence, updated from the systematic review conducted before protocol was designed.
Diagnostic studies
The Standards for the Reporting of Diagnostic accuracy studies (STARD) checklist [9] provides for diagnostic studies what CONSORT does for therapeutic trials. It is a guide for investigators reporting results of protocols that evaluate the accuracy of diagnostic tests, ensuring comprehensive description of methods and results. It requires that authors indicate the study population (eligibility criteria and settings for the study), how subjects were recruited (e.g. based on symptoms or results from previous tests), and whether the study was retrospective or prospective. The spectrum of disease included in the study methods consists of rationale for and description of the index diagnostic test (the new test being examined in the study) and the reference (“gold”) standard. To insure clarity and potential reproduction of the protocol, investigators should describe the procedures for performing and interpreting each test, including the types of personnel who administer the tests, their training, and cut-off values for the results. Critical issues related to study validity include whether all subjects received both the index test and the reference standard, whether both were evaluated independently and in blinded manner (e.g. if the evaluators of the index and reference tests were blinded to the results of the other). Again, a flow diagram is recommended in the “Results” section to demonstrate the progress of the individuals in the study cohort along different protocol checkpoints and to allow the reader to judge the potential for bias. STARD emphasizes the presentation of results in cross-tabulation form with estimates of diagnostic accuracy (e.g. sensitivity, specificity, likelihood ratios) and with measures of uncertainty (e.g. confidence intervals). As for therapeutic studies, investigators are required to put the results into clinical context.
Resources for clinical investigators
Most medical school curricula and postgraduate training programs now require some formal training in fundamental principles of evidence-based medicine. However, the requirements vary considerably between programs and many clinicians who embark on a clinical research career now elect to pursue certificate or degree programs in clinical epidemiology and methodology in order to establish a methodological foundation for their future research. For those individuals with inadequate time or access to such formal programs, there are numerous resources available to support evidence-based practice and research. A few representative leading resources are described below.
JAMA Evidence (jamaevidence.com)
JAMA evidence a comprehensive reference for investigators and clinicians [10]. Although aimed primarily at the evidence consumer with systematic methods for evidence-based clinical practice (it is divided into sections entitled Assess, Ask, Acquire, Appraise, and Apply), the background knowledge is invaluable for those planning primary research. It also links to the User's Guide to the Medical Literature, a leading resource for optimal evaluation and use of the medical literature in clinical practice.
